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DIASTOLOGY: CLINICAL APPROACH TO ISBN: 978-1-4160-3754-5

DIASTOLIC HEART FAILURE

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Library of Congress Cataloging-in-Publication Data

Diastology : clinical approach to diastolic heart failure / [edited by]

Allan L. Klein, Mario J. Garcia.—1st ed.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-4160-3754-5
1. Congestive heart failure. 2. Heart—Left ventricle—Pathophysiology. 3. Diastole (Cardiac cycle) I. Klein,
Allan L. II. Garcia, Mario J. III. Title: Clinical approach to diastolic heart failure.
[DNLM: 1. Heart Failure, Congestive. 2. Diagnostic Techniques, Cardiovascular. 3. Diastole—
physiology. 4. Ventricular Dysfunction, Left. WG 370 D541 2008]

RC685.C53D53 2008
616.1′29—dc22
2007042084

Executive Publisher: Natasha Andjelkovic

Project Manager: Mary B. Stermel
Design Direction: Karen O’Keefe Owens
Marketing Manager: Todd Liebel
Developmental Editor: Pamela Hetherington

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Last digit is the print number: 9 8 7 6 5 4 3 2 1

Contributors

NASER M. AMMASH, MD, FACC ROBERT O. BONOW, MD, FACC

Associate Professor of Medicine Goldberg Distinguished Professor
Mayo Clinic Northwestern University Feinberg School of Medicine
Rochester, Minnesota Chief, Division of Cardiology
Co-Director Bluhm Cardiovascular Institute
CHRISTOPHER P. APPLETON, MD, FACC Northwestern Memorial Hospital
Professor of Medicine Chicago, Illinois
Division of Cardiovascular Diseases
Mayo Clinic Arizona BARRY A. BORLAUG, MD
Phoenix, Arizona Assistant Professor of Medicine
Division of Cardiovascular Diseases
CRAIG R. ASHER, MD, FACC Mayo Clinic
Cardiology Fellowship Director Rochester, Minnesota
Cleveland Clinic Florida
Weston, Florida SHEMY CARASSO, MD
University of Toronto
GERARD P. AURIGEMMA, MD, FACC, FASE, FAHA HCM Clinic, Division of Cardiology
Professor of Medicine and Radiology Department of Medicine, Toronto General Hospital
Director, Cardiology Fellowship Program University Health Network
University of Massachusetts Medical School University of Toronto
Director, Non-Invasive Cardiology Toronto, Ontario, Canada
Umass Memorial Healthcare
Worcester, Massachusetts MANUEL D. CERQUEIRA, MD, FACC, FAHA
Professor of Radiology
CATALIN F. BAICU, PhD Cleveland Clinic Lerner College of Medicine of
Assistant Professor of Medicine Case Western Reserve University
Gazes Cardiac Research Institute Chairman, Department of Nuclear Medicine
Medical University of South Carolina and Staff Cardiologist
Charleston, South Carolina Department of Cardiovascular Medicine
Heart and Vascular Institute
AJAY BHARGAVA, MD Cleveland Clinic
Staff Cardiologist Cleveland, Ohio
Department of Cardiovascular Medicine
Heart and Vascular Institute KRISHNASWAMY CHANDRASEKARAN, MD
Cleveland Clinic Professor of Medicine
Cleveland, Ohio Consultant, Division of Cardiovascular Diseases
Mayo Clinic
EDMUND A. BERMUDEZ, MD, MPH, FACC Rochester, Minnesota
Assistant Professor of Medicine
Tufts University School of Medicine HSUAN-HUNG CHUANG, MBBS, MRCP (UK),
Boston, Massachusetts FAMS, FESC, FACC
Consultant, Cardiac and Vascular Disease Consultant Cardiologist
Florida Cardiac Consultants Mount Elizabeth Hospital
Sarasota, Florida Visiting Consultant
Heart Failure and Transplantation Program
D. DIRK BONNEMA, MD National Heart Center
Cardiology Fellow Singapore
Division of Cardiology
Department of Medicine
Medical University of South Carolina
Charleston, South Carolina
v
vi Contributors

RONAN CURTIN, MD, MSc BRIAN D. HOIT, MD, FACC, FASE

Associate Staff Cardiologist Professor of Medicine and Physiology and Biophysics
Department of Cardiovascular Medicine Case Western Reserve University
Heart and Vascular Institute Director of Echocardiography
Cleveland Clinic University Hospitals Case Medical Center
Cleveland, Ohio Cleveland, Ohio

BENJAMIN W. EIDEM, MD JERRY M. JOHN, MD, MS

Associate Professor of Pediatrics Cardiovascular Fellow
Divisions of Pediatric Cardiology and Cardiovascular Diseases Division of Cardiovascular Medicine
Mayo Clinic University of Toledo
Rochester, Minnesota Toledo, Ohio

KANIZ FATEMA, MBBS, PhD TRACI L. JURRENS, MD

Research Fellow in Cardiovascular Diseases Cardiovascular Fellow
Mayo School of Graduate Medical Education Mayo Clinic
Mayo Clinic Rochester, Minnesota
Rochester, Minnesota ANNE S. KANDERIAN, MD
Advanced Fellow in Cardiovascular Imaging
GARY S. FRANCIS, MD Department of Cardiovascular Medicine
Professor of Medicine Heart and Vascular Institute
Cleveland Clinic Lerner College of Medicine of Cleveland Clinic
Case Western Reserve University Cleveland, Ohio
Head, Section of Clinical Cardiology
Department of Cardiovascular Medicine DAVID A. KASS, MD
Heart and Vascular Institute Abraham and Virginia Weiss Professor of Cardiology
Cleveland Clinic Professor of Medicine
Cleveland, Ohio Professor of Biomedical Engineering
Johns Hopkins Medical Institutions
HIDEKATSU FUKUTA, MD, PhD Attending Physician
Postdoctoral Research Fellow Division of Cardiology, Department of Medicine
Wake Forest University School of Medicine Johns Hopkins Hospital
Wake Forest University Baptist Medical Center Baltimore, Maryland
Winston-Salem, North Carolina
Department of Cardio-Renal Medicine and Hypertension DALANE W. KITZMAN, MD, FACC
Nagoya City University Graduate School of Medical Sciences Professor of Internal Medicine, Cardiology and Gerontology
Nagoya, Japan Wake Forest University Health Sciences
Winston-Salem, North Carolina
WILLIAM H. GAASCH, MD, FACC
Professor of Medicine ALLAN L. KLEIN, MD, FRCP(C), FACC, FAHA, FASE
University of Massachusetts Medical School Professor of Medicine
Worcester, Massachusetts Cleveland Clinic Lerner College of Medicine
Senior Consultant in Cardiology of Case Western Reserve University
Director of Cardiovascular Research Director, Cardiovascular Imaging Research
Lahey Clinic Department of Cardiovascular Medicine
Burlington, Massachusetts Heart and Vascular Institute
Cleveland Clinic
MARIO J. GARCIA, MD, FACC, FACP Cleveland, Ohio
Professor of Medicine and Radiology LIVIU KLEIN, MD, MS
Mount Sinai School of Medicine Fellow in Cardiovascular Disease
Director of Cardiac Imaging Northwestern University, The Feinberg School of Medicine
Mount Sinai Heart Institute Bluhm Cardiovascular Institute
New York, New York Northwestern Memorial Hospital
Chicago, Illinois
RICHARD A. GRIMM, DO, FACC, FASE
Director, Echocardiography Laboratory SANJAY KUMAR, MD
Staff Cardiologist Hospitalist
Department of Cardiovascular Medicine Department of Hospital Medicine
Heart and Vascular Institute Ohio Permanente Medical Group
Cleveland Clinic Kaiser Permanente
Cleveland, Ohio Cleveland, Ohio
 Contributors vii

DOUGLAS S. LEE, MD, PhD, FRCP(C) SHERIF F. NAGUEH, MD, FACC

Assistant Professor of Medicine, University of Toronto Professor of Medicine
Scientist, Institute for Clinical Evaluative Sciences Weill Cornell Medical College
Attending Physician, Division of Cardiology, University Health Associate Director, Echocardiography Laboratory
Network Methodist DeBakey Heart Center
Toronto, Ontario, Canada Houston, Texas

STEVEN J. LESTER, MD, FACC, FRCPC, FASE SATOSHI NAKATANI, MD, PhD, FACC
Associate Professor of Medicine, Mayo Clinic Staff Cardiologist
Director, Cardiovascular Ultrasound Imaging and Department of Cardiology
Hemodynamic Laboratory National Cardiovascular Center
Consultant Division of Cardiovascular Diseases Suita, Osaka, Japan
Mayo Clinic Arizona
Scottsdale, Arizona ARUMUGAM NARAYANAN, MD
Research Fellow
BENJAMIN D. LEVINE, MD, FACC Cardiology Division, Department of Medicine
Professor of Medicine University of Massachusetts Medical School
University of Texas Southwestern Medical Center at Dallas University of Massachusetts Memorial Health Care
Director, Institute for Exercise and Environmental Medicine Worcester, Massachusetts
S. Finley Ewing Jr. Chair for Wellness at Presbyterian Hospital
of Dallas M. GARY NICHOLLS, MD, ChB, FAHA, FACC, FRCP
Harry S. Moss Heart Chair for Cardiovascular Research Professor of Medicine
Presbyterian Hospital of Dallas Department of Medicine
Dallas, Texas Christchurch School of Medicine and Health Sciences
University of Otago
WILLIAM C. LITTLE, MD, FACC Christchurch, New Zealand
McMichael Professor and Vice Chair of Internal Medicine
Chief of Cardiology JAE K. OH, MD, FACC, FAHA
Wake Forest University School of Medicine Professor of Medicine
Winston-Salem, North Carolina Codirector, Echocardiography Laboratory
Director, Pericardial Clinic
VOJTECH MELENOVSKY, MD, PhD Consultant, Division of Cardiovascular Diseases
Department of Cardiology Mayo Clinic
Institute for Clinical and Experimental Medicine-IKEM Rochester, Minnesota
Prague, Czech Republic
MARTIN OSRANEK, MD, MSc
ANNITTA J. MOREHEAD, BA, RDCS, CCRC, FASE Assistant Professor of Medicine
Manager, Cardiovascular Imaging Core, C5 Research Research Associate, Cardiovascular Disease
Department of Cardiovascular Medicine Mayo Clinic
Heart and Vascular Institute Rochester, Minnesota
Cleveland Clinic
Cleveland, Ohio YUTAKA OTSUJI, MD, PhD, FACC
Professor of Medicine
JAMES P. MORGAN, MD, PhD The Second Department of Internal Medicine
Professor of Medicine Director
Tufts University Department of Cardiovascular and Renal Disease
Chief of Cardiovascular Medicine University of Occupational and Environmental Health, Japan
Caritas Carney Hospital and Caritas St. Elizabeth’s Medical School of Medicine
Center Kitakyushu, Japan
Director of the Cardiovascular Center
Caritas Christi Healthcare System ZORAN B. POPOVIĆ, MD, PhD
Boston, Massachusetts Project Staff
Department of Cardiovascular Medicine
ROSS MURPHY, MD Heart and Vascular Institute
Consultant Cardiologist Cleveland Clinic
St James’s Hospital Cleveland, Ohio
Dublin, Ireland
viii Contributors

ANAND PRASAD, MD SRIKANTH SOLA, MD, FACC, FAHA

Interventional Cardiology Fellow Assistant Professor of Medicine
Department of Medicine, Division of Cardiology Cleveland Clinic Lerner College of Medicine of
University of California–San Diego Case Western Reserve University
San Diego, California Staff Cardiologist
Department of Cardiovascular Medicine
MIGUEL A. QUINONES, MD, FACC Heart and Vascular Institute
Professor of Medicine Cleveland Clinic
Weill Cornell Medical College Cleveland, Ohio
Chairman, Department of Cardiology
The Methodist Hospital DAVID H. SPODICK, MD, DSc, FACC
Houston, Texas Professor of Medicine
Cardiovascular Medicine
AMBEREEN QURAISHI, MD University of Massachusetts Medical School
Clinical Instructor St. Vincent Hospital
Senior Cardiovascular Fellow Worcester, Massachusetts
Department of Cardiovascular Medicine
Caritas St. Elizabeth Medical Center RANDALL C. STARLING, MD, MPH, FACC
Boston, Massachusetts Professor of Medicine
Cleveland Clinic Lerner College of Medicine of
HARRY RAKOWSKI, MD, FRCPC, FACC, FASE Case Western Reserve University
Professor of Medicine Vice Chairman, Department of Cardiovascular Medicine
Department of Medicine Section Head, Heart Failure and Cardiac Transplant
University of Toronto Medicine
Douglas Wigle Research Chair in Hypertrophic Medical Director, Kaufman Center for Heart Failure
Cardiomyopathy Heart and Vascular Institute
Development Director Peter Munk Cardiac Imaging Centre, Cleveland Clinic
Division of Cardiology, Department of Medicine Cleveland, Ohio
Toronto General Hospital, University Health Network
Toronto, Ontario, Canada A. JAMIL TAJIK, MD, FACC
Thomas J. Watson, Jr. Professor in honor of Dr. Robert L. Frye
JAY RITZEMA-CARTER, BM, MRCP Professor of Medicine and Pediatrics
Cardiology Research Fellow Chairman (Emeritus) Zayed Cardiovascular Center
Department of Medicine Mayo Clinic
Christchurch School of Medicine and Health Sciences Rochester, Minnesota
University of Otago Consultant, Division of Cardiovascular Diseases, Internal
Christchurch, New Zealand Medicine and Pediatric Cardiology
Mayo Clinic
L. LEONARDO RODRIGUEZ, MD, FACC Scottsdale, Arizona
Director, Stress Laboratory
Program Director, Advanced Cardiovascular Imaging W. H. WILSON TANG, MD, FACC, FAHA
Fellowship Program Assistant Professor of Medicine
Department of Cardiovascular Medicine Cleveland Clinic Lerner College of Medicine of
Heart and Vascular Institute Case Western Reserve University
Cleveland Clinic Staff Cardiologist, Section of Heart Failure and Cardiac
Cleveland, Ohio Transplantation Medicine
Department of Cardiovascular Medicine
JAMES B. SEWARD, MD, FACC Heart and Vascular Institute
John M. Nasseff Sr. Professorship in Cardiology and Professor Cleveland Clinic
of Medicine and Pediatrics Cleveland, Ohio
Consultant, Division of Cardiovascular Diseases
Mayo Clinic CHUWA TEI, MD, FACC
Rochester, Minnesota Professor and Chairman
Department of Cardiovascular, Respiratory, and Metabolic
Medicine
Graduate School of Medicine, Kagoshima University
Kagoshima, Japan
 Contributors ix

JAMES D. THOMAS, MD, FACC, FAHA, FESC RAMACHANDRAN S. VASAN, MD, DM, FACC, FAHA
Professor of Medicine Professor of Medicine
Cleveland Clinic Lerner College of Medicine of Boston University School of Medicine
Case Western Reserve University Framingham Heart Study
Charles and Lorraine Moore Chair of Cardiovascular Imaging Framingham, Massachusetts
Department of Cardiovascular Medicine
Heart and Vascular Institute MICHAEL R. ZILE, MD, FACC
Cleveland Clinic Charles Ezra Daniel Professor of Medicine
Cleveland, Ohio Attending Physician
Department of Medicine, Division of Cardiology
FILIPPOS TRIPOSKIADIS, MD, FESC, FACC Medical University of South Carolina
Professor of Cardiology Director of the Medical Intensive Care Unit
Director, Department of Cardiology Ralph H. Johnson Department of Veteran’s Affairs Medical Center
Larissa University Hospital Charleston, South Carolina
Larissa, Greece
WILLIAM A. ZOGHBI, MD, FACC
RICHARD W. TROUGHTON, MB, ChB, PhD Professor of Medicine
Associate Professor Weill Medical College of Cornell University
Department of Medicine William L. Winters Chair in Cardiovascular Imaging
Christchurch School of Medicine and Health Sciences Director, Cardiovascular Imaging Center
University of Otago The Methodist DeBakey Heart Center
Christchurch, New Zealand Houston, Texas
TERESA S. M. TSANG, MD
Professor of Medicine
Consultant, Division of Cardiovascular Diseases
Mayo Clinic
Rochester, Minnesota
Foreword

Doctors Klein and Garcia have attacked a controversial yet extraor- important intrinsic left ventricular abnormality is slowing of the
dinarily problematic clinical challenge with aggressiveness, insight, rate of left ventricular relaxation and increased stiffness of
and thoroughness. Their text, Diastology: Clinical Approach to the chamber. The nuances of this finding and, indeed, the
Diastolic Heart Failure, is one of the few organized efforts to bring spectrum of definitions are well characterized and addressed in
together noted experts and synthesize today’s knowledge base this text.
regarding this fascinating problem. The depth and breadth of Recognition of the importance of diastolic heart failure has
topics covered in this text are extraordinary, and the editors and been relatively recent, but there is now a large spectrum of data
individual contributors are to be congratulated. The importance of that gives us more precise information regarding the pathophysi-
this subject cannot be overemphasized because it is now well ology, epidemiology, and prognosis, and there are even a few
established that almost half of all patients admitted to the hospital recent trials studying therapy in these patients. Perhaps the latter
for symptomatic congestive heart failure have relatively preserved is the most disappointing with little to guide us regarding the best
or normal left ventricular systolic function. It is assumed that some approaches for reducing the substantive morbidity and mortality
degree of abnormality in diastolic function contributes to the pre- seen with this syndrome. Again, Doctors Klein and Garcia and
sentation of these patients and, indeed, predicts decompensation. their contributing authors are to be applauded for their thorough
Knowing that well over 5 million patients in North America alone review of the current knowledge base regarding diastolic dysfunc-
have heart failure makes, then, the importance of this syndrome tion and heart failure in the setting of preserved or relatively
high. The debate about syndrome nomenclature has been enter- normal left ventricular systolic function. This text will capture the
taining. Should we be referring to the difficulty as “diastolic heart interests of clinicians, clinical investigators, and basic scientists
failure” or “heart failure in the setting of preserved left ventricular interested in gaining insight into heart failure more generally.
systolic function”? Doctors Klein and Garcia are not shy about
their opinion of facts, as the title of the text indicates. James B. Young, MD
Diastolic dysfunction can be defined as the inability of the Chairman, Medicine Division
heart to perform adequately under a normal filling pressure, and Professor and Chairman
this generally results in impaired exercise tolerance resulting from George and Linda Kaufman Chair
varying combinations of inadequate forward cardiac output and Cleveland Clinic
elevated left ventricular end-diastolic pressure. Perhaps the most Cleveland, Ohio

xiii
Foreword

In the past two decades, there have been remarkable advances in such as tissue Doppler imaging and strain rate imaging have given
our appreciation of how cardiac diastolic function is important us a keener ability to quantify and differentiate “normal” and
for patient well being. My first encounter with this occurred as a abnormal diastolic function. A variety of new indices, methods,
fellow in training in the early 1980s, when in Baltimore we were and innovative imaging tools including torsion imaging will
seeing so many elderly, predominantly females, with hypertension undoubtedly help illuminate the field in the years ahead.
and hypercontractile left ventricles—but the seemingly paradoxi- The book is as good as it gets in laying out a comprehensive
cal presentation with heart failure. It is interesting to reflect back assessment of where we are and where we are going in the com-
on how ignorant we were back then with respect to the primacy prehensive field of diastology. Drs. Klein and Garcia and the
of cardiac filling and relaxation and how far we have come since superb group of authors they have engaged have done quite an
that time. exceptional job in providing a panoramic view of a very dynamic
In this book, the field of diastolic function and dysfunction is field. Cardiologists in training, those in practice who have an
fully dissected. All of the major intersecting processes, such as interest in cardiac physiology, and virtually all academic cardiolo-
hypertension, coronary artery disease, pericardial disease, valvular gists and sonographers who want to enhance their understanding
abnormalities, diabetes, and so many others, are tackled. The of the implications of cardiac relaxation and filling will benefit
recent surge in the use of biventricular “resynchronization” and from this fine contribution to cardiovascular medicine.
atrio-ventricular optimization has markedly accentuated the role
of the interaction of systole and diastole in clinical practice—and Eric J. Topol, MD
we still have much to learn in selecting patients who will benefit Professor of Translational Genomics, TSRI
from this “big ticket” technology. The simple notion that ideal Director, Scripps Translational Science Institute
patients would have a markedly dilated heart with left bundle Chief Academic Officer, Scripps Health
branch block certainly has not held up for long. Our enhanced Senior Consultant, Division of Cardiovascular Diseases
understanding of ventricular interaction and diastole, per se, Scripps Clinic
should make a difference. New and improved imaging modalities La Jolla, California

xiv
Preface

A 65-year-old woman with hypertension presents to the emer- our understanding of diastolic function. Over the past 10 years,
gency room with shortness of breath. Chest x-ray shows intersti- new techniques and indices for assessing diastolic function have
tial edema, and two-dimensional and Doppler echocardiography continued to evolve. Recent epidemiology-based studies have
demonstrate an ejection fraction of 60%, concentric left ventricu- shown that diastolic heart failure is increasing in prevalence and
lar (LV) hypertrophy, atrial enlargement, and stage 2 (moderate) that it is as common as systolic heart failure and just as fatal. In
LV diastolic dysfunction. The brain natriuretic peptide level is the past 5 years, there has been a shift from research in developing
elevated at 800 pg/dl. This prototypic patient has evidence of diagnostic techniques to large-scale clinical trials to determine
classical diastolic heart failure, which is the inability to fill the left targeted treatment for patients with diastolic heart failure.
ventricle with normal filling pressures. This timely book addresses
how diastolic heart failure is diagnosed and treated. It also
comprehensively discusses the general principles of diastolic Our Interest in the Field
dysfunction, including the molecular biology, hemodynamics, epi- In the late 1980s, Allan Klein started his interest in this field as
demiology, clinical presentation, and principles of treatment. The a Canadian Heart Foundation fellow at the Mayo Clinic studying
contents of this book are targeted to a broad audience encompass- Doppler assessment of LV filling during acute myocardial infarc-
ing noninvasive and invasive cardiologists, physiology scientists, tion and after reperfusion. His first impression was that the quick
cardiology fellows, and cardiac sonographers. bedside echocardiographic evaluation, including the mitral E/A
Multiple cardiovascular disorders cause diastolic dysfunction ratio and deceleration time, was a simple but powerful measure
and subsequent diastolic heart failure. There is a raging con- of LV diastolic filling, relaxation, and prognosis. Also, he was
troversy about whether diastolic heart failure exists as an inde- struck by how the stages of diastolic filling related to the clinical
pendent entity or whether it is always accompanied by systolic exam, including the extra heart sounds (S3 and S4). As a student
dysfunction in the setting of a normal ejection fraction. In this of the field, he also learned that the study of diastolic function
book, we have elected to use the term diastolic heart failure; was more complex than the simple analysis of the mitral E/A
however, we recognize that systolic-ventricular interaction and ratio. During his training, Dr. Klein was very fortunate to have
arterial stiffening can definitely play a significant role in causing excellent mentors, including Liv Hatle, Jamil Tajik, and James
symptoms of heart failure in these patients. Why study diastolic Seward. Dr. Mario Garcia developed his interest in the field while
heart failure? The answer is that a complete understanding at the Cleveland Clinic in the early days of tissue Doppler echo-
of the pathophysiology of LV filling is essential to managing cardiography, color M-mode Doppler, and strain rate imaging.
the patient with congestive heart failure syndromes. There has His clinical observations and hemodynamic validation of early
been a tremendous interest in diastology during the past 50 years, annular velocities (Em) and the slope of the flow propagation (Vp)
with over 16,000 original manuscripts published during this as well as the relationship of mitral early filling/annular e wave
period. (E/Em) and mitral early filling/flow propagation slope (E/vp) as
measures of LV filling pressure were important for the advance-
ment of the field. Their interest led to many diastology sympo-
Historical Perspective siums where leaders congregated in Cleveland, Ohio, and
Since the heart was determined to be a pump, most biologists and Scottsdale, Arizona, to discuss their advances. These summits
physicians have focused on the study of systolic function. However, sparked our interest to publish a state-of-the-art book on
as early as in the renaissance period, Leonardo da Vinci described diastology.
that the lower cardiac chambers of the heart filled with blood by
drawing it from the upper chambers. In the 1940s, Carl J. Wiggers
proposed the term inherent elasticity to describe the passive prop- Contents of the Book
erties of the heart. In the 1970s, cardiac physiologists assessed This book is organized into five main sections: basic determi-
the properties of active ventricular relaxation and passive filling nants, diagnosis, specific cardiac diseases, emerging topics, and
using invasive quantification of intracavity pressure and volume. treatment. It includes a comprehensive analysis of the major areas
During the following decade, clinicians recognized that diastolic of knowledge in this field from the molecular, genetic, and cellular
heart failure was an important cause of congestive heart failure, mechanisms to clinical presentation and treatment of diastolic
and Doppler echocardiography emerged as an important non- heart failure. This book discusses conventional and newer methods
invasive method to assess the diastolic filling properties of the of diagnosis, including two-dimensional and Doppler echocardio-
heart. The term “diastology” was coined in the early 1990s; graphic techniques as well as cardiac MRI. An important practical
imaging modalities, such as Doppler tissue imaging, color M- chapter of how to actually perform a diastolic function examina-
mode Doppler, and magnetic resonance imaging (MRI), advanced tion written by one of the leading cardiac sonographers in the field
xv
xvi Preface

is also included. A review of the prototypical diseases that mani- ongoing studies, including the Irbesartan in Heart Failure with
fest diastolic dysfunction, including hypertension, coronary artery Preserved Ejection Fraction (I-PRESERVE) and the Treatment
disease, hypertrophic cardiomyopathy, restrictive cardiomyopa- of Preserved Cardiac Function Heart Failure with an Aldosterone
thy, and pericardial diseases, provides an important clinical per- Antagonist (TOPCAT) trials, that address the treatment of dia-
spective. Newer topics that are addressed include the role of stolic heart failure. The importance of new drugs including endo-
neurohormones, pacing, aging, and vascular cardiac interactions thelial receptor antagonists and glucose cross-link breakers that
in diastolic heart failure. Finally, the general treatment, echocar- evaluate the targeted treatment of diastolic heart failure is also
diographic guided therapy, and ongoing clinical trials are covered reviewed in this book.
in depth by the leading experts in the field. Finally, it is important to recognize that the field of diastology
In the past, treatment of heart failure has focused purely on the is a fast-moving target and we have tried to be as current as
treatment of systolic heart failure. However, there have been an possible while also avoiding overlap in the chapters.
increasing number of clinical trials, including The Candesartan in We surely hope that you enjoy this exciting book.
Heart Failure, Assessment of Reduction in Mortality and Mor-
bidity (CHARM) preserved trial, the Perindopril for Elderly Allan L. Klein
Patients with Chronic Heart Failure (PEP-CHF) trial, as well as Mario J. Garcia
Acknowledgments

We would like to thank Marilyn, Jared, Lauren, and Jordan Klein and Cheryl, Melinda,
and Olivia Garcia as well as our parents for their encouragement and support while
editing this book. We especially would like to express our thanks to Marie Campbell, who
helped and guided us in the journey of putting this book together. Finally, we would like
to express our gratitude to the editors of Elsevier for their guidance in making this book
a great success.

xvii
 AMBEREEN QURAISHI, MD
JAMES P. MORGAN, MD, PhD
1
Molecular, Gene, and
Cellular Mechanisms
INTRODUCTION Metabolic processes such as alkalosis, cardiovascular drugs, and
the hypertrophy process itself can also alter the contractile and
PATHOPHYSIOLOGY
metabolic phenotype.4
Excitation-Contraction and Repolarization-
This chapter will focus on the cellular mechanisms of normal
Relaxation Coupling
and impaired myocardial relaxation. Calcium plays a crucial role
The Failing Human Heart
in this process. Its movement into the cytosol, caused by excita-
Abnormal Calcium Regulation in Heart
tion at the surface membrane, stimulates contraction. This physi-
Failure
ologic phenomenon is appropriately termed excitation-contraction
Sarcolemmal Receptors and Mechanisms
coupling. The reverse of this process, which is dependent on
Sarcoplasmic Reticulum
the movement of calcium and sodium, can be thought of as
Altered Calcium Responsiveness of
repolarization-relaxation coupling.4 In normal hearts, sympathetic
Myofibrillar Tension
stimulation can increase contractility by exerting a positive ino-
TREATMENT, GENE THERAPY, AND tropic effect as part of the excitation-contraction (E-C) process
THE FUTURE and can also increase the rate of relaxation, a positive lusitropic
(relaxation-enhancing) effect, by facilitating Ca2+ removal from
the sarcoplasm. Myocyte control of relaxation occurs through the
regulation of calcium concentrations within the cytosol via four
INTRODUCTION main pathways involving sarcoplasmic reticulum (SR) Ca2+-
ATPase, sarcolemmal Na+/Ca2+ exchange, sarcolemmal Ca2+-
Heart failure is an ancient diagnosis. Some of the earliest known ATPase, or mitochondrial Ca2+ uniport.5 The latter two pathways
descriptions are attributed to Hippocrates, circa 460–370 bce. have been studied and appear to have no significant effect on the
He reported dozens of clinical case histories with examples of beat-to-beat regulation of intracellular calcium.6,7
dyspnea, as seen in left heart failure, and dropsy, as seen in right We will discuss the other two mechanisms in detail along with
heart failure.1 Over the centuries, it has become apparent that the myofibrillar calcium responsiveness, as much research is being
symptoms of heart failure are the result of complex pathophysio- directed in trying to develop novel therapeutic interventions
logic processes that alter both anatomic and physiologic proper- targeted toward repolarization-relaxation coupling in an effort
ties of the heart. to maximize positive lusitropic effects.
In the United States alone, approximately 5 million people are
afflicted by heart failure, with an annual incidence of 500,000 new
diagnoses and 300,000 deaths.2,3 One third of patients with
symptomatic heart failure have a normal ejection fraction, and PATHOPHYSIOLOGY
only in the last decade has there been a shift in the paradigm,
Excitation-Contraction and Repolarization-
focusing attention on diagnosing and understanding diastolic dys-
function. In many cases, diastolic dysfunction is caused by one or Relaxation Coupling
more abnormalities of cardiac structure, such as hypertrophy, The E-C coupling process activates contraction by coupling the
fibrosis, infiltrative disease, or pericardial constriction. However, signal generated by the action potential (excitation) at the myocyte
many patients appear to have diastolic dysfunction due to cellular cell surface to the delivery of calcium into the cytosol that initiates
abnormalities of myocyte relaxation, which is reversible and tran- contraction.1 After spontaneous depolarization of the surface
sient and occurs mainly in the setting of ischemia or hypoxia. membrane, Ca2+ enters the myocyte through voltage-gated L-type
Other causes include cellular calcium overload or ATP depletion. channels (which are dihydropyridine receptive and will be referred
3

Ch001-X3754.indd 3 1/17/2008 6:02:21 PM

 4 Chapter 1 • Molecular, Gene, and Cellular Mechanisms

to as DHRs). This influx serves as a trigger for the release of 70:30.15 In the early stages of heart failure, there is an increase in
stored Ca2+ from the SR via Ca2+ release channels called ryano- sympathetic stimulation in order to maintain adequate blood pres-
dine receptor 2 (RyR2). This process is known as calcium-induced sure and cardiac output. As the syndrome progresses, the continu-
calcium release (CICR).8,9 The transverse tubule system, unique ous activation eventually leads to a downregulation of β1 receptors
to the mammalian heart, allows for the close proximity of the by almost 60% to 70% and desensitization of the remaining recep-
DHRs to clusters of RyR2. The initial influx of calcium through tors, which depresses cAMP levels, hence contributing to altered
L-type channels activates the RyR2 channels within its domain calcium regulation and reducing intracellular calcium levels.16–18
in a synchronized fashion, spontaneously increasing local concen- The overall effect is a depressed and negative force-frequency rela-
tration of calcium and producing a Ca2+ spark (named according tionship. In vitro studies of nonfailing and failing human myocytes
to its appearance by confocal microscopy), which can also be have been done of contractility under varying conditions (i.e.,
thought of as a local Ca2+ transient.10 During E-C coupling, varying muscle length and loading conditions as seen with pres-
several thousand Ca2+ sparks occur in synchrony, overlapping in sure or volume changes in vivo, slow rates, [Ca2+], and catechol-
time and space, thus allowing for a global and uniform calcium amine stimulation).19,20 These studies concluded that during basal
transient that is sufficient for myocardial contraction. Another conditions, the contractile properties of normal and failing myo-
channel within the SR membrane, inositol triphosphate, has been cytes is similar. Conversely, the same is not true during increased
reported to induce the release of calcium, but the rate and extent inotropic stimulation. The normal myocyte is able to increase force
of release is much lower, and it is not triggered by CICR. generation, but in failing myocytes, the developed force either
It is important to understand the cardiac contractile apparatus decreases or remains unchanged. Therefore, during low workload
from the vantage point of troponin-C, the Ca2+ receptor protein. states, contractility is preserved, but “contractility reserve” (the
When cytosolic calcium levels are low, there is minimal or no ability to increase contractility with heart rate or sympathetic
calcium bound to troponin-C. The troponin-tropomyosin stimulation) is severely reduced in failing myocytes.13 The pro-
complex inhibits the formation of the actomyosin complex. Once posed mechanism at this time is that the amount of calcium that is
calcium is released from the SR, Ca2+ binds to troponin-C, chang- released by the SR of failing myocytes is less than in normal myo-
ing the configuration of the troponin-tropomyosin complex, cytes, which may be due to decreased SR Ca2+ stores or abnormal
removing the inhibition of the actin-myosin interaction, and thus SR Ca2+ loading21; however, there is a need for more investigational
allowing cross-bridge cycling and contraction. studies to fully understand the mechanisms behind the E-C cou-
Another important messenger that modulates E-C coupling is pling defects that contribute to dysfunctional Ca2+ handling.
cyclic adenosine monophosphate (cAMP). This pathway is initi-
ated by activation of the β-adrenergic receptors, which then
activate adenylate cyclase and generate cAMP. This nucleotide
Abnormal Calcium Regulation in Heart Failure
activates a series of phosphorylating enzymes (i.e., protein kinases). Abnormal modulation of intracellular calcium is a major mecha-
Protein kinase A (PKA) binds to A-kinase anchoring proteins nism that underlies both systolic and diastolic dysfunction and
(AKAPs)11,12 and phosphorylate calcium regulatory proteins at develops with cardiac hypertrophy and failure. The heart spends
multiple subcellular sites. Phosphorylation of both the voltage- more than half of its time in diastole (i.e., relaxation and filling),
gated L-type channels and RyR2 channels (Ca2+ release channels) yet there is controversy in the definition of diastolic dysfunction
leads to a net effect of increased Ca2+ entry and a greater calcium and diastolic heart failure. Abnormal calcium regulation com-
release (a function of the amount of Ca2+ stored) from the SR, prises a spectrum of changes that include slowed force (or pres-
producing an increase in the rate and magnitude of force genera- sure) decline and cellular re-lengthening (increased ventricular
tion (positive inotropic effect).13 This is balanced by the phos- stiffness), increased (or decreased) early filling rates and decelera-
phorylation of phospholamban on the SR, which regulates the tion, an elevated diastolic pressure-volume relationship, and a
sarcoendoplasmic reticulum Ca2+ (SERCA)-ATPase pump and filling-rate–dependent pressure elevation (increased end-diastolic
allows for greater reuptake of calcium from the cytosol, enhancing pressure).22 These changes occur due to abnormal regulation of
the rate of relaxation (positive lusitropic effect). Finally, the phos- Ca2+ homeostasis within the myocyte. Although the cellular and
phorylation of troponin-I, part of the regulatory complex of the molecular regulation of calcium in failing myocardium has been
contractile apparatus, facilitates the dissociation of calcium from studied, the exact mechanism of abnormal calcium regulation is
troponin-C by altering the myofilament calcium sensitivity, also still not well understood (Fig. 1-1).
causing a positive lusitropic effect. These changes increase the Normally, the systolic calcium transient occurs with the release
amplitude of the systolic Ca2+ transient and decrease its duration, of calcium from the SR, which is triggered by the L-type channel
thus increasing myocyte contractility and generation of force. Ca2+ influx. The magnitude of calcium release is dependent on
When the β-adrenergic pathway is activated in times of increased the Ca2+ influx and the amount of calcium stored in the SR.23
cardiac output demand, there is an increased heart rate and simul- Calcium reuptake is mediated by the SR Ca2+-ATPase pump
taneous increase in force (positive force frequency)14 and an and the sarcolemmal Na+-Ca2+ exchanger (NCX), which
increase in rate of relaxation, which ensures that sufficient calcium results in the decay of the Ca2+ transient and normal relaxation.
is available from the SR for the next beat. In failing myocytes, there are numerous changes (e.g., expression
levels of these membrane proteins), which result in abnormal
Ca2+ transient, particularly in its termination. This also causes a
The Failing Human Heart prolonged action-potential duration and delayed relaxation. At
In the failing human heart, adrenergic effects are blunted.13 Numer- slow pacing rates, the Ca2+ transients of normal and failing myo-
ous studies of mammalian heart models have been done to better cytes are very similar. However, when the heart rate increases, the
understand the mechanism that leads to abnormal adrenergic sig- Ca2+ transient becomes significantly different due to a negative
naling. The normal human atrial and ventricular myocardium force-frequency relationship and decreased SR Ca2+ release, as
expresses β1- and β2-adrenergic receptors at a ratio of about discussed earlier.

Ch001-X3754.indd 4 1/16/2008 2:31:17 PM

 Chapter 1 • Molecular, Gene, and Cellular Mechanisms 5

B-ar P NCX
LTC
Na+
cAMP
2 Ca2+
1 X

P
Ca2+

SERCA2
Figure 1-1 Major Cellular Mechanisms of Diastolic
Dysfunction. 1. Inhibition of cyclic AMP (cAMP) for- SR
mation via adenylate cyclase. cAMP mediates phos-
phorylation of SERCA2 and the myofilaments, which Re-uptake X3
reduces Ca2+ uptake and increases myofilament Ca2+
responsiveness (MyoCAr), respectively. Ca2+ entry via Released Ca2+
the L-type Ca2+ channels (LTC) is also increased. Ca2+
2. Enhancement of Na+/Ca2+ exchange. 3. Blockade 4 “MyoCar”
of reuptake of Ca2+ by SERCA2 by non–cAMP-
dependent mechanisms. 4. Decreased myofilament
Ca2+ responsiveness by non–cAMP-dependent Myofilaments
mechanisms. B-ar, β-adrenergic receptor; p, phos-
phorylation site; SR, sarcoplasmic reticulum.

Sarcolemmal Receptors and Mechanisms myocyte and the role of this influx in governing calcium homeo-
stasis. One proposed mechanism suggests that sodium influx
The cardiac sarcolemma is a complex structure that contains mul- occurs through sodium channels and raises levels within the Na+
tiple channels, exchangers, and pumps that are necessary for microdomain activating the NCX in reverse mode (Ca2+ influx),
normal E-C coupling and myocyte contraction. In recent years, which is complementary to the influx generated by L-type calcium
the sarcolemmal NCX has surfaced as one of the primary agents channels. Because the NCX is dependent on the Na+ electro-
necessary to extrude calcium with each heart beat to allow normal chemical gradient for functioning, any changes that occur in
relaxation. By virtue of the NCX mechanism, the role of the sodium regulation in heart failure, when taken to an extreme, can
electrochemical sodium gradient has also been studied in various result in [Ca2+]i overload and diastolic dysfunction. Few studies
mammalian species as a potential determinant of [Ca2+]i.24,25 have addressed the role of the Na+-H+ exchanger in failing myo-
The NCX is a bidirectional electrogenic ion transporter that cytes, which has a 1:1 stoichiometry of Na+ influx for H+ efflux.
utilizes the Na+ electrochemical gradient to exchange one calcium Its stimulation may be increased in heart failure and lead to ele-
for three sodium ions. During repolarization, the negative mem- vated [Na+]i. Decrease in intracellular pH (which increases H+)
brane potential and elevated [Ca2+]i drive the NCX toward a can also increase Na+ by means of the Na+-H+ exchanger, second-
forward mode (Na+ in/Ca2+ out), resulting in extrusion of calcium arily increasing Ca2+ by means of the NCX. Alteration of these
from the cell in diastole. When the membrane potential is positive exchanges may contribute to prolongation of the action potential,
([Na+]i is increased), the NCX functions in reverse mode (Na+ slowed decay of the Ca2+ transient, and a delayed relaxation in
out/Ca2+ in), resulting in calcium influx, which may help regulate failing myocardium.
SR Ca2+ load and also, in conjunction with the Ca2+ current Several models of heart failure and hypertrophy have also
induced by activated DHRs, regulate SR Ca2+ release.21,26 There shown an increase in expression of NCX,31,32 which may be par-
still remain some conflicting data in regard to the effects of CICR tially controlled by the decreased sympathetic stimulation, leading
on SR by the reverse mode INaCa. CICR occurs mainly in the to decreased SERCA activity.33 Terraciano et al.25,34 showed that
dyadic cleft space in the T-tubular regions.27 in myocytes from transgenic (heterozygous) mice with upregula-
Several studies using the detubulation method in rat ventricu- tion of NCX, there was an increase in reverse-mode function
lar myocytes concluded that a majority of the NCX was localized resulting in an increase in SR calcium stores compared with wild-
to the T-tubules.28 However, Scriven et al. studied the distribu- type myocytes. It is important to remember that in smaller
tion of these proteins using high-resolution imaging and showed mammals (mice and rats), the action potential is shorter than the
that the NCX was localized to areas outside of the dyadic cleft duration of the calcium transient, which means that repolarization
space and that the spatial proximity of DHR with RyR2 was is occurring during most of the calcium transient, favoring forward-
higher than with NCX29; therefore, any triggered SR Ca2+ release mode NCX.35 In these species there are lower levels of NCX, so
by the reverse mode INaCa seems highly inefficient.30 any efflux via NCX makes a very small contribution to the decay
Several animal models with myocyte hypertrophy demon- of the calcium transient, even when overexpressed.20 However,
strated elevated [Na+]i compared with normal. Pieske and Houser there is a high [Na+]i in smaller mammals,36 favoring Ca2+ entry by
measured [Na+]i in failing and nonfailing human myocytes using reverse mode during the latter part of the calcium transient, which
multiple techniques and were the first to report elevated [Na+]i becomes more pronounced in myocytes overexpressing NCX,
levels in failing human myocytes.24 The exact mechanism of this explaining the findings reported by Terraciano’s group.
is under further investigation. Several studies have tried to In normal human myocytes, the action-potential duration is
describe the processes that lead to Na+ influx in the failing prolonged, and SERCA release and reuptake occur during the

Ch001-X3754.indd 5 1/16/2008 2:31:17 PM

 6 Chapter 1 • Molecular, Gene, and Cellular Mechanisms

plateau phase, when NCX is not in forward mode, indicating that SERCA2a expression at the level of mRNA or protein is inversely
most of the elimination of cytosolic calcium is dependent on related to duration of cardiac contraction,47–49 correlates with
reuptake by the SERCA pump. However, in failing myocardium, decreased myocardial function, alters the force-frequency
the interaction between these two proteins changes due to an response,50 and may also slow the velocity of relaxation, suggest-
increase in the ratio of NCX to SERCA levels. To better under- ing the importance of SERCA pump level in maintaining
stand whether increased NCX activity in the setting of reduced myocardial function. Yet it is still difficult to describe the actual
SERCA activity affects diastolic function, a study discriminating relationship between cardiac muscle and the SERCA pump
failing human hearts into three groups based on diastolic dysfunc- because of the complexity of its regulation and all the changes in
tion with increased stimulation rate was performed.37 The inves- other calcium-regulating proteins (such as NCX) that occur in
tigators discovered three different phenotypes with varying concert with each other within the myocyte and the heart as the
expression of SERCA and NCX with impaired systolic function, syndrome of heart failure progresses.
but the overall trend in the ratio of NCX to SERCA was an The SERCA pump is modulated by both direct and indirect
increase by a factor of 2 to 4 in all groups of failing myocytes factors. Phospholamban is the primary indirect regulator that
compared with normal. The phenotypes at either end of the spec- activates the SERCA2a pump. In its dephosphorylated state,
trum ranged from increased levels of NCX and unchanged phospholamban inhibits SERCA2a affinity for calcium.
SERCA levels (group I) to decreased levels of SERCA and The phosphorylation of phospholamban can occur at three differ-
unchanged NCX levels (group III). Only the latter phenotype ent sites—serine-16 by cAMP-dependent PKA, threonine-17
demonstrated both systolic and diastolic dysfunction, suggesting by Ca2+/calmodulin-dependent protein kinase II, and serine-10
that both SR calcium uptake and the capacity to eliminate calcium by Ca2+-activated phospholipid-dependent protein kinase.34
from the cytosol are impaired, whereas in group I, the SR calcium When phospholamban is phosphorylated by cAMP-dependent
uptake is impaired (causing systolic dysfunction), and global PKA (the most important mediator), the inhibitory effect is
capacity to eliminate calcium is higher (preserving diastolic dys- removed and the calcium affinity (not the maximal velocity
function). Therefore, the overexpression of NCX has positive of SERCA2a) increases, resulting in enhanced relaxation and
correlation with diastolic function in failing myocytes. an increase in SR Ca2+ load. Ca2+/calmodulin-dependent
protein kinase II (CaMK II) is the other modulator, which
directly phosphorylates SERCA2 and increases Vmax (maximal
Sarcoplasmic Reticulum activity) without altering the calcium affinity of SERCA2.51
The SR is an intracellular structure that is the most important CaMK II also phosphorylates the threonine-17 site in phosphol-
store of calcium in the mammalian heart. The sarcoplasmic mem- amban, which also increases the calcium affinity of SERCA2a. In
brane proteins (RyR2 and SERCA) maintain a tight control of heart failure, the blunting of the β-adrenergic pathway leads to
calcium release and uptake in E-C coupling, contractility, and alteration not only in phosphorylation of phospholamban at the
relaxation. There is a 10,000-fold Ca2+ gradient maintained across serine-16 site, but also in CaMK-dependent phosphorylation,
the SR membrane by the SR Ca2+-ATPase pump.38 Molecular ultimately altering SERCA2a activity. Most studies of human
analysis has identified three homologous genes (SERCA1, heart failure have suggested that although there is a decrease in
SERCA2, and SERCA3) encoding the SERCA pumps. The phospholamban mRNA levels, there is no difference in protein
SERCA2 gene is spliced into four variants that encode the iso- expression between failing and nonfailing myocytes.52,53 There-
forms. SERCA2a is the primary isoform expressed in cardiac fore, protein expression of SERCA2a in relation to phospholam-
muscle39 at high levels; however, there are regional differences, ban is always diminished in heart failure, which may explain the
age-related effects, and variation due to thyroid hormone levels increased phospholamban-to-SERCA2a ratios, leading to an
that affect expression levels. Experimental models in animals and increase in inhibition of the SERCA2a pump and an overall
humans have demonstrated that the expression level of SERCA decrease in its basal activity level and contributing to abnormal
in the atrium versus the ventricle is twofold and may account for calcium handling.
shorter contraction time in atria versus ventricles.40 In fact, in
heart failure models, it is well established that defective SR Ca2+ Altered Calcium Responsiveness of
uptake correlates with decreased contractility, which could be
attributed to significant decline in SERCA protein levels or an Myofibrillar Tension
alteration in SR Ca2+ transport function.41 Cardiac contractility and relaxation are altered not only because
Several studies induced left ventricular pressure overload of changes in calcium availability, but also because of changes in
hypertrophy/failure in rats by thoracic aortic banding and consis- myofilament responsiveness to calcium. In fibers rendered hyper-
tently found an overall decrease in SERCA mRNA levels,42–44 meable to Ca2+, a change in responsiveness can manifest as either
suggesting that downregulation of SERCA2a gene expression in a change in sensitivity or potency or as maximal Ca2+-activated
these models partly occurs at the transcriptional level.38 Feldman force. The actual mechanism responsible for this effect has not
et al. also deduced that decreased SERCA mRNA levels could be been definitively determined, but based on numerous studies, it
a marker of transition from compensated hypertrophy to decom- appears that isoform composition and phosphorylation status of
pensated hypertrophy/failure.43 In human heart models, SERCA the contractile proteins are altered, which increases the Ca2+ sen-
mRNA levels are reduced in failing compared with nonfailing sitivity of the contractile apparatus in end-stage heart failure.
hearts, yet there remains controversy regarding simultaneous Most studies have concentrated on changes of a single factor. Van
decrease in SERCA protein expression.29 Recently, data from der Velden et al.54 focused on a combination of contractile protein
larger studies have successfully shown a reduction of SERCA changes that occur during heart failure by studying isometric
protein levels in failing human hearts, but not in compensated force and its Ca2+ sensitivity in left ventricular myocytes from
hypertrophied human hearts, suggesting that perhaps a decrease nonfailing and end-stage failing donor hearts. They concluded
in protein level is a sign of developing failure.6,45,46 A decrease in that the combined decrease in phosphorylation status of

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 Chapter 1 • Molecular, Gene, and Cellular Mechanisms 7

troponin-I and myosin light chain 2 resulted in an increase in cardiac function.62–64 As discussed earlier, decrease in SERCA2a
Ca2+ sensitivity, and not due to contractile protein isoform change. activity and/or expression has been identified as one of the major
However, other studies have shown that the phosphorylation defective mechanisms responsible for impaired relaxation. By dis-
of myosin light chain 2 increases Ca2+ responsiveness.55 Earlier rupting the SERCA2a gene using homologous recombination,
reports showed that end-stage heart failure in humans is not Periasamy et al.65 obtained a better understanding of how the
associated with myofibrillar Ca2+ sensitivity.56–58 Until now, no pathologic decrease in SERCA2a pump levels can alter cardiac
real consensus has been reached to explain if, why, and how Ca2+ function. In homozygous mice, the outcome was lethal. Hetero-
sensitivity increases in heart failure patients. zygous mice were able to function, but the Vmax of SR Ca2+ uptake
Therapeutically, Ca2+ sensitizers pose a problem due to the was decreased by 35%. The peak amplitude of the Ca2+ transients
mechanism of action. An increased affinity of Ca2+ for troponin-C in normal heterozygous myocyte was decreased by more than
would enhance the actin-myosin interaction, which, theoretically, 30%, which led to a decrease in the maximal rate of contraction
prolongs relaxation. This has been shown in vivo and in vitro in and relaxation, as confirmed by measurements obtained via trans-
animals and in humans.57 ducers in the left ventricles and right femoral arteries of anesthe-
tized mice. These findings prove that there is a direct relationship
between SERCA2a level and cardiac contractility. Therefore,
TREATMENT, GENE THERAPY, AND THE FUTURE recent studies have used the adenoviral-mediated gene transfer to
increase SERCA2a pump activity as a potential means for therapy.
Congestive heart failure is a leading cause of morbidity and mor- Hajjar et al.66 showed that increased expression of SERCA2a in
tality in the United States. The remodeling process that occurs rat myocytes led to increased contractility and faster decay of the
after myocyte injury from multiple causes leads to contractile Ca2+ transient. The question remained in the ability to restore
dysfunction and abnormal intracellular calcium handling, which function in failing human myocytes. Del Monte et al.67 addressed
delays normal relaxation, as discussed in detail thus far. Although this very question by isolating human cardiomyocytes from the
there is no universal agreement regarding the mechanisms, it is left ventricles of 10 patients with end-stage heart failure. Gene
generally accepted that calcium handling is altered in failing transfer of SERCA2a led to an increase in protein expression and
hearts. The NCX and the SERCA2a pump are the two main pump activity, induced a faster contraction velocity, and enhanced
players that regulate cytosolic calcium levels during relaxation on relaxation velocity, thus reversing contractile abnormalities of the
a beat-to-beat basis. Therefore, multiple studies using gene trans- failing heart. Although the results were promising in the in vitro
fer methodologies are exploring the overexpression of these two model, this method did not predict the outcome in vivo. Hajjar
mechanisms that could potentially return calcium handling to and colleagues used a catheter-based technique of gene transfer
normal, as most of the conventional therapies that we currently to allow for global overexpression of SERCA2a in an animal
offer utilize mainly multiple medications, the actions of which are model of pressure-overload hypertrophy in transition to failure.
not completely understood.59 SERCA2a overexpression restored both systolic and diastolic
The sodium-calcium exchanger is a complex transport protein dysfunction to normal levels, decreased left ventricular size, and
that functions in reverse and forward modes. In normal mice myo- restored the slope of the end-systolic pressure-dimension rela-
cytes, it is the most dominant Ca2+ efflux mechanism that helps tionship to that of control levels.68
maintain calcium homeostasis.60 In humans, only 25% of the The SERCA gene therapy studies described above demonstrate
calcium is extruded by the NCX, and the other 75% is removed not only that it is possible to increase the expression of SERCA
by SERCA2a pumps.61 Some models of heart failure have protein but that its effects can normalize the abnormalities of
described an increase in expression of NCX in response to the calcium handling and contraction. However, this raises several
pathologic decrease in SERCA2a pumps attributed to the delayed important concerns, such as the long-term effects of inducing
and smaller Ca2+ transient.14 This is felt to be a compensatory these changes, impacts on the phospholamban and SERCA inter-
mechanism for the decreased efficiency of SR calcium re-uptake. action, and the effect on the NCX. As heart failure continues to
Because the actual quantitative contribution of the two regulatory pose a major clinical challenge for patients and physicians, the
mechanisms under pathologic conditions is poorly understood, so limitations of current treatment modalities are reflected in the
is the relationship between the changes in protein expression and grave statistics of minimal improvement in overall mortality within
the functional consequences.34 Terraciano et al. noted that the the last century. Gene transfer targeted toward specific pathways
degree of compensation that may be achieved with a two- to three- in the failing human heart is a novel therapeutic option that can
fold increase of NCX, the same measured in failing human hearts, potentially reverse the abnormalities of diastolic dysfunction and
has not been tested.34 They compared transgenic mice overex- transform heart failure into a chronic survivable condition.
pressing NCX with nontransgenic mice and confirmed that a
reduction in SERCA2a function can be compensated by overex-
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trigger Ca2+ and SR Ca2+ content in cardiac myocytes. Am J Physiol 2000;32:745–755.
1995;268:C1313–C1319. 48. Gombosova I, Bokník P, Kirchhefer U, et al: Postnatal changes in contractile
24. Pieske B, Houser SR: [Na+]i handling in the failing human heart. Cardio- time parameters, calcium regulatory proteins and phosphatases. Am J
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25. Blaustein MP, Lederer WJ: Sodium/calcium exchange: Its physiologic 49. Cain BS, Meldrum DR, Joo KS, et al: Human SERCA2a levels correlate
implications. Physiol Rev 1999;79:763–854. inversely with age in senescent human myocardium. J Am Coll Cardiol
26. Goldhaber JI, Scott TL, Walter DO, et al: Local regulation of the threshold 1998;32:458–467.
for calcium sparks in rat ventricular myocytes: Role of sodium-calcium 50. Hasenfuss G, Reinecke H, Studer R, et al: Relation between
exchange. J Physiol (London) 1999;520(pt 2):431–438. myocardial function and expression of sarcoplasmic reticulum Ca2+-
27. Reuter H, Pott C, Goldhaber JI, et al: Na+-Ca2+ exchange in the regulation ATPase in failing and nonfailing myocardium. Circ Res 1994;75:
of cardiac excitation-contraction coupling. Cardiovasc Res 2005;67: 434–442.
198–207. 51. Toyofuku T, Kurzydlowski K, Narayanan N, et al: Identification of Ser38
28. Kawai M, Hussain M, Orchard CH: Excitation-contraction coupling in rat as a site in cardiac sarcoplasmic reticulum Ca2+-ATPase that is phosphory-
ventricular myocytes after formamide-induced detubulation. Am J Physiol lated by Ca2+/calmodulin-dependent protein kinase. J Biol Chem
1999;277:H603–H609. 1991;266:11144–11152.
29. Scriven DR, Dan P, Moore ED: Distribution of proteins implicated in 52. Schwinger RH, Böhm M, Schmidt U, et al: Unchanged protein levels of
excitation-contraction coupling in rat ventricular myocytes. Biophys J SERCA II and phospholamban but reduced Ca2+ uptake and Ca2+-ATPase
2000;79:2682–2691. activity of cardiac sarcoplasmic reticulum from dilated cardiomyopathy
30. Sipido K, Macs M, van de Werf F: Low efficiency of Ca2+ entry through the patients compared with patients with non-failing hearts. Circulation
Na+-Ca2+ exchanger as triggers for Ca2+ release from the sarcoplasmic retic- 1995;92:3220–3228.
ulum. A comparison between L-type Ca2+ current and reverse-mode Na+- 53. Meyer M, Schillinger W, Pieske B, et al: Alterations of sarcoplasmic reticu-
Ca2+ exchange. Circ Res 1982;50:651–662. lum proteins in failing human dilated cardiomyopathy. Circulation
31. Hasenfuss G: Alterations of calcium-regulatory proteins in heart failure. 1995;92:778–784.
Cardiovasc Res 1998;37:279–289. 54. Van der Velden J, Papp Z, Zaremba R, et al: Increased Ca2+-sensitivity of
32. Flesch M, Schwinger RHG, Schiffer F, et al: Evidence for functional rele- the contractile apparatus in end-stage human heart failure results from
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55. Morano I, Arndt H, Gärtner C, et al: Skinned fibers of human atrium 62. He H, Giordano FJ, Hilal-Dandan R, et al: Overexpression of the rat
and ventricle: Myosin isoenzymes and contractility. Circ Res 1988;62: sarcoplasmic reticulum Ca2+-ATPase gene in the heart of transgenic mice
632–639. accelerates calcium transients and cardiac relaxation. J Clin Invest
56. Hajjar RJ, Gwathmey JK, Briggs GM, et al: Differential effect of DPI 201– 1997;100:380–389.
206 on the sensitivity of myofilaments to Ca2+ in intact and skinned 63. Baker DL, Hashimoto K, Grupp IL, et al: Targeted expression of the sar-
trabeculae from control and myopathic human hearts. J Clin Invest coplasmic reticulum Ca2+-ATPase increases cardiac contractility in trans-
1988;82:1578. genic mouse hearts. Circ Res 1998;83:1205–1214.
57. Wankerl M, Böhm M, Morano I, et al: Calcium sensitivity and myosin 64. Müeller OJ, Katus HA, Bekeredjian R: Targeting the heart with gene
light chain pattern of atrial and ventricular stunned cardiac fibers from therapy-optimized gene delivery methods. Cardiovasc Res 2007;73:
patients with various kinds of cardiac disease. J Molec Cell Cardiol 453–462.
1990;22:1425. 65. Periasamy M, Reed TD, Liu LH, et al: Impaired cardiac performance in
58. D’Angelo A, Luciani GB, Mazzucco A, et al: Contractile properties and Ca2+ heterozygous mice with a null mutation in the sarco(endo)plasmic reticulum
release activity of the sarcoplasmic reticulum in dilated cardiomyopathy. Ca2+-ATPase isoform 2 (SERCA2) gene. J Biol Chem 1999;274:
Circulation 1992;85:518–525. 2556–2562.
59. Hoshijima M: Gene therapy targeted at calcium handling as an approach 66. Hajjar RJ, Kang JX, Gwathmey JK, et al: Physiological effects of adenoviral
to the treatment of heart failure. Pharmacol Ther 2005;105:211– gene transfer of sarcoplasmic reticulum calcium ATPase in isolated rat myo-
228. cytes. Circulation 1997;95:423–429.
60. Goldhaber JI, Henderson SA, Reuter H, et al: Effects of Na+-Ca2+ exchange 67. Del Monte F, Harding SE, Schmidt U, et al: Restoration of contractile func-
expression on excitation-contraction coupling in genetically modified mice. tion in isolated cardiomyocytes from failing human hearts by gene transfer
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61. Hasenfuss G: Calcium pump overexpression and myocardial function: 68. Miyamoto MI, del Monte F, Schmidt U, et al: Adenoviral gene transfer of
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Ch001-X3754.indd 9 1/16/2008 2:31:18 PM

 D. DIRK BONNEMA, MD
CATALIN F. BAICU, PhD
MICHAEL R. ZILE, MD
2
Pathophysiology of
Diastolic Heart Failure:
Relaxation and Stiffness
INTRODUCTION Left Ventricular Systolic Function in Diastolic
Heart Failure
PATHOPHYSIOLOGY
Abnormal Diastolic Function in
Normal Diastolic Function
Decompensated Diastolic Heart Failure
Measurements of Diastolic Function
Abnormal Diastolic Function in Diastolic
Left Ventricular Diastolic Function During
Heart Failure During Exercise
Exercise
CLINICAL RELEVANCE
CARDIOVASCULAR STRUCTURE AND
Ischemic Diastolic Dysfunction
FUNCTION IN DIASTOLIC HEART FAILURE
Left Ventricular Concentric Hypertrophy
Left Ventricular Chamber Remodeling
Trigger Mechanisms of Noncardiac Factors in
Left Ventricular Diastolic Function in
Acute Decompensated Diastolic Heart
Diastolic Heart Failure
Failure
Cardiomyocyte Diastolic Function in
Diastolic Heart Failure FUTURE RESEARCH

INTRODUCTION symptomatic decompensation) do not have an “isolated” abnor-

mality in systolic properties; rather, from the pathophysiologic
Heart failure (HF) can be defined physiologically as an inability point of view, they have predominant abnormalities in systolic
of the heart to provide sufficient forward output to meet the properties and eccentric remodeling, with associated or secondary
perfusion and oxygenation requirements of the tissues while abnormalities in diastolic function.
maintaining normal filling pressures. Chronic heart failure By contrast, patients with DHF are characterized by normal
can be divided into two broad categories: systolic heart LV volume, concentric remodeling, and normal LV chamber sys-
failure (SHF) and diastolic heart failure (DHF). Classifying tolic properties, but dominant abnormalities in diastolic proper-
patients in these two broad categories should be based on ties.2,7–11 These patients have abnormalities in diastolic relaxation,
characteristic changes in cardiovascular structure and function filling, and/or distensibility. Clinical manifestations of LV dia-
(see Chapter 28).1,2 stolic dysfunction include shortness of breath at rest or with exer-
SHF is characterized by progressive chamber dilation, tion and peripheral edema. However, abnormalities in regional
eccentric remodeling, and dominant abnormalities in systolic systolic shortening have also been identified in some patients with
properties. Clinical manifestations of left ventricular (LV) DHF.2,11 Therefore, patients with DHF do not have “isolated”
systolic dysfunction include decreased cardiac output, increased abnormalities in diastolic properties; rather, from the pathophysi-
heart rate, and peripheral vasoconstriction. However, patients ologic point of view, they have predominant abnormalities in dia-
with SHF frequently have additional symptoms of shortness of stolic properties and concentric remodeling.
breath at rest or with exertion.3 These symptoms of pulmonary “Diastolic dysfunction” and “diastolic heart failure” are not
congestion are due, at least in part, to LV diastolic dysfunction.4–6 synonymous terms.12 Diastolic dysfunction indicates a functional
Therefore, patients with SHF (particularly when they have abnormality of diastolic relaxation, filling, or distensibility of the
11
12 Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness

left ventricle—regardless of whether the ejection fraction is parallel with LV ejection (cardiac output) both at rest and during
normal or abnormal and regardless of whether the patient is exercise. Adequate pulmonary function is also dependent upon
asymptomatic or has symptoms and signs of HF. Thus, diastolic LV diastolic function. During diastole, the left ventricle, left
dysfunction comprises abnormal mechanical (diastolic) proper- atrium, and pulmonary veins form a “common chamber” that is
ties of the ventricle and is present in virtually all patients with continuous with the pulmonary capillary bed. LV diastolic pres-
heart failure. Diastolic heart failure denotes signs and symptoms sure is determined by the volume of blood in the left ventricle
of clinical heart failure with normal ejection fraction and LV dia- during diastole and the diastolic distensibility or compliance of
stolic dysfunction. Similar distinctions apply to the terms “systolic the entire cardiovascular system, principally the left ventricle (but
dysfunction” and “systolic heart failure” (Boxes 2-1 and 2-2). it may also include the left atrium, pulmonary vessels, right ven-
tricle, and systemic arteries). Thus, an increase in LV diastolic
pressure (whether this occurs at rest or during exercise) will
PATHOPHYSIOLOGY increase pulmonary capillary pressure, which, if high enough,
causes dyspnea, exercise limitation, pulmonary congestion, and
The pathophysiology of diastolic heart failure will be reviewed edema (Fig. 2-1).
here, beginning with a discussion of the factors involved in normal Relaxation of the contracted myocardium begins at the onset
diastolic relaxation and filling. Understanding normal diastolic of diastole. This is a dynamic process that takes place during iso-
function permits an easier understanding of some of the clinical volumic relaxation (the period between aortic valve closure and
features of DHF. mitral valve opening during which LV pressure declines with no
change in volume) and then continues during auxotonic relax-
ation (the period between mitral valve opening and mitral valve
Normal Diastolic Function closure during which the left ventricle fills at variable pressure)
Cardiac function is critically dependent upon diastolic physiologic (Fig. 2-2). The rapid pressure decay and the concomitant “untwist-
mechanisms to provide adequate LV filling (cardiac input) in ing” and elastic recoil of the left ventricle produce a suction effect
that augments the left atrial-ventricular pressure gradient and
pulls blood into the ventricle, thereby promoting diastolic filling.
Box 2-1
During exercise in normal patients, relaxation rate is increased
and early diastolic pressures decrease, augmenting elastic
Definitions recoil and diastolic suction and resulting in more rapid filling
Diastolic Dysfunction: Abnormal diastolic properties of LV during a shortened diastolic filling period at increasing heart rates
(abnormal relaxation, filling dynamics, distensibility) (Fig. 2-3).
During the later phases of diastole, the normal left ventricle is
• EF may be normal or low. composed of completely relaxed cardiomyocytes and is very com-
• Patient may be symptomatic or asymptomatic.
pliant and easily distensible, offering minimal resistance to LV
Diastolic Heart Failure: Clinical heart failure, normal filling over a normal volume range. Atrial contraction near the end
ejection fraction, abnormal diastolic function of diastole contributes 20%–30% to total LV filling volume and
Systolic Dysfunction: Abnormal systolic properties of LV increases diastolic pressures by less than 5 mmHg. As a result,
(abnormal performance, function, contractility)
• EF is low (and diastolic dysfunction may coexist).
• Patient may be symptomatic or asymptomatic.
Pulmonary
Systolic Heart Failure: Clinical heart failure, low ejection capillaries
fraction, abnormal systolic function (From Circulation Pulmonary
2006;113:296–304.) vein

Box 2-2

Ao LA
Diastolic Heart Failure—Diagnostic Criteria
Required Criteria
1. Clinical evidence of heart failure
• Framingham or Boston criteria LV
• Plasma brain natriuretic peptide and/or chest x-ray
• Cardiopulmonary exercise testing
2. Normal ejection fraction (= 50%)
Confirmatory Evidence
1. LVH or concentric remodeling
2. Left atrial enlargement (in absence of atrial fibrillation) Figure 2-1 Elevated left ventricular end diastolic pressure causes pulmo-
3. Echo Doppler or catheter evidence of diastolic nary congestion. The heart is seen in diastole when the mitral valve open
dysfunction and the left ventricle (LV), left atrium (LA), and pulmonary veins form a
common chamber, continuous with the pulmonary capillary bed. The left
Exclusion ventricular end diastolic pressure determines the pulmonary capillary
Nonmyocardial disease pressure and the presence or absence of pulmonary congestion or edema.
Ao, aorta.
 Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness 13

REST EXERCISE
20
PLV

mmHg
Aorta
PLA
Isovolumic
pressure
Left decline 0
ventricle Minimum
PLV E
150 E

mL/sec
dV/dt
Left
atrium 0

Systole Diastole 500 msec

LV CHF REST CHF EXERCISE

volume
40 I
PLV

mmHg
Rapid Slow Atrial
MVC MVO filling filling filling PLA
AVO AVC Minimum
Auxotonic
PLV
Isovolumic relaxation
relaxation 0 E
150 E

mL/sec
Figure 2-2 Changes in left ventricular pressure and volume throughout
the cardiac cycle. The cardiac cycle is divided into systole, the time period dV/dt
from mitral valve closure (MVC) to aortic valve closure (AVC), and diastole. 0
Diastole is further divided into isovolumic relaxation (the time period from
AVC to mitral valve opening [MVO] during which LV pressure declines with Figure 2-3 Effects of exercise on left ventricular (LV) filling dynamics.
no change in volume) and auxotonic relaxation (the time period from MVO Changes in LV pressure (PLV), left atrial pressure (PLA), and the rate of
to MVC during which LV volume increases at variable pressure). AVO, atrial change of LV volume (dV/dt) at rest and during exercise. Top panel: During
valve opening. exercise in normal patients, minimal PLV decreases without any change in
PLA, leading to an increase in the peak mitral valve gradient and producing
a higher peak filling rate (E). Bottom panel: In congestive heart failure
(CHF), the peak LV filling rate (E) increases during exercise due to an
LV filling can normally be accomplished by very low filling pres- increase in the early transmitral valve pressure gradient. However, the
sures in the left atrium and pulmonary veins, preserving a low gradient is produced by an increase in PLA instead of a reduction in PLV
as occurs in normal patients. (From Cheng CP et al: Mechanism of augmented
pulmonary capillary pressure (<12 mmHg) and a high degree of rate of left ventricle filling during exercise. Circ Res 1992;70:9.)
lung distensibility. Loss of normal LV diastolic relaxation and
distensibility, from structural and functional causes, impairs LV
pressure decline and filling, resulting in increases in LV diastolic,
left atrial (LA), and pulmonary venous pressures, which directly
increase pulmonary capillary pressure. Left Ventricular Pressure Decline
Isovolumic relaxation can be quantified by measurement of LV
Measurements of Diastolic Function pressure with a high-fidelity micromanometer catheter and calcu-
lation of the peak instantaneous rate of LV pressure decline (peak
Complete characterization of LV diastolic properties requires
− dP/dt) and the time constant of LV isovolumic pressure decline
simultaneous measurement (often using a high-fidelity micro-
(Tau).13 When the natural log of LV diastolic pressure is plotted
manometer) of LV diastolic pressure and LV volume using inva-
versus time, Tau equals the slope of this linear relationship. Stated
sive and/or noninvasive methods. Diastolic function can be
in more conceptual terms, Tau is the time required for LV pres-
assessed using the following measurements:
sure to fall by approximately two thirds of its initial value. When
❒ Rate of isovolumic relaxation: peak (−)dP/dt, the time isovolumic pressure decline is slowed, Tau is prolonged and its
constant of the isovolumic LV pressure decay (Tau) and numerical value increases. Noninvasive estimates of the total
the isovolumic relaxation time (IVRT). When relaxation IVRT can be made using echocardiographic techniques. However,
rate is decreased, (−)dP/dt and Tau are increased no index of relaxation (isovolumic or auxotonic) can be consid-
(Fig. 2-4). ered an index of “intrinsic” relaxation rate unless loading condi-
❒ Rate and extent of LV filling: filling rate, the time-to-peak tions (and other modulators) are held constant or are at least
filling rate (TPFR), transmitral flow velocity, tissue specified. Therefore, changes in afterload (systolic pressure) and
velocity, and strain and strain rate. When there is pro- diastolic load (LA diastolic pressures) may change measurements
longed relaxation, the early filling rate and extent are of isovolumic and auxotonic relaxation without changing intrinsic
decreased, TPFR is prolonged, and the filling rate and relaxation properties.
extent that results from atrial contraction are increased
(Fig. 2-5).
❒ Passive elastic stiffness properties: diastolic pressure-volume
Left Ventricular Filling
(P-V) relationship. When stiffness is increased (distensi- A detailed description of the Doppler echocardiographic assess-
bility is decreased) the diastolic pressure versus volume ment of diastolic dysfunction is provided in other chapters
relationship is shifted upward (Fig. 2-6). (10–12 and 15). The normal left ventricle has a characteristic
14 Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness

5
LV pressure

100 AVC
4 Abnormal

Left ventricular pressure (mmHg)

τ = 55 msec Figure 2-4 Left ventricular (LV) isovolumic
Left ventricular pressure (mmHg)

Peak relaxation. LV pressure versus time and the

(–)dP/dt rate of change of LV pressure (dP/dt) in a
normal subject (solid line) versus a patient
3 with diastolic heart failure (dashed line).
Normal Isovolumic relaxation can be quantified by
τ = 34 msec calculating the peak instantaneous rate of
LV pressure decline (peak −dP/dt) and the
50
2 time constant of LV isovolumic pressure
decline (Tau). When the natural log of LV
diastolic pressure is plotted versus time,
Tau equals the slope of this linear relation-
ship (right panel). Stated in more concep-
1 tual terms, Tau is the time required for LV
pressure to fall by approximately two thirds
MVO P = P0e–t/τ of its initial value. When isovolumic relax-
LV dP/dt
ation is abnormal, LV pressure decline is
0 0 slower, −dP/dt has a more negative value;
0 500 1000 0 50 100 the time constant Tau is prolonged, and its
numerical value is increased (depicted by
Time (msec) Time (msec) the dashed lines in both figure panels).

Peak rapid
filling rate
Time to peak
filling rate
Peak atrial
filling rate
LV dV/dt

LV volume
Contribution
End Figure 2-5 Left ventricular (LV) filling dynamics. LV
of atrial
diastole volume versus time and the rate of change of LV
systole to
volume (dV/dt) in a normal subject (solid line)
LV filling
versus a patient with diastolic heart failure (dashed
line). With the onset of systole, the LV volume
decreases and reaches its minimum at the end
Total systole. Diastolic filling has three distinct phases:
LV stroke rapid filling of the left ventricle, during which dV/dt
Rapid
volume reaches it maximum and the peak filling rate occurs;
filling
a slow filling phase (diastasis), during which there
fraction
is little change in LV volume; and an atrial systole
phase, during which active atrial contraction fills
End the left ventricle and allows it to attain its end dia-
systole stolic volume. Important diastolic parameters
include the peak filling rate, the time to peak filling
rate, the rapid filling fraction (percent of total stroke
Rapid Slow filling Atrial volume reached during rapid filling), and the
filling (diastatis) systole percent contribution of atrial systole to LV filling.

pattern of filling and inflow velocities. LV inflow velocity and the factors, the most important of which are loading conditions. The
rate of LV filling are greatest early (E) in diastole, immediately typical, but nonspecific, mitral filling pattern associated with dia-
after mitral valve opening, and are responsible for the normally stolic dysfunction (termed abnormal relaxation) is a pattern of
tall E wave of the transmitral inflow Doppler echocardiogram increased IVRT and decreased E/A ratio. However, this pattern
(Fig. 2-7). Since most atrial-to-ventricular transfer of blood can be altered or pseudonormalized by changes in LA pressure.
occurs in early and mid-diastole, the amount of blood transported When diastolic dysfunction occurs, relaxation is slowed and
by atrial contraction is relatively small, the velocity imparted by incomplete, early LV diastolic pressures rise, early diastolic suction
the atrial contraction (the A wave of the transmitral inflow falls, and LV filling becomes increasingly dependent on an increase
Doppler echocardiogram) is relatively low, and the normal E/A in LA pressure to push blood into the left ventricle during dias-
wave ratio is greater than 1 and approaches a value of 2 in younger tole. As LA pressures rise, the value of the E wave increases and
individuals. E/A increases to a “normal” (or pseudonormal) value. When LA
Doppler echocardiographic assessment of LV filling has limita- pressures are severely increased, a “restrictive” pattern may develop
tions, since diastolic filling parameters are influenced by multiple in which the IVRT may be decreased and the E/A ratio further
 Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness 15

30

25 DHF

LV diastolic pressure (mmHg)

20
SHF
15

10

5 Normal

0
0 50 100 150 200 250 300
LV diastolic volume (ml)
Figure 2-6 Diastolic pressure versus volume relationships in patients with heart failure. Left ventricular (LV) diastolic pressure-volume data from normal
controls (solid line), patients with diastolic heart failure (DHF) (dotted line), and patients with systolic heart failure (SHF) (dashed line). In patients with DHF,
the diastolic pressure-volume curve is shifted up and left, indicating an increase in passive stiffness and a decrease in distensibility of the left ventricle.
In contrast, in patients with SHF, the diastolic pressure-volume curve is shifted down and right, indicating a decrease in passive stiffness and an increase
in distensibility of the left ventricle. These data clearly indicate that all patients with heart failure, whether diastolic or systolic, have a significant increase
in LV diastolic pressure; however, the mechanisms responsible for these increased pressures are different between these two different patient groups.
(From Aurigemma GP et al: Contractile behavior in the left ventricle in diastolic heart failure: With emphasis on regional systolic function. Circulation
2006;113:296.)

Diastolic dysfunction
Normal Impaired relaxation Pseudonormal Restrictive

LV press Stage 1 Stage 2 Stage 3

Mild Moderate Severe

LA press
E
A E
E
E
A A A
Mitral
Doppler
velocity

Decel
IVRT

Doppler
tissue
A'
imaging E' A'
E' A'
E' A'
E'
Figure 2-7 Doppler findings in diastolic heart failure. Schematic representation of left ventricular (LV) and left atrial (LA) pressures during diastole
(top panel), transmitral Doppler LV inflow velocity (middle panel), and Doppler tissue velocity (bottom panel) in normal patients and in different types of
diastolic dysfunction. This schema divides patients into four filling patterns: normal pattern of relaxation and filling (column 1 far left); impaired relaxation
or stage I mild diastolic dysfunction; pseudonormal relaxation, or stage II moderate diastolic dysfunction; and restrictive filling pattern, or stage III severe
diastolic dysfunction. Patients with an impaired filling pattern have a reduced E′, a prolonged E decel of early diastolic filling, and an increased A.
A pseudonormal filling pattern is denoted by an increased E wave in the face of a decreased E′. A restrictive filling pattern is denoted by an even larger
E wave and even smaller E′, with a shortened IVRT and a decreased E decel. It should be noted that these abnormal filling patterns may also be seen in
patients with systolic heart failure. In all patients with heart failure, these filling patterns have important prognostic value. For example, the presence
of a restrictive pattern predicts an increase in mortality rate, particularly in patients with systolic heart failure. E, peak early diastolic flow velocity; A, peak
late diastolic flow velocity caused by atrial contraction; E decel, E-wave diastolic deceleration time; IVRT, isovolumic relaxation time; S, myocardial velocity
during systole; E′, myocardial velocity during early filling; and A′, myocardial velocity during filling produced by atrial contraction. (From Zile MR, Brutsaert
DL: New concepts in diastolic dysfunction and diastolic heart failure: Part I: diagnosis, prognosis, and measurements of diastolic function. Circulation
2002;105:1387.)
16 Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness

increased.14 Recently developed echocardiographic and Doppler nondistensible ventricle will require higher pressures to achieve
echocardiographic techniques can be used to distinguish these filling of a given volume. Thus, an increase in LV diastolic chamber
three patterns of abnormal LV filling.15 stiffness or a decrease in distensibility shifts the LV diastolic P-V
When transmitral Doppler flow patterns are examined in curve upward and often increases its slope.
concert with more recently developed Doppler echocardiographic Defining the entire LV filling curve throughout diastole requires
techniques, patterns of normal versus impaired relaxation versus the simultaneous measurement of LV diastolic pressure and
pseudonormal versus restriction can be determined because these volume either throughout a single cardiac cycle (to define the
newer techniques provide information about LV filling pressure diastolic P-V relationship) or by way of the end diastolic P-V
and the LA/LV diastolic pressure gradient. These techniques coordinate over variably loaded cardiac cycles (to define the end
include measuring pulmonary venous flow velocity, tissue Doppler diastolic P-V relationship). The volume measurements can be
myocardial velocity, strain and strain rate, and color M-mode flow made by angiography, echocardiography, or radionuclide imaging
acceleration patterns. In particular, measures of myocardial veloci- techniques simultaneous with invasive measurements of LV
ties made by tissue Doppler imaging (TDI) appear less sensitive diastolic pressure. Alternatively, noninvasive Doppler echocardio-
to alteration in LV loading conditions (Fig. 2-8). E′ measures the graphic techniques can be used to estimate PCWP (see earlier
rate of early diastolic myocardial lengthening and, when com- description). Together with echocardiographically measured end
bined with transmitral Doppler E-wave data, can be used to esti- diastolic volume, an index of instantaneous diastolic stiffness
mate pulmonary capillary wedge pressure (PCWP) = 2 + 1.3 (ratio of PCWP-to-end diastolic volume) can be derived.17
(E/E′).16
Left Ventricular Diastolic Function
Left Ventricular Stiffness/Distensibility During Exercise
LV ventricular diastolic stiffness and distensibility are quantified A detailed description of the mechanisms and clinical relevance
by the position and shape of the LV diastolic P-V relationship, of diastolic dysfunction during exercise is provided in Chapter 17.
which plots LV diastolic pressure as a function of LV diastolic The cardiac output can increase several fold during exercise, an
volume throughout diastole (see Fig. 2-6). A relatively stiff, appropriate response to the enhanced needs of exercising muscle.

TISSUE DOPPLER IMAGING

Normal patient DHF patient

Velocity (cm/sec)

4
Velocity (cm/sec)

0 0

–4 –4

–8 –8

0 0
–5 –5
Strain (%)

Strain (%)

–10 –10
–15 –15
–20 –20
Systole Diastole Systole Diastole
3 3
Strain rate (sec–1)

Strain rate (sec–1)

2 2
1 1
0 0
–1 –1
–2 –2
0 0.2 0.4 0.6 0.8 1 0 0.2 0.4 0.6 0.8 1
Time (sec) Time (sec)
Figure 2-8 Examples of tissue Doppler imaging. Derived velocity (top), strain (middle), and strain rate (bottom) in a normal control patient (left) and a
patient with diastolic heart failure (DHF) (right). These tissue Doppler images were taken from the mitral annulus. The relaxation pattern during early dia-
stolic filling is marked by the block arrows. The strain data are similar to a left ventricular (LV) filling curve. The patient with DHF had a slow filling pattern,
as evidenced by a marked decrease in the slope of the line during early diastolic filling compared with the normal patient. The velocity and the strain rate
are both reduced. The relaxation pattern during late diastolic filling is marked by the thin arrows. The strain data show that the patient with DHF had a
more robust filling as a result of atrial contraction than had the normal patient. This indicates a shift in LV filling pattern from early to late diastole. The
velocity and the strain rate are both increased during atrial contraction. (From Aurigemma GP et al: Contractile behavior in the left ventricle in diastolic heart
failure: With emphasis on regional systolic function. Circulation 2006;113:296.)
 Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness 17

Multiple factors contribute to this response, including an increase However, it is the normal stiffness and distensibility of the
in heart rate, a modest rise in stroke volume, a reduction in left ventricle that allows an increase in end diastolic volume
peripheral vascular resistance, and an elevation in contractile with a negligible change in late diastolic pressure and no
force, which increases LV, arterial systolic pressure, and the force significant change in PCWP.
of ejection.
In summary, the normal heart during exercise has an elegant
The increase in LV output must be matched by a rise in LV input.
balance of physiologic mechanisms to ensure that cardiac input
The left ventricle cannot accomplish this task by the same mecha-
keeps pace with cardiac output, with preservation of a low pul-
nisms that increase output during exercise. For example, tachycardia
monary capillary pressure. These mechanisms result in an increase
shortens the duration of diastole, the time during which LV filling
in measured LV distensibility, as manifested by a downward shift
must occur. As a result, the diastolic filling rate during exercise may
of the LV diastolic P-V curve, especially during early diastole
be increased out of proportion to cardiac output.
(Fig. 2-9).23,24
A rise in flow rate across the mitral valve requires an increase
in the transmitral diastolic pressure gradient. If this were achieved
by increasing the pressure in the left atrium, this would have the
deleterious effects of increasing pulmonary capillary pressure and CARDIOVASCULAR STRUCTURE AND FUNCTION
causing pulmonary congestion, dyspnea, and respiratory compro- IN DIASTOLIC HEART FAILURE
mise. Rather, the normal left ventricle permits a remarkable
increase in diastolic filling rate during exercise by rapidly and DHF is typically associated with significant remodeling that
markedly decreasing LV pressure during early diastole, thereby affects the LV and LA chambers, the cardiomyocytes, and the
creating a relative LV “suction” effect, which enhances the trans- extracellular matrix. The structural remodeling that occurs in
mitral pressure gradient without increasing LA pressure (see DHF differs dramatically from that in SHF.
Fig. 2-3).18–21
Several mechanisms contribute to the left ventricular diastolic Left Ventricular Chamber Remodeling
suction effect during exercise:
Patients with DHF generally exhibit a concentric pattern of LV
❒ The increased force of contraction during systole enhances remodeling and a hypertrophic process that is characterized by a
early diastolic myocardial elastic recoil due to greater sys- normal or near-normal end diastolic volume, increased wall
tolic shortening forces and the extent of systolic fiber short- thickness, and an increased ratio of mass-to-volume with an
ening, which is manifested as a smaller end systolic volume increased ratio of wall thickness-to-chamber radius. By contrast,
(ESV).20 Thus, an increase in systolic shortening results in patients with SHF exhibit a pattern of eccentric remodeling with
an increase in restoring forces during diastole, which allow an increase in end diastolic volume (which is usually progressive
enhanced diastolic filling. over time), an increase in LV mass but little increase in wall thick-
❒ Acceleration of myocyte relaxation occurs during exercise, ness, and a substantial decrease in the ratios of mass to volume
due to an increased rate of calcium uptake by the sarco- and thickness to radius (Fig. 2-10).1,2,9,11,17,25,26
plasmic reticulum (SR). Increased cyclic adenosine mono-
phosphate (cAMP), generated by the β-adrenergic response
to exercise, phosphorylates the regulatory SR membrane Cardiomyocyte and Extracellular
protein, phospholamban, to increase the rate of calcium Matrix Remodeling
uptake by the SR during diastole.22 The dramatic differences in organ morphology and geometry
noted previously are paralleled by anatomic differences at the
Some of the mechanisms that allow an increase in cardiac
microscopic level. In DHF, the cardiomyocyte exhibits an
output and in cardiac input during exercise act in concert on
increased diameter, with little or no change in length; this corre-
systolic and diastolic functions:
sponds to the increase in LV wall thickness with no change in LV
❒ The Treppe effect creates a relationship between the heart volume (Fig. 2-11). By contrast, in SHF, the cardiomyocytes are
rate (or frequency of contraction)/LV pressure (or systolic elongated, with little or no change in diameter; this corresponds
force development) and ejection fraction (or shortening) to the increase in LV volume with no change in LV wall thickness.
such that in a normal heart, an increase in heart rate is It is easy to imagine how the geometric structural remodeling of
associated with an increase in stroke volume over a physi- these cardiomyocytes causes the remodeling seen in the LV cham-
ologic range of heart rate. This has been called the systolic bers that they populate.
force-frequency relationship. In addition, the same mecha- In DHF, there is an increase in the amount of collagen, with a
nism governs the relationship between heart rate and dia- corresponding increment in the width and continuity of the
stolic relaxation rate where increased heart rate in a normal fibrillar components of the extracellular matrix (Fig. 2-12). In
heart is associated with an increased relaxation rate, which SHF, at least early in its development, there is degradation and
in part allows LV diastolic pressures and PCWP to remain disruption of the fibrillar collagen.2,25,26 In end-stage SHF, replace-
normal during exercise. ment fibrosis and ischemic scarring may result in an overall
❒ A second example of the determinants of systolic and dia- increase in fibrillar collagen within the extracellular matrix.
stolic function acting in concert during exercise is the rela-
tionship between increased stroke volume and diastolic
Left Ventricular Diastolic Function in
distensibility. During normal exercise, end systolic volume
decreases and end diastolic volume increases. The increase Diastolic Heart Failure
in end diastolic volume allows the left ventricle to use the Abnormal LV diastolic function is a universal finding in patients
Frank-Starling mechanism to augment stroke volume. with DHF. Indeed, these abnormalities in diastolic function form
18 Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness

CONTROL ISCHEMIA SCAR

Rest Rest Rest

40 Exercise 40 Exercise 40 Exercise
LV pressure (mmHg)

LV pressure (mmHg)
LV pressure (mmHg)
30 30 30

20 20 20

10 10 10

0 0 0
60 120 160 200 100 140 180 220 140 180 220 260
Left ventricular Left ventricular Left ventricular
volume (ml) volume (ml) volume (ml)
Figure 2-9 Left ventricular (LV) pressure-volume (P-V) relationships. Shown are the relationships at rest and during exercise at early, mid-, and end diastole.
The simultaneous measurements of LV diastolic pressure and volume define distensibility or compliance. In the normal individual with normal compliance
(left panel), exercise causes a downward shift of the diastolic P-V curve in early diastole, indicating an increase in LV distensibility; the increase in cardiac
output occurs without an increase in LV diastolic pressure. In a patient with ischemia (middle panel), exercise causes a marked upward shift in the curve,
indicating a reduction in LV distensibility, or diastolic dysfunction, and there is a significant increase in LV and pulmonary capillary wedge pressures as LV
volume or cardiac output increases. This may result in the development of pulmonary congestion and respiratory symptoms. In the patient with a previous
myocardial infarction and an LV scar (right panel), the early increase in diastolic distensibility with exercise is lost, but there is no change in the P-V curve
in the absence of ischemia. (From Carroll JD et al: Dynamics of left ventricular filling at rest and during exercise. Circulation 1983;68:59.)

Normal Systolic heart failure Disastolic heart failure

Figure 2-10 Left ventricular (LV) remodeling in heart failure. Autopsy examples of the left ventricle imaged at the midventricular cross section in a normal
heart (left), systolic heart failure (center), and diastolic heart failure (right). Diastolic heart failure is characterized by a pattern of concentric LV remodeling
with a normal or near-normal end diastolic volume, increased wall thickness and mass, and a high ratio of mass to volume. By contrast, patients with systolic
heart failure exhibit eccentric remodeling with an increased end diastolic volume, little change in wall thickness, and a low ratio of mass to volume. (From
Aurigemma GP et al: Contractile behavior in the left ventricle in diastolic heart failure: With emphasis on regional systolic function. Circulation 2006;113:296.)

the dominant pathophysiologic basis for the development of ❒ Inability to sufficiently augment cardiac output during
DHF.7–11,15,17,25,26 exercise
The major abnormalities in LV diastolic function that contrib- ❒ Inability to sufficiently augment relaxation during
ute to or occur during the development of DHF include: exercise
❒ Inability to utilize the Frank-Starling mechanism during
❒ Slowed, delayed, and incomplete myocardial relaxation
exercise
❒ Impaired rate and extent of LV filling
❒ Increased diastolic LV, LA, and pulmonary venous
❒ Shift of filling from early to late diastole
pressures at rest or during exercise
❒ Decreased early diastolic suction/recoil
❒ Augmented LA pressure during the early filling In a given patient, impairment of one or more of these param-
❒ Altered passive elastic properties of the ventricle, resulting eters will result in decreased LV chamber distensibility, as mani-
in increased passive stiffness and decreased diastolic fested by an increase in diastolic pressure at any given LV volume.
distensibility When myocardial relaxation is impaired in diastolic dysfunction,
 Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness 19

POH-Diastolic heart failure POH-Diastolic heart failure

Normal Normal

DCM-Systolic heart failure

DCM-Systolic heart failure

Figure 2-11 Cardiomyocyte remodeling in heart failure. Isolated cardiac

muscle cells taken from (bottom) an animal model of dilated cardiomyopa-
thy (DCM) that produces systolic heart failure; (middle) a normal heart; and
(top) an animal model of pressure-overload hypertrophy (POH) that pro-
duces diastolic heart failure, in which the cardiomyocyte diameter is
increased. By contrast, in systolic heart failure, the cardiomyocyte length is
increased. (From Aurigemma GP et al: Contractile behavior in the left ventricle
in diastolic heart failure: With emphasis on regional systolic function. Circula-
tion 2006;113:296.)

the rate and amount of early diastolic LV filling are reduced, with Figure 2-12 Extracellular matrix remodeling in heart failure. Scanning
electron micrographs taken from (bottom) an animal model of dilated car-
a relative shift of LV filling to the later part of diastole (see Fig. diomyopathy (DCM) that produces systolic heart failure; (middle) a normal
2-5). The Doppler E wave is decreased, the hemodynamic load heart; and (top) an animal model of pressure-overload hypertrophy (POH)
on the atrium is increased, and atrial contraction makes a more that produces diastolic heart failure, in which there is an increase in the
important contribution to ventricular filling than in normal sub- amount of collagen, with a corresponding increment in the width and
continuity of the fibrillar components of the extracellular matrix. By con-
jects. This is reflected by an increase in the Doppler A wave and trast, in systolic heart failure, there is degradation and disruption of the
a decrease in the E/A ratio (see Fig. 2-7). The chronic atrial fibrillar collagen. (From Aurigemma GP et al: Contractile behavior in the left
overload may eventually result in atrial fibrillation, which can ventricle in diastolic heart failure: With emphasis on regional systolic function.
result in the loss of atrial contraction; dramatic reductions in LA Circulation 2006;113:296.)
emptying, LV filling, and LV stroke volume; and a significant
increase in LV diastolic pressures. The redistribution of filling
from early to late diastole also means that LV filling and LA as control cardiomyocytes. These in vitro cell data corresponded
emptying are compromised more in patients with diastolic dys- to an in vivo increase in LV end diastolic pressure in these patients
function than in normal patients by the occurrence of tachycardia. with DHF. These data indicate that cardiomyocytes from patients
An increase in heart rate shortens the duration of diastole and with DHF have increased stiffness and decreased distensibility
truncates the important late phase of diastolic filling. compared with normal cardiomyocytes. Therefore, these clinical
studies, along with studies using animal models of DHF, showed
that there are clear parallels in the abnormalities in diastolic func-
Cardiomyocyte Diastolic Function in tion between the LV chamber and individual cardiac muscle cells
Diastolic Heart Failure that constitute the myocardium.27
The significant abnormalities in LV diastolic function observed at
the chamber level are paralleled by the abnormalities in cardio-
Left Ventricular Systolic Function in
myocyte diastolic function observed at the cellular level. Cardio-
myocyte diastolic function was directly addressed in two studies Diastolic Heart Failure
in which patients with DHF underwent endomyocardial biopsy A detailed description of the systolic function in patients with
and single cardiomyocytes were isolated to assess cellular diastolic DHF is provided in Chapter 28. The dominant functional abnor-
performance.25,26 The cardiomyocytes had an increased resting mality in patients with SHF is abnormal LV systolic function.
tension in the absence of calcium that was almost twice as high Ejection fraction is normal in patients with DHF, but whether
20 Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness

abnormalities in LV systolic properties contribute to the patho- Abnormal Diastolic Function in Decompensated
physiology of DHF has remained an area of active investigation. Diastolic Heart Failure
Recent studies have carefully examined LV global and regional
systolic properties in patients with definite DHF. These studies As previously discussed, abnormal LV diastolic function is a uni-
have clearly demonstrated that global LV systolic properties are versal finding in patients with DHF. Indeed, these abnormalities
normal in patients with DHF. The most commonly used index of in diastolic function form the dominant pathophysiologic basis
LV systolic properties is the ejection fraction; however, a full for the development of DHF. Even in patients with “compensated”
assessment of the contractile behavior of the ventricle requires the DHF (NYHA classes II–III), abnormal relaxation, filling, and
combined use of indices that reflect LV systolic performance, stiffness lead to increased diastolic pressures (Fig. 2-13). Further
function, and contractility, as well as a consideration of global and changes in diastolic function occur when patients develop decom-
regional functions. The following measurements have been made pensated DHF.28,29 For example, atrial fibrillation, tachycardia, or
in patients with definite DHF: uncontrolled hypertension can lead to rapid increases in LA pres-
sures and the development of decompensated DHF. Under these
❒ LV performance measured as stroke work
circumstances, the rise in pressure causes a significant change in
❒ LV function measured as ejection fraction and preload
transmitral Doppler flow pattern (as previously described). There
recruitable stroke work
is pseudonormalization of the ratio of ventricular to atrial filling
❒ LV contractility measured as peak (+)dP/dt, end systolic
velocities (E to A ratio) and when atrial pressures are extremely
elastance, and the endocardial stress-shortening
increased, to a frankly restrictive pattern. These changes in relax-
relationship
ation and filling are associated with changes in distensibility.
Patients with DHF have no significant change in any of these During compensated DHF, the LV diastolic P-V relationship
measurements compared with age- and gender-matched normal shifts upward, indicating decreased diastolic distensibility. During
control subjects.11 While these global measurements of LV sys- the initial development of decompensated DHF (during the
tolic properties are normal in patients with DHF, regional systolic phase of “worsening DHF”), LV volume may increase along a
properties such as midwall fractional shortening and long axis similar abnormal diastolic P-V curve (from point A to point B).
shortening extent and rate may be abnormal in some patients Later, when acute pulmonary edema develops in decompensated
(>50%) with DHF. However, these regional abnormalities do not DHF, there may be a marked upward shift in the diastolic P-V
appear to be causally linked to either the pathophysiology of dia- relationship (from point B to point C), indicating a further
stolic dysfunction or the development of DHF.2 decrease in LV distensibility. Once patients with decompensated

COMPENSATED DHF WORSENING DHF

B
33 33
LV pressure (mmHg)

LV pressure (mmHg)

A A

22 22
Normal

11 11

Figure 2-13 Left ventricular (LV)

0 0 diastolic pressure-volume (P-V) rela-
0 20 40 60 80 100 0 20 40 60 80 100 tionship in compensated and decom-
pensated diastolic heart failure (DHF).
LV volume (ml) LV volume (ml) During compensated DHF, the LV dia-
stolic P-V relationship shifts upward,
indicating decreased diastolic distensi-
ACUTE PULMONARY EDEMA POST TREATMENT bility. During the development of
decompensated DHF initially (during
C C
the phase of “worsening DHF”), LV
33 B 33 volume may increase along a similar
LV pressure (mmHg)

LV pressure (mmHg)

abnormal diastolic P-V curve (from point

A A to point B). Later, when acute pulmo-
nary edema develops in decompen-
22 22 sated DHF, there may be a marked
upward shift in the diastolic P-V
relationship (from point B to point C),
indicating a further decrease in LV dis-
11 11
tensibility. Once patients with decom-
pensated DHF are adequately
treated—for example, with diuretics
0 0 and nitrates—the LV diastolic P-V
0 20 40 60 80 100 0 20 40 60 80 100 relationship moves back to the com-
pensated DHF state (from point C to
LV volume (ml) LV volume (ml) point A).
 Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness 21

DHF are adequately treated—for example, with diuretics and intake in the absence of concentric remodeling or diastolic dys-
nitrates—the LV diastolic P-V relationship moves back to the function does not result in DHF.
compensated DHF state (from point C to point A).
Decompensated DHF may be caused by both cardiovascular Abnormal Diastolic Function in Diastolic Heart
and noncardiovascular factors (or triggers) that act on the already
existing structural and functional abnormalities (composing a sub- Failure During Exercise
strate) to precipitate the development of acute pulmonary edema While studies consistently show that diastolic function is abnor-
(Fig. 2-14). The substrate in patients with DHF consists of mal in patients with DHF at rest, these abnormalities become
structural remodeling of the LV chamber and of the constituent even more exaggerated during exercise (see Chapter 17).37–39 Spe-
cardiomyocytes and extracellular matrix that compose the chamber. cifically, patients with DHF are not able to increase LV end dia-
These structural changes are associated with significant abnormal- stolic volume, recruit Frank-Starling forces, increase relaxation
ities in LV diastolic function, including decreased LV distensibility. rate, or increase filling rate. Consequently, exercise results in a
These changes in LV structure and function form the substrate marked increase in diastolic pressure, a limited ability to increase
from which patients develop the clinical syndrome of DHF. cardiac output, and marked truncation of exercise capacity. These
There are a number of comorbid conditions that may act as abnormal responses to exercise are made worse by the exaggerated
triggers for the development of acute decompensated DHF. These increase in arterial blood pressure that frequently accompanies
include uncontrolled hypertension, increased salt and water exercise in patients with DHF.
intake, tachyarrhythmias, chronic renal failure, anemia, and co- Abnormal diastolic function also plays a role in exercise intoler-
existent lung disease.1,3,30–36 These comorbidities act upon the ance suffered by patients with SHF, in which systolic dysfunction
substrate to precipitate acute decompensated DHF. It should be causes the left ventricle to lose the ability to augment diastolic
noted, however, that in the absence of this substrate, these triggers filling in response to exercise by the normal mechanism of accen-
do not result in DHF. For example, an increase in salt and water tuated elastic recoil and early diastolic suction, previously

Normal

30
LV diastolic pressure (mmHg)
DHF
25 Normal control

20
Decreased
distensibility
15
Diastolic heart failure
10

0
0 20 40 60 80 100 120
LV diastolic volume (ml)

Substrate
LV structure
LV function

Triggers HTN, ↑ Na2/H2O, Diastolic heart failure

Tachy, CRF, ↓ HgB lung disease

Figure 2-14 Diastolic heart failure (DHF) substrate versus trigger. Patients with DHF have structural remodeling of the left ventricular (LV) chamber and
of the constituent cardiomyocytes and extracellular matrix that compose the chamber. These structural changes are associated with significant abnormali-
ties in LV diastolic function, including decreased LV distensibility. These changes in LV structure and function form the substrate from which patients
develop the clinical syndrome of DHF. There are a number of comorbid conditions that may trigger the development of acute decompensated DHF. These
include uncontrolled hypertension, increased salt and water intake, tachyarrhythmias, chronic renal failure (CRF), anemia, and coexistent lung disease.
These comorbidities act upon the substrate to precipitate acute decompensated DHF. It should be noted, however, that in the absence of this substrate,
these triggers do not result in DHF. For example, an increase in salt and water intake in the absence of concentric remodeling or diastolic dysfunction does
not result in DHF.
22 Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness

described.18–20 Early diastolic filling in HF can be increased during sure, indicating a “paradoxical” increase in diastolic compliance.41
exercise by a different mechanism: an elevation in LA pressure to By contrast, during demand ischemia, diastolic compliance falls
create the requisite transmitral gradient rather than the normal acutely.41–43 These opposite initial compliance changes with
decline in early diastolic LV pressure. The increase in LA pressure demand and supply ischemia may be explained by differences in
results in pulmonary congestion with exercise, a hallmark of HF the pressure and volume within the coronary vasculature, by the
(see Fig. 2-3). mechanical effects of the normal myocardium adjacent to the
ischemic region, and by tissue metabolic factors.

CLINICAL RELEVANCE Ischemia/Reperfusion Causing

A variety of cardiac diseases can cause the development of abnor- Diastolic Dysfunction
mal diastolic function, abnormal cardiovascular remodeling, and Ischemic diastolic dysfunction can continue during and after rees-
the development of DHF. The mechanisms by which cardiovas- tablishment of normal myocardial blood flow (i.e., reperfusion).
cular disease causes these outcomes include (but are not limited Reperfusion after a period of ischemia may result in a phase of
to) hemodynamic alterations, nonhomogeneous contraction and post-ischemic diastolic “stunning,” analogous to post-ischemic
relaxation, myocardial ischemia, and LV concentric remodeling stunning of contractile function. For example, diastolic dysfunc-
and hypertrophy. These mechanisms can act individually to alter tion may be present early after cardiac surgery, after the myocar-
diastolic function but often act in concert to cause the develop- dium has been exposed to cardioplegic arrest, or after thrombolytic
ment of DHF. For ease of understanding, these mechanisms will or percutaneous treatment of an acute myocardial infarction. In
first be discussed individually. each of these circumstances, reversible diastolic dysfunction
follows reperfusion after a period of ischemia despite normal
blood flow, with slow recovery to normal levels (Fig. 2-15).44–46
Ischemic Diastolic Dysfunction Post-ischemic mechanical dysfunction results in both systolic and
Ischemia can cause a reversible impairment of myocyte relaxation diastolic dysfunction, and the latter may be a more sensitive
and diastolic function. The resultant slowing or failure of myocyte parameter of ischemic injury.41 During reperfusion, LV diastolic
relaxation causes a fraction of actin-myosin cross-bridges to chamber stiffness is increased.44,45 Over time, diastolic dysfunc-
persist and continue to generate tension throughout diastole, tion resolves, and it is therefore reasonable to refer to this process
especially in early diastole, creating a state of “partial persistent as post-ischemic diastolic stunning. Recognition of this phenom-
systole.” Two kinds of ischemia can alter diastolic function: enon is important because a reduced cardiac output or elevated
demand ischemia, created by an increase in energy utilization that PCWP in the early postoperative period or early after treatment
outstrips the necessary supply (such as during exercise or stress), of acute coronary syndrome may reflect an increase in LV dia-
and supply ischemia, created by a decrease in myocardial blood stolic chamber stiffness rather than a reduction in contractile
flow without a change in energy utilization (such as a myocardial function. This distinction can be made readily with
infarction or coronary artery spasm). The differences between echocardiography.
supply and demand ischemia are transient. After more sustained
ischemia of 30 to 60 minutes or longer, both types result in
decreased diastolic compliance.

Demand Ischemia
20 Post CABG
During demand ischemia, diastolic dysfunction may be related to
myocardial ATP depletion, with a concomitant increase in ADP,
PCWP (mmHg)

resulting in rigor (rigor bond formation).29 Although ischemia is

also associated with the persistence of an increased intracellular
calcium concentration during diastole, one study found that isch-
emic diastolic dysfunction was not directly mediated by an Pre CABG
increase in calcium concentration and a calcium-activated 14
tension.40 As a result of the rigor, LV pressure decay, as assessed
by Tau, is impaired, and the left ventricle is functionally stiffer
than normal during diastole. Typically demand ischemia occurs
during exercise or pharmacologically induced stress; it results
from an increase in oxygen demand in the setting of limited coro- 9.5 10 10.5 11 11.5 12 12.5
nary flow reserve caused by coronary stenosis and/or ventricular LV end diastolic area (cm2)
hypertrophy.
Figure 2-15 Coronary artery bypass graft (CABG) decreases left ventricu-
lar (LV) compliance. The relationship between LV end diastolic area, mea-
Supply Ischemia sured by two-dimensional echocardiography, and the pulmonary capillary
wedge pressure (PCWP), which reflects LV compliance, before and after
Supply ischemia results from a marked reduction in coronary CABG. The PCWP and LV diastolic areas were increased with volume
flow. The net effect is inadequate coronary perfusion even in the loading using isotonic saline. After CABG, the LV diastolic area was smaller
at each level of PCWP, as reflected by a leftward shift of the pressure-area
resting state. Acute supply ischemia causes an initial transient relationship; this indicates a reduction in LV compliance. (From McKenney
downward and rightward shift of the diastolic P-V curve such P, et al: Increased left ventricular diastolic chamber stiffness immediately after
that end diastolic volume increases relative to end diastolic pres- coronary artery bypass surgery. J Am Coll Cardiol 1994;24:1189.)
 Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness 23

Ischemia-Induced Pulmonary Symptoms dysfunction also may contribute to the reduction in coro-
nary reserve, although the response to exogenous nitric
Ischemia, either spontaneous or during exercise, prevents the oxide is preserved.53,54 Thus, when metabolic demand and
normal increase in LV distensibility and, as previously mentioned, the need for oxygen increase, coronary reserve is often
can cause a rapid and marked increase in LV diastolic chamber inadequate to meet the increased oxygen requirements, and
stiffness. In the latter setting, LV diastolic pressures quickly ischemia ensues.52
increase, resulting in acute pulmonary congestion (“flash” pulmo- ❒ Increased LV diastolic pressures can cause vascular com-
nary edema). This upward shift of the LV diastolic P-V curve is pression, thereby reducing coronary flow and perfusion of
completely reversible with recovery of myocardial perfusion.24 the subendocardial layer.49
The effects of ischemia explain why many patients with coronary ❒ The incidence and severity of coronary atherosclerosis is
disease have respiratory symptoms with their anginal pain, includ- increased in the presence of systemic arterial hypertension,
ing wheezing, an inability to take a deep breath, or shortness of a frequent cause of concentric LVH. Thus, patients with
breath. Such respiratory symptoms may occur in the absence of concentric LVH on a hypertensive basis often have signifi-
anginal pain and are often referred to as anginal equivalents. These cant concomitant coronary artery disease.
symptoms are similar to those of HF, which is not surprising,
since the responsible mechanism is an elevation in pulmonary These factors make the heart with concentric LVH exquisitely
capillary pressure. One study, for example, showed that the acute sensitive to subendocardial ischemia.
decrease in LV distensibility and increase in diastolic pressure The hypertrophied ventricle also cannot relax normally in dias-
during angina caused an increase in airway resistance and a reduc- tole with exercise. Thus, to produce the necessary increase in
tion in lung compliance.47 A similar symptom complex can occur ventricular input, there is an increase in LA pressure, rather than
in patients with concentric LV hypertrophy (LVH), even in the the normal reduction in ventricular pressure, which produces a
absence of epicardial coronary artery disease. suction effect, as previously described. This can lead to an eleva-
tion in pulmonary capillary pressure that is sufficient to induce
pulmonary congestion. Exercise-induced subendocardial isch-
Left Ventricular Concentric Hypertrophy emia can produce an “exaggerated” impairment of diastolic relax-
Widespread use of noninvasive methods of cardiac imaging has ation of the hypertrophied myocardium (see Fig. 2-15).
led to the recognition that LV diastolic dysfunction and DHF are These factors often act in concert. For a given degree of isch-
commonly induced by the myocardial hypertrophy associated emia, the functional impairment in relaxation is more severe in
with hypertensive, coronary, or valvular heart disease. Resistance the hypertrophied than in the nonhypertrophied heart.9,48 Thus,
to diastolic filling is usually the result of common structural patients with concentric LVH secondary to chronic hypertension
abnormalities, including concentric LV remodeling, cardiomyo- or aortic stenosis are particularly susceptible to ischemic diastolic
cyte hypertrophy, altered structure and composition of the extra- dysfunction.
cellular matrix, and increased fibrillar collagen. All of these
hypertrophy-associated changes lead to impaired cellular and
myocardial relaxation (see Fig. 2-9). Genetic and Infiltrative Diseases
LVH and ischemia have important interactions. For a given Genetic disease processes, such as hypertrophic cardiomyopathy,
degree of ischemia, a greater decline in diastolic function is seen in and infiltrative diseases, such as amyloidosis, cause diastolic
hypertrophied hearts.9,48 Hearts with concentric LVH are highly dysfunction and lead to the development of DHF. These disease
susceptible to subendocardial ischemia for several reasons49: processes are discussed in detail in Chapters 21 and 23.
❒ There is some evidence of inadequate coronary growth
relative to muscle mass, with a resultant decrease in capil- Trigger Mechanisms of Noncardiac Factors in
lary density.50 The ensuing increase in capillary-to-myocyte
oxygen diffusion distance renders the hypertrophied
Acute Decompensated Diastolic Heart Failure
myocyte more susceptible to ischemia. Patients with DHF are older and have a large number of coexis-
❒ The increase in ventricular wall thickness raises the epicar- tent, comorbid disease processes, each of which may act on
dial-endocardial distance. Coronary arterial circulation the structural and functional substrate that occurs in patients
consists of epicardial vessels that penetrate transmurally, with DHF and may trigger the development of acute decompen-
giving rise to mid-myocardial branches that perfuse the sated DHF (see Fig. 2-14). For example, present in patients with
thickened LV wall before supplying the subendocardium. DHF may be advanced age, poorly controlled diabetes, chronic
Thus, coronary perfusion pressure is dissipated in propor- renal insufficiency, anemia, atrial fibrillation, selected drugs
tion to LV wall thickness, leaving the subendocardium as (e.g., glitazones, acidic nonsteroidal anti-inflammatory drugs
the region most vulnerable to ischemia.49 [ANSAIDs], calcium channel blockers), abnormal sodium and
❒ Coronary arterial remodeling accompanies concentric water balance, chronic lung disease, increased arterial blood
hypertrophy and is manifested by an increase in coronary pressure, and increased effective arterial elastance. When
arterial medial thickness and perivascular fibrosis, which present chronically, some of these factors may contribute to devel-
can restrict the extent of coronary arterial vasodilatation. opment of the structural and functional changes that form the
❒ Vascular tone at rest is often abnormally reduced, and coro- substrate from which DHF develops. For example, diabetes
nary flow at rest is increased in the hypertrophied heart.51,52 may be associated with increases in advanced glycation end-
Enhanced coronary flow is required in the resting state to product–induced collagen cross-links, in collagen content, and in
supply the increased muscle mass. However, since maximal myocardial stiffness. The changes in the structure and function of
achievable coronary flow is similar to that of normal ven- cardiomyocytes and extracellular matrix that are common
tricles, coronary flow reserve is diminished. Endothelial to advanced age may make the myocardium more vulnerable to
24 Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness

the effects of hypertension and coronary artery disease, 11. Baicu CF, Zile MR, Aurigemma GP, et al: Left ventricular systolic perfor-
making the development of DHF more frequent. In addition, mance, function, and contractility in patients with diastolic heart failure.
Circulation 2005;111:2306–2312.
once the structural and functional substrate of DHF has formed 12. Zile MR, Baicu CF, Bonnema DD: Diastolic heart failure: Definitions and
(i.e., concentric remodeling and abnormal diastolic function), the terminology. Prog Cardiovasc Dis 2005;47:307–313.
factors previously listed can act on this substrate to precipitate (or 13. Zile MR, Brutsaert DL: New concepts in diastolic dysfunction and diastolic
trigger) the development of acute decompensated DHF. However, heart failure: Part I: Diagnosis, prognosis, and measurements of diastolic
function. Circulation 2002;105:1387–1393.
in the absence of the substrate structure/function changes of 14. Yusuf S, Pfeffer MA, Swedberg K, et al. and CHARM Investigators and
DHF, these factors by themselves will not result in its Committees: Effects of candesartan in patients with chronic heart failure
development. and preserved left-ventricular ejection fraction: The CHARM-Preserved
Trial. Lancet 2003;362:777–781.
15. Oh JK, Hatale L, Tajik AJ, et al: Diastolic heart failure can be diagnosed by
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16. Nagueh SF, Mikati I, Kopelen HA, et al: Doppler estimation of left ven-
There are many aspects of the pathophysiology of DHF and acute tricular filling pressure in sinus tachycardia. A new application of tissue
decompensated DHF that remain to be completely understood. Doppler imaging. Circulation 1998;98:1644–1650.
In particular, the cellular and extracellular mechanisms causing 17. Ahmen SH, Clark LL, Pennington WR, et al: Matrix metalloproteinases/
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opment of diastolic dysfunction and DHF must be addressed, as 18. Cheng CP, Igarashi Y, Little WC: Mechanism of augmented rate of left
must also the question of whether diastolic dysfunction is an ventricular filling during exercise. Circ Res 1992;70:9–19.
19. Cheng CP, Noda T, Nozawa T, et al: Effect of heart failure on the mecha-
inevitable consequence of aging or can be avoided by a “successful” nism of exercise induced augmentation of mitral valve flow. Circ Res
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diastolic function). We must define whether and how aging plus 20. Little WC, Cheng CP: Modulation of diastolic dysfunction in the
disease processes (hypertension, diabetes, etc.) common in an intact heart. In Lorell BH, Grossman W (eds): Diastolic Relaxation
of the Heart: The biology of diastole in health and disease, 2d ed. Boston,
aging population result in DHF. Finally, we must define the Kluwer Academic Publishers, 1994:167–176.
factors that cause the transition from asymptomatic diastolic dys- 21. Little WC: Diastolic dysfunction beyond distensibility: Adverse effects of
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clinically applicable, noninvasive methods to detect and predict 178.
23. Carroll JD, Hess OM, Hirzel HO, et al: Dynamics of left ventricular filling
this transition. Only with an increased knowledge and under- at rest and during exercise. Circulation 1983;68:59–67.
standing of the pathophysiology of DHF can effective manage- 24. Carroll JD, Hess OM, Hirzel HO, et al: Exercise-induced ischemia: The
ment strategies that target this pathophysiology be developed and influence of altered relaxation on early diastolic pressures. Circulation
successfully applied to patients with DHF to decrease mortality 1983;67:521–528.
25. Borbély A, van der Velden J, Papp Z, et al: Cardiomyocyte stiffness in dia-
and morbidity of this important cause of congestive heart stolic heart failure. Circulation 2005;111:774–781.
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2. Aurigemma GP, Zile MR, Gaasch WH: Contractile behavior in the left pulmonary edema associated with hypertension. N Engl J Med 2001;344:
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tion. Circulation 2006;113:296–304. 29. Vinch CS, Aurigemma GP, Hill JC, et al: Usefulness of clinical variables,
3. Bhatia RS, Tu JV, Lee DS, et al: Outcome of heart failure with preserved echocardiography, and levels of brain natriuretic peptide and norepinephrine
ejection fraction in a population-based study. N Engl J Med 2006; to distinguish systolic and diastolic causes of acute heart failure. Am J
355:260–269. Cardiol 2003;91:1140–1143.
4. Redfield MM, Jacobsen SJ, Burnett JC Jr, et al: Burden of systolic and dia- 30. Owan TE, Hodge DO, Herges RM, et al: Trends in prevalence and outcome
stolic ventricular dysfunction in the community: Appreciating the scope of of heart failure with preserved ejection fraction. N Engl J Med
the heart failure epidemic. JAMA 2003;289:194–202. 2006;355:251–259.
5. Kitzman DW, Little WC, Brubaker PH, et al: Pathophysiological charac- 31. Yancy CW, Lopatin M, Stevenson LW, et al for the ADHERE Scientific
terization of isolated diastolic heart failure in comparison to systolic heart Advisory Committee and Investigators: Clinical presentation, management,
failure. JAMA 2002;288:2144–2150. and in-hospital outcomes of patients admitted with acute decompensated
6. Brucks S, Little WC, Chao T, et al: Contribution of left ventricular diastolic heart failure with preserved systolic function: A report from the Acute
dysfunction to heart failure regardless of ejection fraction. Am J Cardiol Decompensated Heart Failure National Registry (ADHERE) Database.
2005;95:603–606. J Am Coll Cardiol 2006;47:76–84.
7. Zile MR, Gaasch WH, Carroll JD, et al: Heart failure with a normal ejec- 32. Brucks S, Little WC, Chao T: Relation of anemia to diastolic heart failure
tion fraction. Is measurement of diastolic function necessary to make the and the effect on outcome. Am J Cardiol 2004;93:1055–1057.
diagnosis of diastolic heart failure? Circulation 2001;104:779–782. 33. Fukuta H, Sane DC, Brucks S, et al: Statin therapy may be associated with
8. Zile MR: Heart failure with preserved ejection fraction: Is this diastolic lower mortality in patients with diastolic heart failure: A preliminary report.
heart failure? J Am Coll Cardiol 2003;41:1519. Circulation 2005;112:357–363.
9. Aurigemma GP, Gaasch WH: Clinical practice. Diastolic heart failure. 34. O’Meara E, Clayton T, McEntegart MB, et al: Clinical correlates and
N Engl J Med 2004;351:1097–1105. consequences of anemia in a broad spectrum of patients with heart
10. Zile MR, Baicu CF, Gaasch WH: Diastolic heart failure—abnormalities in failure: Results of the Candesartan in Heart Failure: Assessment of
active relaxation and passive stiffness of the left ventricle. N Engl J Med Reduction in Mortality and Morbidity (CHARM) Program. Circulation
2004;350:1953–1959. 2006;113:986–994.
 Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness 25
35. Zile MR: Treating diastolic heart failure with statins. “Phat” chance for 45. McKenney PA, Apstein CS, Mendes LA, et al: Immediate effect of aortic
pleiotropic benefits (editorial). Circulation 2005;112:300–303. valve replacement for aortic stenosis on left ventricular diastolic chamber
36. Katz AM, Zile MR: New molecular mechanism in diastolic heart failure stiffness. Am J Cardiol 1999;84:914–918.
(editorial). Circulation 2006;113:1922–1925. 46. Bolli R: Myocardial “stunning” in man. Circulation 1992;86:1671.
37. Little WC, Zile MR, Klein A, et al: Effect of losartan and hydrochlorothia- 47. Pepine CJ, Wiener L: Relationship of anginal symptoms to lung
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38. Warner JG Jr, Metzger DC, Kitzman DW, et al: Losartan improves exercise 48. Eberli FR, Apstein CS, Ngoy S, et al: Exacerbation of left ventricular isch-
tolerance in patients with diastolic dysfunction and a hypertensive response emic diastolic dysfunction by pressure-overload hypertrophy. Modification
to exercise. J Am Coll Cardiol 1999;33:1567–1572. by specific inhibition of cardiac angiotensin converting enzyme. Circ Res
39. Little WC, Wesley-Farrington DJ, Hoyle J, et al: Effect of candesartan and 1992;70:931–943.
verapamil on exercise tolerance in diastolic dysfunction. J Cardiovasc 49. Isayama S: Interplay of hypertrophy and myocardial ischemia. In Lorell BH,
Pharmacol 2004;43:288–293. Grossman W (eds): Diastolic Relaxation of the Heart: The biology of
40. Eberli FR, Stromer H, Ferrell MA, et al: Lack of direct role for calcium diastole in health and disease, 2d ed. Boston, Kluwer Academic,
in ischemic diastolic dysfunction in isolated hearts. Circulation 1994:203–212.
2000;102:2643–2649. 50. Tomanek RJ, Wessel TJ, Harrison DG: Capillary growth and geometry
41. Apstein CS, Grossman W: Opposite initial effects of supply and demand during long-term hypertension and myocardial hypertrophy in dogs. Am J
ischemia on left ventricular diastolic compliance: The ischemia-diastolic Physiol 1991;261:H1011–H1018.
paradox. J Mol Cell Cardiol 1987;19:119–128. 51. Eberli FR, Ritter M, Schwitter J, et al: Coronary reserve in patients
42. Varma N, Eberli FR, Apstein CS: Increased diastolic chamber stiffness with aortic valve disease before and after successful aortic valve replacement.
during demand ischemia: Response to quick length change differentiates Eur Heart J 1991;12:127–138.
rigor-activated from calcium-activated tension. Circulation 2000;101: 52. Marcus ML, Koyanagi S, Harrison DG, et al: Abnormalities in the coronary
2185–2192. circulation that occur as a consequence of cardiac hypertrophy. Am J Med
43. Varma N, Eberli FR, Apstein CS: Left ventricular diastolic dysfunction 1983;75:62–66.
during demand ischemia: Rigor underlies increased stiffness without 53. Ishihara K, Zile MR, Nagatsu M, et al: Coronary blood flow after the
calcium-mediated tension. Amelioration by glycolytic substrate. J Am Coll regression of pressure-overload left ventricular hypertrophy. Circ Res
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44. McKenney PA, Apstein CS, Mendes LA, et al: Increased left ventricular 54. MacCarthy PA, Shah AM: Impaired endothelium-dependent regulation of
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J Am Coll Cardiol 1994;24:1189–1194. 2000;101:1854–1860.
 DAVID H. SPODICK, MD
3
Role of Pericardium in
Diastolic Dysfunction and
Diastolic Heart Failure
INTRODUCTION (DHF), the current state of knowledge permits only reasonable
extensions and hypothesis generation from what we know of pericar-
PATHOPHYSIOLOGY
dial function and behavior during normal cardiac function and to
CLINICAL RELEVANCE AND some extent during systolic cardiac impairments. Box 3-1 summa-
FUTURE RESEARCH rizes the macrophysiology of the normal pericardium, many elements
of which—subject to investigation—may affect DD and DHF.
ABBREVIATIONS
Box 3-2 summarizes the many cardiac effects of pericardiec-
tomy or sufficiently extensive pericardiotomy.4 Patients who have
INTRODUCTION had pericardiectomy for any indication grossly appear to function
quite well, although the subject has not been intensively studied in
Pericardologists1 were concerned almost exclusively with diastole human patients and certainly not compared for individual patients
(for good reasons of pericardial constriction and cardiac tampon- acutely and especially chronically, which would permit a better
ade) before the late 1980s, when diastolic dysfunction (DD) estimate of the pericardium’s dispensability. In considering the
started to attract widespread attention among other cardiologists. many effects of pericardiectomy and pericardiotomy sufficiently
In many respects, acute and subacute constrictive pericarditis widespread to remove pericardial mechanical influence (see Box 3-
(CP) and cardiac tamponade epitomize DD, usually in the pres- 2), the apparent benignity of pericardiectomy/otomy is at least
ence of normal systolic cardiac function. Indeed, both often have superficially surprising because it implies that there are either
normal or high ejection fractions (EFs)—a consequence of ven- widespread and adequately compensatory adjustments or that the
tricular underfilling with basically normal or compensatorily pericardium is really not indispensable. Nonindispensability
hyperfunctional myocardium.2 However, the normal pericardium would be especially surprising when one considers the items in Box
also affects the cardiac filling dynamics of both normal and dis- 3-1, as well as the very rich pericardial microphysiology5 (not a
eased hearts, although to a lesser degree.3 subject of this discussion). There is, however, broad and deep expe-
rience with experimental pericardiectomy and pericardiotomy (see
Box 3-2) in hearts without cardiac disease, which, like the macro
PATHOPHYSIOLOGY functions of the normal pericardium (see Box 3-1), should be con-
sidered in evaluating and further investigating DD and DHF.
The normal pericardium becomes more important in dilated All pericardial investigations must always be considered in the
hearts and with increased central circulatory volume and less so light of the varied investigational protocols, which have definitely
with hypovolemia and normal responses to other influences that affected experimental results. Thus, it matters quantitatively and
reduce cardiac size, like head-up tilt (HUT), lower body negative even qualitatively whether the experimental subjects are intact
pressure (LBNP), and administration of such agents as nitro- and conscious with a closed chest and having recovered from
prusside and nitroglycerine.3 With the often low compliance of surgery, versus open chest, anesthetized, and/or autonomically
hearts with DD, the influence on filling of the normally stiff, low- blocked experimental subjects, as well as the species of the sub-
compliance pericardium may be either less than normal or addi- jects.3 For example, dog, rabbit, and human pericardial structures
tive, but this relationship has not been investigated. differ significantly; the canine pericardium is much more aniso-
In the absence of formal, specifically targeted investigations of the tropic than the human pericardium.6 Moreover, within the intact
influence of the pericardium on DD and diastolic heart failure pericardium, it matters quantitatively whether the pressure is
27
28 Chapter 3 • Role of Pericardium in Diastolic Dysfunction and Diastolic Heart Failure
Box 3-1

Macrophysiology of the Normal Pericardium*

Mechanical Functions: Promotion of Cardiac Efficiency, II. Provision of closed chamber with slightly
Especially during Hemodynamic Overloads subatmospheric pressure in which:
I. Relatively inelastic cardiac envelope A. The level of transmural cardiac pressures will be low,
A. Maintenance of normal ventricular compliance relative to even large increases in “filling pressures”
(volume-elasticity relation) referred to atmospheric pressure.
B. Defense of the integrity of any Starling curve: B. Pressure changes aid atrial filling via more
Starling mechanism operates uniformly at all negative pericardial pressure during ventricular
intraventricular pressures because presence of ejection.
pericardium C. Diastolic suction can accelerate filling following
1. Maintains ventricular function curves. systole.
2. Limits effect of increased left ventricular end III. “Feedback” cardiocirculatory regulation via pericardial
diastolic pressure. servomechanisms
3. Supports output responses to: A. Neuroreceptors detect lung inflation and (via vagus):
a. Venous inflow loads and atrioventricular valve alter heart rate and blood pressure.
regurgitation (particularly when acute) B. Mechanoreceptors: Lower blood pressure and
b. Rate fluctuations contract spleen.
4. Hydrostatic system (pericardium plus pericardial IV. Limitation of hypertrophy associated with chronic
fluid) distributes hydrostatic forces over epicardial exercise
surfaces.
a. Favors equality of transmural end diastolic Membranous Functions
pressure throughout ventricle, therefore uniform I. Reduction of external friction due to heart movements
stretch of muscle fibers (preload) A. Production of pericardial fluid
b. Constantly compensates for changes in B. Generation of phospholipid surfactants
gravitational and inertial forces, distributing them II. Buttressing of thinner portions of the myocardium:
evenly around the heart Myocardial thickness varies reciprocally with parietal
C. Limitation of excessive acute dilation pericardial thickness.
D. Protection against excessive ventriculoatrial A. Atria
regurgitation (atrial support) B. Right ventricle
E. Ventricular interaction: relative pericardial stiffness III. Defensive immunologic constituents in pericardial fluid
1. Provides a mutually restrictive chamber favoring IV. Fibrinolytic activity in mesothelial lining
balanced output from right and left ventricles V. Prostacyclin (PGE2, PG12 and eicosanoids) released into
integrated over several cardiac cycles pericardial sac in response to stretch, hypoxia and
2. Permits either ventricle to generate greater increased myocardial loading/work
isovolumic pressure from any volume VI. Synthesis and release of endothelin, increased by
3. Reduces ventricular compliance with increased angiotensin III stimulation
pressure in the opposite ventricle (e.g., limits right VII. Barrier to inflammation from contiguous structures
ventricular stroke work during increased impedance Ligamentous Function
to left ventricular outflow) I. Limits undue cardiac displacement
F. Maintenance of functionally optimal cardiac (especially II. Modifies pericardial stress/strain by limiting directions
left ventricular) shape of traction of its fibers

*Condensed from Spoclick DH: The pericardium: A comprehensive textbook. New York, Marcel Dekker, 1997.

measured by an open-ended catheter or a flat balloon transducer, normally negative—therefore numerically additive—intrapericar-
with balloons yielding higher levels of pericardial constraint (spe- dial pressure.3 TMPs are created by having an intact pericardium
cifically radial epicardial stress), especially significant at very low and are approximately equal over both ventricles, although
effusion volumes.7 there may be local effects causing small local differences.10 The
Most of the pathophysiologic effects of pericardiectomy or suf- right ventricular end diastolic pressure-dimension (RVEDPD)
ficiently extensive pericardiotomy must be considered in light of relation, for example, is not flat or zero because of this, and
the fact that the pericardium, specifically the parietal pericardium, as noted in Box 3-2, at matched left ventricular end-diastolic
constrains the heart, which is immediately recognizable by retrac- (LVED) volume, pericardiectomy causes a fundamental alteration
tion of the in situ pericardial tissue when it is incised.3 (The vis- in otherwise normal RV, but not left ventricular (LV), filling.11
ceral pericardium may also have some constraining effect, but this Finally, transmural LVED pressure is a more important deter-
is incompletely investigated.) Indeed, in 1898 Barnard incised the minant of LV mechanoreceptor activity than absolute LVED
pericardium and observed that the heart herniated through the pressure.3,12 Mechanoreceptors are sensitive to changes in ven-
incision, especially in diastole and more so when he squeezed the tricular stretch, determined by ventricular volume and TMP; peri-
abdomen, elevating vena cava pressure.8 Thus it is no surprise that cardial constraint may attenuate their activity by limiting cardiac
pericardial constraint accounts for about 90% of right atrial (RA) distension.3
and 80% of right ventricular (RV) cavitary pressure.9 Whereas, with an intact pericardium, the right ventricle
The immediate filling pressures of the cardiac chambers are their dominates direct ventricular diastolic interaction (ventricular
transmural pressures (TMPs): cardiac chamber pressures minus interdependence), after pericardiectomy or sufficiently extensive
 Chapter 3 • Role of Pericardium in Diastolic Dysfunction and Diastolic Heart Failure 29
Box 3-2 After pericardiectomy, the cardiac chambers operate at differ-
ent TMPs because of the normally slightly negative intrapericar-
Pericardiectomy/Pericardiotomy*: dial pressure (unless, subject to investigation, the ambient pleural
Pathophysiologic Effects and pulmonary pressures of the cardiac fossa could substitute for
this). With DHF, pericardial influence would also be subject to
A. General Considerations investigation to characterize cardiac filling in relation to the
1. Reduced or absent constraint of the cardiac TMPs. Moreover, the force balance affecting cardiac chambers
chambers
2. At matched LVEDV, pericardiectomy causes a
and their corresponding systolic performance is described by the
fundamental alteration in RV but not LV filling. transmural difference between intracavitary and extramural pres-
3. Pericardiectomy shifts LVEDP-V curve to the right. sures.14 Indeed, the chamber collapses seen in cardiac tamponade
4. Pericardiectomy decreases RVEDP-V slope. can be attributed to sometimes even negative transmural diastolic
5. Reduced atrioventricular and ventricular interaction (i.e., pressures (i.e., intrapericardial pressure intermittently sufficiently
parallel interaction, due to pericardium); left ventricle higher than subjacent chamber pressures). In pericardial constric-
dominates. (With an intact pericardium, the right tion (usually completely obliterative), there can be no truly trans-
ventricle dominates.) mural pressures.2
6. Decreased suction (less negative pressure) during Ventricular interaction (ventricular interdependence) reflects
ventricular systole the influence, particularly the filling characteristics, of the contra-
B. Specific Effects lateral ventricle.4 Direct interaction occurs immediately via the
1. Decreased: ventricular septum, while indirect interaction (series interaction)
a. RA mean pressure is by way of the pericardium. For series interaction, an immediate
b. RA filling rate change in one ventricle is not transmitted as directly as through
c. Pulmonary volume overload with intravascular the septum but is transmitted sequentially in subsequent heart-
volume loading beats. Series and direct interaction influence P-V relations, pul-
d. Excess intravascular volume redistribution from
pulmonary systemic circulation
monary-cardiac contact pressure, and coronary engorgement. Of
e. Decreased ventricular isovolumic pressure generation these, the P-V relations are the most important to producing LV
from any volume diastolic pressure. Hypertrophied hearts, which are characterized
f. Decreased base to apex intraventricular pressure by DD, especially with ventricular failure, should be a natural
gradient; filling velocity shifts toward the base subject for further investigation of interaction.
g. E/A and E′ Draining a noncompressing hydropericardium, as occurs in
h. Decreased LV mechanoreceptor activity12 heart failure, induces a state analogous to removing the normal
2. Increased: pericardial constraint, or at least reducing it considerably, since it
a. Cardiac chamber transmural pressures has been shown that any size, small to large, of even clinically
b. RV size nontamponading effusions significantly exaggerate respiratory
c. LV stroke volume, SWI and CI due to Frank-Starling
response to increased preload
effects on cardiac dynamics when measured with appropriate
d. LA compliance with greater increase in conduit than instruments.15 These are a quantitatively small counterpart to the
reservoir function effusions producing cardiac tamponade, which more strongly
e. LV compliance couple the parietal pericardium to the chamber surfaces, grossly
f. Peak dp/dt exaggerating ventricular interaction, especially the respiratory
g. Early LV filling velocity (A) and filling fraction effects due to the existence of an intact pericardium, notably
h. LV end diastolic diameter and volume pulsus paradoxus.16
i. LV early filling rate A particular advantage of an intact pericardium, which could
j. Ventricular series interactions (relative to direct be investigated in DD and DHF, is the pericardial contribution
interaction) to diastolic suction. Diastolic suction, specifically ventricular
k. LV mechanoreceptor activity
l. Rate of myocardial protein synthesis producing
suction, occurs in early diastole and must exist in normal as well
increased LV mass as abnormal hearts.17 The intensity of diastolic suction is propor-
m. Exercise responses tional to the kinetic energy of the preceding systole. Moreover,
i. Maximal O2 consumption diastolic suction is greatest when the heart size is least, after the
ii. Maximal stroke volume and cardiac output end of systole, precisely when it is needed for filling. (Systolic
iii. LA pressure and SV and LASV suction may also exist in the atria during reduction of intraperi-
iv. LV end diastolic pressure cardial contents by ventricular ejection.3) Presence of the pericar-
n. Ventricular pressure-volume curves: Ventricular dium thus permits the kinetic energy acquired during systole to
pressure begins its sharp rise later (at a higher cardiac be applied to filling. Moreover, diastolic suction is more important
volume) and increases more gradually thereafter. at the rapid heart rates common to cardiac failure, which ampu-
tate the late to mid-diastolic diastasis interval so that there is less
*Pericardiotomy = sufficiently wide incision/excision.
“passive” filling. In any case, suction must be necessary for even
normal cardiac filling because, although the Frank-Starling rela-
pericardiotomy, the left ventricle dominates the relationship; thus tion implies that cardiac output should be determined by venous
LV isovolumic pressure generation from any LV volume is filling of the right heart, RA pressure is normally low, and small
decreased and, comparably, after pericardiectomy ventricular changes should not affect the entire heart. Indeed, changes in
pressure-volume (P-V) curves show their customary sharp rise body position and breathing may cause larger changes in pres-
later (i.e., at a higher chamber volume) and thereafter also increase sure.18 This is dramatically seen when excised mammalian hearts
more gradually than before pericardiectomy.13 in buffered solutions continue to empty and refill, where pericar-
30 Chapter 3 • Role of Pericardium in Diastolic Dysfunction and Diastolic Heart Failure

dial absence ensures that there can be no change in extramural CLINICAL RELEVANCE AND FUTURE RESEARCH
pressure. Yet, diastolic suction is directly observed, indeed obvious.
In such hearts, an intact pericardium would facilitate or magnify Pericardial pathophysiology as capsulated in Boxes 3-1 and 3-2
suction. In these isolated hearts, diastolic filling pressure thus applies to investigations of the pericardium and its effect on the
does not uniquely determine fiber length and cannot entirely normal heart, usually the left ventricle. There are as yet no formal
explain the cardiac “output.” investigations of the role of the pericardium in patients and animal
In DD, one might predict that decreased myocardial compli- models with DD or DHF. Although one may generate hypotheses
ance, epitomized by hypertensive hearts, would reduce macro- (e.g., see Box 3-3) and make reasonable projections from the fore-
physiologic pericardial effects by analogy to pericardial effects on going data, clinical relevance can emerge only from specifically
the normal right and left ventricles; the normal right ventricle is designed, controlled investigations tested in appropriate clinical
thinner and far more compliant than the left—especially with LV contexts. For example, does the stiffness of the normal pericar-
hypertrophy—and thus much more directly subject to pericardial dium, accounting for its normal constraint,13 add to or otherwise
constraint and to changing intrapericardial pressure. Indeed, modify the reduced compliance of the hypertensive left ventricle
normal RV compliance is three to four times LV compliance,19 a with DD or DHF? In some circumstances, structural pericardial
relationship predictably affected by DHF but subject to modifications may be a therapeutic option. When pericardiec-
investigation. tomy was tried some years ago for dilated cardiomyopathy, it
Another target for investigation in DD and DHF would be the proved to be more detrimental than helpful. The recent develop-
effect of the pericardium in restricting acute chamber dilation (as ment, however, of a pericardial “garment” for the ventricles (e.g., the
of the left atrium following papillary muscle rupture with acute Acorn mesh) actually compensates for pericardial anisotropy
mitral regurgitation). Constraint is illustrated in reverse in those since it is constructed with special fiber orientations that oppose
cases of “pericardial shock” with severe hypotension immediately the differing directional tensions in the underlying pericardial
after pericardiocentesis, usually in patients with concomitant fibers.22 In addition, there is currently an enlarging field of intra-
heart disease who develop acute LV failure after pericardial drain- pericardial drug and instrumental therapy for investigation in
age due to acute LV dilation.20 Indeed, some of these patients also diastolically as well as systolically and rhythmically abnormal
develop acute pulmonary edema. One could assume that the hearts.23
pericardium and pericardial effusion fluid, especially with cardiac
tamponade, had resisted ventricular dilation, following which
drainage left a lax, nonconstraining, and therefore no longer resist- ABBREVIATIONS
ing (constraining) pericardium.
The effects of pericardiectomy could also be investigated in HUT: Head-up tilt
DHF on a purely mechanistic basis because pericardiectomy LBNP: lower body negative pressure
shifts the LVED P-V relationship to the right or down (Box 3-2), DD: diastolic dysfunction
while DHF shifts it to the left.21 DHF: diastolic heart failure
Some of the major considerations are condensed in Box 3-3. TMP: transmural pressure: cardiac chamber pressures minus nor-
mally negative—therefore additive—pericardial pressure (e.g.,
Box 3-3 LVTMP = left ventricular transmural pressure, and so on)
PTMP: pericardial transmural pressure: intrapericardial pressure
minus pleural pressure
Selected Major Pericardial Functions Potentially*
LV: left ventricle
Applicable to Investigating Diastolic Dysfunction
LA: left atrium
and Diastolic Failure
RV: right ventricle
I. Mechanical effects due to mainly the parietal RA: right atrium
pericardium and minimal in euvolemic individuals with EDP: end diastolic intracavitary pressure (e.g., LVEDP = left
normal hearts ventricular end diastolic pressure, and so on)
A. Decreased by hypovolemia EDPV relation: end diastolic pressure-volume relation
B. Exaggerated by central hypervolemia (and pericardial EDPD relation: end diastolic pressure-dimension relation
effusion with or without tamponade) and by cardiac
dilation
Ventricular interaction (interdependence): Effects of physical
C. Comparative effects in DD/DHF uninvestigated changes and movements in one ventricle on the other. Direct
II. Normally, RV and LV volumes are equally restrained by interaction: septal movement (as during breathing phases)
the pericardium. (Though perhaps due to regional imposed by pericardial constraint (series interaction is the
pericardial effects, cavitary pressures fall more in RV than effect via the vasculature and lungs of one ventricle on the
LV after pericardiectomy.) Effects with DD/DHF other). Pericardium-dependent ventricular interactions are
uninvestigated. almost entirely diastolic, although systolic and atrioventricular
III. Differences in RV and LV filling partly relate to differences interactions also exist.
in atrial compliance and ventricular distensibility. Suction: filling of a cardiac chamber because of negative/relatively
(Volume loading and pericardiectomy affect A-V pressure negative pressure “leading” the direction of blood flow.
gradient.) Effects in DD/DHF uninvestigated.
IV. Nitroglycerine and nitroprusside decrease ventricular
Ventricular diastolic suction is especially important, especially
diastolic pressures, reflecting loss of pericardial at small/relatively small chamber/heart volumes. Most suction
constraint when decreased venous return shrinks cardiac is facilitated by an intact pericardium.
volume. Applications in DD/DHF uninvestigated. CP: constrictive pericarditis
CT: cardiac tamponade
*Pending formal, specific investigation. EF: ejection fraction
 Chapter 3 • Role of Pericardium in Diastolic Dysfunction and Diastolic Heart Failure 31

REFERENCES 13. Spodick DH: Progress in investigation of effusion and tamponade, immu-
nosuppression, and constriction in pericarditis and pericardial diseases. Curr
1. Seferovic PM, Spodick DH, Maisch B (eds): Pericardiology. Belgrade, Op Cardiol 1992;7:476–481.
Science, 1999. 14. Boltwood CM: Ventricular performance related to transmural filling pres-
2. Haffty BG, Singh JB, Spodick DH: Tracking left ventricular performance sure in clinical cardiac tamponade. Circulation 1987;75:941–947.
noninvasively: Response of the peak ear pulse derivative during cardiac 15. Wayne VS, Bishop RL, Spodick DH: Dynamic effects of nontamponading
catheterization. Chest 1983;83:543–546. pericardial effusion: Respiratory responses in the absence of pulsus para-
3. Spodick DH: Threshold of pericardial constraint: The pericardial reserve doxus. Br Heart J 1984;51:202–204.
volume and auxiliary pericardial functions. J Am Coll Cardiol 1985;6: 16. Spodick DH: Pathophysiology of cardiac tamponade. Chest 1998;113:
296–297. 1372–1378.
4. Spodick DH: Pericardial diseases. In Braunwald E, Zipes DP, Libby P (eds) 17. Myers RBH, Spodick DH: Constrictive pericarditis: Clinical and patho-
Heart Disease, 6th ed. Philadelphia, WB Saunders, 2001:1823–1866. physiologic characteristics. Am Heart J 1999;138:219–232.
5. Spodick DH: Macro and microphysiology and anatomy of the pericardium. 18. Robinson TF, Factor SM, Sonnenblick EH: The heart as a suction pump.
Am Heart J 1992;124:1046–1051. Scient Amer 1981;210:84–98.
6. Janicki JS, Weber KT: The pericardium and ventricular interaction, disten- 19. Belenkie I, Dani R, Smith ER, Tyber JV: The importance of pericardial
sility, and function. Am J Physiol 1980;238:H494–H503. constraint in experimental pulmonary embolism and volume loading. Am
7. Tyberg JV, Misbach GA, Glantz SA, et al: A mechanism for shifts in the Heart J 1992;123:733.
diastolic left ventricular pressure-volume curve: The role of the pericardium. 20. Spodick DH: The pericardium: A comprehensive textbook. New York,
Euro J Cardiol 1978;7:163–175. Dekker, 1997.
8. Spodick DH: Acute pericarditis. New York, Grune Stratton, 1959:182. 21. Zile MR, Brutsaert DL: New concepts in diastolic dysfunction and diastolic
9. Hamilton DR, Dani RS, Semlacher RA, et al: Right atrial and right ven- heart failure: Part I: Diagnosis, prognosis, and measurements of diastolic
tricular transmural pressures in dogs and humans: Effects of the pericar- function. Circulation 2002;105:1387–1393.
dium. Circulation 1994;90:2492–2500. 22. Saavedra WF, Tunin RS, Paolocci N, et al: Reverse remodeling and enhanced
10. Spadaro J, Bing OHL, Gaasch WH, Weintraub RM: Pericardial modula- adrenergic reserve from passive external support in experimental dilated
tion of right and left ventricular diastolic interaction. Circ Res 1981; heart failure. J Am Coll Cardiol 2002;39:2069–2076.
48:233–238. 23. Spodick DH: Direct therapy for coronary disease, myocardial disease, and
11. Gaasch WH, Zile MR: Left ventricular diastolic dysfunction and diastolic severe cardiac arrhythmias. In Spodick DH (ed): Intrapericardial therapeu-
heart failure. Annu Rev Med 2004;55:373–394. tics and diasgnostics (IPTD). Clin Cardiol 1999;22:I–1, I–42.
12. Wang SY, Sheldon RS, Bergman DW, Tyberg JV: Effects of pericardial
constraint on left ventricular mechanoreceptor activity in cats. Circulation
1995;92:3331–3336.
 BRIAN D. HOIT, MD
4
Left Atrial Function:
Basic Physiology
INTRODUCTION Left Atrial Function and Diastolic Left
Ventricular Dysfunction
PATHOPHYSIOLOGY
Left Atrial Function in a Model of Atrial
Atrial Function in Health
Systolic Failure
Left Atrial Reservoir Function
Importance of Left Atrial Functions and Their
Left Atrial Conduit Function
Interplay in Left Ventricular Systolic
Global Left Atrial Function
Dysfunction
LEFT ATRIAL FUNCTION IN DISEASE
FUTURE RESEARCH
Left Atrial Function and Systolic Left
Ventricular Dysfunction ACKNOWLEDGMENT

INTRODUCTION left atrium. The four pulmonary veins, upper and lower from each
lung (the left pair frequently opening via a common channel),
A resurgence of interest in atrial function has enhanced our enter the posterior aspect of the left atrium.14
understanding of the atrial contributions to cardiovascular per- The atrial walls consist of two muscular layers, the fascicles of
formance in health and disease (see Chapter 13). The reasons for which both originate and terminate at an atrioventricular ring and
this “renaissance” are multifactorial and include (1) the recogni- follow nearly perpendicular courses. Fascicles in the inner layer
tion that atrial function is an important, at times critical, deter- ascend vertically through a pectinate muscle, change depth and
minant of left ventricular (LV) filling, (2) the increasing number course circumferentially in the outer layer, encircle the atrium,
of drugs, devices, ablative procedures, and surgeries available for dive into the inner layer, and descend vertically within a pectinate
the treatment of atrial fibrillation,1–3 (3) the considerable interest muscle. While some fascicles are intrinsic to one atrium, others
in dual- and three-chamber pacemakers that maintain atrioven- are shared. The muscular terminations of the veins are also
tricular and biventricular synchrony, respectively,4–6 (4) the patho- composed of two layers, the inner longitudinal and the outer
physiological and clinical relevance of chamber-specific structural, circular.15
electrical, and ionic remodeling,7–9 (5) the clinical impact of atrial Ultrastructurally, atrial myocardium differs significantly from
distensibility and stunning, particularly postcardioversion,10,11 ventricular myocardium. For example, myocytes are smaller in
and (6) the important prognostic role of atrial function in heart diameter and have fewer T-tubules and more abundant Golgi
failure.12,13 apparatus in the atrium than in the ventricle.16 Rates of contrac-
Despite this attention, quantifying atrial function is difficult, tion and relaxation and of conduction velocity and anisotropy
in part because the atria are geometrically complex. Because of the differ, as do their respective biophysical underpinnings (i.e.,
obliquity of the atrial septum, the right atrium projects anteriorly, myosin isoform composition and qualitative and quantitative dif-
inferiorly, and to the right of the left atrium. The broad, triangular, ferences in a wide assortment of ion transporters, channels, and
muscular right atrial (RA) appendage protrudes anteriorly, the gap junctional proteins).17–19
superior vena cava opens into the dome of the right atrium, and While there are important differences between left and right
the inferior vena cava opens into its inferior and posterior portion. atrial structures and functions at various organizational hierar-
The body of the left atrium is smaller and thicker than the right chies, the function of the left atrium at the organ level will be used
atrium. The chamber has been modeled as a sphere, cube, or in this chapter to illustrate the atrial contributions to ventricular
ellipse. The left atrial (LA) appendage is longer and narrower than filling. The discussion is drawn largely from studies our group has
the right appendage and contains all the pectinate muscles of the performed over the past 15 years.
33
34 Chapter 4 • Left Atrial Function: Basic Physiology

PATHOPHYSIOLOGY Pressure-Volume Relations of the Atrium

Atrial Function in Health A time-independent representation of the atrial events during the
cardiac cycle can be obtained by plotting instantaneous atrial
Left Atrial Booster Pump Function pressure and volume (Fig. 4-1). During ventricular systole, atrial
The principal role of the left atrium is to modulate LV filling and relaxation and descent of the ventricular base lower atrial pressure
cardiovascular performance through the interplay of atrial reser- (the “x” descent) and assist in atrial filling; the latter results in a
voir, conduit, and booster pump functions. Typically, the impor- “v” wave on the atrial pressure tracing. Thus, during ventricular
tance of the atrial booster pump function (i.e., the augmented systole, the atrium operates as a reservoir, storing systemic and
ventricular filling resulting from active atrial contraction) has pulmonary venous return. When the atrioventricular valves open,
been estimated by measurements of (1) cardiac output and LV blood stored in the atria empties into the ventricles, and atrial
diastolic volume both with and without effective atrial systole,20 pressure falls (the “y” descent), during which time the atria act as
(2) relative LV filling (e.g., early to late [E/A] filling ratios) using conduits for venous blood flow into the ventricles. Atrial contrac-
steady-state Doppler echocardiographic transmitral flow or radio- tion, denoted by an “a” wave on the atrial pressure tracing, actively
nuclide angiography,21 and (3) atrial shortening using methods assists ventricular filling. The resultant P-V loop inscribes a
such as two-dimensional echocardiography, angiography, and “figure-eight” that consists of a clockwise “V” loop due to atrial
sonomicrometry.22 Booster pump function is also evaluated echo- filling and passive emptying, and a counterclockwise “A” loop due
cardiographically by estimating the kinetic energy and force gen- to active atrial contraction.
erated with atrial contraction.23,24 However, measurements of Although Alexander et al. described instantaneous LA P-V
atrial systolic function and the importance of the atrial booster relations by a time-varying elastance in the isolated left atrium
pump are dependent on a multiplicity of factors, including the using computer-simulated LA loading conditions,25 assessment of
timing of atrial systole, vagal stimulation, the magnitude of venous atrial systolic elastance in vivo was hampered by the lack of an
return (i.e., atrial preload), LV end diastolic pressures (i.e., atrial accurate measurement of LA volume with an adequate sampling
afterload), and LV systolic reserve. Not surprisingly, despite con- frequency. Therefore, as a critical initial step, we demonstrated
siderable study, the magnitude and relative importance of the that cast-validated LA volumes could be estimated accurately
atrial contribution to LV filling and cardiac output remain con- with high temporal resolution sonomicrometry using two nearly
troversial. Analogous to end systolic elastance measurements in orthogonal atrial dimensions.26,27 The left atrium was assumed to
the left ventricle (where end systolic elastance is calculated as the be a general ellipsoid of revolution:
slope of the ventricular end systolic pressure-volume [P-V] rela- LA volume = π/6(SAX)2(LAX),
tion), a load-independent index of atrial contraction based on the
instantaneous atrial P-V relation has the potential to explain and where SAX is the short or mediolateral axis, and LAX is the long
minimize the discrepancies and confusion that exist in the litera- or anteroposterior axis. Coupled with high-fidelity micromanom-
ture. Accordingly, understanding and deriving atrial elastance eters, instantaneous P-V loops of the intact left atrium were gen-
require a consideration of the relation between instantaneous erated (Fig. 4-2). The maximum slope of the isochronal P-V
atrial pressure and volume. relation was measured every 10 msec during the “A” loop (from

40
LA pressure
(mmHg)

v a

0
34
LA long axis
(mm)

MVO
16.0 Figure 4-1 A, Analog recording of left
atrial (LA) pressure and dimensions in the
time domain. The vertical lines indicate
LA pressure (mmHg)

28
times of mitral valve opening (A), end of
20.5 passive atrial emptying and onset of atrial
LA short axis

LAed diastasis (B), atrial end diastole (C), and

(mm)

A atrial end systole (D). “a” and “v” represent

respective venous pressure waves. B, LA
LAes pressure-volume loop from a single beat
16.5 MVC illustrating the characteristic figure-eight
V
configuration. Arrows indicate direction
of loop as a function of time. “A” loop rep-
ECG 8.0 resents active atrial contraction. “V” loop
represents passive filling and emptying of
A BC D 4.0 6.0
the left atrium. MVO, time of mitral valve
1 sec. opening; LAed, left atrial end diastole;
LA volume (ml)
Laes, left atrial end systole. (From Hoit BD
A B et al: Circulation 1994;89:1829–1838.)
 Chapter 4 • Left Atrial Function: Basic Physiology 35

BASELINE POST CALCIUM

Slope = 3.6 Slope = 5.4

17.7 26.6

LA pressure (mmHg)
LA pressure (mmHg)
6.7 6.9
5.7 8.9 5.0 10.1
LA volume (ml) LA volume (ml)
A
Slope 3.6 Slope = 5.4
23
18

LA pressure (mmHg)
LA pressure (mmHg)

Figure 4-2 A, Five left atrial pressure-volume

loops at baseline (left) and after calcium infusion
(right). Note the linearity of the end systolic
pressure-volume relations, the greater extent
of atrial systolic shortening, and the increase in
the end systolic pressure-volume slope after 7 7
calcium infusion (the latter indicating a positive 6 9 5 10
inotropic effect). B, Loops are computer-
LA volume (ml) LA volume (ml)
smoothed for clarity. (From Hoit BD et al: Circula-
tion 1994;89:1829–1838.) B

atrial diastasis to atrial end systole) from five variably loaded beats atrial mechanical work. In a study using normal, open-chest dogs,
and were fitted to a time-varying elastance model: A- and V-loop areas were similar and did not change with
increased atrial preload, suggesting that booster pump and reser-
E(t) = P(t)/[V(t) − V(o)],
voir functions of the atrium were balanced over a wide range of
where E(t) is time-varying elastance, V(o) is the volume axis inter- LA pressures. However, calcium-induced increases in contractil-
cept, and P(t) and V(t) are instantaneous isochronal pressure and ity and subsequent volume loading produced significant increases
volume, respectively. Loading conditions were altered with either in the A- but not the V-loop area, indicating that net atrial
phenylephrine boluses or vena caval occlusions. Time-dependent mechanical work was greater and load dependent after calcium
changes in E(t) and maximal atrial systolic elastance (Emax) were infusion. Calcium infusion was also associated with a change in
found to be highly linear and sensitive to pharmacologically induced the trajectory of the A loop resulting in a decrease in the time
changes in inotropic state. In addition, LA systolic P-V relations from Emax to end systole; thus the atrial A loop, which resembled
using either the non-isochronal maximal P-V ratio (Emax P/V) or end a right ventricular (RV) P-V loop before, looked like the LV P-V
systole (Ees) were shown to be useful estimates of Emax. loop after calcium infusion, suggesting an effect of calcium on
In addition to assisting the quantitation of ejection phase (i.e., ventricular input impedance.
ejection fraction, stroke volume, mean normalized systolic ejec- While atrial P-V loops can be generated in humans using inva-
tion rate [MNSER], and velocity of circumferential shortening sive and semi-invasive means,28–31 these methods are cumber-
[Vcf ]) and load-independent indices of contraction (i.e., Emax, Ees, some, time consuming, and difficult to apply. Clearly, there is a
and Emax P/V), P-V loops of the left atrium offered possibilities for need for an objective, noninvasive measurement of atrial myocar-
study of atrial energetics in vivo. Specifically, the planimetered “A” dial performance and contractility. Measurement of myocardial
loop P-V area (total mechanical work done by the atrium) minus strain and strain rate, which represent the magnitude and rate of
the “V” loop P-V area (work done on the atrium by pulmonary myocardial deformation, are indices that have the potential to
venous blood flow during ventricular systole) represents the net overcome these limitations.32
36 Chapter 4 • Left Atrial Function: Basic Physiology

Left Atrial Reservoir Function mitral E velocity) increases directly with operative atrial compli-
ance.40 Thus it is interesting to speculate that regions of increased
Grant et al. estimated that 42% of the LV stroke volume and its distensibility in the left atrium may facilitate early diastolic filling
associated energy are stored in the left atrium during LV systole.33 of the left ventricle. One such region of the left atrium with
The subsequent dissipation of this energy during the reservoir increased distensibility is the atrial appendage.
phase acts as a ventricular restorative force during the ensuing LV In isolated canine atria, the slope of the P-V relation for the
diastole. Reservoir function is governed by atrial distensibility left atrium without the appendage is significantly greater than
during ventricular systole (although LA reservoir function has with the appendage intact.41 We subsequently showed that in the
been shown to be related to LA contraction and descent of the intact dog, the pressure-strain relation is steeper (i.e., more stiff
LV base during systole34 and to LA systolic shortening and LV or less distensible) in the body than in the appendage of the left
end systolic volume35), which is measured rigorously by fitting atrium (Fig. 4-4). Atrial systolic shortening and reservoir capacity
atrial pressures and dimensions—taken either at the time of (measured as the change in dimension during atrial systole, and
mitral valve opening over a range of atrial pressures and volumes the maximum minus minimum dimension, respectively) increased
or from one of the limbs of the “V” loop in a static P-V loop—to in both the body and the appendage during volume infusion and
an exponential equation.36,37 Although atrial dimensions and were greater in the appendage than in the body of the left atrium.
pressures are required for its measurement, the relative reservoir Thus, for a given increase in LA pressure, there was a greater
function can be estimated simply with pulmonary vein Doppler increase in the end diastolic atrial dimension, with greater utiliza-
(Fig. 4-3). Thus, the proportion of LA inflow during ventricular tion of the Frank-Starling mechanism by the appendage than by
systole provides an index of the reservoir capacity of the atrium.38 the body of the left atrium. Moreover, biochemical studies indi-
In this regard, we showed that LA compliance is an important cate that atrial natriuretic factor is concentrated in the LA append-
independent determinant of the pattern of pulmonary venous age,42 which may, by virtue of its increased distensibility, be better
flow, using an experimental protocol that excluded the LA append- suited for the regulation of intravascular volume. In addition,
age and produced an isolated decrease in atrial compliance and greater distensibility of the appendage than the body of the left
relative reservoir-to-conduit flow.22 As a consequence, alterations atrium would be potentially beneficial in the context of increased
in atrial compliance in various disease stages should be considered LV filling pressures and decreased global atrial distensibility.
when the pattern of pulmonary venous flow is used to estimate It is interesting that relative blood flow to the LA appendage
LA pressure, assess LV diastolic function, or quantify mitral was increased with experimental LA hypertrophy,43 and the
regurgitation. appendage-to-nonappendage LA blood flow ratio was increased
Suga showed that atrial compliance was a significant determi- during severe exercise in dogs, further suggesting that the LA
nant of cardiac performance in a circulatory analog model.39 Spe- appendage may become functionally important during stress.
cifically, decreased atrial compliance was associated with greater These data suggest that the substantial contributions of the
phasic and mean atrial pressures but a lower mean level of atrial appendage to overall LA compliance may have important negative
pressure during ventricular filling; this resulted in a smaller LV implications for routine atrial appendectomy at the time of mitral
end diastolic volume and decreased venous return. We confirmed valve surgery and for the use of percutaneous appendage exclusion
earlier mathematical predictions that early LV filling (i.e., Doppler devices.44,45

1 sec

40 K
J
PV Doppler
(cm/sec)

JVTI KVTI
200
(ml/min)

0
flow
PV

1 sec Figure 4-3 Representative pulmonary

vein (PV) Doppler with flow-probe wave-
form superimposed (top panel) and a
40 ECG
K schematic of the pulmonary venous flow
J velocity (bottom panel). J and K are peak
PV Doppler

systolic and diastolic velocities; Jvti and Kvti

(cm/sec)

are systolic and diastolic integrals, respec-

tively. The ratio of systolic-to-diastolic
velocities (and integrals) represents the
JVTI KVTI relative reservoir-to-conduit function of
the left atrium. (From Hoit BD et al: Circula-
0 tion 1992;86:651–659.)
 Chapter 4 • Left Atrial Function: Basic Physiology 37

20 20
LA LA
*

Mean LA pressure (mmHg)

Mean LA pressure (mmHg)
APP 18 APP

16

14
10 *
12

10

8
*
0 6
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.0 0.1 0.2 0.3 0.4 0.5
Natural strain (ln[D/Dmin]) Natural strain (ln[D/Dmin])
A B
Figure 4-4 A, Representative mean left atrial (LA) pressure–natural strain relationships for the LA body and appendage from a single dog. Data are fitted
to an exponential function. Pressure-strain relationship of appendage is shifted to the right of the body. B, Mean pressure–natural strain data for 12 dogs.
Error bars represent SE. Data indicate that the appendage is more distensible than the body of the left atrium. (From Hoit BD, Walsh RA, Am J Physiol 1992;262:
H1356–H1360.)

Myocardial strains can be obtained noninvasively using Global Left Atrial Function
either tissue Doppler imaging (TDI) or 2D speckle imaging.
Recently, atrial strain and strain rates (representing the Although it is clear that atrial reservoir, conduit, and booster
magnitude and rate of myocardial deformation, respectively) pump functions (and their modulation by the pericardium) play
during ventricular systole predicted the 9-month atrial fibrillation important roles in maintaining ventricular filling, a global measure
recurrence rate in patients with lone atrial fibrillation after a suc- (i.e., throughout the entire atrial cycle) of atrial function is lacking.
cessful cardioversion.11 Coupled with an estimate of atrial pres- A potential candidate property suitable for quantitation is syn-
sure,46 strain has the potential to estimate atrial distensibility chrony. Therefore, we correlated time-tissue Doppler velocity
noninvasively. curves from the lateral left and right atria and the lateral left
atrium and interatrial septum over three cycles every 10 msec to
obtain indices of inter- and intra-atrial phase heterogeneity,
Left Atrial Conduit Function respectively. The intra-atrial phase heterogeneity index was 0.90
Atrial conduit function occurs primarily, but not exclusively, ± 0.06, indicating that the time-velocity curves over the entire
during ventricular diastole and represents the volume of blood cardiac cycle for the septum and lateral LA segments were highly
that passes through the left atrium that cannot be attributed to correlated (i.e., in phase). In contrast, the inter-atrial phase index
reservoir or booster pump functions; in a well-characterized of 0.66 ± 0.10 indicated a greater degree of heterogeneity between
model, atrial conduit function accounted for 35 ± 8% of all flow the lateral LA and RA segments. These indices may be particu-
through the atrium.47 A reciprocal relationship exists between larly useful to understand the effect of altered atrial conduction
conduit and reservoir functions of the left atrium. Indeed, the on atrial function and ventricular filling in various pathological
redistribution of atrial functions was reported as an important states.
compensatory mechanism that facilitates LV filling in patients
with myocardial ischemia, acute myocardial infarction, hyperten-
sive heart disease, and mitral stenosis.48–51 LEFT ATRIAL FUNCTION IN DISEASE
Although it has been postulated that a more distensible atrium
reduces atrial conduit flow, we showed that while pericardiectomy Although LV adaptation to chronic hemodynamic loading has
decreased the atrial stiffness constant (increased distensibility), been studied extensively, the mechanisms by which the left atrium
the relative conduit function, measured as the ratio of flow probe- compensates for sustained increases in pressure and volume are
determined systolic-to-diastolic pulmonary vein flow, actually less clear. We considered that adaptation may be due to the addi-
increased.38 However, it should be noted that the LA reservoir tion of contractile units (hypertrophy), an alteration in the molec-
volume (max − min LA volume) and absolute systolic pulmonary ular composition of the contractile machinery (e.g., protein
venous flow also increased post pericardiectomy. In addition, isoform transitions), or a reduction of atrial systolic stress by
removal of the pericardium was associated with an increase in the structural remodeling. In pathological studies of human atria,
peak early velocity and deceleration time of transmitral diastolic increases in the amount of the slow, β-myosin isoform were cor-
flow, consistent with the increase in LV compliance after pericar- related with the severity and duration of pressure and volume
diectomy. Thus it is possible that the decreased systolic to dia- overload. In this context, a switch from the fast (α) to the slow
stolic P-V ratio reflects a greater change in compliance of the left (β) myosin heavy chain (MHC) isoform in the ventricles of small
ventricle than of the atrium. Irrespective of the mechanisms, these mammals is accompanied by decreased myosin ATPase activity
data underscore the complexity of pericardial influences on atrial and velocity of contraction, reduced oxygen consumption, and a
and ventricular filling and the multifactorial determinants of P-V greater efficiency of contraction. Thus, these isoform switches are
relations. likely to represent adaptations to the functional requirements
38 Chapter 4 • Left Atrial Function: Basic Physiology

imposed by sustained hemodynamic loads in a chamber such as diastolic dysfunction and normalization of both atrial Ees and
the left atrium, which contains predominantly α MHC. net atrial work despite the persistent abnormalities of load-
dependent indices of LA systolic function (e.g., ejection fraction,
systolic ejection rate). LA stiffness and reservoir volumes also
Left Atrial Function and Systolic Left remained abnormal. Changes in systolic and diastolic function of
Ventricular Dysfunction the left atrium were accompanied by persistent upregulation of
Experimental studies that examine atrial adaptation use models the atrial β MHC isoform and incomplete regression of LA
of mitral regurgitation,36 myocardial infarction,12 LV diastolic hypertrophy, indicating an apparent dissociation of myosin
dysfunction,52 and pacing-induced myocardial failure (ventricular isoform shifts, myocardial hypertrophy, and atrial work.
and atrial tachypacing53,54). In the ventricular tachypacing model
of heart failure, we found a significant upregulation of β MHC Left Atrial Function in a Model of
in the LA body that was associated with LA hypertrophy,
increased atrial mechanical work (A-loop area, Fig. 4-5), main- Atrial Systolic Failure
tained force generation (Emax and Ees), and decreased velocity of We examined global and regional LA pump functions after one
LA contraction. Another important finding of our study was that week of isolated atrial flutter (atrial pacing at 400 bpm) in closed-
atrial MHC isoform switches vary by region. Despite hypertro- chest, sedated dogs.55 LV function, as assessed by the echocardio-
phy of the appendage, the percent of β MHC did not increase in graphic LV area shortening fraction, was preserved. Global and
comparison with controls, suggesting that adaptation to hemody- regional atrial pump functions were determined by mitral and LA
namic overload includes differentially determined quantitative appendage waveform analysis, and relative conduit and reservoir
(e.g., hypertrophy) and qualitative (e.g., isoform switch) compo- functions by pulmonary venous waveform analysis with Doppler
nents and that there are fundamental differences in the atrial velocimetry. We found that after one week of rapid atrial pacing,
response to stress hypertrophy, which occurs in the body, versus global and regional atrial booster pump functions (i.e., body and
“strain” hypertrophy, which occurs in the appendage. appendage) were impaired, and relative reservoir-to-conduit func-
tion of the left atrium was reduced (Fig. 4-6). Similar changes in
the absence of atrial hypertrophy were noted in a highly instru-
Left Atrial Function and Diastolic Left mented preparation treated with similar atrial tachypacing for
Ventricular Dysfunction 6 weeks.
In carefully studied animal models, the improvement in systolic
function that occurs after cessation of tachypacing is associated Importance of Left Atrial Functions and Their
with residual abnormalities of LV isovolumic relaxation and
chamber compliance, and in some instances, the development of Interplay in Left Ventricular Systolic Dysfunction
LV hypertrophy. Since LV diastolic dysfunction represents a The redistribution of atrial reservoir and conduit functions
source of excess afterload on the left atrium, we examined the and an augmented booster pump function are important
gravimetric, myosin biochemical, and functional changes in the compensatory mechanisms that facilitate LV filling in patients
left atrium that accompany regression of pacing-induced heart with myocardial ischemia, acute myocardial infarction, and hyper-
failure. Animals were rapidly paced for 3 weeks to produce heart tensive heart disease. However, considerably less is known about
failure, and hemodynamic and functional studies were performed how these mechanisms operate in the setting of LV dysfunction.
3 weeks after pacing cessation.52 We showed that improvement Therefore, we tested the hypothesis that in contrast to dogs with
of LV systolic dysfunction was associated with persistent LV a normal left ventricle, cardiac output falls with the loss of atrial

24.0 22.4
Left atrial pressure (mmHg)
Left atrial pressure (mmHg)

Figure 4-5 Left atrial pressure-volume loops

V from three variably loaded beats in a control
A dog (A) and in a dog with pacing-induced heart
A
failure (B). The A loop represents active atrial
contraction; the V loop represents passive
10.0 9.5 filling and emptying of the left atrium. The
5.5 8.4 17.4 21.4 increase in A loop area after pacing indicates
increased atrial systolic work. Loops are
Left atrial volume (ml) Left atrial volume (ml) computer-smoothed for clarity. (From Hoit BD
A B et al: Cardiovasc Res 1995;29:469–474.)
 Chapter 4 • Left Atrial Function: Basic Physiology 39

Baseline 1 week rap

MV
velocity
A
A

E
80 cm/sec E
80 cm/sec

a e
40 cm/sec

e 40 cm/sec
a
LAA
velocity

Figure 4-6 Doppler waveforms of trans- K

mitral (MV, top panel), left atrial append- 40 cm/sec J2 K
age (LAA, middle panel), and pulmonary 40 cm/sec
vein (PV, bottom panel) flows at baseline J1
and after one week of rapid atrial pacing J2
(RAP). E, early transmitral diastolic veloc- PV
ity; A, late transmitral diastolic velocity; velocity
e, early LAA emptying velocity; a, late
LAA emptying velocity; J1 and J2, J1
systolic velocities; K, diastolic PV velocities.
The corresponding electrocardiogram is
shown in each panel. (From Hoit BD et al:
J Am Soc Echo 1997;10:805–810.)

systolic contraction in dogs with concomitant LV dysfunction LV dysfunction was produced by 2 weeks of rapid RV pacing
because atrial compensatory mechanisms fail. (220 bpm). Two weeks of rapid ventricular pacing superimposed
Chronic atrial and ventricular dysfunction (both singly and in on rapid atrial pacing during the second week produced combined
combination) were modeled with rapid pacing in dogs with radio- LA and LV dysfunction. As previously noted, isolated LV dys-
frequency atrioventricular nodal ablation and implantation of RA function increased atrial booster pump and reservoir functions,
and RV pacing catheters.56 Serial echocardiographic analyses of whereas isolated rapid atrial pacing decreased atrial booster pump
global and regional LA pump function were estimated from and increased the relative conduit function of the left atrium. In
mitral and LA appendage Doppler velocimetry, and relative res- contrast, the decreased atrial booster pump function in animals
ervoir and conduit functions of the left atrium were determined with combined atrial and ventricular dysfunction was incom-
from pulmonary venous Doppler. Right heart catheterization pletely compensated by the redistribution of the reservoir and
studies were performed simultaneously to assess right heart pres- conduit functions of the left atrium. As a result, cardiac output
sures and cardiac output. Isolated atrial systolic failure was pro- decreased and right heart pressures increased only after super-
duced by 1 week of rapid atrial pacing (400 bpm), and moderate imposed atrial and ventricular pacing.
40 Chapter 4 • Left Atrial Function: Basic Physiology

FUTURE RESEARCH 15. Thomas CE: The muscular architecture of the atria of hog and dog hearts.
Am J Anat 1959;104:207–236.
16. McNutt NS, Fawcett DW: The ultrastructure of the cat myocardium. II.
While knowledge of atrial function lags considerably behind that Atrial muscle. J Cell Biol 1969;42:46–67.
of the ventricle, the chasm is rapidly closing. The studies discussed 17. Thomas C, Coker B, Zellner J, et al: Increased matrix metalloproteinase
herein describe the role of atrial function to ventricular filling in activity and selective upregulation in LV myocardium from patients with
normal physiology and provide a framework for understanding end-stage dilated cardiomyopathy. Circulation 1998;97:1708–1715.
18. Li GR, Lau CP, Shrier A: Heterogeneity of sodium current in atrial vs epi-
mechanical, energetic, and biochemical mechanisms responsible cardial ventricular myocytes of adult guinea pig hearts. J Mol Cell Cardiol
for atrial adaptation to chronic hemodynamic loading. Important 2002;34:1185–1194.
future directions include distinguishing the role of atrial function 19. Tuteja D, Xu D, Timofeyev V, et al: Differential expression of small-
in early versus late LV systolic dysfunction, investigating the role conductance Ca2+-activated K+ channels SK1, SK2, and SK3 in mouse
atrial and ventricular myocytes. Am J Physiol Heart Circ Physiol 2005;289:
of matrix metalloproteinases (and other molecules) in structural H2714–H2723.
remodeling of the atria, characterizing the biochemical and 20. Mitchell JH, Gupta DN, Payne RM: Influence of atrial systole on effective
molecular biological changes that accompany atrial adaptation ventricular stroke volume. Circ Res. 1965;17:11–18.
and failure, and identifying the relation between structural 21. Hoit BD, Rashwan M, Verba J, et al: Instantaneous transmitral flow using
and electrical remodeling of the left atrium. These goals are likely Doppler and M-mode echocardiography: Comparison with radionuclide
ventriculography. Am Heart J 1989;118:308–314.
to be met with the development of novel techniques to evaluate 22. Hoit BD, Shao Y, Tsai LM, et al: Altered left atrial compliance after atrial
atrial reservoir, conduit, and booster pump functions of the appendectomy. Influence on left atrial and ventricular filling. Circ Res
atrium. 1993;72:167–175.
23. Stefanadis C, Dernellis J, Lambrou S, Toutouzas P: Left atrial energy in
normal subjects, in patients with symptomatic mitral stenosis, and in
patients with advanced heart failure. Am J Cardiol 1998;82:1220–
ACKNOWLEDGMENT 1223.
24. Manning WJ, Silverman DI, Katz SE, Douglas PS: Atrial ejection force:
This work was supported in part by a Grant in Aid award from A noninvasive assessment of atrial systolic function. J Am Coll Cardiol
the American Heart Association Ohio Valley Affiliate 1993;22:221–225.
(0355198B). 25. Alexander J, Sunagawa K, Chang N, Sagawa K: Instantaneous pressure-
volume relation of the ejecting canine left atrium. Circ Res 1987;61:
209–219.
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9. Wijffels MC, Kirchhof CJ, Dorland R, et al: Electrical remodeling due to during ventricular systole. Am J Med 1964;37:36–43.
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41. Davis CA, Rembert JC, Greenfield JC: Compliance of the left atrium 49. Matsuda Y, Toma Y, Moritani K, et al: Assessment of left atrial function
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42. Hintze TH, McIntyre JJ, Patel MB, et al: Atrial wall function and plasma 50. Matsuda Y, Toma Y, Ogawa H: Importance of left atrial function in patients
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44. Kamohara K, Fukamachi K, Ootaki Y, et al: A novel device for left atrial 52. Hoit BD, Shao Y, Gabel M, et al: Left atrial systolic and diastolic function
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46. Nagueh SF: Noninvasive evaluation of hemodynamics by Doppler echocar- 54. Hoit BD, Shao Y, Gabel M, Walsh RA: Left atrial mechanical and bioc-
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 JAMES D. THOMAS, MD
ZORAN B. POPOVIĆ, MD
5
Physical Determinants of
Diastolic Flow
INTRODUCTION Understanding Pulmonary Vein Flow
Through Computer Modeling of the Heart
PATHOPHYSIOLOGY
Lumped Parameter Model of the Heart and
Mechanical Properties of Left Ventricular
Circulation
Chamber Diastole
Understanding Intraventricular Flow
CLINICAL RELEVANCE
FUTURE RESEARCH
Physical Factors Governing Left Ventricular
Filling Velocities ABBREVIATIONS

INTRODUCTION veins) into the left ventricle, while keeping filling pressures to a
minimum. During exercise, this task is compounded by the short-
Comprehensive assessment of ventricular diastolic function is a ening of time allowed for filling and the increase of volume needed
complex process. Full elucidation generally requires invasive mea- to get into the left ventricle. Of the various chamber-wall proper-
surements, such as left ventricular (LV) end diastolic pressure, the ties that affect this process, we will briefly cover three: chamber
time constant of isovolumic LV relaxation (τ), the pressure- stiffness, relaxation, and early diastolic suction.
volume (P-V) relationship of the ventricle at end diastole,
and mean left atrial (LA) pressure. Such invasive measurements Chamber Stiffness
are inappropriate for routine clinical purposes, and thus
diastolic function is generally assessed using Doppler echocar- Chamber stiffness can be defined as the instantaneous change of
diography, largely through the observation of transmitral pressure for a given volume increment, mathematically the first
and pulmonary venous flow, supplemented by myocardial velocity derivative of LV pressure by volume (dP/dV). LV pressure is a
and color M-mode Doppler information. In order to intelligently complex nonlinear function of LV volume, meaning that stiffness
use these noninvasive indices to infer actual diastolic function changes with diastolic volume. Although the LV P-V relationship
of the heart, however, it is critical that a conceptual framework was initially considered to be exponential in shape (concave
be in place that reflects the physical and physiological upward),1 more recent work suggests that it is sigmoidal in
determinants of intracardiac blood flow. In this chapter, we will shape (Fig. 5-1), with a concave downward portion to the left of
outline in both basic physical principles and computer simula- the usual rising exponential.2,3 This sigmoidal curve can be
tions the relationship between basic parameters of diastolic func- expressed as:
tion and the intracardiac flow patterns that can be obtained P = A ∗ e(V−Vd0)Kp+ + Pb+ V ≥ Vd0
clinically.
P = −B ∗ e(Vd0−V)Kp− + Pb− V < Vd0,
where Vd0 is the inflection point, A and B are the exponential
PATHOPHYSIOLOGY curve multipliers of the upper and lower part, Pb+ and Pb− are
Mechanical Properties of Left Ventricular pressure offsets of the upper and lower part, while Kp+ and Kp− are
the diastolic chamber stiffness indices, determining the overall
Chamber Diastole steepness of the end diastolic P-V relationship (EDPVR) above
The major function of the heart in diastole is to let the blood and below the inflection volume. Frequently, EDPVR is concep-
column flow from the antechambers (left atrium and pulmonary tually simplified by assuming that Vd0 equals 0,1 and even further
43
44 Chapter 5 • Physical Determinants of Diastolic Flow

120
vasively by systolic blood pressure and an estimate of LA
pressure.
Importantly, LV relaxation is a never-ending process that
LV pressure (mmHg)

90 critically affects the end diastolic pressure that the patient

achieves, particularly during exercise. Consider Figure 5-2A,
60 showing a series of P-V curves representing successive
intervals of τ, and Figure 5-2B, the same curves magnified on
diastolic pressures. Note that after 6τ, the filling curve is
30
virtually indistinguishable from the end diastolic P-V curve, as
relaxation is 99.8% complete. When relaxation rate is normal,
0 the end diastolic filling curve is completely relaxed at normal
0 50 LVd0 100 150 heart rates (12.5τ, 2C) and almost complete during exercise
(5τ, 2D); with delayed relaxation, however, while the EDPV
LV volume (ml)
curve is fully relaxed at rest (6.25τ, 2E), it becomes stiff with
exercise (3τ, 2F).
Figure 5-1 Passive pressure-volume (P-V) loop relationships. The thick
continuous and thick dotted lines represent the upper and lower part of
The combination of relaxation and the EDPVR results in a
the sigmoid end diastolic pressure-volume relationship, respectively. The dynamic P-V relationship, represented by the round dots in
curvature of the upper part is determined by the chamber stiffness index, Figure 5-2A. Note that in early diastole, LV pressure continues
which can be interpreted as the inverse of the volume needed to increase to fall even though volume is increasing, meaning that the instan-
the steepness of the P-V curve by a factor of 2.72. taneous stiffness is actually negative, which some consider dia-
stolic suction. Two other definitions of “diastolic suction” are also
relevant. Consider ventricular filling from a very low end systolic
volume (where the EDPVR is concave downward). If relaxation
simplified by neglecting Pb+, leaving us with the equation is very rapid or filling is delayed (by mitral stenosis or experimen-
P = AeK×EDV, or in other words ln P = a + K × EDV (see also tally with a mitral occluder2), then LV pressure can fall below
Chapter 2).1 By differentiating this equation, we see that end atmospheric pressure.2,10 Alternatively, suction has been used to
diastolic stiffness dP/dV is K × AeK×EDV or K × PEDV. Another refer to the small (1 to 3 mmHg) differences in pressure between
parameter of note is the average stiffness,4 that is, the stroke the base and the apex, which assist in the low-pressure filling of
volume divided by the LV pressure increment during diastole, a the ventricle, particularly with exercise, and which will be dis-
simple overall measure of how stiff the patient’s LV is during cussed later.11
diastole over a given (working) set of conditions.5 The fact that
myocardial relaxation is a continuous process throughout diastole
results in changing relationships between pressure and volume Determinants of Intracardiac Blood Flow
from very stiff end systole P-V relationships to much more com-
pliant EDPVR. In the most general sense, the motion of blood inside the heart,
as the motion of any fluid, is determined by the Navier-Stokes
equations, a complex set of four multidimensional partial differ-
Relaxation ential equations, which must be solved simultaneously at every
Myocardial relaxation occurs because of calcium reuptake at the point in space and moment in time:
end of systole, producing a shift downward and rightward, leading 䉮·v = 0
to a fall in LV pressure (at a given volume). The rate of pressure
decrease during relaxation depends on the velocity of calcium and
reuptake and on the LV volume: The smaller the volume, the
lower the potential for pressure to fall,2 limited by the end dia- Dv
stolic pressure curve shown in Figure 5-1. Rate of calcium reup- ρ = −∇P + B + μ∇2 v
Dt
take is further modified by LV lengthening during relaxation, so
true relaxation can be measured only during the isovolumic These equations appear deceptively simple but contain such
period.6 Several equations have been proposed to describe the rate complex mathematical concepts that except in the simplest of
of isovolumic pressure decay,7 the most general being: geometries, they can never be solved either analytically or with
powerful supercomputers. Fortunately, considerable simplifica-
P(t) = (Po − Pb) × e−t/τ + Pb,
tions can be made to these equations that will facilitate a
which can be, with some caveats, simplified to: conceptual and computational approach. The most important
simplification is to take the distribution of blood throughout the
P(t) = Po × e−t/τ,
heart and replace it with just a few measurements at specific
and further to8,9: points inside the heart. For instance, instead of describing pres-
sure in every cubic millimeter inside the left ventricle, we assume
τ ≈ IVRT/(ln PAVC − ln PMVO),
that LV pressure can be approximated by an average of these and
where IVRT is the isovolumic relaxation time (the time between give a single number for LV pressure, which is precisely how we
aortic valve closure and mitral valve opening), and PAVC and PMVO measure and report LV pressure in practice. Similarly, instead of
are LV pressure at aortic valve closure (AVC) and mitral valve describing the direction and speed of blood flow at every point
opening (MVO), respectively, which can be approximated nonin- within the heart, we focus on points where blood velocity is
 Chapter 5 • Physical Determinants of Diastolic Flow 45

Systole
200 50
Systole 1τ 1τ 2τ 3τ

150 4τ
Pressure (mmHg)

Pressure (mmHg)
5τ
2τ
6τ
100 25

3τ
50 Diastole
4τ
5τ
6τ
Diastole
0 0
0 50 100 150 0 50 100 150
Volume (ml) Volume (ml)
A B

Systole Systole
50 50
1τ 2τ 3τ 1τ 2τ 3τ

4τ 4τ

Pressure (mmHg)
Pressure (mmHg)

5τ
5τ
6τ 6τ
25 25

12.5τ
Diastole Diastole

0 0
0 50 100 150 50 100 150
Volume (ml) Volume (ml)
τ = 40 msec, HR = 75, DFP = 500 msec τ = 40 msec, HR = 150, DFP = 200 msec
C D

Systole Systole
50 50
1τ 2τ 3τ 1τ 2τ 3τ

4τ 4τ
Pressure (mmHg)
Pressure (mmHg)

5τ 5τ
6τ 6τ
25 25

Diastole Diastole

0 0
0 50 100 150 0 50 100 150
Volume (ml) Volume (ml)
τ = 80 msec, HR = 75, DFP = 500 msec τ = 80 msec, HR = 120, DFP = 240 msec
E F
Figure 5-2 Diastolic pressure-volume (P-V) relationships shown as a function of the duration of diastole. Duration of diastole is measured by the multiples
of a time constant of relaxation (τ). Panel A shows a series of P-V relationships that occur after successive intervals of τ, while panel B shows the same
curves zoomed on diastolic pressures. The combination of relaxation and the end diastolic P-V (EDPV) relationship results in a dynamic diastolic part of
the P-V loop represented by the round dots in A. Note that in early diastole, left ventricular pressure continues to fall even though volume is increasing,
meaning that the instantaneous stiffness is actually negative, which some consider diastolic suction. When relaxation rate is normal, the end diastolic
filling curve is completely relaxed at normal heart rates (arrow 12.5τ, C) and almost complete during exercise (arrow 5τ, D); with delayed relaxation, however,
while the EDPV curve is fully relaxed at rest (arrow 6.25τ, E), it becomes stiff with exercise (arrow 3τ, F).
46 Chapter 5 • Physical Determinants of Diastolic Flow

maximum, such as the tips of the mitral leaflets and the pulmo-
nary vein orifices. Finally we assume fluid incompressibility and
zero viscosity and heat conduction losses. In this way, the thou-
sands of partial differential equations that would have to be solved
simultaneously throughout the heart are replaced by a few ordi-
nary differential equations that can be solved quite easily on a
personal computer.
To understand how these equations can model the flow within
the heart, we first start by replacing the Navier-Stokes equations
with the well-known Bernoulli equation, which applies to flow
across discrete points such as valves. Here we present it with its
inertial and convective terms (we still omit the viscous term, since
it is negligible in almost every intracardiac situation): Inertial term Convective term
Figure 5-3 Combination of convective (right) and inertial (left) term to
dv 1
Δp = M + ρΔ v2 ,
dt 2
( ) produce an intraventricular pressure gradient. (From Thomas JD, Popovic
ZB: Intraventricular pressure differences: A new window into cardiac function.
Circulation 2005;112:1684–1686.)
where Δp is the pressure difference between two points; M is
the inertial constant and represents the “effective” mass being
accelerated; dv/dt is the instantaneous temporal acceleration of
flow through the region; ρ is blood density; and Δ(v2) is the regions of the heart: mitral valve, pulmonary vein, and left
change in the square of velocity from one point to another ventricle.
(with pressure in mmHg and velocity in m/sec, 1/2ρv2 reduces to
4v2 in the simplified Bernoulli equation). The first product is the
inertial term of the Bernoulli equation and corresponds to the Physical Factors Governing Left Ventricular
energy used accelerating and decelerating flow; the second Filling Velocities
term is the convective term and represents kinetic energy of flow. To describe mathematically flow through the mitral valve, we first
The effective mass of blood in a narrow orifice is small, and consider a very simplified construct, consisting of the left ventri-
thus M is a negligible quantity in, for example, valve stenosis, but cle, which has pressure as a function of time pV(t); the left atrium,
the dominant term when flow is not obstructed, such as in the which has pressure as a function of time (pA(t)); and the mitral
normal mitral valve. For constant flow through an orifice of valve, which has area AMV and contains a mass of blood M that
minimal diameter D, the inertial constant M varies approximately is accelerating in passing from the left atrium to the left ventricle.
in proportion to D, while the kinetic term 1/2ρv2 varies inversely To a first approximation, M is the blood within a cylinder that
to D4. can fit inside the narrowest portion of the mitral leaflet tips and
For nonobstructive flow through the body of heart chambers, whose length is approximately the diameter of the valve. In reality,
where pressure changes gradually over a distance, not at a discrete though, since pressure is applied across the mitral valve, the most
point, we must use the Euler equation, a differential version of the relevant hydrodynamic concept is the length of this cylinder,
Bernoulli equation for pressure change along a streamline of termed the mitral inertance, related linearly to the diameter of that
flow: structure. We will use this construct to discuss three parameters
∂p ⎛ ∂v ∂v ⎞ of transmitral flow: mitral acceleration, peak mitral flow, and
= −ρ ⋅ ⎜ + v ⋅ ⎟ ,
∂s ⎝ ∂t ∂s ⎠ mitral deceleration.

where the inertial and convective terms are in the same order
as in the Bernoulli equation, but the discrete terms (Δp and Acceleration of Mitral Flow
Δ(v2)) have been replaced by their spatial derivatives, yielding the
rate of pressure change per centimeter of distance along the To understand the acceleration of blood across the mitral valve,
streamline. To return the total pressure drop between points A we apply Newton’s second law of motion: The rate at which an
and B along the streamline, this equation must be integrated object accelerates is given by the force exerted on that object
numerically: divided by its mass. In this case, the acceleration would be recorded
by Doppler echocardiography as the velocity acceleration detected
B ⎛ ∂v ∂v ⎞ for mitral inflow, while the force is the difference in pressure on
Δp = − ρ ⋅ ∫ ⎜ + v ⋅ ⎟ ds.
A ⎝ ∂t ∂s ⎠ either side of the mitral valve multiplied by the area of the
valve13:
Figure 5-3 shows schematically how these partial derivatives
are summed together to produce the pressure gradient map.12 F ΔpA Δp
Another practical fact is that we can obtain the same map by a= = ≈ .
m ρM ρL
applying the Euler equation to a color Doppler M-mode tracing.
Here we have taken advantage of the fact that valve area appears
in both the numerator and the denominator (through the defini-
CLINICAL RELEVANCE tion of inertial mass) to simplify the relationship. Clearly the
higher the pressure difference across the valve and the smaller the
In this section, we will demonstrate how interaction of solid and length of the blood column within the mitral valve, the more
fluid mechanics determines intracardiac flow within three specific rapidly the velocity will accelerate. This is why mitral velocity
 Chapter 5 • Physical Determinants of Diastolic Flow 47

increases almost instantaneously in mitral stenosis, which has a dΔp/dt = ρv dv/dt.

very high pressure gradient across the valve and a very small blood
mass, due to the small diameter of the mitral orifice. If the blood But dΔp/dt can also be expressed in terms of flow across the
within the mitral valve were subject to an instantaneously applied mitral valve (Av) and net atrioventricular stiffness:
pressure difference (as if the relaxation of the left ventricle dΔp/dt = −AvSn.
occurred suddenly), mitral velocity would start to rise linearly. In
the physiological situation, the pressure gradient is not abruptly Substituting for dΔp/dt yields:
applied but rather increases gradually (roughly linearly) with time ρv dv/dt = −AvSn,
as the ventricle relaxes, resulting in a roughly parabolic mitral
velocity acceleration curve.14 or, rearranging,
dv/dt = ASn/ρ.

Peak E-Wave Velocity and Conservation of Energy Thus, the stiffer the ventricle (or atrium) and the larger the valve
area, the faster the deceleration.
Mitral valve acceleration eventually decreases over time because Alternatively, one can represent this as a purely inertial system
the maximal velocity generated by a pressure difference is limited (with a nonrestrictive orifice), which yields a simple harmonic
by conservation of energy (expressed in the Bernoulli equation). motion, in which case the velocity across the valve is described
Within the heart, energy in the blood takes on three principal roughly by a sine wave:
forms: pressure (a form of potential energy), kinetic energy, and
⎛ t ⎞
heat; the total energy in the system must remain constant. In the v (t ) = v0 sin ⎜ ⎟,
left atrium, where blood velocity is low, most of the energy is in ⎝ m k⎠
the form of pressure, but as it moves toward the mitral valve, its
where v0 is the peak E-wave velocity, m is mitral inertance, and
velocity rises and it acquires a kinetic energy (1/2ρv2), which
k is the stiffness constant of the ventricle. The deceleration time
causes the local blood pressure to fall. If no energy losses appear,
(time for the E wave to fall from its peak to zero velocity) can be
pressure difference and velocity are related by the simplified
solved for as:
Bernoulli relation, which becomes roughly Δp = 4v2 when pres-
sure is measured in millimeters of mercury and velocity in meters π ρ⋅L 1
per second. The velocity reaches the target gradient asymptoti- tdec = ⋅ ,
2 A k
cally, but this is delayed by the amount of inertance present.
Reaching the asymptote can be even further delayed by the gradi- where ρ, L, and A are blood viscosity, mitral valve length, and
ent not being imposed abruptly but slowly, as seen in a normally mitral valve area, respectively. Therefore, the stiffer the ventricle,
relaxing left ventricle. the shorter the deceleration time. This is intuitively very under-
standable: Tighter springs oscillate fast. Note that in this simpli-
fication, one assumes that active relaxation is complete at the time
Deceleration of Mitral Flow of interest.13
Returning to our general model of the mitral valve, once flow has Modeling of Mitral Valve Flow
been accelerated to maximal velocity by the pressure difference Up until now, we have been discussing specific features of the
across the mitral valve, it begins falling as the pressure difference transmitral E wave through significant simplifications that allow
between the left atrium and the left ventricle equilibrates. This is closed-form mathematical solutions. To permit more realistic
analogous to flow between two tanks stopping when the level of modeling of transmitral flow, however, one needs more general
water in the two tanks becomes the same. When we speak of the equations that can be solved only numerically. A generalized equa-
change in pressure with a change in volume, we are dealing with tion for blood flow through the mitral valve and its interaction
the concept of compliance or its inverse, stiffness, the change in with the transmitral gradient is15:
pressure for a given change in volume, which is a major determi-
dv dt = ⎛ PA − Pv − ρv2 ⎞ M ,
1
nant of the deceleration of flow across the mitral valve. Since the
stiffer the ventricle, the more rapidly the pressure equilibrates ⎝ 2 ⎠
across the mitral valve to decelerate the flow, we can understand where v is velocity, t is time, PA and Pv are instantaneous atrial and
why short deceleration time across the mitral valve is associated ventricular pressures, and M is mitral inertance. Conversely, the
with increased ventricular stiffness. Note that in this situation, we impact of mitral flow on LA and LV pressures is expressed
must consider atrial and ventricular stiffness together, since both through the equations
chambers are involved in determining how quickly pressure equil-
ibrates across the mitral valve. For ventricular stiffness SV and dPA/dt = −Av/CA
atrial stiffness SA, the net atrioventricular stiffness Sn is simply and
SA + SV. To obtain a mathematical expression for mitral velocity
deceleration rate, we first note that for a restrictive mitral valve dPv/dt = Av/Cv + ∂Pv/∂t,
with area A (i.e., mitral stenosis, though even for a normal mitral where A is mitral valve area, and CA and CV are atrial and
valve), the overall principle holds: ventricular compliance (inverse of stiffness), respectively. By
1 solving these three differential equations, we can assess how
Δp = ρv2 , changing the parameters of the equation that represent
2 passive diastolic properties, LV relaxation, mitral inertance, and
which simplifies to 4v2 when Δp is in mmHg and v in m/sec. preload can affect transmitral flow. We start with a preliminary
Differentiating this yields: discussion of these interactions before presenting an even more
48 Chapter 5 • Physical Determinants of Diastolic Flow

detailed model that includes pulmonary vein flow in addition to by the time of the peak of the E wave, and small changes in τ have
transmitral flow. little effect on deceleration; on the other hand, if τ is significantly
Impact of Relaxation: Changes in relaxation affect the earli- longer, the relaxation remains an important aspect of the decelera-
est part of the mitral flow (Fig. 5-4A and B). They have a pro- tion phase, and further lengthening of τ will cause a decrease in
found effect on the peak values of E-wave velocity. The overall the deceleration rate (that is, prolongation in deceleration time).
effect of relaxation on the descending phase of the E wave is more Passive Diastolic Properties of the Left Ventricle:
complex: When τ is very short, relaxation is essentially complete Increasing the steepness of the diastolic P-V curve affects

LV RELAXATION CONSTANT (MSEC) LV RELAXATION CONSTANT (MSEC)

25 140 LV relaxation TAU E A D VTI

constant 20 91 16.2 7.8 13.1
LV pressure (mmHg)

120
20

Velocity (cm/sec)
(msec) 40 82 12.3 6.9 12.7
100
60 73 10.0 5.8 12.0
15 80
60
10
40 40
60 20 40 60
5 20
20
0
0
30 50 70 90 110 130 0 100 200 300 400 500
LV volume (cm3) Time (msec)
A B
LV VOLUME CONSTANT (CM3) LV VOLUME CONSTANT (CM3)

25 140
Vvk E A D VTI
120
LV pressure (mmHg)

40 58 9.2 8.4 6.6

20
Velocity (cm/sec)

100 60 82 12.3 6.9 12.7

90 93 13.7 4.8 16.3
15 80
40 60
10 40
60 40 60
90 90
5 20
0
0
30 50 70 90 110 130 0 100 200 300 400 500
LV volume (cm3) Time (msec)
C D
LA PRESSURE (mmHg) LA PRESSURE (mmHg)

25 140
LAP E A D VTI
120
LV pressure (mmHg)

20 5 40 4.5 3.5 6.9

Velocity (cm/sec)

5 10 20 100 10 82 12.3 6.9 12.7

20
15 80 20 124 24.1 9.6 17.7
60 10
10
40
5
5 20
0
0
30 50 70 90 110 130 0 100 200 300 400 500
LV volume (cm3) Time (msec)
E F
Figure 5-4 Effect of left ventricular relaxation constant (τ; panels A and B), volume constant (inverse of chamber stiffness index; panels C and D) and left
atrial pressure (preload; panels E and F) on a left ventricular pressure volume curve (left panels) and mitral valve velocity profile (right panels). Prolonged
relaxation blunts the lower left corner of pressure volume curve and decreases peak mitral valve flow. Increased stiffness (i.e., decreased volume constant)
moves lower left corner of the pressure volume loop to the left and upwards, decreases peak mitral valve flow and increases its deceleration rate. Finally,
increased left atrial pressure shifts lower right corner of the pressure volume loop to the right while increasing peak mitral valve flow. E, peak velocity
of E wave (cm/sec); A, peak acceleration rate of E wave (m/sec2); D, peak deceleration rate of the E wave (m/sec2); VTI, E wave velocity time integral (cm).
(From Thomas JD, Weyman AE: Echocardiographic Doppler evaluation of left ventricular diastolic function. Physics and physiology. Circulation 1991;84:
977–990.)
 Chapter 5 • Physical Determinants of Diastolic Flow 49

primarily deceleration time, that is, operative chamber stiffness trends may offset each other, with the result that diastolic pres-
(Fig. 5-4C and D). However, a caveat has to be introduced. sures are constant or falling despite an increase in LV volume,
The ventricular P-V curve (as well as the atrial P-V curve) is giving the impression of negative stiffness in early diastole. Figure
exponential in shape. Since operative chamber stiffness is equal to 5-4A and B show how τ effects mitral valve flow and end diastolic
the slope of these curves, stiffness and mitral deceleration P-V relationships.15 We reiterate here that while τ affects the early
rise when operative chamber volumes increase. This change is part of the diastolic P-V curve, τ has an effect on end diastolic
indistinguishable from the change that may arise from material volume only when dramatically prolonged. The situation is differ-
properties of the ventricle, leading to a steeper curve at all pres- ent during exercise, where shortening of the diastolic interval and
sures (that is, a true change in the diastolic properties of the the increase of arterial blood pressures produce incomplete relax-
ventricle). ation (with a rise in end diastolic pressure) rather than simply
Preload Alterations: Preload affects all components of the delayed relaxation (which has little impact on LV end diastolic
mitral velocity curve (Fig. 5-4E and F). However, its most promi- pressure).17
nent effect is on the E wave. For mitral deceleration, the effects
depend on the initial position of the P-V curve. If the preload
increase does not move the P-V loop too much into the steeper Understanding Pulmonary Vein Flow Through
portion of the EDPVR, the effects may be negligible. It is not so
in the severely diseased ventricles operating close to the limit of Computer Modeling of the Heart
the preload reserve. Such conceptual thought experiments as those previously
Mitral Inertance: Mitral inertance affects both acceleration discussed can be helpful in understanding general trends in
and deceleration of the mitral valve. It changes acceleration of the relationship between invasive parameters and noninvasive
mitral valve inflow and leads to flattening of the parabolic curve measurements, but a more comprehensive approach can be
of velocity rise. Mitral inertance essentially acts by introducing obtained with a computer model that invokes realistic descrip-
the time lag between the transmitral pressure gradient and the tions of chamber and valvular functions. The reason for this is
mitral velocity curve: It makes the peak of the velocity curve occur that the flows of blood through different parts of the circulatory
after the peak of the transmitral pressure gradient curve (Fig. system are interdependent. A change in a single parameter (e.g.,
5-5). It also introduces the difference between the true mitral resistance in systemic arterioles) affects flow throughout the
valve pressure gradient and the pressure gradient calculated from system. Thus, changes in pulmonary circulation affect systemic
application of the simplified Bernoulli equation to transmitral circulation even if not assuming any ventricular-ventricular
velocity (see Fig. 5-5). As it correlates with the mitral valve area, interactions.
it can be largely neglected in patients with mitral stenosis, but it
is an important factor in the nonstenotic valve. We have shown,
by using the combination of echocardiography and direct pressure Lumped Parameter Model of the Heart
recordings, that the average value of mitral inertance in humans
is 3.82 ± 1.22 g/cm2, corresponding to an effective length of the and Circulation
blood column of about 3.6 cm within the mitral valve.16 Future Since the mid-1980s, the authors and colleagues have worked to
research may allow direct estimation of inertance from echocar- develop models of the heart with increasing complexity, beginning
diography data alone. from a very simple isolated model of the mitral valve used to
Interaction of Ventricular Compliance and Relaxation: understand the mitral pressure half-time; to models incorporat-
Importance of Heart Rate: During early filling, relaxation is ing more realistic diastolic characteristics of the ventricle and
not yet complete. This means that filling occurs while the dynamic atrium; to models that simulated all the cardiac chambers and
P-V curve continuously shifts downward and toward the right. valves, as well as the peripheral and pulmonary vasculature; to
Thus, as the ventricle fills, it moves to the steeper part of the most recently a simulation that links knowledge of basic myocyte
EDPVR, which in turn becomes progressively “flatter.” These two and fiber function to the gross architecture of the heart. We will
use a lumped parameter model to explore some of the determi-
nants of transmitral and pulmonary venous flow inside the
heart.3
P underestimation The lumped parameter approach assumes that blood flow is
similar to the flow of a current through an electric circuit, which
Actual ΔP by catheter can be represented at specific nodes of the circuit (left atrium, left
ventricle, aortic valve, etc.). Each of these nodes is represented by
Calculated ΔP
from velocity
a specific ordinary differential equation. The principle of the con-
servation of flow (Kirchoff ’s first law) is applied throughout the
circuit, and the parameters of the system are obtained by simul-
taneously solving all differential equations. Our model consists of
24 coupled differential equations representing eight different
chambers (the right atrium and ventricle, pulmonary arteries and
veins, left atrium and ventricle, aorta, and systemic veins) as well
Phase lag as the valves and vascular beds connecting them (Fig. 5-6), giving
time-varying flows and pressures throughout the model. Figure
Figure 5-5 Impact of mitral inertance: Transmitral velocities lag behind
transmitral pressure differences. (From Nakatani S et al: Mitral inertance 5-7 displays normal Doppler velocity tracing of pulmonary vein
in humans: Critical factor in Doppler estimation of transvalvular pressure and transmitral flow recorded in the normal subject by trans-
gradients. Am J Physiol Heart Circ Physiol 2001;280:H1340–1345.) esophageal echocardiography (left) and a model output of corre-
50 Chapter 5 • Physical Determinants of Diastolic Flow

Pulmonary tions have opposite effects. Mitral valve regurgitation (through

capillaries the parameter MV ERO) has its effect mostly on the systolic
Pulmonary artery Pulmonary vein
waveform, while Kp+ and τ have effect mostly on AR. The results
Pulmonic valve of this sensitivity analysis illustrate the complexities of these rela-
tionships, which are not intuitively apparent. In contrast, for the
Right Left
mitral inflow, as expected, the greatest influence was exerted by
ventricle atrium preload. Importantly, τ showed the opposite effects on E and A
waves, in congruence with the E/A ratio being reversed in the
setting of impaired relaxation. Table 5-1 should be kept in mind,
Tricuspid valve Mitral valve as very often pulmonary vein flow is used as a surrogate marker
of LA function, with S, D, and AR reflecting the LA reservoir,
Right Left
conduit, and pump functions, respectively. Our table indicates
atrium ventricle that for none of these is there a straightforward relationship
between the specific waveform and specific material parameters
of the pulmonary vein flow waveform.
Aortic valve
Venae cavae Aorta Impact of Pulmonary Vein–Left Atrial Pressure
Systemic
capillaries Gradient and Left Atrium Size
Figure 5-6 A lumped parameter model of the heart. (From Thomas JD Similar to mitral valve inertance is pulmonary vein inertance. Its
et al: Physical and physiological determinants of pulmonary venous effect on pulmonary vein flow is similar to its effect on transmitral
flow: Numerical analysis. Am J Physiol 1997;272:H2453–H2465.)
flow. Inertance leads to a lag of pulmonary vein flow behind the
PV–LA pressure gradient. This is intuitively understandable: the
pressure is needed to push the blood column, which then keeps
sponding pulmonary vein and transmitral flow velocities, along moving because of its kinetic energy.18 Another interesting obser-
with simulated pressure curves. Starting from this normal shape vation is the impact of the change of LA size, induced by clipping
of velocity and pressure tracings, we first modeled a delayed re- of the LA appendage, on pulmonary vein flow. The only affected
laxation pattern, by increasing τ from 50 to 120 msec. Then, to pulmonary vein flow wave was the S wave, indicating that LA size
model restrictive filling, we shifted the end systolic P-V relation- affects primarily LA reservoir function.19
ship by 10 ml to the right and decreased contractility from 4.0 to
2.5 mmHg/ml, thus moving the P-V loop toward the steeper
part of the EDPVR. The model outputs are displayed in Figure Understanding Intraventricular Flow
5-7, along with actual Doppler and pressure tracings of a repre- The previous model formulations seem like child’s play when one
sentative patient with delayed relaxation (panel B) and restrictive is confronted with the task of simulating intraventricular flow
filling (panel C). One can observe a close correspondence between with its demands for representing pressure and velocity through-
the modeled and actual shapes, with a correlation coefficient out the chamber. Three major phenomena develop simultane-
approaching 1. ously during filling: An intraventricular gradient appears at the
Figure 5-8 shows the impact of some of the model parameters beginning of LV filling, the blood column slows after exiting the
on pulmonary vein and mitral valve flow. LA systolic and diastolic mitral valve while continuing as laminar flow toward the apex, and
function had opposing effects on the S and AR waves of the pul- finally vortices start appearing due to propagation of the blood
monary vein, with minimal effect on the D wave (panels A through column past the tips of the mitral leaflets, while the left ventricle
D). Finally, all waveforms showed strong positive response to continually changes its size.
preload (panels E and F). Worse LV relaxation decreases the It is well documented that a small LV base-to-apex pressure
mitral valve E/A ratio and blunts diastolic waves of pulmonary gradient develops in early diastole (Fig. 5-9A). We have already
vein flow (panels G and H). These observations are analyzed in discussed that this gradient is of utmost importance for the low-
depth in Table 5-1, by showing the sensitivities of peak velocity pressure filling of the ventricle and is commonly termed diastolic
of the three pulmonary vein flow waves and of two mitral inflow “suction.” However, the exact mechanisms causing it are unclear.
waves on model parameters. The sensitivities represented here The most probable mechanisms are isovolumic conformational
were obtained by calculating a normalized Jacobian matrix, changes in LV shape that are driven by elastic forces within the
showing the proportional change in an output index for a given myocyte and/or the myocardial interstitium, explored in greater
incremental change in an input parameter. A sensitivity of 1 depth below.
means that for each 1% change of a model parameter value, the As blood emerges from the mitral valve, it slows down as the
output variable will change by 1%. A value of 2 indicates a 2% flow stream expands to fill the left ventricle. Interestingly, within
change for a 1% increase. Negative numbers indicate inverse rela- the first four centimeters of the left ventricle, the velocity of prop-
tionships. Because of the highly nonlinear nature of the model, agation of the blood column is fairly constant, despite the dra-
these observations are relevant to only very small increments but matic change of the chamber size, but it is generally less than the
do provide an overall sense of the dependency of Doppler indices actual velocities within the bolus of blood traversing the mitral
on hemodynamic parameters. valve. For example, pulsed-wave Doppler may record a velocity of
For example, one can readily observe the dramatic effect of 100 cm/sec, while the normal propagation velocity will be only
preload on all three pulmonary vein flow waves, in particular AR, 60 or 70 cm/sec, and even lower in diseased hearts, due to the
which increases almost 6-fold the increment in blood volume. bleeding off of vortices at the front of the bolus of blood. We and
Furthermore, one can observe that LA diastolic and systolic func- others have shown that in heart disease, the amount of slowing
 Chapter 5 • Physical Determinants of Diastolic Flow 51

TRANSMITRAL FLOW PULMONARY VENOUS FLOW

0
Velocity (cm/s)

Velocity (cm/s)
y = 0.95x S

Velocity (cm/s)
0 60 y = 1.02x

Velocity (cm/s)
r = 0.94 D 60 S
r = 0.92 D
50 p < 0.0001 p < 0.0001
0 0
Δ = –1.53±9.38 Δ = 0.76±7.69
A A AR AR
100 E cm/sec E cm/sec
100 –60 –60
0 0.5 1.0 0 0.5 1.0 0 0.5 1.0 0 0.5 1.0
Time (sec) Time (sec) Time (sec) Time (sec)
A

TRANSMITRAL FLOW TRANSMITRAL FLOW

0
0 y = 0.99x 0
Velocity (cm/s)

Velocity (cm/s)

Velocity (cm/s)

Velocity (cm/s)
0 y = 0.95x
r = 0.93 A
r = 0.92
E p < 0.0001 A
50 E 40 p < 0.0001
A Δ = 0.70±8.35 A Δ = 3.52±8.65
cm/sec E
80 E cm/sec
100 100 100
0 0.5 1.0 0 0.5 1.0 0 0.3 0.6 0 0.3 0.6
Time (sec) Time (sec) Time (sec) Time (sec)
PULMONARY VENOUS FLOW PULMONARY VENOUS FLOW

Velocity (cm/s)

Velocity (cm/s)
y = 1.02x y = 0.96x
Velocity (cm/s)

Velocity (cm/s)

40 80 D 80
S D 40 D
r = 0.96 D r = 0.91 S
S S
p < 0.0001 p < 0.0001
0 Δ = –1.54±3.32 0 0 Δ = 3.72±11.81
AR 0
AR cm/sec AR cm/sec AR
–40 –40 –60 –60
0 0.5 1.0 0 0.5 1.0 0 0.3 0.6 0 0.3 0.6
Time (sec) Time (sec) Time (sec) Time (sec)
LA PRESSURE LA PRESSURE

30 30
Pressure (mmHg)

Pressure (mmHg)
20 20
Pressure (mmHg)

Pressure (mmHg)

y = 0.84x y = 1.16x
r = 0.97 r = 1.0
p < 0.0001 p < 0.0001
Δ = –1.04±1.04 Δ = 1.99±1.61
mmHg mmHg
0 0 0 0
0 1 0 1 0 0.6 0 0.6
Time (sec) Time (sec) Time (sec) Time (sec)
LV PRESSURE LV PRESSURE
Pressure (mmHg)

Pressure (mmHg)
Pressure (mmHg)

Pressure (mmHg)

120 120 100 100

y = 0.94x y = 0.80x
r = 0.96 r = 0.99
p < 0.0001 p < 0.0001
Δ = –3.63±11.30 Δ = –5.01±8.69
mmHg mmHg
0 0 0 0
0 1 0 1 0 0.6 0 0.6
Time (sec) Time (sec) Time (sec) Time (sec)
B C
Figure 5-7 Actual and modeled pressures and filling patterns in a normal subject (A), patient with delayed relaxation (B), and patient with restrictive
filling (C). Note similarities between observed and modeled data. (From Thomas JD et al: Physical and physiological determinants of pulmonary venous flow:
Numerical analysis. Am J Physiol 1997;272:H2453–H2465.)
52 Chapter 5 • Physical Determinants of Diastolic Flow

TRANSMITRAL FLOW PULMONARY VEIN

90 60
A

Velocity (cm/sec)

Velocity (cm/sec)
E S D
60 30 0.32

0.48*
30 0
0.64
AR
0 –30
0 0.5 1 0 0.5 1
LA end-systolic elastance LA end-systolic elastance
(mmHg/ml) (mmHg/ml)
A B
90 60
A
Velocity (cm/sec)

Velocity (cm/sec)
E
S D
60 30 0.2*

0.25
30 0
0.3
AR
0 –30
0 0.5 1 0 0.5 1
LA end-diastolic elastance LA end-diastolic elastance
(mmHg/ml) (mmHg/ml)
C D
150 100
S
Velocity (cm/sec)

Velocity (cm/sec)

E D
A 50
100
3800*
0
4180
50
–50 4560
AR
0 –100
0 0.5 1 0 0.5 1
Preload (ml) Preload (ml)
E F
120 60
Velocity (cm/sec)

Velocity (cm/sec)

E S D
A
80 30
0.05*
40 0 0.10
AR 0.15
0 –30
0 0.5 1 0 0.5 1
LV relaxation time LV relaxation time
constant (sec) constant (sec)
G H
Figure 5-8 Simultaneous modeling of pulmonary vein and transmitral velocities using lumped-parameter approach. Increased left atrial systolic elastance
(i.e., higher contractility) increases A wave of the transmitral flow and AR wave of the pulmonary vein flow (panels A and B); increased left atrial diastolic
elastance (i.e., higher passive stiffness) has the opposite effect (panels C and D); increased preload increases all components of transmitral and pulmonary
vein flow (panels E and F); finally, prolongation of ventricular relaxation decreases E and increases A wave velocities of the transmitral flow and decreases
diastolic pulmonary vein flow (panels G and H). (From Thomas JD et al: Physical and physiological determinants of pulmonary venous flow: Numerical analysis.
Am J Physiol 1997;272:H2453–H2465.)
 Chapter 5 • Physical Determinants of Diastolic Flow 53

TABLE 5-1 of the blood column relative to the component velocity (that is,
the so-called E/Vp ratio) is related to LV filling pressures,20,21
RESULTS OF SENSITIVITY ANALYSIS FOR THE though the exact mechanistic relationship between these two phe-
PULMONARY VEIN AND TRANSMITRAL FLOW nomena is unclear (Fig. 5-9B).
As noted, intraventricular flow during diastole characteristi-
PULMONARY VEIN TRANSMITRAL
FLOW FLOW cally forms circular eddies lateral to the main flow, which can be
seen when the heart is imaged by echocardiography with high-
S D AR E A frequency transducers, or after the contrast injection, and can be
quantified by magnetic resonance velocity mapping (Fig. 5-9C).22
Parameters Creation of vortices plays a crucial role in mitral valve closure and
Preload 2.38 2.33 5.88 1.53 1.9
LV compliance index –0.45 –0.12 –1.15 –0.24 –0.04 in the transfer of blood toward the apex and then into the LV
LV systolic elastance –0.2 0.05 –0.44 –0.09 –0.19 outflow tract. Again, full elucidation of vortex generation and
LV τ 0.05 –0.19 –1.76 –0.33 0.16 movement is unclear.
LA systolic elastance 0.8 –0.14 0.97 –0.38 –0.25
LA diastolic stiffness –0.79 0.6 –1.27 –0.11 0.97
Mitral valve area –0.06 0.12 –0.16 0.07 –1.02 Modeling of the Intraventricular Flow by
MV ERO –2.73 0.17 –0.18 0.32 –0.11
Fluid-Mechanical Computer
A, atrial wave; AR, atrial reversal wave; D, diastolic wave; E, early wave; ERO, Modeling of the intraventricular flow is demanding because ven-
effective regurgitant orifice; LA, left atrial; LV, left ventricular; MV, mitral valve; S, systolic tricular motion effects blood flow, but blood flow itself effects
wave.
From Thomas JD et al: Physical and physiological determinants of pulmonary venous
ventricular motion. Some simplification is possible with compu-
flow: Numerical analysis. Am J Physiol 1997;272:H2453–H2465.

25
P
ECG
20
Pressure (mmHg)

15 MVO

10 LVP Base
LA
LVP Apex
5

0
IVPG

–5
A
30
MV

25

20
pw (mmHg)

15

10
r = 0.80
p < 0.001 LV
5 y = 5.27x+4.66
SEE = 3.1
0
0.5 1 1.5 2 2.5 3 3.5 4
E/vp ratio
B C
Figure 5-9 Three consecutive early diastolic intraventricular phenomena: A, Intraventricular pressure gradient formation in early diastole; B, relationship
between the slowing of the blood column in the early diastole with preload; and C, formation of vortices. (B, From Garcia MJ et al: An index of early left
ventricular filling that combined with pulsed Doppler peak E velocity may estimate capillary wedge pressure. J Am Coll Cardiol 1997;29:448–454; C, From Kilner
PJ et al: Asymmetric redirection of flow through the heart. Nature 2000;404:759–761.)
54 Chapter 5 • Physical Determinants of Diastolic Flow

tational fluid dynamics (CFD) models, where LV motion is

prescribed based on images from echocardiography or magnetic
resonance imaging, but these models lack fluid feedback on the
myocardium. Full fluid-structure interaction (FSI) models are
being developed in which movement of the blood and muscle is
not known a priori but is computed during the simulation on a
∼mm three-dimensional grid at ∼msec intervals, an extraordinary
computational challenge. Furthermore, most commercially avail-
able software programs allow only small strain deformations (up
to 5%) and are inadequate for cardiac modeling, where strains
may exceed 50%. Fortunately, large strain solvers recently have
been implemented in commercial codes, which enabled several
researchers to begin true fluid-solid interaction modeling of LV
function.23–25 Although these models have simplified geometry
and muscle properties, they give us insight into the flow propaga-
tion in the normal heart.
Flow Propagation Inside the Ventricle
We will first discuss the filling modeled by an axi-symmetric
thin-walled FSI model of the left ventricle containing both LV
outflow and inflow.26 During the rapid filling phase, a jet starts its
propagation through the mitral valve into the ventricular chamber.
Driven by this jet, a doughnut-shaped vortex is formed around
the jet just downstream from the mitral orifice. During filling, the
vortex ring travels toward the middle of the expanding ventricle,
while a weak vortex is formed within the aortic outflow tract,
which dissipates late during diastasis. After the vortex ring reaches
Figure 5-10 Computer modeling of vortices during left ventricular filling.
the middle of the ventricle, its anterior part becomes stationary During the rapid filling phase, initial inflow through the mitral valve forms
while the posterior part continues forward. During atrial contrac- a doughnut-shaped vortex downstream from the mitral orifice. This vortex
tion, a new, weaker vortex ring that encompasses a part of the ring then travels toward the middle of the expanding ventricle, while a
outflow tract is formed, while the posterior side of the initial weak vortex of brief duration is formed within the aortic outflow tract.
After the initial vortex ring reaches the middle of the ventricle, its anterior
vortex ring continues to move into the posterior apical region of part becomes stationary while the posterior part continues forward.
the ventricle. At the end of the filling, the posterior part of the During the atrial contraction, a new, weaker vortex ring that encompasses
second vortex ring merges with the first one, forming a large a part of the outflow tract is formed, while the posterior side of the initial
vortex in the posterior apex (Fig. 5-10). vortex ring continues to move into the posterior apical region of the ven-
tricle. In the end of the filling, the posterior part of the second vortex ring
Effect of Ventricular Dilation on Flow merges with the first, forming a large vortex in the posterior apex. (From
A fascinating conundrum in echocardiography is the possibil- Cheng Y et al: Fluid-structure coupled CFD simulation of the left ventricular
flow during filling phase. Ann Biomed Eng 2005;33:567–576.)
ity of having very high velocities of mitral valve inflow, while the
flow propagation velocity (velocity of the blood column inside
the left ventricle) may be several times slower. Baccani et al.
created a simple CFD simulation of this problem in dilated car-
diomyopathy.27 They showed that LV dilation slows down flow a vortex off the tips of the mitral valve that propagates beside the
propagation velocity. Furthermore, they have shown that this is E wave into the ventricle. The ventricle expands under the
associated with the initial vortex staying attached to the mitral influence of decreased elasticity and increased strain due to LV
valve (Fig. 5-11). filling. As the relaxation finishes after about 200 msec, the E
wave loses strength, and velocity slowly decreases as the expansion
Pressure Propagation Inside the Ventricle of the ventricle ceases. After the E wave ends, atrial pressure
Flow and velocity propagation, though tightly linked, are sepa- increases and the A wave enters the ventricular cavity, forming
rate phenomena. To analyze this relationship, we developed a another vortex off the mitral valve. As the A wave propagates
two-dimensional axi-symmetric thick-walled FSI model. The toward the apex, this vortex is taken up by the first vortex that
fluid domain was represented by 6321 triangular elements, while is still present. By now, ventricular stresses have significantly
the solid domain was represented by 1206 bricklike quadrilateral increased, raising LV pressure and slowing down filling. The fill-
elements. The time-varying pressure at the mitral valve opening ing behavior described here corresponds with clinically observed
was generated by the numerical simulations of the lumped param- behavior.
eter model. The fluid domain was represented by incompressible Using this fluid-structure interaction model, we have investi-
Navier-Stokes equations. The LV wall was given time-varying gated the influence of changes in relaxation (τ) and end diastolic
stiffness properties, with strains calculated using a large strain stiffness. In Figure 5-12, color Doppler M-mode images are
deformation code. Finally, the decrease in stiffness of the wall shown from four different conditions: (A-B) baseline, (C-D)
during ventricular relaxation was modeled as an exponential shorter τ, (E-F) longer τ, and (G-H) increased ventricular dia-
decay from systolic stiffness to diastolic stiffness.28,29 stolic stiffness. At baseline, the E and A waves are roughly bal-
The baseline ventricular filling pattern is illustrated in Figure anced (equal color-mapped peak velocities). Intraventricular
5-12, showing the E wave entering the cavity, with formation of pressure gradients (IVPGs) are slightly above normal due to the
 Chapter 5 • Physical Determinants of Diastolic Flow 55

0 1
0.02
0.02 0.5
0.01

0 0.04
0

z
0.01 0.06
–0.5
0.02 0.08
0.08 0.06 0.04 0.02 0 –1
0 0.2 0.4 0.6 0.8 1
t

Figure 5-11 Impact of ventricular dila-

tion on flow. Images represent a com-
puter model of left ventricular flow in
mid-diastole. In a normal ventricle (upper
left panel), the proximal vortex becomes 0
unattached and freely moves toward 0.02
the apex, enabling prompt filling of
the ventricle, as evidenced by high flow 0.03
propagation velocity (upper right

z
panel). In contrast, left ventricular dila- 0
0.06
tion prohibits the movement of vortices
toward the apex (lower left panel), and
slows down flow propagation velocity 0.02 0.09
(lower right panel). (From Baccani B et al:
Fluid dynamics of the left ventricular filling
in dilated cardiomyopathy. J Biomech 0 0.2 0.4 0.6 0.8 1
2002;35:665–671.)

mild mitral stenosis inherent in the model. With shorter τ, the Distorted Left Ventricular Geometry
E-wave velocity, Vp, and IVPG increase, while a longer τ produces In a recent sheep study, myocardial aneurysm was induced by
the classic appearance of delayed relaxation (i.e., low E velocity, the ligation of coronary arteries subtending the LV apex.40 Flow
slow propagation, large A wave, and reduced IVPG).29–32 Because propagation velocity abruptly decreased when blood flow column
of the mild mitral stenosis, E-wave deceleration time is prolonged; entered LV aneurysms and the point of this deceleration coin-
for very large time constants, the E wave is no longer separated cided with the edge of the aneurysm (Fig. 5-13). The infarct size
from the A wave.29 With a stiffer ventricle, velocities and IVPG correlated with the distance from the apex to the point of the
are reduced, reflecting lower stroke volume, the expected behavior deceleration of flow propagation. However, no point of abrupt
when atrial pressure is held at baseline so no pseudonormaliza- decrease was detected when myocardial infarct was induced by
tion will occur. The A wave is particularly blunted, reflecting circumflex occlusion. Also, significantly, the presence of break-
ineffective filling of the stiff ventricle.31,33 As support for these point coincided with loss of the IVPG. In a clinical study that is
findings, we have recently shown that in humans, IVPG in the congruent with these findings, we have shown that removal of the
elderly becomes blunted with worsened relaxation.9 In addition, aneurysm by infarct exclusion surgery improves IVPGs.41 These
elderly people with preserved ventricular compliance (i.e., a less data show that in order for flow to enter the heart cavity, heart
stiff ventricle), still had worsened IVPGs, reflecting the depen- walls have to be compliant.
dence of IVPGs on intact relaxation, without an impact of
compliance. Effect of Isovolumic Processes
During the isovolumic period of LV relaxation, the left ventri-
cle changes its shape in the absence of any change of volume. The
Insights from Experimental Studies most dramatic aspect of this is that the left ventricle untwists, a
process that is linked to the elastic elements of the ventricle that
Currently, no model can predict the impact of structural changes induce early LV suction. Untwisting is a necessary successor to
of LV shape on flow propagation within the LV. In that situation, systolic torsion (twist). Systolic torsion and diastolic untwisting
we are left with some experimental studies. We will discuss briefly occur because myocardial fibers form a leftward helix in the sub-
some of them. epicardium.42 The contraction of these fibers rotates the base and
the apex of the left ventricle clockwise and counterclockwise,
Presence of Ischemia respectively. However, unlike systolic torsion that increases pro-
Acute ischemia delays apical filling34,35 and is associated with portional to systolic volume change, untwisting is a phenomenon
the loss of IVPGs.36,37 Beppu et al. described the altered apical that peaks prior to the opening of the mitral valve.11,43 The reason
blood flow pattern in dogs with apical akinesis after coronary this occurs is that systolic torsion builds potential energy within
ligation.38 Ischemia decreases the maximal distance of mitral flow the elastic elements of the heart.44 With relaxation, energy is
into the ventricle during diastole, with blood flow in the region of released, and elastic elements promptly restore the original,
the infarction becoming either static or eddied.38,39 untwisted LV shape. It is no surprise that untwisting is inversely
56 Chapter 5 • Physical Determinants of Diastolic Flow

6 1.4 6 10
A B
E-wave A-wave
5 1.2 5 8

Relative pressure (mmHg)

4 1 4
LV 6
Distance (cm)

Distance (cm)
Velocity (m/s)
3 0.8 3
4
2 VP 0.6 2
MV
2
1 0.4 1

0 0.2 0 0
LA
–1 0 –1 –2
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7
Time (s) Time (s)
6 1.4 6 10
C D
5 1.2 5 8

Relative pressure (mmHg)

4 1 4
6
Distance (cm)

Distance (cm)
Velocity (m/s)
3 0.8 3
4
2 0.6 2
2
1 0.4 1

0 0.2 0 0

–1 0 –1 –2
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7
Time (s) Time (s)
6 1.4 6 10
E F
5 1.2 5 8

Relative pressure (mmHg)

4 1 4
6
Distance (cm)

Velocity (m/s)

Distance (cm)

3 0.8 3
4
2 0.6 2
2
1 0.4 1

0 0.2 0 0

–1 0 –1 –2
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7
Time (s) Time (s)
6 1.4 6 10
G H
5 1.2 5 8

Relative pressure (mmHg)

4 1 4
6
Distance (cm)

Distance (cm)
Velocity (m/s)

3 0.8 3
4
2 0.6 2
2
1 0.4 1

0 0.2 0 0

–1 0 –1 –2
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7
Time (s) Time (s)

Figure 5-12 Modeling of fluid-structure interaction showing influence of changes in relaxation (τ) and end diastolic stiffness. Pseudo–M-mode images of
time-velocity (left panels) and time-pressure data from four different conditions: A and B, baseline; C and D, shorter τ; E and F, longer τ; and G and H,
increased ventricular diastolic stiffness. At baseline, the E and A waves are roughly balanced (equal color-mapped peak velocities). IVPGs are slightly above
normal due to the mild mitral stenosis inherent in the model. With shorter τ, the E-wave velocity, Vp, and IVPG increase, while longer τ produces the classic
appearance of delayed relaxation (low E velocity, slow propagation, large A-wave and reduced IVPG). Because of the mild mitral stenosis, E-wave decelera-
tion time is prolonged and for very large time constants no longer fully separated from the A wave. With a stiffer ventricle, velocities and IVPG are reduced,
reflecting lower stroke volume, the expected behavior when atrial pressure is held at baseline to prevent pseudonormalization. The A wave is particularly
blunted, reflecting ineffective filling of the stiff ventricle.
 Chapter 5 • Physical Determinants of Diastolic Flow 57

7
: r2 = 0.99

IVPG (mmHg)
5

–1
4 2 0
Normal Apex-to-base distance (cm)

Apex (A)

A-D 5
(23 mm) : r2 = 0.97
4

IVPG (mmHg)
3 : r2 = 0.67

2
Figure 5-13 Effect of apical aneurysm on intraventricular Abrupt 1
flow propagation. Flow propagation velocity decreases decrease in
abruptly when blood enters the aneurysm. This sudden 0
propagation
deceleration coincides with the loss of intraventricular velocity (D) –1
pressure gradient. (From Asada-Kamiguchi J et al: Intraven-
4 2 0
tricular pressure gradients in left ventricular aneurysms
determined by color M-mode Doppler method: An animal
study. J Am Soc Echocardiogr 2006;19:1112–1118.) LV aneurysm

related to τ, and its magnitude may be used as a surrogate measure 4 p < 0.00001
of relaxation.
Events during early diastole in a normal left ventricle can be Normal
summarized in the following way. Relaxation leads to prompt LV exercise
untwisting, the peak of which coincides with mitral valve opening;
this is immediately followed by peak early mitral annulus velocity; p < 0.00001
Peak IVPG (mmHg)

finally, formation of the IVPG facilitates early LV filling. We

have shown a strong correlation between untwisting and
IVPG at rest and during exercise.11 Furthermore, we have shown
2
that essentially the same slope of untwisting-IVPG relationship HCM
exists in patients with severe hypertrophic cardiomyopathy Normal exercise
rest
(Fig. 5-14). This indicates that untwisting and the IVPG are P = NS
tightly coupled and that either untwisting is necessary to
produce the IVPG or that some strong third factor binds them, HCM
expressed simultaneously by untwisting and by the IVPG. Thus, rest
it seems that three major factors determine flow propagation and P = NS
IVPGs: chamber dilation, worsened relaxation, and loss of
compliance. 0
0 –5
Peak untwisting velocity (rad/s)
FUTURE RESEARCH
Figure 5-14 Relationship between left ventricular untwisting and intra-
The number of flow-based diastolic parameters that are proposed ventricular pressure gradients (IVPGs) at rest (open markers) and during
exercise (closed markers). Normal subjects are marked by squares, while
to be helpful in clinical practice is staggering. Still, more and more hypertrophic cardiomyopathy patients are marked by triangles. While the
indices are proposed every year. This review of the physics behind same slope of untwisting-IVPG relationship exists in normal hearts and in
diastolic flows aims to elucidate common underlying processes those with severe hypertrophic cardiomyopathy, hearts of patients with
that are manifested through various diastolic parameters. In this hypertrophic cardiomyopathy cannot generate the increase of untwisting
during the exercise, leading to smaller IVPG increase. (From in Notomi Y
manner, we are trying to bring another “Rosetta stone” to the et al: Enhanced ventricular untwisting during exercise: A mechanistic manifes-
cardiology community.45 In the remainder of this book, many of tation of elastic recoil described by Doppler tissue imaging. Circulation
these indices will be shown in application to various diseases of 2006;113:2524–2533.)
58 Chapter 5 • Physical Determinants of Diastolic Flow

diastolic function; it is hoped that by keeping these physical prin- 9. Popovic ZB, Prasad A, Garcia MJ, et al: Relationship between diastolic
ciples in mind, the reader will better be able to assess diastolic intraventricular pressure gradients, relaxation, and preload: Impact of age
and fitness. Am J Physiol Heart Circ Physiol 2005.
dysfunction clinically. 10. Nikolic SD, Yellin EL, Dahm M, et al: Relationship between diastolic shape
Despite numerous published studies, our current understand- (eccentricity) and passive elastic properties in canine left ventricle. Am J
ing of physical properties is limited. One field that is largely Physiol 1990;259:H457–H463.
undefined is the modeling of structural-fluid relationships within 11. Notomi Y, Martin-Miklovic MG, Oryszak SJ, et al: Enhanced ventricular
untwisting during exercise: A mechanistic manifestation of elastic recoil
the left ventricle, which is a structure so complex that to accurately described by Doppler tissue imaging. Circulation 2006;113:2524–2533.
calculate mechanical events during diastole, one needs several 12. Thomas JD, Popovic ZB: Intraventricular pressure differences: A new
days even with the use of the most powerful supercomputers. window into cardiac function. Circulation 2005;112:1684–1686.
Therefore, until computer processing power is increased by an 13. Thomas JD, Weyman AE: Echocardiographic Doppler evaluation of left
order of magnitude, we will lack the ability to answer such seem- ventricular diastolic function. Physics and physiology. Circulation
1991;84:977–990.
ingly simple questions as: Is torsion necessary to LV contraction? 14. Courtois M, Kovacs SJ Jr, Ludbrook PA: Transmitral pressure-flow velocity
and What happens to end diastolic pressure if we eliminate an relation: Importance of regional pressure gradients in the left ventricle
increase in the IVPG during diastole? To paraphrase Sir Isaac during diastole. Circulation 1988;78:661–671.
Newton, we are still like children playing on the seashore and 15. Thomas JD, Newell JB, Choong CY, Weyman AE: Physical and physiologi-
cal determinants of transmitral velocity: Numerical analysis. Am J Physiol
diverting ourselves now and then, finding a smoother pebble or a 1991;260:H1718–H1731.
prettier shell than ordinary, whilst the great ocean of truth lies all 16. Nakatani S, Firstenberg MS, Greenberg NL, et al: Mitral inertance in
undiscovered before us. humans: Critical factor in Doppler estimation of transvalvular pressure gra-
dients. Am J Physiol Heart Circ Physiol 2001;280:H1340–H1345.
17. Hay I, Rich J, Ferber P, et al: Role of impaired myocardial relaxation in the
production of elevated left ventricular filling pressure. Am J Physiol Heart
ABBREVIATIONS Circ Physiol 2005;288:H1203–H1208.
18. Firstenberg MS, Greenberg NL, Smedira NG, et al: Doppler echo evalua-
A: atrial tion of pulmonary venous–left atrial pressure gradients: Human and numer-
AR: atrial reversal ical model studies. Am J Physiol Heart Circ Physiol 2000;279:
CFD: computational fluid dynamics H594–H600.
19. Kamohara K, Fukamachi K, Ootaki Y, et al: Evaluation of a novel device for
D: diastolic left atrial appendage exclusion: The second-generation atrial exclusion
E: early device. J Thorac Cardiovasc Surg 2006;132:340–346.
EDPVR: end diastolic pressure-volume relationships 20. Garcia MJ, Ares MA, Asher C, et al: An index of early left ventricular filling
FSI: fluid-structure interactions that combined with pulsed Doppler peak E velocity may estimate capillary
wedge pressure. J Am Coll Cardiol 1997;29:448–454.
IVPG: intraventricular pressure gradient 21. Firstenberg MS, Vandervoort PM, Greenberg NL, et al: Noninvasive esti-
LA: left atrium mation of transmitral pressure drop across the normal mitral valve in
LV: left ventricular humans: Importance of convective and inertial forces during left ventricular
MV: mitral valve filling. J Am Coll Cardiol 2000;36:1942–1949.
P-V: pressure-volume 22. Kilner PJ, Yang GZ, Wilkes AJ, et al: Asymmetric redirection of flow
through the heart. Nature 2000;404:759–761.
PV: pulmonary vein(s) 23. Vierendeels JA, Dick E, Verdonck PR: Hydrodynamics of color M-mode
S: systolic Doppler flow wave propagation velocity V(p): A computer study. J Am Soc
Vp: flow propagation velocity Echocardiogr 2002;15:219–224.
τ: time constant of isovolumic pressure decay (Tau) 24. Vierendeels JA, Riemslagh K, Dick E, Verdonck PR: Computer simulation
of intraventricular flow and pressure gradients during diastole. J Biomech
t: time Eng 2000;122:667–674.
25. Verdonck P, Vierendeels J, Riemslagh K, Dick E: Left-ventricular pressure
gradients: A computer-model simulation. Med Biol Eng Comput
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34. Stugaard M, Smiseth OA, Risoe C, Ihlen H: Intraventricular early Doppler method: An animal study. J Am Soc Echocardiogr 2006;19:
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 HIDEKATSU FUKUTA, MD, PhD
WILLIAM C. LITTLE, MD
6
General Principles,
Clinical Definition,
and Epidemiology
INTRODUCTION Is Measurement of Diastolic Function
Necessary?
PATHOPHYSIOLOGY
Prognostic Utility of Doppler
Systolic Performance
Echocardiography
Diastolic Performance
Practical Recommendations
Definition of Systolic and Diastolic Heart
Failure EPIDEMIOLOGY
Terminology Epidemiology of Diastolic Dysfunction
Epidemiology of Diastolic Heart Failure
CLINICAL APPLICATIONS
Diagnosis of Diastolic Heart Failure CONCLUSIONS AND FUTURE RESEARCH
Timing of Ejection Fraction Measurement

INTRODUCTION tion, or an ejection fraction (EF): a ratio of stroke volume-to-end

diastolic volume. Thus, LV systolic dysfunction is defined as a
Heart failure (HF) is defined as the pathological state in which decreased EF. The EF can be obtained by determining the LV
the heart is unable to pump blood at a rate required by the metab- volume by use of two-dimensional echocardiography with or
olizing tissues or can do so only with an elevated filling pressure. without contrast, radionuclide ventriculography, or magnetic res-
Inability of the heart to pump blood sufficiently to meet the needs onance imaging.
of the body’s tissues may be due to the inability of the left ventricle The EF has been used as an index of myocardial contractile
to fill (diastolic performance) or eject blood (systolic performance) performance. However, it is influenced not only by myocardial
or both. Thus, consideration of the systolic and diastolic perfor- contractility but also by LV afterload.1 Furthermore, in the pres-
mance of the left ventricle provides a conceptual basis to classify ence of a left-sided valvular regurgitation (mitral or aortic regur-
and understand the pathophysiology of HF. gitation) or a left-to-right shunt (ventricular septal defect or
patent ductus arteriosus), the LV stroke volume may be high,
while the forward stroke volume (stroke volume minus regurgi-
PATHOPHYSIOLOGY tant volume or shunt volume) is lower. Thus, the effective EF is
defined as the forward stroke volume divided by end diastolic
Systolic Performance volume.2 The effective EF is a useful means to quantify systolic
Left ventricular (LV) systolic performance is the ability of the left function, for two reasons: First, the effective EF represents the
ventricle to empty, which can be quantified as an emptying frac- functional emptying of the left ventricle that contributes to cardiac
63
64 Chapter 6 • General Principles, Clinical Definition, and Epidemiology

output. Second, the effective EF is relatively independent of LV propagation of mitral inflow to the apex (VP) is reduced in condi-
end diastolic volume over the clinically relevant range. tions with impaired LV relaxation.9
An operational definition of systolic dysfunction is an effective A pseudonormalized LV filling pattern can be distinguished
EF of less than 0.50.2 When defined in this manner, systolic dys- from a normal filling pattern by demonstrating reduced EM and
function results from impaired myocardial function, increased LV VP. Furthermore, since early diastolic mitral inflow velocity (E)
afterload, structural abnormalities of the left ventricle, or a com- becomes higher and relaxation-related parameters (EM and Vp)
bination thereof.2 remain reduced as filling pressure increases, the E/EM and E/VP
can estimate LV filling pressure with a reasonable accuracy over
a wide range of an EF.10–12 Last, color M-mode imaging provides
Diastolic Performance a noninvasive measurement of the diastolic intraventricular pres-
For the left ventricle to function effectively as a pump, it must be sure gradient between the apex and the base during early
able not only to eject but also to fill, which is its diastolic function. diastole.13
Diastolic function conventionally has been assessed on the basis Finally, analysis of pulmonary venous flow patterns provides
of the LV end diastolic pressure-volume (P-V) relation (see useful information on LV compliance and LA pressure.14 With
Chapter 7).3 A shift of the curve upward and to the left has been increase in LV end diastolic pressure, the reversal velocity of pul-
considered to be the hallmark of diastolic dysfunction (Fig. 6-1, monary venous atrial flow increases, and duration increases longer
curve A). In this situation, each LV end diastolic volume is associ- than that of mitral late diastolic velocity. With decrease in LV
ated with a high end diastolic pressure, and thus the left ventricle compliance and increase in mean LA pressure, the systolic compo-
is less distensible. Decreased LV distensibility is caused by nent of pulmonary venous flow decreases and the diastolic compo-
aging, systemic hypertension, and hypertrophic or restrictive nent of pulmonary venous flow increases. Table 6-1 and Figure 6-2
cardiomyopathy.2 show stages of diastolic dysfunction incorporatingpulmonary
Diastolic function also has been assessed based on LV filling venous flow, tissue Doppler, and color M-mode indices.9
patterns by use of Doppler echocardiography.4,5 In the absence of
mitral stenosis, three patterns of LV filling indicate progressive
impairment of diastolic function: (1) reduced early diastolic filling Definition of Systolic and Diastolic Heart Failure
with a compensatory increase in importance of atrial filling When the HF is associated with a reduced EF, the pathological
(impaired relaxation); (2) most filling early in diastole but with state may be called systolic HF. In contrast, when the HF is asso-
rapid deceleration of mitral flow (pseudonormalization); and (3) ciated with diastolic dysfunction in the absence of a reduced EF,
almost all filling of the left ventricle occurring very early in dias- the pathological state may be called diastolic HF. It is important
tole in association with very rapid deceleration of mitral flow to recognize that the HF, whether it results from systolic or dia-
(restrictive filling) (Fig. 6-2).6 stolic dysfunction, is a clinical syndrome and that both systolic
These Doppler LV filling patterns, however, are influenced not HF and diastolic HF are heterogeneous disorders. Patients with
only by LV diastolic properties but also by left atrial (LA) pres- systolic HF have abnormalities of diastolic function,2,3 and those
sure. In contrast, tissue Doppler measurement of mitral annular with diastolic HF may have abnormalities of systolic contractile
velocity and color M-mode measurement of the velocity of propa- function that are not detected by measurement of an EF.15
gation of mitral inflow to the apex appear to be less load sensitive.
The peak early diastolic mitral annular velocity (EM) provides a
relatively load insensitive measure of LV relaxation.7 EM is Terminology
decreased with increasing severity of diastolic dysfunction.8,9 The Diastolic Dysfunction and Diastolic Heart Failure
color M-mode imaging performed from the apex provides a tem-
poral and spatial map of the velocities of blood flow in early The term diastolic dysfunction is used to describe abnormal mechan-
diastole along the long axis of the left ventricle. The velocity of ical (diastolic) properties of the ventricle and includes decreased LV
distensibility, delayed relaxation, and abnormal filling, regardless of
whether the EF is normal or reduced and whether the patient is
symptomatic or asymptomatic. In contrast, the term diastolic HF is
LV end diastolic pressure

A used to describe patients with the symptoms and signs of HF and

Normal B a normal EF and diastolic dysfunction.

Diastolic Heart Failure and Heart Failure with

ΔP Normal Ejection Fraction
ΔV There are many clinical conditions that cause HF with a normal
EF. These include diastolic dysfunction, valvular diseases, pericar-
dial diseases, and intracardiac mass; among them, diastolic dys-
LV end diastolic volume function is the most common cause of HF with a normal EF.
Figure 6-1 A shift of the curve to A indicates that a higher left ventricular Diastolic HF is associated with LV diastolic abnormalities. It is
(LV) pressure will be required to distend the LV to a similar volume, indicat- important to recognize that although patients with diastolic HF
ing that the ventricle is less distensible. The slope of the LV end diastolic have diastolic dysfunction, frequently they also have systolic con-
pressure-volume relation indicates the passive chamber stiffness. Since the tractile abnormalities (despite the normal EF). In addition,
relation is exponential in shape, the slope (ΔP/ΔV) increases as the end
diastolic pressure increases. (Data from Little WC: Diastolic dysfunction comorbidities such as hypertension, anemia, and renal dysfunc-
beyond distensibility: Adverse effects of ventricular dilatation. Circulation tion are commonly seen in patients with diastolic HF and may
2005;112:2888–2890.) contribute to the development of HF.
 Chapter 6 • General Principles, Clinical Definition, and Epidemiology 65

Impaired
Normal relaxation Pseudonormal Restrictive

E E
Mitral E E A
A A
inflow A
velocity

D
S S
D D D
S S
Pulmonary
vein
velocity

Figure 6-2 Transmitral inflow velocity, SM

pulmonary vein flow velocity, mitral SM SM SM
annular velocity, and color M-mode Mitral
imaging in stages of diastolic dysfunc- annular
tion. E, early diastolic mitral inflow veloc- velocity
ity; A, late diastolic mitral inflow velocity; EM EM
EM AM AM
S, systolic pulmonary vein velocity; D, AM
diastolic pulmonary vein velocity; SM, AM
systolic mitral annular velocity; EM, early EM
diastolic mitral annular velocity; AM, late
diastolic mitral annular velocity; and Vp,
velocity of propagation of mitral inflow Color VP
to the apex. (Data from Fukuta H, Little M-mode
WC: Diastolic versus systolic heart failure. imaging
In Smiseth OA, Tendera M (eds): Diastolic
Heart Failure. London, Springer, 2007.)

TABLE 6-1
STAGES OF DIASTOLIC DYSFUNCTION
PARAMETER NORMAL (YOUNG) NORMAL (ADULT) DELAYED RELAXATION PSEUDONORMAL FILLING RESTRICTIVE FILLING

E/A >1 >1 <1 1–2 >2

DT (msec) <220 <220 >220 150–200 <150
IVRT (msec) <100 <100 >100 60–100 <60
S/D <1 ≥1 ≥1 <1 <1
AR (cm/sec) <35 <35 <35 ≥35 ≥25*
Vp (cm/sec) >55 >45 <45 <45 <45
Em (cm/sec) >10 >8 <8 <8 <8

*Unless atrial mechanical failure is present.

AR, pulmonary venous peak atrial contraction reversed velocity; DT, early left ventricular filling deceleration time; E/A, early-to-atrial left ventricular filling ratio; Em, peak early
diastolic myocardial velocity; IVRT, isovolumic relaxation time; S/D, systolic-to-diastolic pulmonary venous flow ratio; Vp, color M-mode flow propagation velocity.
From Garcia MJ et al: New Doppler echocardiographic applications for the study of diastolic function. J Am Coll Cardiol 1998;32:865–875.

Comparison of Pathophysiology in Systolic and other hand, the pathophysiology of diastolic HF is dependent
Diastolic Heart Failure predominantly on concentric LV hypertrophy and abnormal dia-
stolic function.
Table 6-2 shows the comparison of LV structural and functional
characteristics in systolic and diastolic HF (see Chapter 2). Sys-
tolic HF and diastolic HF have several similarities in LV struc-
tural and functional characteristics, including increased LV mass CLINICAL APPLICATIONS
and increased LV end diastolic pressure. The most significant
difference between the two forms of HF is in LV geometry and
Diagnosis of Diastolic Heart Failure
LV function: Systolic HF is characterized by LV dilatation, eccen- A distinction between systolic and diastolic HF is important
tric LV hypertrophy, and abnormal systolic and diastolic function, because these two forms have different pathophysiologies and
whereas diastolic HF is characterized by concentric LV hypertro- thus might potentially require different therapeutic approaches.5
phy, a normal EF, and abnormal diastolic function. Thus, the Nevertheless, clinical symptoms and signs are similar in systolic
pathophysiology of systolic HF is dependent predominantly on and diastolic HF (Table 6-3).16,17 This may be because systolic
progressive LV dilatation and abnormal systolic function. On the HF is often accompanied by diastolic dysfunction, by which
66 Chapter 6 • General Principles, Clinical Definition, and Epidemiology

TABLE 6-2 TABLE 6-3

COMPARISON OF LEFT VENTRICULAR (LV) RPREVALENCE OF SPECIFIC SYMPTOMS AND SIGNS
STRUCTURAL AND FUNCTIONAL FEATURES IN SYSTOLIC AND DIASTOLIC HEART FAILURE (HF)
BETWEEN SYSTOLIC AND DIASTOLIC HEART
SYSTOLIC DIASTOLIC
FAILURE (HF) HF (%) HF (%)
CHARACTERISTICS SYSTOLIC HF DIASTOLIC HF
Symptoms
Dyspnea on exertion 96 85
Remodeling Paroxysmal nocturnal dyspnea 50 55
LV end diastolic volume ↑ N Orthopnea 73 60
LV end systolic volume ↑ N Physical examination
LV mass ↑ eccentric ↑ concentric Jugular venous distension 46 35
Relative wall thickness ↓ ↑ Rales 70 72
Cardiomyocyte ↑ length ↑ diameter Displaced apical impulse 60 50
Extra cellular matrix collagen ↓ ↑ S3 65 45
Diastolic properties S4 66 45
LV end diastolic pressure ↑↑ ↑↑ Hepatomegaly 16 15
Relaxation time constant ↑ ↑↑ Edema 40 30
Filling rate ↓ ↓↓ Chest radiograph
Chamber stiffness N–↓ ↑ Cardiomegaly 96 90
Myocardial stiffness N–↑ ↑ Pulmonary venous 80 75
Systolic properties hypertension
Performance
Stroke volume ↓ N–↓
Stroke work ↓ N From Zile MR, Brutsaert DL: New concepts in diastolic dysfunction and diastolic heart
Function failure. Part I: Diagnosis, prognosis, and measurement of diastolic function. Circulation
2002;105:1387–1393.
Ejection fraction ↓ N
Ejection rate ↓ N
PRSW ↓ N
Contractility
congestion may be due to transient systolic dysfunction or acute
Positive dp/dt ↓ N mitral regurgitation produced by hypertension and/or myocar-
Ees ↓ N–↑ dial ischemia that had resolved by the time the LV EF was mea-
FS vs. stress ↓ N sured. To address this issue, Gandhi et al. used Doppler
Preload reserve Exhausted Limited echocardiography to evaluate LV EF, regional wall motion, and
Ea ↓ ↑
Arterial-ventricular coupling ↓ N
mitral regurgitation in 38 patients both during an acute episode
(Ea/Ees) of hypertensive pulmonary edema and 24 to 72 hours later, after
treatment and resolution of the hypertension and pulmonary con-
Ea, effective arterial elastance; EEs, end systolic elastance; FS, fractional shortening; gestion.20 They found that LV EF and regional wall motion were
PRSW, preload-recruitable stroke work. similar, both during the acute episode of hypertensive pulmonary
Data from Zile MR, Baicu CF, Bonnema DD: Diastolic heart failure: Definitions and
terminology. Prog Cardiovasc Dis 2005;47:307–313.
edema and after resolution of the congestion and control of blood
pressure (Fig. 6-3).21 No patient had severe mitral regurgitation
during the acute episode. They also found that 50% of the patients
symptoms and signs related to pulmonary congestion are com- had an EF equal to or greater than 0.50 during their presentation
monly observed.2 Thus, clinical history and physical examination with acute pulmonary edema and that 88% of the patients with
do not provide useful information in discriminating between sys- an EF equal to or greater than 0.50 after treatment had an EF
tolic and diastolic HF. equal to or greater than 0.50 during the acute episode, and all of
Several criteria have been proposed for the diagnosis of dia- these patients had an EF of at least 0.43. Thus, they concluded
stolic HF.18,19 In summary, for the diagnosis of diastolic HF to be that the EF obtained 1–3 days after the acute presentation of
made, the following evidence is required: patients with hypertensive pulmonary edema accurately identified
patients with a preserved EF during acute presentation. This
❒ clinical evidence of HF,
study suggests that measuring the EF within 72 hours of an acute
❒ normal systolic function (LV EF >0.50), and
episode of pulmonary congestion is sufficient to meet the diag-
❒ objective evidence of impaired LV relaxation or LV passive
nostic criteria proposed by Vasan and Levy. However, measure-
stiffness.
ments of diastolic filling could have changed within the 72-hour
If strictly applied, the definition of diastolic HF would include period.
patients with acute mitral or aortic regurgitation, mechanical
causes of diastolic dysfunction (mitral stenosis or constrictive
pericarditis), right-sided HF, intracardiac mass, or congenital Is Measurement of Diastolic Function Necessary?
heart diseases; these conditions could be avoided by additional Recognizing the difficulties inherent in the clinical assessment of
echocardiographic screening.5 LV diastolic performance, Zile et al. tested the hypothesis that
measurements of LV relaxation and passive stiffness were not
necessary to make the diagnosis of diastolic HF.22 They studied
Timing of Ejection Fraction Measurement 47 patients with a history of HF, a normal LV EF (>0.50), and
Vasan and Levy criteria require a normal EF within 72 hours of at least mild LV hypertrophy (LV mass ≥125 g/m2) or concentric
an episode of pulmonary congestion to make a definite diagnosis LV remodeling (LV chamber dimension <55 mm combined with
of diastolic HF.19 It is possible, however, that the acute pulmonary LV wall thickness ≥11 mm and relative wall thickness ≥0.45).
 Chapter 6 • General Principles, Clinical Definition, and Epidemiology 67

LV EJECTION FRACTION
SYSTOLIC BLOOD PRESSURE
0.9
260
0.8
240
0.7
220
0.6
200 198
mmHg

0.5 0.50 0.50

180
0.4
160

140 0.3
138
120 0.2

100 0.1
During acute After treatment During acute After treatment
pulmonary oedema pulmonary oedema
Figure 6-3 The systolic arterial pressure of patients at presentation with hypertensive acute pulmonary edema and after treatment 24–72 hours later.
Despite the substantial difference in blood pressure, the left ventricular (LV) ejection fraction was similar on admission with acute pulmonary edema and
after treatment. (From Little WC: Hypertensive pulmonary oedema is due to diastolic dysfunction. Eur Heart J 2001; 22:1961–1964.)

DIASTOLIC FUNCTION EJECTION FRACTION

1.0 1.0
Normal

EF = 0.4–0.5
Grade 1
Fraction alive

Fraction alive

0.9 0.9
EF >0.5
Grade 2

0.8 0.8
Grade 3 EF <0.4

p = 0.19
p = 0.0077
0.7 0.7
0 250 500 750 1000 1250 0 250 500 750 1000 1250
Time (days) Time (days)
Figure 6-4 Kaplan-Meier survival curves for 104 heart failure (HF) patients with an ejection fraction (EF) less than 0.50 and 102 HF patients with an EF
equal to or greater than 0.50. Progressively more severe diastolic dysfunction is strongly associated with decreased survival. The EF does not significantly
affect survival. For stages of diastolic dysfunction, see Table 6-1 and Figure 6-2. (Data from Brucks S et al: Contribution of left ventricular diastolic dysfunction
to heart failure regardless of ejection fraction. Am J Cardiol 2005;95:603–606.)

The authors then assessed LV diastolic function during cardiac peptide levels. They also found that greater diastolic dysfunction
catheterization and found that all the patients had evidence of but not a reduced EF was associated with worse 2-year survival
abnormalities of LV relaxation and passive stiffness.22,23 Thus, (Fig. 6-4). When analysis was limited to HF patients with an EF
they concluded that objective evidence of abnormalities of LV less than 0.50, both reduced EF and the greater diastolic dysfunc-
relaxation or distensibility during cardiac catheterization was tion were associated with worse survival.
unnecessary to make the diagnosis of diastolic HF if there was Rihal et al. examined the association of systolic and diastolic
evidence of LV hypertrophy or concentric remodeling. function with HF symptoms and 3-year survival in 102 patients
with dilated cardiomyopathy and an EF of 0.23 ± 0.08.25 They
found that markers of diastolic dysfunction, including short
Prognostic Utility of Doppler Echocardiography deceleration time and increased peak early diastolic LV inflow
Noninvasive assessment of diastolic dysfunction using Doppler velocity, were more strongly associated with symptoms than was
echocardiography provides useful information on the severity of reduced EF. They also found that the short (<130 msec) decelera-
HF and prognosis.15,24–27 Specifically, Brucks et al. examined the tion time had incremental prognostic value to the reduced (<0.25)
association of systolic and diastolic function with severity of HF EF. Similarly, Wang et al. showed that the reduced (<3 cm/sec)
assessed by plasma B-type natriuretic peptide levels and progno- EM was a powerful predictor for 4-year mortality and provided
sis in 104 HF patients with an EF less than 0.50 and in 102 HF incremental prognostic value to other clinical risk factors and
patients with an EF equal to or greater than 0.50.15 They found Doppler echocardiographic variables in 182 HF patients with an
that an increasing grade of diastolic dysfunction but not a reduced EF less than 0.50.26 Recently, Troughton et al. showed in the
EF was associated with increased plasma B-type natriuretic ADEPT study that the newer diastolic indices of E/EM and E/VP
68 Chapter 6 • General Principles, Clinical Definition, and Epidemiology

provide independent prediction of clinical outcomes in systolic [SD] age, 51 [14] years) in Augsburg, Germany.31 The prevalence
HF (EF <35%) that are equal or additive to conventional markers of diastolic abnormalities in the setting of a preserved EF (≥0.45),
including, EF and E deceleration time.28 as defined by the European Study Group on Diastolic Heart
These observations suggest that diastolic dysfunction is associ- Failure (i.e., normal isovolumic relaxation time, 92–105 msec;
ated with the severity of HF and prognosis independent of the normal ratio of early-to-late LV filling [E/A ratio], 1:0.5, depend-
EF. Thus, although measurement of diastolic function may not be ing on age), was 11.1%. The prevalence of diastolic dysfunction,
necessary for the diagnosis of diastolic HF, its measurement with defined as diastolic abnormalities with LA enlargement or treat-
Doppler echocardiography is critical for risk stratification in all ment with diuretics, was 3.1%. Of the subjects with diastolic
HF patients. abnormalities, only 2.3% had an EF less than 0.45. Independent
predictors for diastolic abnormalities or diastolic dysfunction
included hypertension, LV hypertrophy, myocardial infarction,
Practical Recommendations obesity (body mass index ≥27.3), diabetes, ratio of fat mass-to-
If patients have clinical evidence of HF, the EF should be mea- fat-free mass greater than 0.70, and male gender. Smoking and
sured within 72 hours of an acute episode of pulmonary conges- low-density-lipoprotein cholesterol levels were not predictors for
tion. If the EF is less than or equal to 0.50, the diagnosis of diastolic abnormalities or dysfunction. Importantly, in the absence
systolic HF can be made. If the EF is greater than 0.50 and there of these risk factors, diastolic abnormalities and diastolic dysfunc-
is evidence of LV hypertrophy or concentric remodeling, the diag- tion were rare even in the subjects older than 50 years of age (4.6%
nosis of diastolic HF can be suggested. In the absence of LV and 1.2%, respectively). The prevalence of diastolic abnormalities
hypertrophy or concentric remodeling, the diagnosis of diastolic is lower in the study by Fischer et al.31 than in the study by
HF may be supported by the presence of left atrial enlargement.29 Redfield et al.30 This may be due to the difference in age between
When the diagnosis of diastolic HF needs confirmation, Doppler cohorts studied and the diagnostic criteria for diastolic dysfunc-
echocardiography or cardiac catheterization provides a definitive tion using Doppler echocardiography.
diagnosis. Furthermore, assessment of diastolic function using These observations suggest that diastolic dysfunction is more
Doppler echocardiography, particularly with tissue Doppler common than systolic dysfunction in community-dwelling
imaging, provides useful information on the severity of HF and patients and that risk factors for diastolic dysfunction are similar
prognosis regardless of the EF. Thus, it is important to evaluate to those for systolic dysfunction. Thus, treatment of these risk
both systolic and diastolic functions not only for making a defini- factors may reduce the prevalence of both diastolic and systolic
tive diagnosis of diastolic HF but also for identifying high-risk dysfunction, thereby reducing the incidence of overt HF.
patients.
Prognosis of Diastolic Dysfunction
EPIDEMIOLOGY Three studies have shown that diastolic dysfunction is associated
with increased morbidity and mortality in the community. In the
For assessment of the prevalence and prognosis of diseases, large Cardiovascular Health Study,32 standard Doppler echocardio-
unselected subjects should be evaluated at a given time and fol- graphic variables, including the Doppler E/A ratio, were mea-
lowed prospectively. Thus, in this section, we review population- sured in 2671 participants who were free of coronary artery
based cohort studies reporting the frequency of diastolic disease, chronic HF, or atrial fibrillation. Both high (>1.5) and
dysfunction and/or HF with normal EF in the community. low (<0.7) E/A ratios were predictive of the incidence of HF
during a mean follow-up of 5.2 years (Fig. 6-5). After adjustment
for covariates including age, blood pressure, stress-corrected LV
Epidemiology of Diastolic Dysfunction systolic function, and LV mass, the predictive value of both high
Prevalence of Diastolic Dysfunction
Two studies have shown that diastolic dysfunction assessed by 16
Doppler echocardiography is more common than systolic dys-
function in the community. Specifically, Redfield et al. investigated 14
% with incident CHF

the prevalence of diastolic dysfunction assessed by comprehensive 12

tissue Doppler imaging in 2042 randomly sampled subjects aged 10
45 years and older (mean [SD] age, 63 [11] years) in Olmsted
County, Minnesota.30 Overall, 28% had diastolic dysfunction 8
(20.8%, mild; 6.6%, moderate; 0.7%, severe), whereas 6% had an 6
EF less than or equal to 0.50 and 2% had an EF less than or equal 4
to 0.40. An EF of 0.50 or less was present in 1.4% of participants
with normal, 10.5% with mild, 19.5% with moderate, and 61.5% 2
with severe diastolic dysfunction. The prevalence of diastolic dys- 0
function increased with age. Diastolic dysfunction was equally < 0.7 0.7–1.5 > 1.5
common in men and women and more common in participants Doppler E/A ratio
with hypertension, diabetes, coronary artery disease, and
obesity. Figure 6-5 Unadjusted incident congestive heart failure (CHF) rates by
Doppler E/A ratio. Incident CHF is higher at the extreme values of this ratio.
Similarly, Fischer et al. investigated the prevalence of diastolic (From Aurigemma GP et al: Predictive value of systolic and diastolic function
dysfunction assessed by standard Doppler echocardiography in for incident congestive heart failure in the elderly: The Cardiovascular Study.
1274 randomly sampled subjects aged 25 years or older (mean J Am Coll Cardiol 2001;37:1042–1048.)
 Chapter 6 • General Principles, Clinical Definition, and Epidemiology 69

and low E/A ratios remained significant (adjusted hazard ratios severe diastolic dysfunction were independent predictors for
[HRs] [95% CI] of high and low E/A ratios, 3.50 [1.80–6.80] death (adjusted HRs [95% CI] of mild and moderate or severe
and 1.88 [1.33–2.68], respectively). diastolic dysfunction, 8.31 [3.00–23.1] and 10.2 [3.28–31.0],
Similarly, in the Strong Heart Study,33 the prognostic value of respectively).
high and low E/A ratios was investigated in 3008 American These observations suggest that diastolic dysfunction, particu-
Indian participants. Both high (>1.5) and low (<0.6) E/A ratios larly of moderate or severe degree, is a powerful predictor for
were predictive of all-cause and cardiac mortality during a mean increased morbidity and mortality in the community. Regression
follow-up of 3 years (Fig. 6-6). After adjustment for age, sex, body of LV hypertrophy by antihypertensive agents has been shown to
mass index, systolic blood pressure, cholesterol level, hyperten- improve LV diastolic filling.34 The impact of these interventions
sion, diabetes, coronary artery disease, smoking, LV hypertrophy, on clinical outcomes requires further studies.
and low (<0.40) EF, high E/A ratio was an independent predictor
for all-cause and cardiac mortality (adjusted HRs [95% CI] for
all-cause and cardiac death, 1.73 [0.99–3.03] and 2.8 [1.19– Epidemiology of Diastolic Heart Failure
6.75], respectively). However, low E/A ratio was not an indepen- Reported frequency of diastolic HF in overt HF and that of dia-
dent predictor for either all-cause or cardiac mortality (adjusted stolic HF in the community vary widely.35 This may be due to the
HRs [95% CI] for all-cause and cardiac death, 1.2 [0.8–1.6] and difference in diagnostic criteria for diastolic HF between studies.
1.2 [0.7–2.1], respectively). Thus, in this section, we review community-based cohort studies
Finally, in the study by Redfield et al.,30 the prognostic value that used the Framingham criteria for a diagnosis of HF and 0.50
of diastolic dysfunction assessed by comprehensive tissue for separating a normal EF from a reduced EF.
Doppler imaging was investigated. Both mild and moderate or
severe diastolic dysfunctions were predictive of all-cause
death during a median of 3.5 person-years of follow-up (Fig. 6-7). Prevalence of Diastolic Heart Failure
After adjustment for age, sex, and EF, both mild and moderate or Four studies have shown that nearly half of patients with HF have
a normal EF. Specifically, Senni et al.36 evaluated all patients
receiving first diagnosis of HF in Olmsted County, Minnesota, in
25 1991 (n = 216), of whom 137 had an assessment of EF within 3
weeks before or after the diagnosis of HF. In these patients, 59
20 (43%) had a normal EF (≥0.50) and 78 (57%) had a reduced EF
(<0.50). Compared with HF patients with a reduced EF, those
15 with a normal EF were older and more likely to be female and
less likely to have had prior myocardial infarction and left bundle
10 branch block. Similarly, Vasan et al.37 evaluated the echocardio-
grams of 73 Framingham Heart Study subjects with HF. They
5 found that 37 (51%) had a normal EF (≥0.50) and 36 (49%) had
a reduced EF (<0.50). Compared with HF patients with a reduced
0
EF, those with a normal EF were more likely to be female and less
likely to have had prior myocardial infarction. These studies,
All-cause death Cardiac death
however, did not enumerate the base population. Thus, the preva-
Figure 6-6 Incidence of all-cause and cardiac death among participants lence of diastolic HF in the community cannot be estimated from
with E/A less than 0.6 (blue bars), 0.6 to 1.5 (purple bars), and greater than
1.5 (green bars). (From Bella JN et al: Mitral ratio of peak early to late diastolic these studies.
filling velocity as a predictor of mortality in middle-aged and elderly adults: Two other studies have reported both the frequency of a normal
The Strong Heart Study. Circulation 2002;105:1928–1933.) EF in overt HF and the prevalence of HF with a normal EF in

25
Diastolic function
Moderate or severe dysfunction
20 Mild dysfunction
Normal
Mortality (%)

15

10 Log rank p <.001

Figure 6-7 Kaplan-Meier survival curves for participants

with normal diastolic function versus subjects with mild or 0
moderate or severe diastolic dysfunction. Progressively 0 1 2 3 4 5
more severe diastolic dysfunction is strongly associated
Year
with decreased survival. For stages of diastolic dysfunction,
see Table 6-1 and Figure 6-2. (Data from Redfield MM et al: No. at risk
Burden of systolic and diastolic ventricular dysfunction in the Normal 1277 1277 1275 885 404 38
community: Appreciating the scope of the heart failure epi- Mild 371 366 361 246 122 8
demic. JAMA 2003;289:194–202.) Moderate or severe 131 129 126 94 39 5
70 Chapter 6 • General Principles, Clinical Definition, and Epidemiology

the community. In the study by Redfield et al.,30 the prevalence Importantly, survival (adjusted for age, sex, and other covariates,
of HF was 2.2%. They also found that among the HF patients, including diabetes, smoking, and blood pressure) did not signifi-
44% had an EF greater than 0.50 and 56% had an EF equal to or cantly differ between HF patients with a normal EF and those
less than 0.50. Similarly, Cortina et al. assessed the prevalence with a reduced EF (adjusted HR [95% CI] of normal EF vs.
of HF in 391 randomly selected subjects aged 40 years or reduced EF, 0.65 [0.31–1.35], p = 0.25).
older (mean [SD] age, 60 [13] years) in Asturias, northern These observations suggest that both patients with
Spain.38 They found that the prevalence of HF was 5% and that diastolic HF and those with systolic HF have poor prognosis and
among the HF patients, 59% had an EF greater than or equal to that the mortality difference between the two groups may be
0.50 and 41% had an EF less than 0.50. These studies, however, minimal.
have the limitation that the EF was not determined at the onset
of HF.
Taken together, these observations suggest that the prevalence
of diastolic HF is similar to that of systolic HF and that the CONCLUSIONS AND FUTURE RESEARCH
prevalence of diastolic HF in adult and elderly populations may
be 1%–3%. These studies also suggest that patients with diasto- Diastolic function can noninvasively be assessed by Doppler
lic HF are older and more likely to be female than those with echocardiography. Diastolic dysfunction assessed by Doppler
systolic HF. echocardiography is more common than systolic dysfunction in
the community and is associated with increased morbidity and
mortality. Risk factors for diastolic dysfunction are similar to
Prognosis of Diastolic Heart Failure those for systolic dysfunction and include hypertension, LV
Two studies have shown that both patients with a normal EF and hypertrophy, myocardial infarction, diabetes, and obesity. Thus,
those with a reduced EF have poor prognosis. Specifically, in the treating these risk factors may reduce the prevalence of both sys-
study by Senni et al.,36 the prognosis of patients with a new diag- tolic and diastolic dysfunction and may ultimately reduce the
nosis of HF was worse than age- and gender-matched controls. incidence of overt HF.
Survival of HF patients was 86 ± 2% at 3 months, 76 ± 3% at 1 A diagnosis of diastolic HF can be made by clinical evidence
year, and 35 ± 3% at 5 years. There was no significant difference of HF in the setting of a normal EF, and objective evidence of
in unadjusted survival between HF patients with an EF greater diastolic dysfunction and abnormal biomarkers can help confirm
than or equal to 0.50 and those with an EF less than 0.50 (Fig. the diagnosis (Fig. 6-9). However, assessment of diastolic func-
6-8). After adjustment for age, sex, functional class, and coronary tion using Doppler echocardiography provides useful information
artery disease, survival did not significantly differ between the on the severity of HF and prognosis regardless of the EF. Thus,
two groups (adjusted HR of normal EF vs. reduced EF, 0.8, it is important to evaluate both systolic and diastolic function not
p = 0.37). only for making a definite diagnosis of diastolic HF but also for
In the study by Vasan et al.,37 during a median follow-up of 6.2 identifying high-risk patients.
years, HF patients with a reduced EF (<0.50) had significantly Diastolic HF and systolic HF are similarly prevalent in the
higher annual mortality than age- and gender-matched cases community, and both patients with diastolic HF and those with
(18.9% vs. 4.1%; adjusted HR [95% CI], 4.31 [1.98–9.36]). systolic HF have a poor prognosis.39,40 Patients with diastolic HF
Similarly, HF patients with a normal EF (≥0.50) had significantly are older and more likely to be female than those with systolic
higher annual mortality than age- and gender-matched cases HF. Thus, given the aging population, the public health burden
(8.7% vs. 3.0%; adjusted HR [95% CI], 4.06 [1.61–10.3]). of diastolic HF is substantial. Nevertheless at the present time,
there is no known therapy for the improvement of survival in
diastolic HF, thus emphasizing the urgent need for the establish-
ment of optimal treatment for this condition.
1.0 Although evidence has accumulated for the contribution of
diastolic abnormalities to diastolic HF, the pathophysiology of
0.8 diastolic HF remains to be fully understood.
1. What causes the transition of asymptomatic diastolic dys-
Survival

0.6
function to overt diastolic HF?
0.4 2. Does mild contractile dysfunction, which is not
detected by measurement of an EF, contribute to diastolic
Expected
0.2 EF < 50% p = 0.279 HF?
EF ≥ 50% 3. Do systemic factors including neurohumoral activation
0.0 and renal dysfunction contribute to diastolic HF?
0 1 2 3 4 5 6 4. What are the common causes of death in patients with
diastolic HF?
Years
5. Despite the similarities in the clinical manifestations of
EF < 50% 78 58 51 44 36 16 HF, why are the dramatic differences in the type of LV
EF ≥ 50% 59 44 35 32 29 15 remodeling seen in diastolic HF and systolic HF?
Figure 6-8 Survival of heart failure patients with an ejection fraction (EF)
of equal to or greater than 50% and less than 50%. (Data from Senni M et
A better understanding of the pathophysiology of diastolic HF
al: Congestive heart failure in the community: A study of all incident cases in will provide a rationale for the development of the plausible thera-
Olmsted County, Minnesota in 1991. Circulation 1998;98:2282–2289.) peutic strategies for the disorder.
 Chapter 6 • General Principles, Clinical Definition, and Epidemiology 71

HOW TO DIAGNOSE HFNEF

Symptoms or signs of heart failure

Normal or mildly reduced left

ventricular systolic function
LVEF >50%
and
LVEDVI <97 ml/m2

Evidence of abnormal LV relaxation, filling,

diastolic distensibility, and diastolic stiffness
Figure 6-9 Diagnostic flow chart
showing how to diagnose heart failure
with normal ejection fraction (HFNEF) in Invasive Hemodynamic TD Biomarkers
a patient suspeted of HFNEF, diastolic measurements NT-proBNP >220 pg/ml
heart failure. LVEDVI, left ventricular end- E/E' >15 15 > E/E' > 8
mPCW >12 mmHg or
diastolic volume index; mPCW, mean or BNP >200 pg/ml
pulmonary capillary wedge pressure; LVEDP >16 mmHg
LVEDP, left ventricular end-diastolic pres- or
sure; τ, time constant of left ventricular τ >48 msec
relaxation; b, time constant of left ven- or Biomarkers Echo–bloodflow doppler TD
tricular chamber stiffness; TD, tissue b >0.27 NT-proBNP >220 pg/ml E/A>50 yr <0.5 and E/E' >8
Doppler; E, early mitral valve flow veloc-
ity; E′, early TD lengthening velocity; NT- or DT>50 yr >280 msec
proBNP, N-terminal-pro brain natriuretic BNP >200 pg/ml or
peptide; BNP, brain natriuretic peptide; Ard–Ad >30 msec
E/A, ratio of early (E) to late (A) mitral or
valve flow velocity; DT, deceleration time; LAVI >40 ml/m2
LVMI, left ventricular mass index; LAVI, or
left atrial volume index; Ard, duration of LVMI >122 g/m2 ( );
reverse pulmonary vein atrial systole >149 g/m2 ( )
flow; Ad, duration of mitral valve or
atrial wave flow. (From Paulus WJ, Tschope Atrial fibrillation
C, Sanderson JE, et al: How to diagnose
diastolic heart failure: A consensus
statement on the diagnosis of heart
failure with normal left ventricular ejection
fraction by the Heart Failure and Echocar-
diography Associations of the European
Society of Cardiology. Eur Heart J 2007;
HFNEF
28(21):2686.)

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1998;21:5–9. catheterization study. Circulation 2000;102:1788–1794.
5. Oh JK, Hatle L, Tajik AJ, et al: Diastolic heart failure can be diagnosed by 13. Greenberg NL, Vandervoort PM, Firstenberg MS, et al: Estimation of dia-
comprehensive two-dimensional and Doppler echocardiography. J Am Coll stolic intraventricular pressure gradients by Doppler M-mode echocardiog-
Cardiol 2006;47:500–506. raphy. Am J Physiol 2001;280:H2507–H2515.
6. Fukuta H, Little WC: Diastolic versus systolic heart failure. In Smiseth 14. Oh JK, Appleton CP, Hatle LK, et al: The noninvasive assessment of left
OA, Tendera M (eds): Diastolic Heart Failure. London, Springer, ventricular diastolic function with two-dimensional and Doppler echocar-
2007. diography. J Am Soc Echocardiogr 1997;10:246–270.
7. Hasegawa H, Little WC, Ohno M, et al: Diastolic mitral annular velocity 15. Brucks S, Little WC, Chao T, et al: Contribution of left ventricular diastolic
during the development of heart failure. J Am Coll Cardiol 2003;41: dysfunction to heart failure regardless of ejection fraction. Am J Cardiol
1590–1597. 2005;95:603–606.
8. Sohn DW, Chai IH, Lee DJ, et al: Assessment of mitral annulus velocity by 16. Kitzman DW, Little WC, Brubaker PH, et al: Pathophysiological charac-
Doppler tissue imaging in the evaluation of left ventricular diastolic func- terization of isolated diastolic heart failure in comparison to systolic heart
tion. J Am Coll Cardiol 1997;30:474–480. failure. JAMA 2002;288:2144–2150.
9. Garcia MJ, Thomas JD, Klein AL: New Doppler echocardiographic applica- 17. Zile MR, Brutsaert DL: New concepts in diastolic dysfunction and diastolic
tions for the study of diastolic function. J Am Coll Cardiol heart failure. Part I: Diagnosis, prognosis, and measurement of diastolic
1998;32:865–875. function. Circulation 2002;105:1387–1393.
72 Chapter 6 • General Principles, Clinical Definition, and Epidemiology
18. European Study Group on Diastolic Heart Failure. How to diagnose heart 30. Redfield MM, Jacobsen SJ, Burnett JC Jr., et al: Burden of systolic and dia-
failure. Eur Heart J 1998;20:990–1003. stolic ventricular dysfunction in the community: Appreciating the scope of
19. Vasan RS, Levy D: Defining diastolic heart failure: A call for standardized the heart failure epidemic. JAMA 2003;289:194–202.
diagnostic criteria. Circulation 2000;101:2118–2121. 31. Fischer M, Baessler A, Hense HW, et al: Prevalence of left ventricular dia-
20. Gandhi SK, Powers JC, Nomeir AM, et al: The pathogenesis of acute stolic dysfunction in the community. Results from a Doppler echocardio-
pulmonary edema associated with hypertension. N Engl J Med graphic-based survey of a population sample. Eur Heart J 2003;24:
2001;344:17–22. 320–328.
21. Little WC: Hypertensive pulmonary oedema is due to diastolic dysfunction. 32. Aurigemma GP, Gottdiener JS, Shemanski L, et al: Predictive value of sys-
Eur Heart J 2001;22:1961–1964. tolic and diastolic function for incident congestive heart failure in the elderly:
22. Zile MR, Gaasch WH, Carroll JD, et al: Heart failure with a normal ejec- The cardiovascular study. J Am Coll Cardiol 2001;37:1042–1048.
tion fraction: Is measurement of diastolic function necessary to make the 33. Bella JN, Palmieri V, Roman MJ, et al: Mitral ratio of peak early to late dia-
diagnosis of diastolic heart failure? Circulation 2001;104:779–782. stolic filling velocity as a predictor of mortality in middle-aged and elderly
23. Zile MR, Baicu CF, Gaasch WH: Diastolic heart failure—abnormalities in adults: The Strong Heart Study. Circulation 2002;105:1928–1933.
active relaxation and passive stiffness of the left ventricle. N Engl J Med 34. Wachtell K, Bella JN, Rokkedal J, et al: Change in diastolic left ventricular
2004;350:1953–1959. filling after one year of antihypertensive treatment: The Losartan Interven-
24. Vanoverschelde JL, Raphael DA, Robert AR, et al: Left ventricular filling tion for Endpoint Reduction in Hypertension (LIFE) Study. Circulation
in dilated cardiomyopathy: Relation to functional class and hemodynamics. 2002;105:1071–1076.
J Am Coll Cardiol 1990;15:1288–1295. 35. Owan TE, Redfield MM: Epidemiology of diastolic heart failure. Prog Card
25. Rihal CS, Nishimura RA, Hatle LK, et al: Systolic and diastolic dysfunction Dis 2005;47:320–332.
in patients with clinical diagnosis of dilated cardiomyopathy: Relation to 36. Senni M, Tribouilloy CM, Rodeheffer RJ, et al: Congestive heart failure in
symptoms and prognosis. Circulation 1994;90:2772–2779. the community: A study of all incident cases in Olmsted County, Minnesota,
26. Wang M, Yip G, Yu CM, et al: Independent and incremental prognostic in 1991. Circulation 1998;98:2282–2289.
value of early mitral annulus velocity in patients with impaired left ventricu- 37. Vasan RS, Larson MG, Benjamin EJ, et al: Congestive heart failure in sub-
lar systolic function. J Am Coll Cardiol 2005;45:272–277. jects with normal versus reduced left ventricular ejection fraction: Prevalence
27. Dokainish H, Zoghbi WA, Lakkis NM, et al: Incremental predictive power and mortality in a population-based cohort. J Am Coll Cardiol 1999;
of B-type natriuretic peptide and tissue Doppler echocardiography in the 33:1948–1955.
prognosis of patients with congestive heart failure. J Am Coll Cardiol 38. Cortina A, Reguero J, Segovia E, et al: Prevalence of heart failure in
2005;45:1223–1226. Asturias (a region in the north of Spain). Am J Cardiol 2001;87:1417–
28. Troughton RW, Prior DL, Frampton CM, et al: Usefulness of tissue doppler 1419.
and color M-mode indexes of left ventricular diastolic function in predicting 39. Bursi F, Weston SA, Redfield MM, et al: Systolic and diastolic heart failure
outcomes in systolic left ventricular heart failure (from the ADEPT Study). in the community. JAMA 2006;296:2209–2216.
Am J Cardiol 2005;96:257–262. 40. Bhatia RS, Tu JV, Lee DS, et al: Outcomes of heart failure with preserved
29. Yturralde RF, Gaasch WH: Diagnostic criteria for diastolic heart failure. ejection fraction in a population-based study. N Engl J Med 2006;335:
Prog Cardiovasc Dis 2005;47:314–319. 260–269.
 JAMES B. SEWARD, MD
KRISHNASWAMY CHANDRASEKARAN, MD
MARTIN OSRANEK, MD, MSc
KANIZ FATEMA, MBBS, PhD
TERESA S. M. TSANG, MD
7
Invasive Physiology:
Clinical Cardiovascular
Pathophysiology and
Diastolic Dysfunction
INTRODUCTION CLINICAL RELEVANCE
Epidemic of Diastolic Heart Failure
PATHOPHYSIOLOGY
Myocardial Disease and Diastolic
Clinical Diastolic Dysfunction
Dysfunction
Pressure and Volume
Arterial Stiffening and Diastolic Dysfunction
INVASIVE VERSUS NONINVASIVE Physiologic Coupling of the Cardiovascular
ASSESSMENT System
Systolic Function Forward Dysfunction: End-Organ and
Diastolic Function Microvascular Damage
Vascular Stiffening: Summary
STATE-OF-THE-ART INVASIVE AND
NONINVASIVE PHYSIOLOGY CLUSTERING OF CARDIOVASCULAR RISK
Myocardial Relaxation Diastolic Heart Failure With Normal Ejection
Ventricular Stiffness Fraction and Systolic Heart Failure:
Filling Pressures Pathophysiologic Subgroups
Comprehensive Diastolic Function
FUTURE RESEARCH
Assessment
GLOSSARY
NORMAL DIASTOLIC MYOCARDIAL
PHYSIOLOGY ABBREVIATIONS
Temporal-Spatial Pressure and Flow: Suction
of Blood into the Left Ventricle
Left Atrial Pressure and Left Ventricular
Suction

73
74 Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction

INTRODUCTION describe patients with CHF symptoms and normal systolic con-
tractility (i.e., normal ejection fraction [EF]), although a preferred
In the era of classical cardiovascular (CV) medicine (ending term would be HF associated with preserved systolic function. Thus,
around the year 2000), CV function was validated predominantly the distinction between DHF and diastolic dysfunction is merely
by invasive means.1,2 Classic studies established the end systolic the presence of CHF symptoms. The CHF symptom complex
and end diastolic pressure-volume relationships as a meaningful associated with systolic HF (SHF) or DHF is most strongly cor-
and useful way of characterizing intrinsic ventricular pump prop- related with the elevation of filling pressure.
erties.3 These concepts then evolved such that they could be In order for the left ventricle to function as an effective pump,
applied to basic and clinical research. it must be able to empty and fill without requiring abnormal ele-
In the present era of CV intervention (projected to last until vation of left atrial (LA) pressure. Atrial pressure is directly
approximately 2020), CV imaging and molecular science are related to the ability of the left atrium to expel its contents into
emphasized. Mathematical modeling and further clarification of the ventricle during diastole. Thus, the principal determinant of
diastolic function through the use of invasive and noninvasive risk and symptoms of CHF is the increased pressure reflected
technologies is evolving.2,4 backward into the left atrium and pulmonary veins during dia-
Around 2020, CV medicine is envisioned to evolve toward an stolic filling of the ventricle.10 The stroke volume must be able to
“era of CV disease prevention.”5 Prevention will emphasize system increase in response to stress, such as exercise, without any appre-
physiology complemented by mathematical probability. A portfo- ciable increase in LA pressure (Fig. 7-1).6 Drugs that produce a
lio of physiologic models will be used as surrogate expressions sustained decrease in ventricular filling pressures enhance effort
of disease, and primary prevention of disease will be based on tolerance, breathing capacity, and HF outcome.11
the intensity or burden of a physiologic or molecular/chemical
risk model. Information acquisition will move from invasive to Pressure and Volume
noninvasive.
Research and clinical physiologic approaches2,6,7 are currently Diastolic function conventionally has been assessed on the basis
evolving from invasive to noninvasive means to elucidate funda- of the left ventricular (LV) diastolic pressure-volume relationship
mental CV physiology.4,8,9 Clinical physiology is no longer limited and an upward shift of the curve or increase in LV end diastolic
to catheterization, and the noninvasive echocardiologist can be pressure (LVEDP) (Figs. 7-2 and 7-3).6,7 The LV end diastolic
redefined as an “echophysiologist.” pressure-volume relationship is the most important means of
This chapter attempts to relate classical invasive physiology to characterizing global filling properties. The pressure-volume loop
the current evolution toward Doppler echocardiographic physiol- (see Fig. 7-2) depicts the amount of diastolic filling (ml of blood)
ogy. It is increasingly recognized and emphasized that contraction relative to a specified filling pressure (mmHg) and is therefore a
(systolic function) is dependent on relaxation (diastolic function). key physiologic determinant of preload.13 Any delay or impedance
It is important to appreciate the two distinct, although intimately
interrelated, aspects of the assessment of cardiac properties:
(1) of the ventricle as a hemodynamic pump and (2) of the intrin-
200
sic properties of the cardiac muscle.3 Systolic and diastolic
ventricular properties are dependent on systolic and diastolic Exercise
myocardial properties, as well as muscle mass, chamber architec-
ture, and chamber geometry. Pressure-volume constructs are used 150
to directly assess ventricular properties.
Rest
LV pressure (mmHg)

PATHOPHYSIOLOGY 100

Cardiac dysfunction, with or without systolic dysfunction, is

associated with diastolic dysfunction (i.e., elevation of filling
pressure). Cardiac dysfunction can be broadly viewed as a 50
derivative of altered cardiac geometry and cardiomyocyte dys-
function or altered extracardiac loading, which is most commonly
attributed to arterial stiffening. Once the sentinel cardiac or
arterial perturbation is initiated, the dysfunctional state is propa- 0
gated throughout the contiguous CV system (arteries, pump,
and reservoir), becomes cyclical and self-perpetuating, and
accounts for the clustering of a portfolio of common adverse 20 28 36 44 52
events (e.g., heart failure [HF], atrial fibrillation, stroke, cognitive
dysfunction). LV volume (ml)
Figure 7-1 Left ventricular (LV) pressure-volume loops at rest and during
exercise. Each loop was generated by averaging the data obtained during
Clinical Diastolic Dysfunction a 15-second recording of simultaneous pressure and volume, spanning
Diastolic dysfunction refers to abnormal mechanical relaxation several respiratory cycles. During exercise, the early diastolic portion of the
LV pressure-volume loop is shifted downward (arrow) so that the early
(diastolic) properties of the ventricle, which are present in the diastolic LV pressure is lower during exercise than at rest. (From Cheng CP
majority of patients with congestive heart failure (CHF). The et al: Mechanism of augmented rate of left ventricular filling during exercise.
term diastolic heart failure (DHF) is conventionally used to Circ Res 1992;70:9–19. Used with permission.)
 Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction 75

160
ESPVR
160 End
systole
Ejection 120
120

Pressure (mmHg)
Pressure (mmHg)

80

contraction
Isovolumic
Isovolumic
80 relaxation

Ees
40
40

Filling End
diastole EDPVR
0
0
0 20 40 60 80 100 120 140 0 20 40 60 80 100 120 140

A Volume (ml) B Vo Volume (ml)

160

Figure 7-2 The hemodynamic events occurring during the cardiac cycle
are displayed by plotting instantaneous pressure versus volume. A, A
normal pressure-volume loop. The four phases of the cardiac cycle are
120 displayed on the pressure-volume loop, which is constructed by plotting
Pressure (mmHg)

instantaneous pressure and volume. The loop repeats with each cardiac
cycle and shows how the heart transitions from its end diastolic state to
the end systolic state and back. B, Decrease in filling pressure (preload).
80 With a constant contractile state and afterload resistance, a progressive
reduction in ventricular filling pressure causes the loops to shift toward
lower volumes at both end systole and end diastole. When the resulting
end systolic pressure-volume points are connected, a reasonably linear
end systolic pressure-volume relationship (ESPVR) is obtained. The linear
40
ESPVR is characterized by a slope (Ees, ventricular elastance) and a volume
axis intercept (Vo). EDVPR denotes end diastolic pressure-volume relation-
ship. C, Increased afterload (blood pressure). When afterload resistance is
increased at a constant preload, the loops get narrower and longer, and
0 under ideal conditions the end systolic pressure-volume points fall on the
same ESPVR as obtained with preload reduction. (From Burkhoff D et al:
0 20 40 60 80 100 120 140 Assessment of systolic and diastolic ventricular properties via pressure-volume
analysis: A guide for clinical, translational, and basic researchers. Am J Physiol
C Volume (ml) Heart Circ Physiol 2005;289:501–512.)

of myocardial relaxation will increase the filling pressure, which venous pressure, secondary pulmonary hypertension, and decrease
will be reflected backward into the left atrium and pulmonary in clinical exercise capacity.15–18
veins.
The end diastolic pressure-volume relationship is intrinsically INVASIVE VERSUS NONINVASIVE ASSESSMENT
nonlinear (see Fig. 7-3), a characteristic attributed to the different
types of structural fibers being stretched in different pressure-
Systolic Function
volume ranges.14 In the low pressure-volume range, with only a Cardiac function assessment traditionally has focused on decreased
small increase in pressure for a given increment in volume, the contractility and the measure of EF. The noninvasive measure of
stretch of compliant elastin fibers and of the myocytes with sar- systolic function, EF, is almost exclusively used in clinical trials and
comeric titin molecules15 is believed to account for stiffness. As medical practice. Although EF is clinically considered an impor-
volume is increased to a higher range, pressure rises more steeply tant index of LV systolic function, it is not exclusively governed by
as slack lengths of collagen fibers and titin are exceeded and LV properties. Rather, EF is determined by the interaction of arte-
stretch is more strongly resisted by these stiff elements. Therefore, rial and ventricular properties.20–23 A normal EF suggests that
chamber stiffness increases as end diastolic pressure or volume contractility and arterial stiffness are well matched. EF is very load
increases.3 dependent and normally increases up to 30% during stress.24 EF is
With diastolic dysfunction, any abnormal increase in diastolic thus limited by many factors, including marked preload depen-
filling pressure corresponds to a less distensible or less compliant dence25 and low reproducibility when measured by different
ventricle during the filling phase of the cardiac cycle. Conse- imaging modalities.26 Furthermore, EF greater than 45% does not
quently, a “stiff ” ventricle is less able to increase its stroke volume contribute to assessment of CV risks in patients with HF.27 In
without further elevation of LA pressure. Pressure reflected back- patients with CHF and elevated filling pressure, diastolic dysfunc-
ward through the open mitral valve into the atrium and pulmo- tion correlates better with B-type natriuretic peptde concentration
nary veins can cause shortness of breath, elevation of pulmonary and mortality than with EF or LV volume.12,26
76 Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction

A
B
Normal

LV end diastolic pressure

ΔP ΔP
ΔV ΔV
ΔP
ΔV

LV end diastolic volume

Figure 7-3 Left ventricular (LV) end diastolic pressure-volume curves showing the relationship between end diastolic volume and pressure. Stiffness, at
different points on the curve, is reflected as the change in pressure (ΔP) divided by the change in volume (ΔV). During normal LV filling, the myocardium
must efficiently relax in order to prevent resistance to atrial emptying and elevation of atrial pressure. As the left ventricle relaxes, the diastolic volume
and pressure increase. The ventricular filling pressure is reflected backward into the left atrium. Flow ultimately stops or transiently reverses when the
atrial and ventricular pressures equilibrate. Normal atrial emptying thus must occur without requiring significant elevation of left atrial pressure. In this
early period of diastole more than two thirds of the LV stroke volume normally enters the left ventricle. The severity of heart failure and prognosis are
related to the severity of filling abnormalities regardless of the ejection fraction.12
A shift of the curve upward and to the left is considered the hallmark of diastolic dysfunction (curve A). A “stiff ” left ventricle in early diastole disturbs
the normal suction gradient between the left ventricle and the left atrium (see Fig. 7-6C). The LV pressure increases rapidly, thus impeding the normal
filling of the ventricle. Pressure is reflected backward into the left atrium, increasing atrial wall stress and pulmonary venous pressure. This pressure-volume
curve is typical for isolated diastolic dysfunction with preserved ejection fraction and delayed relaxation, elevated diastolic pressure, and near-normal
ventricular volume.
In a heart with abnormal geometry, as found in dilated, ischemic, or hypertrophic cardiomyopathy, the LV end diastolic pressure-volume curve is shifted
to the right (curve B). Decreased diastolic suction (see Fig. 7-6B) is disturbed because of abnormal chamber geometry, which is commonly associated with
uncoordinated wall motion or impaired myocardial contractility. The disturbed LV suction forces the left ventricle and left atrium to function at a higher
filling pressure, decreasing ventricular filling and increasing atrial and pulmonary venous pressure. (From Little WC: Diastolic dysfunction beyond distensibility:
Adverse effects of ventricular dilatation. Circulation 2005;112:2888–2890.)

Diastolic Function STATE-OF-THE-ART INVASIVE AND

Although the invasive research “testing ground” has made impor- NONINVASIVE PHYSIOLOGY
tant contributions to the understanding of pressure-volume rela-
Diastolic function assessment by both invasive2 and noninvasive
tionships and diastolic physiology,3,10 only recently has assessment
means is plagued by ambiguities surrounding the dynamic nature,
of diastolic function been extensively incorporated into clinical
indirectness, and difficulty of reproducibly measuring ever-
practice. Assessment of diastolic function was neglected because
changing diastolic function. Dynamic measures include:
there was no reliable noninvasive method to assess diastolic dys-
function, and invasive confirmation of elevated filling pressure 1. Decrease in pressure during the period of isovolumic
was deemed impractical if not unethical. Invasive monitoring relaxation (invasive: time constants of relaxation; noninva-
through a pulmonary artery catheter or implantable transducer sive: deceleration time and longitudinal fiber relaxation)
can provide continuous data. Pulmonary artery catheters, however, 2. Passive and active chamber stiffness or, its inverse, compli-
appear to contribute to morbidity and mortality29 and contribute ance (invasive: elastance; noninvasive: diastolic grade and
little to clinical assessment.30 Even when LV cardiac catheteriza- LA volume)
tion is performed, the principal measure of diastolic function is 3. End diastolic pressure (invasive: LVEDP; noninvasive:
LVEDP, which measures only the load-dependent filling pressure Doppler E/E′ ratio, end diastolic mitral versus pulmonary
and reflects conditional physiologic circumstances only at the vein Doppler flow) (Table 7-1)
time of data acquisition.
With the advent of noninvasive Doppler echocardiography,
Myocardial Relaxation
clinical assessment of diastolic function has become increasingly
attainable and validated. However, early impediments to Invasive Assessment
clinical use of Doppler echocardiographic diastolic function
Pressure relaxation can be measured invasively by placing a micro-
assessment became apparent. The first measures of diastolic func-
manometer catheter into the left ventricle. The rate of pressure
tion, which relied on mitral and pulmonary vein flow, were load
decrease, which begins during the isovolumic period, is influenced
dependent—similar to EF and LVEDP—and changed dynami-
by several physiologic factors2:
cally even during the examination. Because of the dynamic nature
of these physiologic events, measures of diastolic function were 1. Capacity and rapidity with which the sarcoplasmic reticu-
limited for use in the assessment of long-term morbidity and lum and sarcolemmal Na+/Ca2+ exchanger restores cellular
mortality. Ca2+ levels to low diastolic levels
 Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction 77

TABLE 7-1
DIASTOLIC FUNCTION ASSESSMENT BY INVASIVE AND NONINVASIVE MEANS
METHOD

Functional parameter Invasive Noninvasive ultrasonography

Myocardial relaxation Mathematical models of pressure-volume loops2 Tissue Doppler annular velocity, E′31–33
Ventricular and arterial stiffness Analysis of viscoelastic properties2: simultaneous Measures of “stiffness”9,34–36: effective arterial elastance (Ea),
measurement of pressure, volume, and flow end systolic elastance (Ees); Doppler-derived diastolic
Vascular: pulse pressure, central blood pressure dysfunction.
Vascular stiffness37–39: pulse wave velocity, augmentation
index
Filling pressure Left ventricular end diastolic pressure40 Doppler E/E′31,41–45: acute load-dependent filling pressure
Left atrial volume46–48: chronic average increase in filling
pressure

2. Extent of elastic recoil (suction) within the heart caused by logic state of filling pressure under the conditions existing at the
compression by myocyte contraction during the prior time of the examination as well as the likelihood of a favorable
systole and history of prior systolic ejection, which is largely response to a therapeutic manipulation (modifiability).32,36–40 The
determined by the aortic input impedance (stiffness) tissue Doppler E′ velocity reflects the relaxation velocity of the
3. Other chamber-level factors, such as dyscoordination and myocardium and expresses both passive and active myocardial
heterogeneity relaxation.31 Variations in long-axis shortening have relatively
little effect on the EF or stroke volume. Most of the stroke volume
Isovolumic pressure relaxation traditionally starts when pres-
is produced by shortening of the minor axis dimension,41 which
sure decay is maximal, generally occurring shortly after aortic
explains why either decreased diastolic (E′) or decreased systolic
valve closure, and extends to a point when LV pressure decreases
annular tissue Doppler can be observed in the presence of a
just below a threshold equal to the end diastolic pressure plus
normal EF.
5 mmHg. Recorded pressure-time curves can be mathematically
analyzed to extract the rate of pressure decrease.2 However, the
type of model used to describe relaxation can have marked influ- Ventricular Stiffness
ences on the apparent changes with drug and chamber-loading
interventions.2 Model-dependent analysis of relaxation is com- Invasive Assessment
monly fraught with systematic deviations from the real data, Ideally, to analyze the viscoelastic properties of the ventricle, one
particularly with depressed cardiac function.30 Some diseases, should take simultaneous measurements of chamber pressure,
including hypertrophic cardiomyopathy, are characterized by volume, and flow. Passive elastic properties are those that relate a
regional heterogeneity of loading and material properties, which change in pressure to a given change in volume, whereas viscous
result in nonuniform relaxation. Diseases with a complex process properties are those that relate change in pressure to the rate of
of pressure decrease, such as hypertrophic cardiomyopathy, in change in volume or flow. As opposed to noninvasive Doppler, no
general cannot be easily expressed in a single time constant. invasive methods are readily applicable for measuring flow rates
of filling in the human heart. Therefore, most analyses must
obtain flow data from the derivative of volume.2 The invasive
Noninvasive Assessment measurement of pressure uses a high-fidelity micromanometer
Diastolic dysfunction is associated with substantial abnormalities catheter. Measurement of volume is more challenging, with inves-
of active relaxation and passive stiffness of the ventricle.31 Doppler tigators commonly using various imaging-based methods to con-
transmitral velocity deceleration time (DT) and tissue Doppler struct a volume-time curve. This approach is labor intensive,
early diastolic mitral annular velocity (E′) are commonly used non- typically yielding a limited number of samplings of volumes
invasive indices of myocardial relaxation. DT fluctuates with the during the diastolic period, and is subject to various sources of
dynamic changes in ventricular loading pressure, whereas E′ is rela- noise given the extensive processing required.2 A notable alterna-
tively load independent. DT is useful for estimating intensity32,33 or tive is intracardiac electrical impedance, which can serve as a con-
“grade” of dysfunction34 at the time of the examination. Tissue tinuous measure of chamber volume.42–45
Doppler E′ velocity is touted as less load dependent and can distin- The association between diastolic pressure and volume from a
guish pseudonormal from normal filling patterns. The pseudonor- single cardiac cycle does not necessarily follow a simple mathe-
mal filling pattern is commonly encountered when using mitral matic relationship.2 Only limited filling property data can be
inflow Doppler to characterize diastolic function grade.32 obtained from a single cardiac cycle. Various solutions have been
Active (e.g., Ca2+-dependent) and passive (e.g., fibrosis) struc- used to overcome these limitations. After a diastolic pressure-
tural mechanisms regulate the rates of ventricular pressure decay volume curve is obtained, these data are typically subjected to a
and early diastolic ventricular filling.35 Active relaxation repre- mathematical curve-fitting process to extract parameters of
sents the speed of transition from the contracted state (systole) chamber or muscle stiffness. As with relaxation analysis, there are
to the relaxed state (diastole) and is strongly related to the uptake important limitations of such fitting when applied to a diastolic
of calcium for the contracted myocyte. Passive relaxation is most curve, owing to the nature of the mathematics.2 Unless the dia-
strongly related to myocardial compliance and the effects of tissue stolic data are perfectly monoexponential, which is rarely the case,
fibrosis. Load-dependent measures reflect the dynamic physio- simply evaluating the same curve or restricting analysis to slightly
78 Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction

different ranges of volume and pressure can influence the derived loading amplification associated with age.48,55 Diastolic HF with
parameters. Ultimately, derived stiffness parameters must be preserved EF appears to be best correlated with increased ven-
viewed cautiously, particularly if the data themselves do not clearly tricular-arterial stiffness. Relaxation of the “stiff ” ventricular myo-
follow an exponential rise waveform.2 Even if directly measured cardium is delayed when the ventricle is exposed to increased
by invasive pressures and volumes, the relationship between the systolic pressure during ejection (i.e., increased afterload).58 Dia-
two variables during filling does not necessarily provide informa- stolic dysfunction, as reflected in increased filling pressure, is
tion solely related to the cardiac chamber. directly related to greater prolongation of diastolic relaxation and
increased ventricular-vascular stiffening.55,59
A major hemodynamic consequence of arterial stiffening is
Noninvasive Assessment widening of the arterial pulse pressure, which also increases cyclic
Limited success has been achieved in replicating pressure-volume changes in arterial flow. Increased arterial stiffness increases sys-
loops by noninvasive Doppler echocardiography.8,46,47 However, tolic pressure and decreases diastolic pressure. Coronary perfu-
several noninvasive studies have identified a relationship between sion occurs principally during diastole; thus, in persons with stiff
limitation of exercise capacity, increased CV stiffness,48–51 and conduit vessels and lower diastolic pressure, coronary micro-
DHF.52,53 Noninvasive Doppler echocardiographic assessment of vascular perfusion is adversely affected.60 Impaired myocyte
“stiffness” appears to be an excellent means of expressing ventricu- relaxation of the subendocardial longitudinal fibers is an age-
lar and arterial stiffening.9,54 Effective arterial elastance (Ea), which associated finding. Reduced myocardial relaxation is best mea-
reflects vascular stiffening, and end systolic elastance (Ees), which sured as a decrease in tissue Doppler E′ velocity.
reflects ventricular stiffening, can be calculated noninvasively9,54 Structural remodeling and functional disturbances are essen-
and validated against invasive assessment (Fig. 7-4).21,46,54–56 Ea, tial to the development of diastolic dysfunction and HF, but acute
Ees, and diastolic stiffness increase with age and correlate with one or subacute decompensation with CHF generally requires a pre-
another.21 Normally, there is an inverse relationship between Ees cipitant, or “trigger.”61 The stiff arterial system is particularly sensi-
and Ea. As arterial compliance decreases (increased stiffness), ven- tive to acute dysfunction, as occurs with excessive sodium intake,
tricular compliance would be expected to increase (decreased hypertension, atrial fibrillation, myocardial infarction, or marked
stiffness).55 In order for EF to increase during exercise, the cou- bradycardia (prolonged diastasis). High arterial pulsatility is
pling ratio of Ea and Ees must decrease. However, with aging, noted to have detrimental effects on blood flow regulation62 and
the increase in exercise EF becomes blunted,23,57 suggesting age- contributes to adverse mechanical forces, which affect vascular
associated differences in the coupling ratio (Ea/Ees) and its com- tone, atherogenesis, angiogenesis, hemostasis, and microvascular
ponents. Both arterial and ventricular stiffness tend to increase to autoregulation.
a similar degree—Ea/Ees remains constant despite an increase in
arterial stiffness (see Fig. 7-4). Thus, ventricular stiffness tends to
increase with age. Filling Pressures
As ventricular and arterial stiffness increase, the system becomes
more pressure labile and sensitive to loading conditions.21 This Invasive Assessment
physiologic change is most evident with aging, as reflected in LVEDP is the most common measure of diastolic dysfunction
increased systolic and pulse pressure after age 50 to 60 years. recorded during clinical cardiac catheterization. Increased filling
These changes explain decreased exertional capacity and pressure- pressure is not a requisite of diastolic dysfunction but is a universal

Young Elderly
180
Elderly
Systolic pressure (mmHg)

Ees Ea
150
LV pressure (mmHg)

150
Ees Ea
100
120

50
90
Young

0 60
0 50 100 0 50 100 40 60 80 100 120
A LV volume (ml) LV volume (ml) B LV EDV
Figure 7-4 Graphs showing the relationship between left ventricular (LV) pressure and volume. A, Pressure-volume loops from a 19-year-old man (Young)
and an 87-year-old woman (Elderly) show increases in ventricular elastance or stiffness (Ees, solid line) that match increases in arterial elastance or stiffness
(Ea, dashed line). Ea and Ees are normally equal in absolute magnitude, which yields optimal and efficient matching of the heart and artery. However, the
elderly patient shows marked increases in both Ea and Ees (arterial and ventricular stiffening). The change in loop shape in the elderly patient reflects stiff
arteries with a wider pulse pressure. B, As is shown by plotting systolic pressure versus LV end diastolic volume (EDV), the diastolic pressure-volume rela-
tionship also becomes steeper in the elderly patient. Ea, Ees, and diastolic stiffness increase with age and correlate with one another.22 Patients with
decreased arterial compliance (Ea) show increased ventricular stiffness (Ees), which has important implications for blood pressure lability and loading sen-
sitivity. These findings help explain heart failure with preserved ejection fraction.68,69 (From Kass DA: Ventricular arterial stiffening: Integrating the pathophysi-
ology. Hypertension 2005 Jul;46:185–193.)
 Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction 79

feature of both systolic and diastolic dysfunction.63 Increased 30

Average LA filling pressure (mmHg)

filling pressure is not specifically representative of either systolic or
diastolic dysfunction64 but is a potent marker of evolution toward 25
overt CHF and hospitalization.65 Diastolic filling pressure reflects
20 Atrial volume and
the load-dependent changes in chamber stiffness, with diastolic pressure begin to exceed
dysfunction uniformly occurring before or coincident with overt the LA and pulmonary vein
systolic dysfunction.63 The decrease in cyclic adenosine mono- 15 reservoir capacity
phosphate needed to impair diastolic relaxation is much smaller
than is required to impair contractility. Abnormal diastolic dys- 10
function is thus an earlier and more sensitive marker of a deficient
energy state in HF than are abnormalities of systolic perfor- 5
Normal LA enlargement
mance.66 For example, if EF is greater than 45%, it does not further
0
contribute to assessment of CV risk in patients with HF.26 The
principal determinant of HF risk is the inability of the ventricle to 16 28 40
properly fill during diastole (i.e., inability to “prime the pump”). LA volume index (ml/m2)
Figure 7-5 Graph showing the relationship of left atrial (LA) size (LA
volume index) to average filling pressure. Pressure overload of the left
Noninvasive Assessment atrium is present if the medial mitral annular tissue Doppler E′ velocity falls
The easiest and most reproducible noninvasive measure of filling below 10 cm/sec (i.e., abnormal myocardial relaxation) and the atrial
volume exceeds 28 ml/m2 (i.e., increased atrial wall tension). The cumula-
pressure elevation is the ratio of early diastolic transmitral inflow tive burden of increased volume and/or pressure overload is related to the
velocity (E) to E′ (Doppler E/E′ ratio).32,36,37,67–69 The E/E′ ratio magnitude of atrial enlargement. The atrial volume remodels slowly and
has been well correlated with invasive measures of LV filling pres- best reflects burden. Filling pressure at the time of examination (intensity)
sure and pulmonary capillary wedge pressure.36,67,68 The ratio is best reflected in the E/E′ ratio, whereas atrial enlargement due to pres-
depicts the relationship between dynamic changes in LA pressure sure overload reflects the chronicity or average burden of increased LA
filling pressure. Conversely, atrial enlargement with a normal E′ velocity
and LV compliance. As LA pressure increases, E increases, depict- is consistent with “benign” isolated atrial volume overload, as seen in
ing the increased pressure gradient between atrium and ventricle. athletes, chronic disease, and anemia.
Conversely, myocardial relaxation, as depicted by tissue Doppler
E′ velocity of the mitral annulus, is unchanging and relatively
unaffected by loading dynamics.31 The E/E′ ratio, which is load function.3,80 Patients with compensated systolic dysfunction have
dependent, reflects filling pressure at the time of the recording. lesser degrees of diastolic dysfunction. Conversely, patients with
An E/E′ ratio greater than 10 is highly sensitive (92%) and spe- overt CHF have higher grades of diastolic dysfunction.81 Dia-
cific (80%) for the prediction of pulmonary wedge pressure greater stolic dysfunction82,83 is not a part of “normative aging” but an
than 15 mmHg.37,70 Filling pressure is dynamic; thus, it is common age-related risk associated with the development of increased
to record a normal filling pressure at rest and an elevated filling total CV risk, including increased HF, atrial fibrillation, and mor-
pressure with exercise. E/E′ should be viewed as a measure of the tality,63,84 independent of age and sex.85
intensity of the filling pressure abnormality at the time of As advances in noninvasive methods continue to evolve,86–88
recording. reliance on invasive methods will continue to decrease.2 The inva-
Increased LA size reflects the average burden of volume or pres- sive examination remains the physiologic testing ground for
sure overload or both. Atrial volume index is the preferred means understanding instantaneous physiology. However, the Doppler
of expressing atrial size because the atria enlarge asymmetrically echocardiographic examination, although not ideal, is now the
and in direct relationship to the body surface area. Atrial enlarge- gold standard for clinical assessment of diastolic function and
ment because of abnormal pressure overload is substantiated by physiologic CV burden, in addition to complementing CV
the coexistence of abnormal tissue relaxation (i.e., low E′ velocity) research.68,89
(Fig. 7-5); conversely, atrial enlargement because of benign volume
overload is associated with a normal Doppler E′ velocity. LA
volume index increases slowly and changes little with acute pres- NORMAL DIASTOLIC MYOCARDIAL PHYSIOLOGY
sure or volume overload.71,72 Indexing LA volume to body surface
area accounts for plasma volume throughout life.73–75 During LV contraction, potential energy is normally stored as the
LA volume index best reflects “chronicity,” or average filling myocytes are compressed and the elastic elements in the LV wall
pressure, and the E/E′ ratio best reflects the “intensity” of filling are compressed and twisted.6,90,91 Relaxation of the myocardial
pressure elevation at the time of the recording.76–78 For example, contraction allows this potential energy to be released as the
persons with chronic, yet intermittent, elevation of filling pressure elastic elements recoil.6,92 The release of wall tension (potential
(increased LA volume index and abnormal E′) can have a normal energy) is normally rapid enough to cause the LV pressure to
E/E′ at rest and an abnormal E/E′ with exertion. Clinical outcome decrease despite an increase in LV volume (see Fig. 7-1).93
is more strongly related to the average burden of filling pressure Although there is a relative decrease in early diastolic enhanced
elevation as reflected in the atrial volume79 and not the resting LV relaxation and elastic recoil from tachycardia and adrenergic
grade of diastolic dysfunction.34 stimulation during exercise,94–97 LA pressure does not increase to
an abnormal level.98–101 Neither an increase in atrial pressure nor
more vigorous atrial contraction contributes to the increased
Comprehensive Diastolic Function Assessment mitral valve pressure gradient and resulting increase in dV/dtmax
The pressure-volume loop and tissue Doppler echocardiography that occurs during exercise.93 The intraventricular pressure gradi-
both demonstrate the close link between systolic and diastolic ent is greater in normal subjects than in patients with HF.102,103
80 Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction

In order for LV contraction to release the store of elastic potential Left Atrial Pressure and Left Ventricular Suction
energy, LV volume must decrease below a critical value during
contraction. The minimum end systolic volume required to gener- The ability to dynamically decrease early LV filling pressure is
ate suction equals the equilibrium volume, the volume of the fully particularly important in response to stress, which allows an
relaxed ventricle at zero pressure.97 If either the equilibrium increase in LV stroke volume without an appreciable increase in
volume decreases or the end systolic volume increases, the ven- LA pressure.95,97,106,108–114 Diastolic intraventricular pressure gra-
tricle will be unable to release potential energy capable of suction- dients are the result of the interaction of inertial (local) and con-
ing blood into the ventricle.91,97,104 Other determinants of suction vective forces caused by unsteady intracardiac flow and pressure
are the time constant of LV relaxation105 and the degree of large- distribution.102 Inertial forces are caused by the impulse (potential
scale LV torsion and twist.91 pressure) developed by myocardial restoring forces related to the
inotropic state (LV contraction and the creation of potential
energy).97,115 Convective deceleration is determined by spatial-
Temporal-Spatial Pressure and Flow: Suction of temporal filling flow velocity and, most particularly, the presence
of a normal cone-shaped ventricular geometry (see Fig.
Blood into the Left Ventricle 7-6A).116
Peak flow across the mitral valve normally equals or exceeds the When the mitral valve opens and blood is normally sucked into
peak flow rate across the aortic valve. The rapid movement of the left ventricle, the gradient between that ventricle and the left
blood from the left atrium into the left ventricle in early diastole atrium begins to decrease, and flow ultimately stops or transiently
is due to a pressure gradient from the left atrium all the way to reverses when these pressures equilibrate. Under normal circum-
the LV apex (Fig. 7-6A).102 Ventricular filling is thus primed by stances, relaxation is completed during rapid filling as the LV
a rapidly developing pressure envelope extending between the left pressure attains its near minimum.58,117 More than two thirds
atrium (highest pressure) and the LV apex (lowest pressure).106 of the LV stroke volume normally enters the left ventricle during
As a consequence of the early diastolic intraventricular this earliest phase of diastole. The time of pressure deceleration
gradient between the left atrium and ventricular apex, blood is is determined by normal vigorous suction (active force) or by
virtually “sucked” into the left ventricle. Suction is initiated “stiff ” noncompliant LV muscle (passive force) associated with
during isovolumic ventricular relaxation and continues during disease states.118–120 The normal response to stress is an increase
early rapid filling.105 The lower the early diastolic LV pressure, the in the gradient between the left atrium and the LV apex.102 β-
greater the suction, which allows the heart to function at lower adrenergic stimulation increases contractility, myocardial restor-
LA pressure.95,107 Diastolic suction contributes to filling more ing forces, and the resulting enhanced ventricular suction.97,110,115
than one order of magnitude greater than does passive atrial Increased diastolic suction facilitates rapid filling and lowers
decompression.105 minimum LV pressure.108,113 Enhanced diastolic suction acts as a

A B C
Figure 7-6 Diagrams of diastolic left ventricular (LV) filling. The relative spacing and shape of the dots reflect pressure (widely spaced = low pressure) and
velocity (elongated = fast). A, In the normal heart, recoil of elastic elements produces a pressure gradient from the LV apex (lowest pressure) to the left
atrium (higher pressure). This results in acceleration (suction) of blood out of the left atrium, which produces rapid diastolic filling that quickly propagates
to the LV apex. The release of diastolic wall tension (potential energy) is normally rapid enough to cause the LV pressure to decrease despite an increase
in LV volume.97 B, Dilated, ischemic, and hypertrophic cardiomyopathy typically contribute to heart failure. The normal intraventricular diastolic pressure
gradient, which sucks blood from the left atrium into the left ventricle, is disturbed. The dilated, hypocontractile, or geometrically abnormal left ventricle
produces a lower intraventricular pressure gradient in early diastole as a result of decreased elastic recoil and increased convective deceleration (i.e.,
decreased blood velocity with respect to distance). The pressure envelope in early diastole becomes dispersed, decreasing the pressure gradient between
the left atrium and the left ventricle.106 The left atrium enlarges in response to increased filling pressure. Early forward flow from the pulmonary veins is
commonly replaced by flow and pressure reversal in late diastole (arrows). C, Heart failure with preserved systolic function and a normal-sized left ventricle
more commonly occurs in older persons, often in the absence of apparent clinical CV disease. The increased filling pressure (often due to arterial-ventricular
stiffening) is transmitted backward from the aorta to the left ventricle, impeding the efficient transit of blood from the left atrium to the left ventricle. The
increased filling pressure is transmitted backward to the left atrium causing LA enlargement and increased pulmonary venous pressure.34 Early forward
flow from the pulmonary veins (large arrows) is commonly replaced by reversal of flow and pressure into the pulmonary veins (small arrows) in late
diastole.
 Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction 81

compensatory mechanism to maintain low pulmonary venous butes of invasive and noninvasive cardiac and vascular physiology
and arterial pressure in situations of increased contractility.102 used in the assessment and understanding of diastolic and systolic
The gradient between the left atrium and the LV apex is deter- function.
mined by inertial acceleration (elastic recoil) and convective decel- Symptoms of CHF are strongly related to the elevation of
eration (chamber geometry) of blood.102 Inertial acceleration is filling pressure, which accounts for breathlessness, exercise intol-
the change in velocity with respect to time, and convective decel- erance, and reduced quality of life.133,137–139 CV dysfunction
eration is proportional to the decrease in velocity with respect to leading to elevation of filling pressure and the clustering of adverse
distance.121 Convective deceleration is increased when the dis- events can be broadly grouped as a consequence of either altered
tance or architecture of the left ventricle is altered and intraven- cardiomyocyte function accompanied by distorted ventricular
tricular blood flow is diverted away from the longitudinal axis of geometry81,140 or abnormal cardiac loading, which most com-
the left ventricle. An increase in convective deceleration caused by monly begins as a consequence of extracardiac stiffening of the
altered ventricular geometry thus decreases the normal gradient conduit arterial system (see Fig. 7-2).54,81,133,137,140–142
between the left atrium and the LV apex (see Fig. 7-6). Diastolic disorders from cardiomyocyte dysfunction include
Late in diastole, atrial contraction produces a second LA-to-LV dilated cardiomyopathy, hypertrophic cardiomyopathy, and isch-
pressure gradient that again propels blood into the left ventricle. emic heart disease. Diastolic disorders beginning with increased
After atrial systole, as the left atrium relaxes, its pressure drops pressure loading are most commonly ascribed to increased
below LV pressure, which initiates closure of the mitral valve. The pulse pressure and central systolic blood pressure (i.e.,
onset of ventricular systole produces a rapid increase in LV pres- hypertension).141,143–145
sure that seals the mitral valve and ends diastole. Energy-dependent myocardial relaxation (diastolic function) is
metabolically more vulnerable than systolic contraction. Resis-
tance to ventricular filling reflects pressure backward into the atria
CLINICAL RELEVANCE and the pulmonary veins during diastole when the atria and ven-
tricles are directly exposed to each other. As the volume in the
A thorough understanding of normal and abnormal myocardial atrium and pulmonary vein increases, their combined reservoir
physiology is vital to the determination of cause and effect. CHF capacity is ultimately exceeded. The dynamics of the left atrium
and the clustering of associated risk factors cannot be assumed to and pulmonary veins undergo a transition from physiologic
represent cause and effect. Although risk factors modify and volume overload to abnormal pressure overload (see Fig. 7-5). The
enhance the severity of the physiologic condition, most risk events, transition from a state of benign atrial volume overload to pres-
such as CHF, atrial fibrillation, and stroke, are best viewed as sure overload is commonly slow and intermittent. The transition
consequences and not causes. In particular, age-associated CV to a pressure overload state is clinically more apparent with stress
disease appears to have a common physiologic basis, which best intolerance and acute congestive symptoms after a stressful trigger
accounts for the clustering of common adverse events.83,85,122 (e.g., illness, surgery, infarction). Stress-induced increase in atrial
pressure accounts for breathlessness and exercise intolerance. Sus-
tained increase in pulmonary venous pressure accounts for symp-
Epidemic of Diastolic Heart Failure toms ascribed to the syndrome of CHF.
As the world’s population has increased, the average life expec-
tancy has also increased by approximately 3 months per year since
1840.123,124 This fact best accounts for the existence of an artifac- Myocardial Disease and Diastolic Dysfunction
tual age-associated global epidemic of CV risk.5,125,126 HF is the Abnormal suction of blood into the left ventricle has been repli-
most common indication for hospitalization of older persons. cated with various HF models,91,108 such as myocardial isch-
However, it is also well known that at least 50% of patients with emia114,146,147 and hypertrophic cardiomyopathy (see Fig. 7-6B).148
CHF have a normal EF,127–131 and two studies report that more Any condition that interferes with normal regional systolic func-
than 70% of older patients with symptomatic HF have a normal tion might be expected to modify the pattern of the normal early
EF and fit the diagnosis of DHF.131,132 In addition, more than half diastolic intraventricular pressure gradients.147 With LV muscle
of patients with CHF are relatively asymptomatic, which contrib- disease, the end diastolic pressure-volume curve is shifted sub-
utes to a substantial underestimation of the true incidence of HF, stantially to the right, and the diastolic pressure curve is shifted
particularly in older persons. However, patients with HF and upward, reflecting the increase in filling pressure (see Fig. 7-3B).6
preserved EF (i.e., DHF) have exercise intolerance,19 shortness of Abnormal LV filling dynamics are seen, along with increased LA
breath on exertion, episodes of pulmonary edema requiring hos- pressure and inability to increase stroke volume without abnor-
pitalization, and increased mortality, similar to patients with mal elevation of LA pressure. In patients with dilated cardiomy-
SHF.52,53,133–135 In general, mortality with CHF is approximately opathy, the normal pressure gradient from the left atrium to the
50% at 5 years.136 Patients with DHF tend to be older and more LV apex is substantially decreased.102 Hypertrophic cardiomyop-
likely to have a history of hypertension, atrial fibrillation, and athy is a myocardial disease with abnormal ventricular geometry
fewer symptoms, whereas patients with SHF are more likely to and preserved systolic function and is also accompanied predomi-
have a longer history of CHF, ventricular arrhythmias, and clini- nantly by abnormal diastolic function.
cal manifestations of coronary artery disease.131 Diastolic suction is disturbed because of abnormal changes in
Clinical and research emphasis is increasingly placed on the chamber geometry, which are commonly associated with uncoor-
physiology of cardiac dysfunction and not merely systolic contrac- dinated wall motion or impaired myocardial contractility. The
tility (i.e., EF). State-of-the-art noninvasive Doppler echocardio- decreased capacity to generate suction contributes to the abnor-
graphic physiology has become the standard of clinical and mal increase in filling pressure.102 Limited suction response to
investigative assessment of CV function. Thus, any discussion of stress causes LV filling pressure to increase disproportionately
CV function must incorporate the strengths and unique attri- and causes exercise-related shortness of breath.102 Decreased
82 Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction

suction shifts the pressure-volume curve toward a higher contiguous system, analogous to a conventional water pump. The
minimum diastolic pressure (see Fig. 7-3B). With dobutamine- heart is a pump delivering pulsatile flow to the arterial system.
induced stress, the gradient between the left atrium and the LV The arterial and capillary vascular system is an extensive hydraulic
apex can be demonstrated to be impaired.102 Altered geometry of filter, which converts pulsatile flow to continuous flow at the end
the ventricle impairs inertial acceleration (decreased global elastic organ. The atria and veins act as a distensible reservoir that stores
recoil) and enhances convective deceleration. Myocardial disease, blood during ventricular contraction and fills the ventricle during
associated with impaired elastic recoil and enhanced convective diastole, thus initiating the conversion of continuous flow back to
deceleration, is proportional to the magnitude of altered LV pulsatile flow. Any abnormality that interferes with efficient
geometry.118 Cardiomyopathic ventricles show abnormal suction forward-directed flow initiates deterioration in the forward and
at baseline and have a limited ability to recruit suction when backward directions to the adjoining components of the contigu-
undergoing inotropic stimulation.102 The minimum diastolic ous system.
pressure of the failing heart increases during exercise.108 The age-associated epidemic of HF appears to be principally
Although the increase in filling pressure accounts for the symp- related to an increase in arterial stiffness. Increased arterial stiff-
toms of CHF (i.e., increased filling pressure and decreased EF), it ness affects the ventricle (reverse direction) and distal arterial bed
is not directly related to the hemodynamic cause of decreased (forward direction). The concept of coupling disease54 can be
cardiac output and distorted LV geometry. Thus, simply decreas- expanded to include the interdependence of the whole CV system
ing filling pressure will decrease symptoms but will fall short of (i.e., arteries, pump, and reservoir).
eliminating the primary problem. Lasting clinical improvement
requires reversal of the LV remodeling and return of the cardiac Arterial-Ventricular Coupling
output and renal perfusion to near-normal values to prevent
It is necessary to address the interaction of the whole CV system
relapse of fluid retention and subsequent clinical deterioration.139
as a discipline in order to understand the vascular and cardiac reg-
ulatory mechanisms associated with the contiguous relationship
Arterial Stiffening and Diastolic Dysfunction of ventricular and arterial function.57 The interaction of ventricu-
Widening of the arterial pulse is common to aging and lar and arterial properties, or coupling, is an important and largely
generally reflects the stiffening or senescence of the conduit underappreciated determinant of cardiac performance.19–22,161
arteries49,54,149–151 and a dominant hemodynamic risk for cardiac Elastance is the change in pressure for a given change in volume of
dysfunction.141,152–154 In response to an increase in preload volume, the ventricle. Arterial elastance (Ea) indexed to body surface (EaI)
the increase in systolic and diastolic blood pressure is exaggerated, represents a steady-state arterial property that characterizes the
which accounts for the shortness of breath, exercise intolerance, functional properties of the arterial system (see Fig. 7-4).20 Ea is a
and hypertensive pulmonary edema seen in patients with DHF.53 lumped parameter that accounts for aortic impedance, peripheral
The blood vessels are coupled in tandem with the ventricle resistance, and arterial compliance. Ea is equal to the LV end sys-
(pump), which undergoes simultaneous systolic and diastolic tolic pressure divided by the stroke volume. Ea shares common
stiffening (see Figs. 7-3 and 7-6C).21,55 Combined stiffening alters units with elastance measures of ventricular function (Ees or Ees
how the heart-arterial system interacts at rest, but particularly indexed to body surface [EesI]); their ratio (EaI/EesI), an index of
under stress by exertional demands,54 and is particularly evident arterial-ventricular coupling,20 is inversely related to EF.162 In
in patients with CHF and preserved EF, smaller-than-normal end healthy subjects free of CV disease, EF increases by up to 30%
diastolic volume,31 and normal ventricular geometry.55 Delayed during exercise.23 However, in order for the EF to increase during
active and passive relaxation of the stiff left ventricle in early exercise, the coupling ratio, EaI/EesI, must decrease (Fig. 7-7).19
diastole disturbs the normal suction gradient between the left Studies show that with aging, the normal increase in EF during
ventricle and the left atrium. HF with preserved EF and a normal- exercise (i.e., EF reserve) becomes blunted,23,57 suggesting age-
sized and -shaped left ventricle more commonly occurs in older associated differences in the shift of coupling ratio and its compo-
persons, women,151,155–157 and obese persons81,133,137,140,142 and is nents during exercise. Suboptimal vascular-ventricular coupling
associated with a lower rate of myocardial infarction.158 helps explain the age-associated blunting of maximal exercise EF
Vascular stiffness affects CV reserve, coronary and peripheral and its underlying mechanisms.19
flow regulation, endothelial function, and mechanical signaling
and causes blood pressure lability and diastolic dysfunction. Age- Stiffening
associated ventricular systolic and diastolic stiffness occurs even Stiffening of any component of the CV system signals the dys-
in the absence of other CV disease and is thought to be the functional state to contiguous (i.e., coupled) systems. Stiffening
dominant cause of age-related HF with preserved EF.9,49,55,151,159,160 within the CV system is accompanied by changes that do not
Stiffening of arterial-ventricular function is referred to as coupling require renal disease or cardiac hypertrophy to be present.21
disease and is considered to be the principal contributor to the Patients with low arterial compliance (e.g., increased stiffness; Ea)
epidemic of age-associated CV adverse events such as HF, atrial have increased ventricular stiffening (Ees),55 which has important
fibrillation, stroke, and cognitive dysfunction.54 implications regarding blood pressure lability and loading sensi-
tivity. To maintain optimal interaction with the stiffened arterial
Physiologic Coupling of system, the LV itself must also develop greater systolic stiff-
the Cardiovascular System ness.21,163–166 Arterial-ventricular stiffening alters the way in which
the CV system responds to stress demands and changes in volume
Reservoir, Pump, and Arteries and pressure loading.54 The physiologic changes of increased stiff-
The concept of “continuity disease” has been proposed to describe ness are associated with decreased exertional capacity, which
the relationship and shared physiology between the arteries and contributes to the clinical complex of CHF with preserved
the rest of the CV system.54 The CV system is best viewed as a systolic EF.48
 Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction 83

90 0.7

85 <40 yr 0.6

80 0.5

Eal/Eesl
EF (%)
75 >60 yr 0.4
>60 yr
70 0.3

65 0.2 <40 yr

60 0.1
A Supine Sit 50% max Max B Supine Sit 50% max Max

3.2 30
3.0 >60 yr
25 <40 yr
<40 yr
2.8 >60 yr 20
2.6

Eesl
Eal

15 <40 yr
2.4 <40 yr
10 >60 yr
2.2
2.0 5

1.8 0
C Supine Sit 50% max Max D Supine Sit 50% max Max
Figure 7-7 Comparison of ejection fraction (EF), ventricular-vascular coupling index (EaI/EesI), arterial elastance index (EaI), and ventricular elastance index
(EesI) by analysis of variance. Men aged <40 years (red circles) and >60 years (yellow squares) and women aged <40 years (blue circles) and >60 years (green
squares) were compared at rest (Supine Sit) and at half-maximal (50% max) and maximal (Max) exercise capacities. A, The EF is augmented with exercise
in both age groups and sexes. B, Correspondingly, the EaI/EesI (i.e., the inverse of EF) decreases in both age groups and sexes. In both men and women, the
decrease in EaI/EesI ratio at maximal exercise is greater (improved function) in younger than in older subjects. C, At maximal exercise, EaI is greater in older
women (stiffer arteries) than in younger women, even though heart rate, which is a determinant of EaI, is greater at peak exercise in younger versus older
women. In contrast, there is no difference in the EaI between the two age groups in men, even though heart rate is also significantly higher in younger
than in older men at peak exercise. D, EesI increases with exercise in both age groups and sexes. At maximal exercise, EesI is greater (better) in younger men
than in older men and is slightly greater in younger women than in older women. These results show that EF increase in older persons is blunted and
associated with less corresponding decrease in the ventricular-vascular index with exercise. With aging, women show a smaller decrease in both arterial
(Ea) and ventricular (Ees) elastance than men. However, both men and women show similar blunting in EF augmentation and decrease in EaI/EesI ratio with
aging. Increased stiffness (lower compliance) of the ventricular myocardium accounts for age-associated delay in myocardial relaxation, increased filling
pressure, and atrial enlargement, which contribute to the onset of adverse cardiovascular events. (From Najjar SS et al: Age and gender affect ventricular-
vascular coupling during aerobic exercise. J Am Coll Cardiol 2004;44:611–617.)

Diastole and Stiffness pressure is directly related to the primary hemodynamic abnor-
mality. In these patients, an absolute change in LV filling pressure
Cardiac relaxation is delayed when the heart (pump) is exposed and cardiac output are potent predictors of clinical outcome.
to increased systolic pressure during ejection (i.e., increased after- Intravascular volume depletion should be avoided, and therapy
load), as occurs with vascular stiffening or enhanced systemic should concentrate on blood pressure reduction with vasodilators
resistance.54,58 Ejecting into a stiff thoracic aorta decreases total that affect the renin-angiotensin-aldosterone system and sympa-
compliance and substantially increases pulse pressure.167 Arterial- thetic nervous system.138,139
ventricular stiffening changes the mechanical forces to which the
endothelial cells and arterial smooth muscles are exposed. These
mechanical forces have key roles in regulating wall tone, athero-
genesis, angiogenesis, and other features of vascular hemostasis. Forward Dysfunction: End-Organ and
Cardiac maladaptations such as hypertrophy and increased ven- Microvascular Damage
tricular Ees make the net effects of vascular stiffening even worse,
particularly from the standpoint of net CV reserve, blood pres-
End-Organ Pulsatility
sure regulation, and blood volume distribution.54 Coupling A complex network of small arteries and arterioles represents the
between altered systems helps explain the cause-and-effect physi- resistance vasculature. Increased vascular capillary resistance may
ologic manifestations observed in many CV disease states.143 result from decreased lumen diameter, a longer vessel length, or
Severe cardiac dysfunction can occur in spite of normal LV con- rarefaction (decreased number of vessels connected in paral-
tractility (i.e., EF) and geometry.168 lel).144,149 High resistance at the capillary level decreases both
In patients with LV diastolic dysfunction and preserved EF pulsatile flow and steady flow, resulting in a steady blood flow
caused by arterial stiffening, the abnormal increase in LV filling through resistance vessels and tissue. Arterial pulsations, which
84 Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction

cannot enter the high-resistance vessels, are reflected backward artery pulsations are normally transmitted through the pulmo-
and summate with the pressure of the approaching waves. The nary capillaries to the left atrium.15,16,178
distribution of these phenomena is not identical along the arterial The notable feature of the kidney and brain, compared with
tree and differs according to age, anatomy, and physiology of the the heart, is that they are continually and passively perfused at
vascular bed in question.144 In elderly people, increased vascular high-volume flow throughout both systole and diastole,145 whereas
stiffness and higher systolic blood pressure and pulse pressure the heart is perfused principally during diastole. The vascular
increase arterial pulsatility closer to the end organ, which favors capillary resistance in these organs is very low, so that in compari-
end-organ damage, particularly in the heart, brain, and son with other vascular beds, resistance is closer to input and
kidneys.144 characteristic impedance. Wave reflections from the brain and
Pressure pulsatility has major effects on microvascular struc- kidney are very low, and pulsatile pressure and flow extend well
ture and function. Deleterious effects on vascular reactivity and into these organs, similar to the lungs.15,16 The brain and kidneys
end-organ function are amplified in the setting of increased arte- thus literally “throb” with each beat of the heart.145
rial stiffness and elevated pulse pressure. Reduced regional Whereas other organs are protected by relatively intense vaso-
vascular resistance can diminish the decrease in pressure in the constriction upstream, the brain and kidneys are susceptible to
precapillary arterioles and expose the capillaries to potentially influences upstream that can increase fluctuations in flow and
harmful levels of pressure pulsatility.169 If changes in the relation- pressure and contribute to age-associated end-organ or microvas-
ship between mean arterial pressure and flow involve microvascu- cular damage.179–181 As with the lungs, exposure of the small
lar structural remodeling or rarefaction, as opposed to a reversible vessels of the brain and kidneys to highly pulsatile pressure and
change in microvascular tone, impaired responsiveness to meta- flow can explain microvascular damage151 and the resulting cogni-
bolic demand may result, causing altered autoregulatory flow tive and renal dysfunction commonly encountered in the aging
modulation.170 population.145

Heart and Coronary Perfusion Vascular Stiffening: Summary

Coronary circulation is autoregulated but with two particulari- Age-associated vascular stiffening increases systolic blood pres-
ties.144,171 First, because of nearly exclusive coronary perfusion sure and pulse pressure. Pulsatile forces acting on large and small
during diastole, perfusion pressures are determined by diastolic arteries, down to the microvessels, contribute substantially to
blood pressure and not mean arterial pressure. Flow into the coro- increased CV risk and selective end-organ damage in addition to
nary arteries during systole is caused entirely by passive distention diastolic dysfunction.179,182
of the epicardial arteries.172 Second, as arterial stiffness increases
in association with systolic hypertension, atherosclerosis, or both, Reverse Continuity Disease (Aorta to Coronary
aortic branches with decreased lumen diameter and shorter height
cause the arterial pressure reflections to arrive in the aortic root Artery, Ventricle, and Atrial Reservoir)
in late systole, rather than in diastole. The consequence is systolic The age-associated increase in arterial stiffness is not explained
pressure summation closer to the aortic valve, which impairs dia- on the basis of vascular disease such as atherosclerosis, which is
stolic coronary perfusion.21,151,161,173 Age-associated increase in commonly encountered in older persons; instead, the most unify-
arterial vascular stiffness thus contributes to decreased coronary ing feature is that of major conduit vessels becoming larger and
perfusion and secondary myocardial dysfunction, which begins as physiologically stiffer.144 Stiffening of the vascular system causes
an abnormality in diastolic function (elevation of filling pres- an increase in systolic blood pressure due to reflected pulse
sure).36 The ensuing alteration in myocardial relaxation causes a waves.144 Antegrade energy is “reflected” backward, with the inci-
measurable increase in ventricular stiffness (decreases active and dent and reflected waves summating. Summated pressure pro-
passive relaxation), initiating a cascade of physiologic and struc- gressively increases the afterload in the aortic root, coronary
tural changes, which lower the threshold for the occurrence of arteries, ventricle, and atrial reservoir.
adverse CV events.
Coronary Perfusion
Brain and Kidney A stiff aorta causes pressure reflections to arrive more rapidly and
Mean arterial blood pressure normally decreases by less than reach the aortic root in late systole, instead of in diastole as they
1 mmHg between the ascending aorta and a peripheral artery normally do, thus impairing coronary perfusion. The coronary
such as the cerebral and renal arteries.145,174,175 Exposure of small ischemia causes altered Ca2+ regulation, which appears to have a
vessels to highly pulsatile arterial pressure and flow can explain fundamental role in diverse age-associated diseases and associated
microvascular damage and can result in stroke and cognitive dys- increased cardiac stiffness.57,183 With age, mitochondrial seques-
function,145,176 as well as renal insufficiency.177 Normally pulsatile tration of Ca2+ decreases, release of Ca2+ from stores is greatly
arterial energy is restricted to the major arteries and is absorbed enhanced, and extrusion of intracellular Ca2+ is diminished. These
in these vessels as a consequence of blood and arterial wall elas- changes delay the myocyte transition from a contracted to a
tance. However, the renal, brain, lung, and coronary beds are dif- relaxed state. Thus, when the atrioventricular valve opens, the
ferent from all other vascular beds.145 The brain and myocardium atrium is confronted with a variable degree of increased ventricu-
receive (relatively) torrential flow at rest to sustain sensitive brain lar myocardial stiffness and filling pressure.
cells and maintain cardiac function, respectively. The heart pul- After age 50, aortic diastolic blood pressure and coronary
sates because it fills and empties, but the brain and kidneys also artery perfusion tend to decrease, whereas systolic blood pressure
pulsate because of the high pulsatile flow into and within these and pulse pressure increase.184 For example, increased central
organs. The lungs also pulsate in a similar manner, and pulmonary pulse pressure is superior to peripheral pulse pressure in the pre-
 Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction 85

diction of myocardial infarction.182 Conduit arterial physiology ture (rarefaction) and surrounding tissue (tissue fibrosis). End-
and morphology have strong relationships to age-associated organ perfusion is particularly vulnerable to diastolic hypotension
decrease in coronary perfusion, which in turn can account for the and volume depletion. The natural history of CV dysfunction
delay in myocyte relaxation and increase in filling pressure. “forward continuity disease” revolves around end-organ damage,
which is most evident in the heart, kidney, and brain.
Ventricular and Atrial Reservoir Stiffness
Age- or disease-associated increase in vascular stiffening and arte- CLUSTERING OF CARDIOVASCULAR RISK
rial afterload cause ventricular systolic and diastolic stiffening.
The induced cascade of altered filling dynamics is typified by Is is apparent that CV dysfunction potentiates the development
abnormal myocardial relaxation and increased filling pressure. of adverse CV events. Heart failure (cause: altered myocardial
The atrial appendage and pulmonary veins are normally three geometry and/or ventricular stiffening), atrial fibrillation (cause:
to four times more distensible than the body of the atrium.185,186 atrial stretch, cell death, fibrosis, and electrical heterogeneity),
Distensibility of the atrium plays a major role in normal cardiac cognitive and renal dysfunction (cause: microvascular end-organ
function. Increased atrial distensibility benefits cardiac hemody- damage), and stroke (cause: atrial stretch/dysfunction, reduced
namics and increasing cardiac output187 through augmented atrial circulating nitroso products, increased thrombosis) all “cluster”
reservoir function.188 An increase in atrial distensibility prevents around age- and disease-associated CV dysfunction. Today, CV
an increase in atrial pressure.189 Thus, a highly compliant left investigators are much closer to a physiologic understanding of a
atrium, with large reservoir capacity, low pressure during atrial common causal relationship among these diverse yet interrelated,
filling, and relatively high mean atrial pressure during ventricular commonly age-associated, adverse CV events.
filling, best maintains ventricular hemodynamics.187
A stiff ventricle and increased filling pressure is reflected back- Diastolic Heart Failure with Normal Ejection
ward into the atrial reservoir. During ventricular diastole, the atrium
Fraction and Systolic Heart Failure:
and ventricle are directly exposed to each other, and any increase in
filling pressure is reflected backward, causing atrial and pulmonary Pathophysiologic Subgroups
vein walls to become stretched. The normal reservoir capacity and Although HF with normal EF is commonly thought to be the
distensibility of the atrium and pulmonary veins can become result of a single hemodynamic mechanism, data indicate that
exceeded.190 Atrial pressure overload causes atrial myocyte stretch, subgroups exist with distinctly different underlying pathophysi-
upregulation of the local renin-angiotensin system, cell death, and ologies.159,195 Diastolic dysfunction refers to mechanical and func-
collagen deposition.78,88,191–193 A stiff, noncompliant atrial reservoir tional abnormalities present during relaxation and filling, which
has decreased capacity to store blood during ventricular systole and is usually associated with concentric hypertrophy. DHF refers to
is unable to increase output on demand. In older persons, incremen- clinical syndromes in which patients with HF have little or no
tal increase of atrial volume more commonly represents the burden ventricular dilation, dominant diastolic dysfunction, and pre-
of pressure overload caused by the inability of a stiff ventricle to served EF. Systolic dysfunction refers to the decreased ability of the
efficiently receive blood during diastole.78,194 ventricle to develop tension and shorten, which generally leads to
eccentric hypertrophy.
The mechanisms leading to HF with normal EF differ among
Pulmonary Venous Stiffness and Pulmonary
patient subgroups. Subjects with preserved EF fall into two dis-
Artery Pressure Increase tinct subgroups: those who are nonhypertensive (e.g., idiopathic
The symptom of breathlessness is caused by backward transition hypertrophic cardiomyopathy, infiltrative diseases) and those who
of the increased atrial pressure into the pulmonary veins, capillar- are hypertensive.159 Subjects in the nonhypertensive group have an
ies, and arteries.15,16 Dyspnea is typically caused by an increase in upward or leftward shift of the end diastolic pressure-volume
either pulmonary interstitial fluid17 or physiologic dead space.18 curve, indicative of passive diastolic dysfunction and the classical
The stiff hypertrophied LV, coupled with increased LA and pul- paradigm of DHF. The LV chamber is normal or smaller than
monary venous pressures, produces shortness of breath.17,18 As normal and hypertrophied. The hypertensive group also has an
the resistance to forward flow increases, variable resting or exercise- increase in LV mass and in LV end diastolic volume and a normal
induced pulmonary artery hypertension develops. or even rightward shift in the end diastolic pressure-volume rela-
tionship. Within the hypertensive subgroup of patients, some have
significantly higher than normal values of ventricular and arterial
Forward Continuity Disease (Aorta to Arteries,
elastance. The rightward shift of the pressure-volume curve may
Arterioles, and Capillaries) not always be the predominant factor contributing to HF in
Increased conduit stiffness is characterized by increased central patients with hypertension. The extracardiac factors, including
systolic pressure and decreased diastolic pressure. The systolic renal dysfunction, obesity, and anemia, among others, are specu-
pressure is augmented by pressure waves reflected from the periph- lated to account for the volume overload state. Plasma volume
ery. The increased pulsatile pressure is transmitted into the arter- overload may be an important factor contributing to HF.159
ies. The brain and kidney, which are not protected by an extensive SHF is the clinical syndrome in which patients with HF have
compliant precapillary arterial bed, are particularly vulnerable to distorted ventricular geometry, ventricular enlargement, and
pressure-induced microvascular damage and perfusion deficits. In reduced EF. Diastolic dysfunction, which is closely related to ele-
response to increased systolic pressure, the microvessels increase vation of filling pressure, is found in patients with both DHF and
their intima at the expense of the lumen (i.e., the intima-to-lumen SHF and relates most closely to symptoms of breathlessness and
ratio increases) and the normal autoregulatory function of the exercise intolerance196 but does not accurately reflect the underly-
microvasculature. Increased pressure damages the microvascula- ing pathophysiology or HF phenotype.195,197 DHF and SHF
86 Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction

share many clinical and hemodynamic features but are increas- FUTURE RESEARCH
ingly recognized to be caused by different pathophysiologic mech-
anisms.195,197 LV systolic performance (stroke work), function Diastolic function assessment by invasive2 and/or noninvasive
(EF), and contractility (dP/dt, stress vs. shortening and ventricu- means is plagued by ambiguities surrounding the dynamic nature,
lar elastance) are not significantly different in patients with DHF lack of directness, and difficulty of reproducibly measuring ever-
and in normal controls.168 SHF is characterized by eccentric changing diastolic function. Advances in noninvasive methods
hypertrophy, progressive LV dilation, and abnormal systolic prop- continue to erode the need for invasive validation. The invasive
erties. DHF exhibits concentric hypertrophy, normal or reduced examination remains the physiologic “testing ground” for under-
LV volume, concentric remodeling, and abnormal diastolic func- standing instantaneous physiology. However, the Doppler echo-
tion (i.e., reduced LV long-axis shortening,198 decreased tissue cardiographic examination is now the gold standard for clinical
Doppler myocardial systolic velocity,199 disturbed ventriculoarte- assessment of dynamic and chronic manifestations of diastolic
rial coupling,55 slow LV relaxation, and high LV stiffness31). function.
However, DHF and elevation of filling pressure also occur in Energy-dependent diastolic relaxation is more vulnerable to
patients with SHF in whom diastolic abnormalities correlate dysfunction than is systolic contraction. Thus, diastolic dysfunc-
better with symptoms than with LV EF.196 tion is expectedly found with both systolic and diastolic cardiac
The most striking difference between SHF and DHF is the dysfunction. Understanding of the complexities and redundancies
tendency of the end diastolic volume to increase in SHF. Cardio- of the CV system is being translated into clinical practice. Forward
myocyte diameter is larger in DHF, and collagen volume is larger and reverse coupling, CV stiffness, risk factor clustering, elastance,
in DHF but increases similarly in SHF and DHF as fibrosis distensibility, and other terms are becoming incorporated into the
progresses.195 The excess cardiomyocyte hypertrophy in DHF is vernacular of the “echophysiologist.” The future of CV medicine
strongly related to a history of arterial hypertension, which in one hinges on the acquisition and understanding of the physiologic
study was present in 73% of DHF patients and only 13% of SHF model(s) of disease. Filling pressure, myocyte contraction and
patients.195 This distinction, which can be attributed to activation relaxation, and spatial-temporal event recording are increasingly
of different proliferative signaling mechanisms, has important viewed as the keys to determining systolic and diastolic function
implications, because therapy that improves prognosis of SHF and the development of primary prevention and physiologic treat-
may not slow progression in DHF.197 ment scenarios.
Evidence suggests that cardiomyocytes in SHF and DHF
express different gene products. Van Heerebeek et al.195 described
an abnormal distribution of titin isoforms in the hearts of patients
with these two clinical syndromes. Titin is a huge cytoskeletal GLOSSARY
protein found in the cardiomyocyte. Mammalian hearts contain
either or both of two titin isoforms, N2BA and N2B.200 A key Terms
difference is that the N2B isoform is stiffer than the N2BA Clustering:
isoform. N2B tends to predominate in stiffer ventricles, whereas Common risk factors attributed to cause diastolic dysfunction
N2BA occurs in more compliant hearts. The less stiff N2BA cluster around one another, which suggests the existence of a
isoform has been reported in human dilated cardiomyopathy,201 common underlying physiologic perturbation.
and the stiffer N2B is more prominent in DHF with high dia- Continuity disease:
stolic stiffness.195 The cardiomyocyte stiffness observed in DHF Dysfunction in one component of the cardiovascular system
could be attributed to the titin isoform shift. (arteries, ventricle, or atria) is transmitted to an adjoining
The myocardial structure and function differ in SHF and DHF system(s)
because of distinct cardiomyocyte abnormalities. Given the pro-
found differences in LV volume, mass geometry, and systolic prop- Forward continuity:
erties in patients with SHF and DHF, long-term treatment will Example: Arterial stiffening causes contiguous stiffening of the
likely be fundamentally different.168 Elevated filling pressure, distal arterial, arteriolar, and microvascular systems.
common to both SHF and DHF, best accounts for symptoms, Reverse continuity:
rather than the fundamental pathologic abnormality causing the Example: Arterial stiffening causes contiguous stiffening of
symptoms. Thus, fluid manipulation and alleviation of breathless- coronary, ventricular, atrial, and pulmonary venous functions.
ness may not adequately address the problem, which may account
for the high incidence of rehospitalization of HF patients. In Coupling disease:
patients with SHF, therapies that reverse eccentric remodeling Stiffening of the contiguous arterial-ventricular system function
(i.e., reverse remodeling) by decreasing LV volume and restoring Echophysiologist:
LV EF result in decreased morbidity and mortality.202,203 Treat- A diagnostician who uses noninvasive ultrasonography to assess
ment of DHF should be directed at reversing the cellular and and model physiologic function.
extracellular mechanisms that lead to concentric remodeling,
fibrosis, and abnormal diastolic function.168 A reversal of collagen Stiffening:
turnover—decreasing its synthesis while increasing its degrada- Increased rigidity; decreased compliance and elastance
tion—would appear to accompany pharmacologic inhibition of
angiotensin II, through the use of angiotensin-converting enzyme
inhibition and antagonism of its AT1 receptor.204 Because a high ABBREVIATIONS
percentage of patients with DHF have diabetes mellitus, collagen
cross-links formed by advanced-glycation end products205 could CHF, congestive heart failure
also contribute to increased myocardial stiffness. CV, cardiovascular
 Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction 87

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 SRIKANTH SOLA, MD
8
Evaluation of
Diastolic Function by
Cardiovascular Magnetic
Resonance Imaging
INTRODUCTION Dilated Cardiomyopathy
Constrictive Pericarditis
PRINCIPLES OF MAGNETIC RESONANCE
Restrictive Cardiomyopathy
IMAGING
Cardiac Amyloidosis
Physics of Magnetic Resonance Imaging
Cardiac Sarcoidosis
Basic Imaging Sequences
Hemochromatosis
CLINICAL RELEVANCE
LIMITATIONS OF CARDIAC MAGNETIC
Hypertropic Cardiomyopathy
RESONANCE IMAGING
Hypertension and Aortic Stenosis
Coronary Artery Disease FUTURE RESEARCH

INTRODUCTION PRINCIPLES OF MAGNETIC

RESONANCE IMAGING
Recent advances in image acquisition techniques and scanner
hardware have allowed magnetic resonance imaging (MRI) to Physics of Magnetic Resonance Imaging
become a useful tool in the noninvasive assessment of cardiovas- All atoms have nuclei that are composed of one or more protons.
cular diseases. In addition to high-resolution anatomical images, These protons have a small positive electric charge and spin at a
cardiovascular magnetic resonance (CMR) provides quantitative rapid rate. The rapid spinning motion of a positively charged
assessment of ventricular function, myocardial perfusion, viability, proton produces a very small but measurable magnetic field that
and shunt flow and measurements of valvular velocities and gra- in a sense is like a tiny bar magnet. Normally, the magnetic fields
dients.1–3 In addition, coronary, pulmonary, and systemic vascula- of these protons are randomly oriented throughout the body.
tures can be assessed with contrast-enhanced magnetic resonance When placed within an MRI scanner, the protons within the body
angiography (MRA) without the use of ionizing radiation or will align themselves with the external magnetic field of the
nephrotoxic contrast agents. CMR’s comprehensive ability to scanner, just like a compass would align itself with Earth’s mag-
image the heart also makes it a useful tool in the evaluation of netic field. By applying specific radiofrequency (RF) waves, some
diastolic function. of these protons will change their alignment (“resonate”) to a more
93
94 Chapter 8 • Evaluation of Diastolic Function by Cardiovascular Magnetic Resonance Imaging

RV RV
LV LV
LV Liver
Liver
Liver

A B C
Figure 8-1 Hypertrophic obstructive cardiomyopathy. A, Short axis spin echo image. Moving blood is black, whereas myocardium and fat have intermedi-
ate and high signal intensities, respectively. Note the prominent interventricular septum (arrow). The right ventricle is not well seen on this image. B, GRE
still-frame image at the same level. Blood is bright (white) on this image. C, DE-MRI image at the same level. Note the area of hyperenhanced (bright)
myocardium in the inferoseptal wall (arrow) near the right ventricular (RV) insertion point, which represents scarred or fibrotic tissue. LV, left ventricle.

excited state. As these protons relax and return to their original

MVO

MVC
AVO

AVC
alignment, they give off an RF signal that can be measured and
used to generate a clinical image. Since hydrogen (1H) is the most A B C D E F
abundant atom in the body capable of generating a clinically useful 140
image, 1H protons form the basis of clinical MRI. 130
120

LV cavity volume (ml)

Basic Imaging Sequences 110
MRI depends on using gradient coils within the scanner to send 100
RF pulses in specific patterns to stimulate the 1H protons within 90
the body. As these protons relax, they emit signals that are detected
80
by receiver coils placed over the surface of the body. Pulse
sequences are combinations of different types of RF pulses that 70
are placed together to create images with specific characteristics. 60
Combinations of different pulse sequences can be used to evaluate 50
parameters that define both global and regional diastolic func- 0 100 200 300 400 500 600 700
tions. These parameters include: flow mapping of the mitral valve,
pulmonary vein, and tricuspid valve; global and regional rotation; Time (msec)
translation and radial motion; peak filling rate (PFR) and time-
A: Ejection
to-peak filling rate (TPFR) of contrast; and phosphorus-31 mag- B: Isovolumic relaxation
netic resonance (31P-MR) spectroscopy to measure myocardial C: Early filling
energy content. The most common types of pulse sequences rele- D: Diastasis
vant to diastolic function are the following. E: Atrial contraction
F : Isovolumic contraction

Spin Echo or “Black Blood” Images Figure 8-2 Volume-time curve of the left ventricle during the cardiac cycle
in a 27-year-old healthy volunteer. Cine MRI, using a GrE (balanced steady-
These pulse sequences are designed so that flowing blood pro- state-free precession) technique, was used to generate a stack of short axis
duces no signal and appears black (Fig. 8-1A). However, because images encompassing the left ventricle. Planimetry of the left ventricular
(LV) endocardial border of each short axis image creates a time-volume
of the time required to stimulate and then saturate the signal curve. The onset of ejection (A), characterized by decrease in LV volume,
emitted from the flowing blood, spin echo pulse sequences coincides with aortic valve opening (AVO). At aortic valve closure (AVC), the
produce still images. Spin echo sequences can be “weighted” to minimal LV volume is obtained. The difference in volume between AVO and
highlight different relaxation properties of the protons, resulting AVC represents the stroke volume (SV). The time period between AVC and
mitral valve opening (MVO) is the isovolumic relaxation (B). At the moment
in T1 (T1w) or T2 (T2w) weighted images. Although spin echo of MVO, ventricular filling starts. This is characterized by an early, fast-filling
sequences are not used specifically to evaluate cardiac diastolic phase (C), a period with nearly no filling (diastasis, D), and a final phase of
function, they do provide good tissue contrast and anatomical filling caused by atrial contraction (E). The last part (i.e., isovolumic contrac-
detail, making them useful for visualizing morphology. tion) starts with mitral valve closure (MVC) and ends with AVO. (From
Bogaert J: Cardiac function. In Bogaert J et al (eds): Clinical Cardiac MRI.
Springer-Verlag, 2005:99–141.)
Gradient Echo or “White Blood” Images
These pulse sequences are fast enough to “catch” the signal
coming from excited blood so that blood appears white (Fig. GRE sequences yield accurate and highly reproducible mea-
8-1B). Gradient echo (GRE) sequences produce cine images with surements of ventricular volumes and indices of cardiac systolic
good temporal resolution (typically 20–30 fps; up to 70 fps for function without the need for geometric assumptions.4,5 From the
perfusion imaging). GRE sequences are used for evaluating contours describing the endocardial and epicardial borders of the
cardiac function as well as turbulent flow due to valvular disease myocardium, time-volume curves can be derived that assess global
or intracardiac shunts. diastolic function (Fig. 8-2). The peak filling rate (PFR) from
 Chapter 8 • Evaluation of Diastolic Function by Cardiovascular Magnetic Resonance Imaging 95

these curves describes the maximum change in cm2 per second using PC-MRI allows accurate assessment of peak velocities and
during the rapid filling phase of ventricular systole, whereas time volume flow of early (E) and late or atrial (A) filling waves (Fig.
to PFR is measured between end systole and the point at which 8-3), showing good correlation with Doppler-derived data.8–10
PFR occurs. Both PFR and time to PFR are typically prolonged Similar techniques are also used to map pulmonary and caval
when diastolic function is impaired.6,7 venous flow (Fig. 8-4).11 More recently, PC-MRI measurements
of tissue velocities have been used to quantify myocardial veloci-
ties, enabling calculation of local strain. Strain rate can also be
Phase Velocity or Phase Contrast Imaging quantified for regions of myocardium as well as for each myocar-
As hydrogen nuclei move through a magnetic field, they shift their dial voxel.12
particular phase (the manner in which protons rotate about a
particular axis) in a way that is proportional to their velocity.
Phase-contrast MRI (PC-MRI), which is somewhat analogous Myocardial Tagging
to pulsed-wave Doppler echocardiography, takes advantage of this A unique feature of CMR is that it allows the myocardium to be
change in phase with velocity to measure the velocity of blood magnetically labeled with a rectangular or radial grid that acts as a
moving through an area of interest. Clinically, PC-MRI is used marker of myocardial deformation during contraction (Fig. 8-5)
to calculate transvalvular velocities as well as gradients, regurgi- and also shows abnormal myocardial tagging. The creation of tags
tant volumes, and ratios of pulmonary-to-systemic blood flows requires the application of specific RF pre-pulses in one or more
(Qp/Qs). Flow mapping of mitral and tricuspid valve inflow planes perpendicular to the imaging plane, prior to the application

30
35
E 25
30
20
25
15
Velocity cm/sec
S D
Velocity cm/sec

20
A 10
15 5
10 0

–5 A
5

0 –10

–15
–5
0 85 170 255 340 425 510 595 680 765 850 935
0 100 200 300 400 500 600 700
A Time (msec)
A Time (msec)
30
25
A
25
20
20
D
Velocity cm/sec

15 15
Velocity cm/sec

S
10
10
E 5
5
0
A
0 –5

–10
0 85 170 255 340 425 510 595 680 765 850 935
0 100 200 300 400 500 600 700
B Time (msec)
B Time (msec)
Figure 8-4 Venous flow patterns using PC-MRI in a 39-year-old healthy
subject through the inferior vena cava (A) and pulmonary vein (B). In the
Figure 8-3 A, Mitral inflow pattern using PC-MRI in a 24-year-old healthy inferior vena cava, the systolic (S) forward-flow velocity is slightly larger
subject, depicting normal E/A ratio. B, Severe myocardial relaxation distur- than the diastolic (D) flow. Line A represents the reversed flow caused by
bance leading to reversal of the E/A ratio. The early filling velocities are atrial contraction. In the pulmonary vein (B), diastolic forward-flow veloci-
strongly decreased (E), whereas the late-filling velocities are increased (A). ties slightly exceed systolic forward-flow velocities. (From Bogaert J: Cardiac
(From Bogaert J: Cardiac Function. In Bogaert J et al (eds): Clinical Cardiac MRI. Function. In Bogaert J et al (eds): Clinical Cardiac MRI. Springer-Verlag,
Springer-Verlag, 2005:99–141.) 2005:99–141.)
96 Chapter 8 • Evaluation of Diastolic Function by Cardiovascular Magnetic Resonance Imaging

of RF pulses that are used for cine (bright blood) imaging.13 The evaluation of myocardial deformation in both two-dimensions and
tagging pre-pulses cause the tissue in the tag planes to be “satu- three-dimensions.21
rated” so that they appear as hypointense or black lines compared
with the normal surrounding tissue. By measuring tag displace-
ment and deformation during the cardiac cycle, myocardial defor- Delayed Hyperenhancement
mation can be analyzed, which serves as the basis for strain and In areas where the myocardium is scarred or fibrotic, there is
strain rate analysis using CMR (Fig. 8-6).14–16 Images can be delayed “wash-in” and “wash-out” of MRI contrast agents. These
obtained every 20 msec, allowing very high temporal resolution.17 fibrotic or scarred areas show up as bright or “hyperenhanced”
Clinically, myocardial tagging is used in the evaluation of diastolic areas of myocardium when “delayed” images are taken, typically
function, of abnormal myocardial deformation in patients with 10–15 minutes after injection of gadolinium-DTPA (diethylene-
hypertrophic cardiomyopathy (HCM) or complex congenital triamine penta-acetic acid) (see Fig. 8-1C). A special inversion
heart disease, and of pericardial motion in patients with suspected signal given prior to the main pulse sequence is used to “null” the
constrictive pericarditis and in the differentiation of solid struc- signal from the normal myocardium so that it can be more easily
tures (e.g., muscular tissue from tumor or thrombus).18–20 Differ- distinguished from abnormal, hyperenhanced myocardium. Spe-
ent myocardial tagging techniques are currently available that allow cific patterns of hyperenhancement correspond with certain car-
diovascular diseases and can be used to distinguish ischemic from
non-ischemic cardiomyopathy, as well as to differentiate among
different forms of infiltrative cardiomyopathies (Fig. 8-7).

RV RV Magnetic Resonance Spectroscopy

Besides 1H, other magnetic nuclei in the human body, such as
LV LV 23
Na, 13C, 19F, and 31P, can also generate MRI signals, though nor-
mally with much less intensity and under much more technically
demanding conditions. 31P-MR spectroscopy provides a profile of
A B regional adenosine triphosphate (ATP) and phosphocreatine
Figure 8-5 Myocardial tagging in a healthy individual demonstrating (PCr) contents and thus an estimate of energy status and viability
normal patterns of myocardial deformation between end diastole (A) and
end systole (B). A-wave (SRA)

E-wave (SRE)
E-wave (SRE) A-wave (SRA) 1.5
1.5
1.0
1.0
Strain rate (1/sec)
Strain rate (1/sec)

0.5
0.5
0
0
–0.5
–0.5
–1.0

–1.0 –1.5
Peak systolic
Peak systolic
strain rate (SRS)
strain rate (SRS)
5
5
0
0
Strain (%)

Strain (%)

–5 –5

–10 –10

–15 –15

–20
–20
0 200 400 600 800 1000 1200 0 200 400 600 800 1000 1200
A Time (msec) B Time (msec)
Figure 8-6 A, Representative strain rate (upper) and strain (lower) profiles from a healthy subject. Profiles were measured using tagged GrE images from
the anterior wall segment of a short axis slice at a midventricular level. The markers on the strain and strain rate traces represent the time resolution
(54 msec). B, Strain rate (upper) and strain (lower) from a person with left ventricular hypertrophy. Note the depressed SRE lower than 1.0 s−1 and the intact
systolic function. (From Edvardsen T et al: Regional diastolic dysfunction in individuals with left ventricular hypertrophy measured by tagged magnetic resonance
imaging—the Multi-Ethnic Study of Atherosclerosis (MESA). Am Heart J 2006;151:109–114.)
 Chapter 8 • Evaluation of Diastolic Function by Cardiovascular Magnetic Resonance Imaging 97

HYPERENHANCEMENT PATTERNS

Ischemic Non-ischemic

A. Subendocardial infarct A. Mid-wall HE

• Idiopathic dilated • Hypertrophic • Sarcoidosis

cardiomyopathy cardiomyopathy • Myocarditis
• Myocarditis • Right ventricular • Anderson-Fabry
pressure overload • Chagas disease
(e.g. congenital
heart disease,
pulmonary HTN)
B. Epicardial HE

B. Transmural infarct

• Sarcoidosis, myocarditis, Anderson-Fabry,

Chagas disease

C. Global endocardial HE

Figure 8-7 Hyperenhancement (HE) patterns seen in

common clinical conditions. If hyperenhancement is present,
the endocardium should be involved in patients with isch-
emic disease. Isolated midwall or epicardial hyperenhance-
ment strongly suggests a non-ischemic etiology. (From Shah
et al, in Edelman RR et al (eds): Clinical Magnetic Resonance • Amyloidosis, systemic sclerosis, post cardiac
Imaging, 3rd ed. Elsevier, 2005.) transplantation

of the myocardium.22 Myocardial relaxation is an active, energy- hypertrophied myocardium,24–26 to distinguish different forms of
dependent process, and changes in the ratio of myocardial PCr HCM,27,28 to differentiate obstructive from nonobstructive forms
and ATP levels (PCr/ATP) by 31P-MR spectroscopy are seen in of the disease,29 and to define prognosis.30,31
abnormal diastolic function.23 On a cellular level, these abnormali- Diastolic dysfunction is thought to be one of the major patho-
ties in PCr/ATP ratios are thought to result in impaired Ca2+ physiological mechanisms in patients with HCM,32 frequently
sequestration, leading to impaired relaxation in cardiac myocytes. leading to diastolic heart failure. These diagnostic abnormalities
can be evaluated using cine tagging, DE, PC-MRI, and MRI
spectroscopy sequences.
CLINICAL RELEVANCE The effect of myocardial hypertrophy on regional and global
left ventricular (LV) and right ventricular (RV) function can be
This section reviews the role of CMR in evaluating diastolic precisely characterized by MRI. Global systolic function in HCM
function in a spectrum of cardiac disorders, including HCM, is often increased with high ejection fractions and low end systolic
ischemic heart disease, constrictive pericarditis, and restrictive volumes. In the hypertrophied myocardium, however, cine tagging
cardiomyopathies. sequences demonstrate reduced or absent systolic wall thickening,
which is related to muscle disorganization (Fig. 8-8).33 Strain
analysis in these same regions show that systolic myocardial
Hypertrophic Cardiomyopathy strains are invariably decreased, with reduced longitudinal and
The characteristic finding of HCM is an inappropriate myocar- circumferential shortening.34,35 Three-dimensional CMR tagging
dial hypertrophy in the absence of an obvious cause, such as aortic demonstrates specific patterns of myocardial deformation among
stenosis or hypertension. Although transthoracic echocardiogra- the different forms of HCM, although all forms have abnormally
phy is the primary imaging modality in HCM, CMR is an excel- small circumferential curvatures in hypertrophied segments.36,37
lent alternative in the diagnosis and follow-up of patients. The Abnormal DE of the myocardium after imaging by
array of MRI sequences used in the evaluation of HCM includes gadolinium-DTPA is found in approximately 80% of patients
spin echo MRI, GRE MRI, PC-MRI, MRI tagging, delayed with HCM.38,39 Invariably, the enhancement occurs in the hyper-
enhancement (DE), and MR spectroscopy. A combination of trophied regions, with a mean volume of enhancement of 8% to
these sequences is used to identify the presence and severity of 11% of LV mass. The pattern of enhancement is usually patchy
98 Chapter 8 • Evaluation of Diastolic Function by Cardiovascular Magnetic Resonance Imaging

data demonstrate a delay and prolongation of diastolic untwist-

ing, as well as a reduction in regional strain in patients with LV
hypertrophy in comparison with normals.48,49
RV
LV
Coronary Artery Disease
Resting impairment of diastolic function is common in ischemic
heart disease. Such diastolic dysfunction precedes systolic dys-
function and occurs as the earliest sign of myocardial ischemia.
A B
Diastolic filling patterns in ischemic heart disease are often
Figure 8-8 Abnormal myocardial deformation in hypertrophied myocar- complex, reflecting regional heterogeneity of myocardial function
dium in patients with hypertrophic cardiomyopathy. Short axis view of the due to different degrees of ischemia, infarction, postinfarction
heart during diastole (A) and systole (B). Note the decreased pattern of remodeling, and myocardial stunning and hibernation.
deformation in the hypertrophied anteroseptal wall of the left ventricle
(arrow) compared with the normal surrounding areas of myocardium Three-dimensional tagging by CMR is well suited to assess
during systole. these regional changes in diastolic function. In a model of post-
infarction LV remodeling, a reduction of regional strains was
observed in both the infarcted region and, to a lesser extent, the
with multiple foci, predominantly involving the middle third of remote regions.50 Diastolic untwisting tended to be nonuniform,
the ventricular wall, especially near the insertion points of the RV delayed, and prolonged in areas of both infarcted and hibernating
free walls onto the interventricular septum (see Fig. 8-1C).37 This myocardium.51 Similar changes were seen in an animal model of
pattern of enhancement is distinct from the predominantly sub- transmural ischemia,52 with restoration of the normal untwisting
endocardial distribution of hyperenhancement seen in patients motion after reperfusion. PC-MRI can be used to evaluate
with coronary artery disease. Histologically, these abnormally regional diastolic function by quantifying tissue velocities in
enhanced areas of myocardium are thought to represent scarred patients with previous myocardial infarction. PC-MRI measure-
myocardium due to microinfarction or are in relation to myocar- ments of mitral valve inflow after myocardial infarction demon-
dial disarray and consequent interstitial expansion.40 In a highly strate the typical changes in transvalvular flow patterns and closely
select group of patients with HCM, the degree of myocardial correlate with Doppler echocardiography.53
enhancement was associated with progressive disease and
increased risk for sudden cardiac death.36 It has been proposed
that the degree of diastolic dysfunction is linked to the extent of Dilated Cardiomyopathy
myocardial fibrosis quantified by DE-MRI.41 While the diagnosis of dilated cardiomyopathy can be easily made
Impaired myocardial relaxation can be identified using with transthoracic echocardiography, CMR can provide a com-
GRE-derived time-volume curves of the left ventricle, which dem- prehensive evaluation of cardiac function, myocardial stress per-
onstrate prolonged time-to-peak rapid filling and time-to-peak fusion, and viability. CMR has been shown to reliably discriminate
wall thickness thinning rates. In 31 patients with HCM, regional between ischemic and non-ischemic causes of cardiomyopathy,
prolongation of time-to-peak wall thinning rate was detected in and CMR remains the gold standard for the evaluation of LV and
segments with extensive myocardial fibrosis and decreased perfu- RV volumes, masses, ejection fractions, and viabilities.54,55
sion.42 Other MRI techniques, such as 31P-MR spectroscopy, Diastolic dysfunction is common in dilated cardiomyopathy,
demonstrate abnormal myocardial high-energy phosphate metab- and its severity is related to prognosis. The same CMR techniques
olites in both symptomatic43 and asymptomatic patients44 with previously described can be used for the comprehensive evalua-
HCM. Lower myocardial energy content is thought to contribute tion of both systolic and diastolic function in these patients—
to relaxation abnormalities in hypertrophied hearts. Finally, PC- GRE-based time-volume curves for analysis of global diastolic
MRI of flow patterns in the caval and pulmonary veins, as well as function; PC-MRI to determine inflow curves as well as tissue
the diastolic inflow in the tricuspid/mitral valves, can be used to velocities; myocardial tagging to evaluate strain and, more recently,
evaluate diastolic function, similar to echocardiography. ventricular dyssynchrony; and 31P-MR spectroscopy to determine
PCr/ATP ratios as a measure of myocardial energy content.
Hypertension and Aortic Stenosis
Chronic pressure overload in systemic hypertension and aortic Constrictive Pericarditis
stenosis leads to hypertrophy of the left ventricle, with the addi- The pericardium is well characterized by CMR because of its
tion of new sarcomeres in parallel to existing ones to normalize excellent contrast resolution and multiplanar imaging capability.
wall tension.45 Hypertrophy, coupled with a variable degree of Typically, T1- and T2-weighted spin echo, GRE, and tagged cine
altered passive elastic properties of the myocardium, leads to dia- sequences are used in patients with suspected pericardial disease
stolic dysfunction. In LV hypertrophy, changes in ventricular to evaluate cardiac function and morphology, pericardial thick-
time-volume curves, including prolonged TPFR, early-to-late ness and tethering, and the presence of ventricular interdepen-
filling ratio, and early filling percentage measured from GRE dence. In patients with acute pericarditis, T2-weighted spin echo
sequences, can be demonstrated before changes in the classical or DE images after administration of gadolinium-DTPA can be
mitral Doppler pattern.46 Other early changes include a decreased used to detect pericardial inflammation and edema.56
PCr/ATP ratio on 31P-MR spectroscopy, even before the devel- On T1-weighted spin echo images, the normal pericardium is
opment of evident LV hypertrophy.22 Later in hypertrophy, PC- most easily identified over the right ventricle and appears as a
MRI demonstrates typical changes in mitral valve inflow that are thin band of low signal intensity between the high signal intensi-
similar to the classical mitral Doppler patterns.47 CMR-tagged ties of the external pericardial fat and the internal epicardial fat
 Chapter 8 • Evaluation of Diastolic Function by Cardiovascular Magnetic Resonance Imaging 99

(Fig. 8-9). The low signal intensity of the pericardium on CMR cardial constriction due to its inability to differentiate respiratory
images is attributable to the fibrous, low proton density compo- changes in flow patterns.
nent of the pericardium in combination with a small quantity of Although a normal-thickness pericardium does not necessarily
pericardial fluid.57 The normal pericardial thickness is approxi- exclude constriction,60 irregular thickening of the pericardium is
mately 2 mm, although thicknesses of up to 4 mm are not neces- seen in up to 80% of individuals with constrictive pericarditis. A
sarily abnormal. The appearance of pericardial effusions may vary pericardial thickness of 5–6 mm has a high specificity for con-
depending on the protein and cellular content of the effusion; strictive pericarditis. Pericardial thickening is often not general-
transudative pericardial effusions appear dark on T1-weighted ized, and focal pericardial thickening in strategic locations such
spin echo images and bright on T2-weighted images due to their as the atrioventricular grooves can give rise to a full clinical picture
high water content. Exudative effusions, which have relatively of constrictive pericarditis even when the morphological abnor-
lower water content, have the opposite appearance.58 In patients malities are not that impressive. In patients with extensive fibrosis
with pericardial effusions, GRE sequences are useful to distin- or calcification, the pericardium will have low signal intensity
guish the pericardium from pericardial fluid. The latter typically (black) on T1-weighted and T2-weighted spin echo images.
has a bright appearance on GRE sequences. However, the extent of pericardial calcification or fibrosis is often
Characteristic findings of constrictive pericarditis by CMR are better depicted by computed tomography, due to the signal loss
described in Box 8-1. The classical CMR finding in patients with of calcified tissues by MRI.
constrictive pericarditis is tethering or adhesion of the parietal
pericardium to the visceral pericardium/epicardial surfaces.59
This finding is best appreciated on cine tagged sequences and Restrictive Cardiomyopathy
differs markedly from the normal free sliding motion of the pari- Diastolic dysfunction and restrictive filling patterns are common
etal pericardium over the visceral pericardium/epicardium in to all of the restrictive cardiomyopathies. By CMR, the abnormal
normal individuals (Fig. 8-10). Other techniques, such as free- diastolic function is evident on cine tagged images, PC-MRI,
breathing cine GRE sequences, can be used to evaluate ventricular ventricular time-volume curves, and 31P-MR spectroscopy using
interdependence. In patients with constrictive pericarditis, the the techniques we have described. Although it is often not feasible
interventricular septum can be seen to shift toward the left ven- to differentiate among different restrictive cardiomyopathies on
tricle during inspiration, whereas the opposite motion occurs with
expiration. The characteristic septal shift is often most prominent
on the first heart beat that follows the beginning of inspiration. Box 8-1
PC-MRI, while useful for evaluating flow patterns across the
cavae and atrioventricular valves, is less useful in evaluating peri- Characteristic Findings of Constrictive Pericarditis
by Cardiovascular Magnetic Resonance (CMR)
• Pericardial tethering
• Pericardial calcification
• Increased pericardial thickness (>4 mm)
• Tubular or conical narrowing of one or both ventricles
• Enlargement of one or both atria
• Dilatation of the vena cava and hepatic vein
• Abnormal flow across the vena cava and atrioventricular
valves on phase-contrast sequences of magnetic
resonance imaging
• Diastolic restraint
A B
• Abnormal diastolic motion
Figure 8-9 Normal pericardium in a healthy individual, four-chamber • Pericardial effusion (in patients with effusive-constrictive
view. A, The pericardium appears as a thin band of low signal intensity pericarditis)
(black) on a spin echo image. B, The pericardium appears as a band of • Pleural effusion
intermediate signal intensity (grey) on a GRE image.

RV
LV
RA

LA

A B C
Figure 8-10 Characteristic CMR findings in a patient with constrictive pericarditis. A, Four-chamber GRE image depicting the common tubular-shaped
deformity of the ventricles and atrial dilatation. Note the thickened fibrous pericardium over the right ventricular free wall (arrows) and the darker area of
calcified pericardium over the lateral wall of the left ventricle (arrowheads). B, C, Diastolic and systolic still frame from cine tagged four-chamber images
shows the characteristic tethering of the pericardium to the epicardial surface during diastole. RV, right ventricle. RA, right atrium. LV, left ventricle. LA, left
atrium.
100 Chapter 8 • Evaluation of Diastolic Function by Cardiovascular Magnetic Resonance Imaging

the basis of diastolic filling patterns alone, CMR can help to Cardiac Sarcoidosis
identify the etiology of restrictive cardiomyopathy based on its
functional and morphological characteristics. Myocardial involvement of sarcoidosis is present at autopsy in
20% to 30% of patients with this disease, although clinical involve-
ment is evident in only 5%. GRE sequences may demonstrate
Cardiac Amyloidosis normal or impaired LV systolic function, often with regional wall
Cardiac involvement is common in certain forms of systemic amy- motion abnormalities, depending on the degree of sarcoid involve-
loidosis and is a major determinant of treatment options and ment of the heart. In the early stages of sarcoidosis, the myocar-
prognosis. Several CMR findings have been described in cardiac dium may demonstrate patchy areas of high signal intensity on
amyloidosis, but the most characteristic feature of this disorder is T2-weighted black blood images due to localized inflammation,
a diffuse pattern of hyperenhancment on DE-MRI images that along with focal, patchy areas of hyperenhancement (i.e. bright)
occurs in a noncoronary distribution (Fig. 8-11). Maceira et al. that occur in a noncoronary distribution. The latter corresponds
evaluated 29 patients by CMR who had biopsy-proven systemic to areas of noncaseating granulomas that are the typical histologi-
amyloidosis and were considered to have cardiac amyloidosis on cal findings of sarcoidosis. These areas of hyperenhancement are
the basis of the presence of morphological and diastolic filling also seen in more chronic cases of cardiac sarcoidosis, along with
changes on echocardiography. They found a global subendocardial ventricular wall thinning and aneurysms, most commonly along
pattern of hyperenhancment in 20 of the 29 patients (69%) by the basal anteroseptal wall (Fig. 8-12).
CMR.61 In addition, the distribution of gadolinium-DTPA
within both the myocardium and the LV blood pool was abnor- Hemochromatosis
mally prolonged, with a modest correlation between T1
relaxation times of gadolinium-DTPA and diastolic function Initially, myocardial iron overload in patients with primary or
(r = −0.42, p = 0.025). secondary hemochromatosis is asymptomatic. There is a mild
Morphologically, the infiltration by amyloid protein results in increase in LV wall thickness and end diastolic chamber diameter.
a homogeneously increased thickness of ventricular and atrial Diastolic dysfunction usually precedes systolic dysfunction and is
walls, with occasional involvement of the papillary muscles and characterized by a restrictive filling pattern.63,64 Global systolic
valve leaflets. Ventricular cavity size is usually normal or decreased, abnormalities do not occur until the iron concentration reaches a
but the atria are usually enlarged due to the diastolic dysfunction, critical level, but then there is often a rapid deterioration in sys-
valvular dysfunction from amyloid deposition, or both. Approxi- tolic function. At the time of diagnosis, these patients typically
mately 5% to 15% of patients develop asymmetric septal hyper- have a dilated cardiomyopathy on GRE sequences, as well as evi-
trophy in combination with a systolic anterior motion of the dence of abnormal myocardial deformation on cine tagged images.
mitral valve in a pattern that may mimic HCM.62 Pleural and In addition, both the myocardium and the liver appear dark on
pericardial effusions are not infrequent. Systolic function is T2-weighted spin echo sequences due to loss of signal as a result
usually preserved or mildly impaired until late in the disease. of iron accumulation in these tissues (Fig. 8-13).

LIMITATIONS OF CARDIAC MAGNETIC

RESONANCE IMAGING

Despite its increasing robustness, important limitations still

remain in CMR imaging. The electromagnetic forces created by
the MRI scanner can induce important thermal and nonthermal
effects in some patients. Therefore, the presence of contraindica-
tions to MRI must be identified before the patient enters the
RV scanner (Table 8-1). Pacemakers and defibrillators are increas-
ingly common in the cardiac population, although these devices
RA should pose less of a hazard as experience in CMR imaging of
LV these patients increases and new, MRI-compatible devices become
available. Nonferromagnetic metallic devices, such as mechanical
LA
heart valves, sternal wires, and retained (nonlooped) pacing wires
after cardiac surgery, are safe to image, although they are often a
source of image artifact.
Patient cooperation is critical to successful cardiac imaging.
Patient movement during image acquisition can result in degraded
image quality, and uncooperative patients may require oral or
intravenous sedation to prevent unwanted motion artifacts. Mul-
tiple breath holds of 10–15 seconds each are often utilized in
adults to limit cardiac motion caused by respiration. Children and
adult patients who are unable to hold their breaths can still be
Figure 8-11 Four-chamber delayed hyperenhancement image in a patient imaged successfully, although acquisition times are often increased
with amyloidosis. The diffuse pattern of hyperenhancement in the left
ventricle is characteristic of amyloidosis and distinguishes this condition to preserve image quality. As previously noted, clinically available
from other causes of hyperenhancement, such as ischemic heart disease, PC-MRI sequences are unable to distinguish respiratory varia-
hypertrophic cardiomyopathy, and sarcoidosis. tion in flow patterns across the systemic veins or atrioventricular
 Chapter 8 • Evaluation of Diastolic Function by Cardiovascular Magnetic Resonance Imaging 101

LV LV

A B
Figure 8-12 Two-chamber (A) and midventricular short axis (B) delayed hyperenhancement images of a patient with cardiac sarcoidosis. Note the typical
patchy pattern of hyperenhancement that occurs in a noncoronary distribution. Cine GrE images (not shown) demonstrated reduced systolic function
with regional wall motion abnormalities.

RV LV RV
LV
Figure 8-13 Secondary hemochromatosis in a patient with iron overload RA
due to recurrent blood transfusions for hereditary anemia. A, Short axis LA
GrE image demonstrates the characteristic low signal over the liver due to Liver
accumulation of iron particles. B, Axial T2-weighted spin echo image dem-
onstrates the abnormally low signal intensity of the myocardium due to
iron accumulation within myocardial tissue. A B

TABLE 8-1
CONTRAINDICATIONS TO MAGNETIC RESONANCE IMAGING (MRI)
CONCERN

ABSOLUTE CONTRAINDICATIONS
Cerebral aneurysm clips May become displaced by the strong external magnetic field of the scanner, causing
severe local injury. Aneurysm clips that are “nonferromagnetic” or “weakly
ferromagnetic” are safe to image.
Implanted neural stimulator; cochlear implant; implanted Most implantable devices employ a strong internal magnet or electronic circuitry that
insulin or other drug pump can be damaged by the strong external magnetic field of the scanner.
Cardiac pacemaker or defibrillator Pacemakers/defibrillators are important contraindications to MRI due to the potential
for device malfunction. Small studies suggest that some non–pacer-dependent
patients with pacemakers can be imaged, although the devices must be
interrogated and potentially reprogrammed before and after imaging. MRI-
compatible devices are in development.
Ocular foreign body; metal shrapnel or bullet fragment Metallic foreign objects within the body can become displaced by the strong external
magnetic field of the scanner, causing severe local tissue injury.
Temporary pacemaker wires or pulmonary artery catheters Wires and catheters contain metallic tips that may become heated during MRI,
causing local tissue damage.
RELATIVE CONTRAINDICATIONS
Hearing aids Same concerns as cochlear implants; must be removed prior to entering the scanner.
Pregnancy Considerable evidence suggests that exposure to MRI is safe. However, exposure
during the first trimester, particularly to MRI contrast agents, should be avoided.
Claustrophobia Some claustrophobic patients may have difficulty within the confines of an MRI
scanner. Oral anxiolytics (e.g., alprazolam) may be useful in such patients.
102 Chapter 8 • Evaluation of Diastolic Function by Cardiovascular Magnetic Resonance Imaging

valves. Arrhythmias are problematic due to image degradation 17. Fischer SE, McKinnon GC, Scheidegger MB, et al: True myocardial motion
and make velocity assessment and flow quantification by PC- tracking. Magn Reson Med 1994;31:401–1413.
18. Hatabu H, Gefter WB, Axel L: MR imaging with spatial modulation
MRI unreliable. of magnetization in the evaluation of chronic central pulmonary thrombo-
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19. Naito H, Arisawa J, Harada K, et al: Assessment of right ventricular regional
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magnetic resonance study with presaturation myocardial tagging. Br Heart
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resolution images of the heart without the need for breath holding, 373–374.
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tions include improved software analytical tools for tagged cine CSPAMM. J Magn Reson Imaging 2002;16:320–325.
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developed, which include specific MRI-compatible catheters for 23. Lamb HJ, Beyerbacht HP, van der Laarse A, et al: Diastolic dysfunction in
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 MANUEL D. CERQUEIRA, MD
9
Evaluation of
Diastolic Function by
Radionuclide Techniques
INTRODUCTION Coronary Artery Disease
Heart Failure
PATHOPHYSIOLOGY
Hypertrophic Cardiomyopathy
Basic Principles of Radionuclide Assessment
Hypertension
of Diastolic Function
Aging
Equilibrium Radionuclide Angiocardiography
Methods in Diastolic Assessment LIMITATIONS
First Pass Radionuclide Angiography
FUTURE RESEARCH
CLINICAL RELEVANCE

INTRODUCTION similar information on diastolic function and is portable and

highly flexible, which offers practical advantages. In addition,
For over 30 years, in the diagnosis and management of patients echocardiography provides assessment of valves, wall thickness,
with known or suspected heart disease, nuclear cardiology proce- left ventricular (LV) mass, chamber pressures, flow dynamics, and
dures have made extensive use of radioactive tracers that can be the integrity of the pericardium from the same study, which makes
injected as a bolus and tracked during first pass through the vas- it much more valuable for patient evaluation and management.
cular system, attached to red blood cells and in equilibrium within For these reasons, echocardiography has been the most practical
the vascular space or as myocardial perfusion tracers that define method for the assessment of diastolic function. Due to practical
the endocardial borders of the left ventricle.1 First pass radio- and economic factors, FPRNA and ERNA techniques are rarely
nuclide angiography (FPRNA) and equilibrium radionuclide performed in general clinical practice, and even less for evaluation
angiocardiography (ERNA) have been the most commonly used of diastolic function.
techniques capable of assessing global and regional systolic and However, many of the concepts and methods developed
diastolic function at rest and following supine or upright exercise. for diastolic function analysis for FPRNA and ERNA in the
They were used extensively in the 1970s and 1980s. The advan- 70s and 80s may be applicable today to the information available
tages of these modalities over other cardiac tests available at that from the 8 million radionuclide myocardial perfusion imag-
time included counts based on true three-dimensional measure- ing studies performed annually in the United States. Early
ments (independent of geometric assumptions), high accuracy, radionuclide perfusion imaging did not allow the assessment of
reproducibility, and absolute quantitation. However, such accu- systolic or diastolic ventricular function. In the mid-1990s,
rate measurements of diastolic function were difficult to perform several methods for assessment of systolic ventricular function
using the standard methods of acquisition, and processing in using 8 time frames in the heart cycle were developed, and recently
clinical practice and efforts to achieve greater accuracy and repro- this technique has been modified to allow greater temporal
ducibility were time consuming, computer intensive, and not sampling through 16 time frames, which can be used for the
practical in most clinical settings.2 Echocardiography provides evaluation of diastolic function.3,4 This may provide incremental
105
106 Chapter 9 • Evaluation of Diastolic Function by Radionuclide Techniques

information to the assessment of perfusion and systolic function. volumes per second (EDV/sec), and the time at which this peak
In some circumstances, diastolic dysfunction may identify pre- ejection occurs, expressed as time to peak filling rate (TPFR). For
clinical abnormalities in the absence of alterations of systolic ventricles with muscle damage or infiltration, pericardial abnor-
function. malities, or ischemia, the rate of emptying is decreased and there
Given the current limited utilization of FPRNA and ERNA is prolongation of the time when the peak emptying rate is
for assessment of diastolic function, this review will focus on the achieved. Diastole is represented to the right of end systole in
concepts and methods that have been found to be useful in the Figure 9-1 and is a much more complicated process, which con-
past and will then look at the opportunities for obtaining diastolic sists of four distinct phases:
information from radionuclide myocardial perfusion studies that
1. Isovolumic relaxation
are currently being performed in such large numbers.
2. Peak filling rate (PFR)
3. Diastasis
4. Atrial systole
PATHOPHYSIOLOGY
Isovolumic relaxation starts at end systole, is an energy-
Basic Principles of Radionuclide Assessment of dependent process, has a short duration (usually <50 msec), and
Diastolic Function ends when pressures in the left ventricle fall below the left atrial
All radionuclide approaches for assessing systolic and diastolic LV (LA) pressure, the mitral valve opens, and rapid filling begins.
function require the generation of a curve plotting the changes in PFR represents the most rapid ventricular filling and is normal-
radioactivity, which is proportional to changes in LV volume over ized to EDV/sec, which is normally greater than 2.5. Generally,
time, as shown in Figure 9-1. From this time-activity curve it has been shown to be rapid in young and healthy hearts but
(TAC), the first derivative, which measures the change in volume declines in the elderly, even in the absence of pathology.6,7 TPFR
over time, is derived and used to calculate the most rapid changes is an important measure of diastolic function and is less than 180
in ejection and filling and the time when the maximal rate occurs. milliseconds in normal ventricles. There have also been attempts
The typical ranges of normal values for these diastolic parameters to look at the percent of stroke volume filling that occurs during
in humans are shown in Box 9-1.5 the rapid filling phase as an indicator of disease. Generally, more
The left side of the curve prior to end systole (ES) in Figure than 69% of the stroke volume should fill during the rapid filling
9-1 provides information on the systolic function of the ventricle portion.
as expressed by the rate of ejection, measured as end diastolic Following rapid filling, there is a separate phase, diastasis, with
minimal changes in volume, which is followed by atrial systole. At
slower heart rates, a distinct atrial component can be identified
and the peak measured to calculate an E/A ratio similar to that
Box 9-1 obtained by echocardiography. For nuclear techniques, a ratio of
less than 1 : 4 is normal but increases with age. At faster heart
Important Radionuclide Parameters of Diastolic rates, the duration of diastasis decreases and the rapid ventricular
Function and Normal Values filling and atrial systolic portions of the TAC merge, making it
difficult to calculate ratios and assess the relative contribution of
1. Peak filling rate (PFR) (>2.5 end diastolic volumes/
second)
the two phases.
2. Time to peak filling rate (TPFR) (<180 msec) This chapter will focus on disorders of diastolic function result-
3. Filling fraction (% of stroke volume at one third, one half, ing from abnormalities of the myocardium and ischemia and
or two thirds of diastole) not address abnormalities resulting from valvular or pericardial
4. E/A ratio, 1 : 40 disease. Caution must be used in applying these normal value
ranges to a particular patient, as the method of acquisition and
processing, as well as patient-specific parameters, will result in
great variability in the values independent of any changes caused
Atrial by cardiac pathology. As shown above, factors such as age, heart
ED ED
systole rate, systolic function (ejection fraction [EF]), end diastolic
volume, adrenergic state, and medications will alter these param-
Diastasis eters in the absence of pathology.2 Given the influence of these
Volume EDV/sec

multiple factors on the derived diastolic values, it is easy to see

that single or even multiple variables may not accurately identify
the presence or absence of pathology in a given individual.
PER PFR Figure 9-2 is a schematic representation of a normal TAC
in the presence of diastolic dysfunction, shown as the dashed line.
ES With decreased relaxation, the rate of filling, expressed as
EDV/sec, decreases and the TPFR is delayed and shifted to the
IR
left. Under such circumstances, the contribution of atrial systole
may be increased and the E/A ratio shifted to a greater reliance
Time (msec) on atrial filling. In patients with very stiff ventricles, such as in
hypertrophic cardiomyopathy (HCM) or diminished systolic
Figure 9-1 The relationship between left ventricular volume over time
and the derived systolic and diastolic parameters. ED, end diastole; EDV, ventricular function, the loss of the atrial contribution to filling
end diastolic volume; PER, peak ejection rate; ES, end systole; IR, isovolumic caused by rhythms other than sinus can rapidly lead to pulmonary
relaxation; PFR, peak filling rate. edema.
 Chapter 9 • Evaluation of Diastolic Function by Radionuclide Techniques 107

ED Atrial
systole ED
Diastolic function
Normal
Diastasis
Abnormal
Volume EDV/sec

PFR
PER

ES

IR Figure 9-3 Left anterior oblique planar equilibrium radionuclide angiocar-

diogram at end diastole (ED) and end systole (ES) in a patient with normal
systolic and diastolic function. The time-activity curves for analysis are
Time (msec) obtained from sequential definition of the edges of the left ventricle.

Figure 9-2 Schematic of normal and abnormal diastolic function time-

activity curves. The blue line shows that PFR has a flatter slope and is
shifted to the right, indicating a delay in filling in comparison with the allows the best separation of the right and left ventricles for inde-
normal curve. ED, end diastole; EDV, end diastolic volume; PER, peak ejec- pendent and accurate volume measurements in each chamber.8,9
tion rate; ES, end systole; IR, isovolumic relaxation; PFR, peak filling rate. An example of a typical LAO view is shown in Figure 9-3. The
labeled red blood cells circulate in the vascular space, and
Box 9-2 the patient’s electrocardiographic (ECG) signal is used to set the
timing for acquisition of each heart beat at individual time points,
Basics of Equilibrium Radionuclide which may vary from 10 to 150 msec, depending on heart rate
Angiocardiography (ERNA) Acquisition for and the preset parameters. Information for each time point for
Diastolic Function Analysis each beat (usually >400 beats are acquired) is summed so that the
final TAC is an average rather than information from a single beat
1. 20–30 millicuries Tc-99m labeled red blood cells
or a small number of beats, as is provided by other modalities.
2. Labeling methods
a. In vivo: fastest and least expensive but lowest binding For this reason, this technique may be more representative of
efficiency overall function than are other methods, due to the large number
b. Modified in vivo/in vitro: compromise with good of beats averaged.
labeling efficiency Unlike systolic function analysis, where changes in heart rate
c. In vitro: longest time and expense but best labeling and arrhythmias have relatively little influence on the time to end
efficiency systole and EF, diastolic parameters are markedly affected by heart
3. Planar or single photon emission computed tomography rate variability during acquisition and processing. To avoid volume
(SPECT) and filling inconsistencies due to heart rate variability and arrhyth-
4. Positioning: Best septal separation, left anterior oblique mias from such a large number of beats, the R-R interval is
(LAO)
sampled prior to acquisition and the parameters set up to reject
5. Arrhythmia rejection: ±10% of mean R-R interval and
drop postpremature beat individual beats that vary by ±10% of the mean R-R. Since the
6. Temporal resolution: <50 milliseconds or 16–32 beat following a rejected beat has a longer filling period and will
frames/cycle add variability to the measurements due to differences in end
7. Acquisition diastolic volume and EF, it is also rejected.
a. Frame mode: simplest and least data intensive There are three computer methods used to acquire ERNA
b. List mode: optimal but adds considerable processing studies: frame, list, and buffered beat acquisition. Frame mode is
time and data storage the simplest method. It samples the R-R interval prior to acquisi-
c. Forward-backward with buffered beat: compromise tion, determines the number of time frames for each beat, and
puts data into the appropriate time frame in real time for each
beat using the set parameters until a new ECG gating signal
identifies the beginning of a new contraction. Once a beat has
Equilibrium Radionuclide Angiocardiography been added to the particular time bin, it cannot be removed. If
Methods in Diastolic Assessment there is an early beat, a new ECG trigger resets the acquisition so
that the time bins toward the end of the heart cycle will have fewer
Data Acquisition beats contributing counts. The TAC generated from this method
Important variables for performing diastolic function analysis of acquisition suffers from count dropoff in the terminal frame(s)
using ERNA are listed in Box 9-2. Technetium (Tc)-99m pertech- due to heart rate variability; and although accurate for EF mea-
netate is the radioisotope of choice and is attached to the patient’s surements, these curves cannot be analyzed for diastolic parame-
own red blood cells using one of three possible labeling methods, ters using harmonic analysis. Although this is not the best method,
which vary in the time to perform labeling, expense, and labeling it is universally used because of its simplicity and the small storage
efficiency.1 Both planar and single photon emission computed size of the retained data.
tomography (SPECT) methods of acquisition are available, but List mode acquisition is the best method. It retains the X,Y
nearly all studies are performed using planar techniques, with the spatial distribution of the radiotracer for every millisecond of
patient positioned in the left anterior oblique (LAO) view, which acquisition, along with the ECG trigger signal so that the data set
108 Chapter 9 • Evaluation of Diastolic Function by Radionuclide Techniques

can be reformatted into any timing interval and use the appropri- resolution results in even more detail during the diastolic filling
ate arrhythmia rejection during postprocessing. It provides period.
maximal flexibility relative to heart rate variability, but unfortu- Once the TAC has been generated, there are two general
nately at the expense of prolonged processing time and massive methods of diastolic function analysis: digital filtering and math-
data storage. This technique was used exclusively for all studies ematical curve fitting.10 With digital filtering or harmonic analy-
performed by the group at the U.S. National Institutes of sis, three to five harmonics are applied to smooth noise in the
Health.10 TAC, and the first derivative is taken to define the point at which
A hybrid method, the buffered beat approach, is an attempt to the greatest change in volume is present; this change and the time
provide realistic flexibility for heart rate variability while keeping at which it occurs represents the PFR and TPFR. An example is
data size to a manageable limit. It uses a temporary memory shown in Figure 9-6. An absolute requirement for harmonic
buffer to examine each beat and the ECG gating signal with analysis is that the EDV from the TAC start and end at the same
regard to the set baseline parameters and makes an instant deci- volume point. Figure 9-7 shows an example of count dropoff due
sion to keep or reject the beat.6,7 An additional feature of this to arrhythmias in a study acquired by frame mode. In the presence
method is a forward-backward curve generation technique to of count dropoff, error is introduced into the derived values from
avoid discontinuities or count dropoff in the last several frames, harmonic analysis. Discontinuity occurs in the terminal frames
which precludes harmonic analysis of the TAC. with frame mode acquisition, and for this reason, list or buffered
beat acquisition with forward and backward reconstruction of the
TAC is required to use harmonic methods of analysis.
Data Analysis Diastolic function values derived using a mathematical curve
For analysis of diastolic indices, there needs to be adequate tem- fitting technique generally take the available data and apply a
poral sampling of LV volume to capture the fine detail required third-order polynomial equation to derive PFR and TPFR from
to detect minor or subtle alterations in diastolic filling. The actual the slope changes in the TAC. This method is less susceptible to
sampling interval will vary with heart rate. To achieve a temporal discontinuities in the TAC.
resolution under 50 msec usually requires 16–32 frames per heart The basic concepts of diastolic function analysis for ERNA
cycle with frame mode or buffered beat. At slow heart rates, more were developed and performed in the late 1970s and early 1980s,
frames are required than at faster heart rates. The processed when the technical requirements were recognized and observed.
images are filtered to reduce statistical noise, the edges of the left Currently, most software packages on nuclear cardiology worksta-
ventricle are defined using manual or automated edge detection tions are capable of generating diastolic function values from any
software, and background subtraction is performed. The radioac-
tive counts within these boundaries represent the total volume in
the ventricle and are used to produce a TAC. A TAC from a frame
mode of 16 time intervals acquired from a clinical study is shown
in Figure 9-4. All the fine detail shown schematically in Figure
9-1 is retained in this curve, which does not have any dropoff in
counts in the terminal frames that may be seen in the presence
of even minor sinus arrhythmias but is much more pronounced
in the presence of atrial or ventricular arrhythmias. Figure 9-5
is from a study with 32 frame intervals. In comparison with
the 16-frame study shown in Figure 9-4, the higher temporal

70000
A
60000
20000
50000
Count (count)

40000 15000
Count (count)

30000
10000
20000

10000
5000
0
0 50 150 250 350 450 550 0
0 100 300 500 700 900 1100
Time (msec)
Figure 9-4 A 16 time interval frame mode time-activity curve from the B Time (msec)
study in Figure 9-3. The individual time points and triangles and the fitted Figure 9-5 An equilibrium radionuclide angiocardiogram, shown in rep-
curve are shown. All the fine diastolic detail shown in the schematics for resentative end diastole and end systole for the actual study and with the
Figures 9-1 and 9-2 can be seen in this curve, even though the 16 time 32 time frame derived curve. With 32 frames, finer detail can be seen for
intervals provide less temporal sampling than a 24- or 32-frame study. all four phases of diastole.
 Chapter 9 • Evaluation of Diastolic Function by Radionuclide Techniques 109

FITTING RESULTS
8.00e4
ED
Item Value
6.00e4 PER
PFR EDC (count) 64162
ES ESC (count) 36386
4.00e4

(dv/dt ⫻ 10) : (count)

TES (msec) 202
TPE (msec) 92
2.00e4 PER(/SV) (%/sec) 718.8
TPE/T (%) 15.5
0 1/3EF(/SV) (%) 31.7
1/3ER(/SV) (%/sec) 471.4
–2.00e4 TPF (msec) 94
PFR(/SV) (%/sec) 637.2
Figure 9-6 The graph shows the third –4.00e4 TPF/TF (%) 24.0
harmonic fitted curve superimposed by 1/3FF(/SV) (%) 59.8
the first derivative curve with the peak –6.00e4 1/3FR(/SV) (%/sec) 460.2
ejection rate and peak filling rate. To the 1/2FF(/SV) (%) 11.2
right is the print-out of all the variables –8.00e4
that can be derived from the data. ED, 0 50 100 150 200 250 300 350 400 450 500 550
end diastole; PER, peak ejection rate; ES,
end systole; PFR, peak filling rate. Time (msec)

30000 Box 9-3

25000 Basics of First Pass Radionuclide Angiography

(FPRNA) Acquisition for Diastolic Function Analysis
20000
1. Radiopharmaceutical
Counts

a. 10–30 millicuries of Tc-99m sulfur colloid, DTPA

15000
b. Bolus injection of Tc-99m sestamibi or tetrofosmin in
conjunction with perfusion, given rapidly in small
10000 volume
c. Total dose injected adjusted for count rate capabilities
5000 of camera
2. Injection site
0 a. Antecubital vein or external jugular with minimum of
18-gauge IV cannula
0 100 200 300 400 500 600 700 800
3. Camera types
Time (msec) a. Multicrystal preferred due to high count rates
b. Single crystal must be capable of 150,000 counts/sec
Figure 9-7 Time-activity curve from a 32-frame study showing terminal
frame dropoff in the last two frames due to an arrhythmia.
4. Temporal resolution: Usually 25 msec
5. Acquire images in anterior position

TAC obtained from ERNA or ECG gated SPECT studies. A

typical print-out of results is shown in the right-hand panel of right and left ventricles at rest or following exercise or pharmaco-
Figure 9-5. Unfortunately, details such as the accuracy of the logic stress. There was a dramatic decline in the use of this tech-
ECG gating mechanism, the presence or absence of count dropoff nique in the 1980s and 1990s due to a lack of high count rate
in the terminal frames, information density, and temporal resolu- multicrystal camera systems, which are optimal for the technique.
tion are ignored. These systems are capable of generating values Performing FPRNA studies with a conventional single crystal
for diastolic function indices but are not used clinically. gamma camera system is not optimal due to the low count rate.
The basic requirements for performing studies are shown in Box
9-3 and will be discussed in the following section.
First Pass Radionuclide Angiography Any Tc-99m radiolabeled compound can be used for bolus
administration. When assessment is to be made at rest and fol-
Data Acquisition lowing stress on one day, an agent that is cleared by the kidneys
A method for diastolic radionuclide analysis involves FPRNA. At (Tc-99m DMSO or DTPA) can be given first, followed by an
one time this technique was being performed with equal frequency agent that is cleared by the liver (Tc-99m sulfur colloid) or a heart
to myocardial perfusion imaging and ERNA for detection of coro- perfusion tracer (Tc-99m tetrofosmin or sestamibi), so that there
nary artery disease (CAD) and systolic function assessment. is no interference during the second study from the initial dose.
Today it is rarely performed. First pass techniques for assessment The total dose administered can be lower when a multicrystal
of diastolic function require administration of a compact intrave- camera is used, but with a single crystal camera that is not capable
nous (IV) bolus of radioactivity and use of a very high temporal of high count rates, 25–30 millicuries are required. The total dose
resolution and high count rate camera system to follow the radio- must be given as a tight IV bolus over 2 or 3 seconds, which
activity as it traverses the right and left ventricles. Serial gated requires at least an 18-gauge IV in the antecubital fossa or the
images at 25–50 msec of temporal resolution are acquired, and the external jugular. If such venous access is not available, the study
resultant TACs allow systolic and diastolic function analysis of the should not be attempted.
110 Chapter 9 • Evaluation of Diastolic Function by Radionuclide Techniques

Anterior images are acquired with the patient supine or upright Box 9-4
with the chest directly on the camera head. Exercise is best per-
formed on a bicycle, which allows the chest to be relatively station- Clinical Patient Populations Evaluated Using
ary and the images free of motion artifacts. Studies have been Radionuclide Diastolic Function Analysis
acquired during treadmill exercise, but this requires placement of
external radioactive markers that can be used to correct for 1. Coronary artery disease (CAD)
motion. Since only eight to ten beats can be used to analyze right a. Diagnosis of CAD
b. Monitoring therapy
ventricular (RV) or LV function without having bolus overlap in 2. Heart failure
the chambers, heart rate variability or arrhythmias will further a. Normal systolic function
limit the number of beats that can be processed and will result in b. Abnormal systolic function
sampling bias or overlap of tracer activity in more than one 3. Hypertrophic cardiomyopathy
chamber. These sampling limitations may result in poor study 4. Hypertension
quality and limit the conclusions that can be reached. Echocar- 5. Aging
diography, computed tomography (CT) ventriculography, and
cardiac magnetic resonance have similar sampling limitations.
ERNA, which averages more than 400 beats, provides a more
robust assessment of overall function. Depending on the count and a decrease in relaxation reflected in a decreased PFR and an
rate capabilities, diastolic and systolic parameters can be acquired increased TPFR. These are usually measurements of global
from a single beat, or beats can be summed using ECG gating to changes, but regional analysis can also be performed in an attempt
give higher information density and allow better edge detection. to increase sensitivity by measuring the small changes that may
Conventional gamma camera acquisition provides low counts and not be detected by a global filling value or time.11
generally requires gating and summing of multiple beats for accu- Using ERNA, Bonow et al. found a very high percentage of
rate results. abnormal diastolic function in the resting state in patients with
documented CAD.12 In 231 patients with chronic CAD, PFR
and TPFR were abnormal in 91%, in 85% of those without Q
Data Analysis waves, and in 82% of patients with normal resting LV EFs, no
From a single beat or summed beats, the data are Fourier filtered resting regional wall motion abnormalities, and no Q waves.
using a third- to fifth-order harmonic with appropriate back- These findings suggest a high rate of abnormalities in patients
ground subtraction, and the first derivative of the resultant TAC with CAD at rest independent of LV systolic function or previous
is used to measure filling rates and the time to peak filling. This myocardial infarction. Using FPRNA, Reduto et al. performed
technique remains the most accurate for assessment of RV func- rest and bicycle exercise measurements of PFR and of PFR in the
tion and for the detection of pulmonary hypertension. first third of diastole in 32 normal and 68 CAD patients.13 In
comparison with normals, patients with CAD had a lower PFR
overall and a lower PFR in the first third of diastole during exer-
CLINICAL RELEVANCE cise. Although the CAD patients also had an abnormal EF
response to exercise, diastolic parameters were more sensitive for
Radionuclide methods for diastolic function analysis have been detection of disease. It has also been shown among patients with
performed predominantly on a research basis in specific patient CAD and with normal LV systolic function at rest that impaired
populations and are not used on a day-to-day basis in general LV filling and regional asynchrony predict a greater degree of
clinical cardiology practice. This is due, in part, to the lack of exercise-induced ischemia, suggesting a greater extent of jeopar-
appropriate equipment, difficulty in accurately performing the dized myocardium.14,15
measurements, and variability in the measurements due to factors Despite the documented efficacy of diastolic function analysis
other than cardiac pathology, such as age-related changes and the for CAD diagnosis, it is not being used in the practice of cardiol-
effects of medications. This variability makes it difficult to measure ogy today due to the limitations previously listed. With the
diastolic parameters in a given patient and meaningfully apply the potential for deriving similar information from 16-frame ECG
values for purposes of diagnosis, management, or monitoring of gated perfusion studies, the technique may provide ancillary
therapy. Is the abnormal value due to the patient’s age, systolic information beyond perfusion that may have a role for diagnosis
function, myocardial stiffness, ischemia, or other variables? Even and monitoring. This needs to be validated.
with all of these limitations, the technique has been useful in
certain disease states and clinical scenarios, as listed in Box 9-4. Monitoring Treatment of Coronary Artery Disease
These will be discussed in detail.
Once a diagnosis of CAD has been made, diastolic function anal-
ysis has also been used to document the response to treatment.
Coronary Artery Disease Bonow et al. documented improvement in abnormal diastolic
function following revascularization.16 Again, diastolic abnor-
Diagnosis malities were present in the resting state and did not require stress
Although CAD diagnosis using radionuclide methods is usually to provoke dysfunction. In a study of only 25 patients with single-
performed by measuring myocardial perfusion or changes in sys- vessel CAD, all had abnormal resting diastolic dysfunction despite
tolic function at baseline and following stress, analysis of diastolic normal systolic function. With exercise, 23 of the 25 developed a
function alone or in conjunction with these other measures pro- drop in EF, indicating the development of ischemia. Following
vides an accurate diagnosis5 based on the induction of LV isch- percutaneous transluminal coronary angioplasty, resting diastolic
emia, which causes a transient increase in myocardial “stiffness” function normalized in all patients; and with exercise, EF
 Chapter 9 • Evaluation of Diastolic Function by Radionuclide Techniques 111

increased. These findings suggest that resting diastolic dysfunc- normal contribution to ventricular filling in these abnormal
tion is a very sensitive indicator of significant CAD, even in the ventricles.
absence of systolic abnormalities, and that following successful However, at this stage of our understanding of the etiology and
revascularization, resting diastolic dysfunction improves. management of HCM, it is accepted that diastolic dysfunction is
present and that there is no need to document its existence inde-
pendently of the results available from echocardiography, which
Heart Failure is an essential test in HCM.
Normal Systolic Function
Patients with clinical symptoms of congestive heart failure gener- Hypertension
ally have abnormal systolic function, but as many as 30% to 40% In the presence of hypertension, there are alterations in diastolic
of these patients may have normal systolic function and their function independent of alterations in systolic function or the
symptoms are on the basis of diastolic dysfunction.17,18 Common presence of CAD that can be measured by radionuclide
causes of diastolic dysfunction include increased resistance to methods.27,28 Cuocolo et al. evaluated 41 essential hypertensive
ventricular inflow caused by constrictive and restrictive pericar- patients without CAD at rest and with exercise by ERNA.27
dial disease, hypertrophy, scarring due to infarction, and volume With exercise, 22 patients had an appropriate increase in EF and
overloading. Two other causes include impaired myocardial relax- 19 had a drop in EF. In the patients with a drop in EF, resting
ation due to ischemia or cardiomyopathies and increased resis- PFR and TPFR were reduced. This suggests that resting diastolic
tance to atrial emptying in patients with mitral stenosis. Although function detects early changes in myocardial function at rest in
radionuclide methods may be useful for detection of diastolic patients with essential hypertension that predict an abnormal
abnormalities in these groups, the information provided is less response during stress. These changes were not directly related to
useful than that provided by echocardiography, which should be previously identified modifiers of diastolic parameters such as age,
the first diagnostic test performed. heart rate, and the extent and severity of hypertension. Abnor-
Soufer was able to show in 58 patients with congestive heart malities were directly related to myocardial mass.
failure and normal systolic function that 38% had a reduction in The acute effects of verapamil on diastolic function in hyper-
PFR below 2.5 EDV/sec, and an additional 24% had probable tensive patients have also been studied in the cardiac catheteriza-
diastolic dysfunction with values of 2.5–3.0 EDV/sec. The etiol- tion laboratory. Patients had resting diastolic abnormalities that
ogy was CAD and hypertension in the majority of patients. improved with the acute administration of verapamil.29 These
studies suggest that diastolic function analysis may be used for
Abnormal Systolic Function preclinical detection of myocardial dysfunction in patients with
hypertension.
Although it has been shown using ECG techniques that patients
with heart failure and abnormal systolic function also have
diastolic abnormalities, radionuclide methods have not been in- Aging
vestigated in this population.19,20 In these patients, diagnostic There are age-related changes in ventricular relaxation and filling
abnormalities were associated with worse symptoms and increased that are independent of the increasing prevalence of hypertension,
event rate. Due to complex hemodynamics, neurohumoral factors, CAD, increased LV mass, and altered response to catecholamines
arrhythmias, and medications, the values for diastolic indices are and that suggest that there are primary effects of aging on dia-
difficult to measure and interpret. For these reasons, radionuclide stolic function.7,30,31 It has been documented by many methods
methods have limited application. that with increasing age, there is a decrease in PFR and TPFR
and an increase in the atrial component of diastole. The etiology
of these changes is multifactorial but may be reversed, in part,
Hypertrophic Cardiomyopathy through exercise training and with the use of calcium blockers.7,30
Patients with HCM have been extensively evaluated in terms of It is also possible that fibrosis or protein deposition within the
diagnosis and management using radionuclide techniques because myocardium may mediate the abnormalities.32 Documentation of
of the interest and expertise of the group at the National Insti- these abnormalities is most useful when diastolic radionuclide
tutes of Health.21–26 The major abnormalities in HCM patients parameters are being used to diagnose ischemia, in order not to
include prolonged isovolumic relaxation caused by myocardial confuse age-related changes with the presence of CAD. Adjusting
ischemia and intracellular calcium overloading, as well as delayed for age is critical.
rapid ventricular filling and a greater dependence on the atrial
contribution to filling. In addition to documenting these abnor-
malities, radionuclide techniques have been used to monitor the LIMITATIONS
effects of treatment. The calcium blockers verapamil and nifedip-
ine have been shown to improve LV relaxation and filling with IV Despite the extensive literature on the use of radionuclide methods
administration and with long-term oral administration. In addi- for analysis of diastolic function, the technique is not being used
tion to improving hemodynamic parameters, there are also clinical in clinical settings due to several factors. These include the lack
improvements in exercise tolerance and heart failure symp- of clinical utilization of these techniques for diagnosis of CAD
toms.21,22 It was shown that the early and late improvement in and systolic function and the absence of special gamma cameras
symptoms with verapamil was related to the extent of improve- that optimize performance of the measurements. Such measure-
ment in diastolic filling. These findings also explain why HCM ments were difficult to perform using the standard methods of
patients can go into severe heart failure when they are not in sinus acquisition and processing in clinical practice, and efforts to
rhythm and lose atrial contraction, which makes a larger than achieve greater accuracy and reproducibility were time consum-
112 Chapter 9 • Evaluation of Diastolic Function by Radionuclide Techniques

ing, computer intensive, and not practical in most clinical set- the mitral valve plane at the base of the heart is also difficult, as
tings.2 In addition, techniques such as echocardiography and the transition from the left atrium, which has little uptake, to the
cardiovascular magnetic resonance provide similar information myocardium in the area of the valves and membranous septum
on diastolic function and much more information on heart valves, is difficult to identify. Failure to clearly delineate this separation
wall thickness, LV mass, chamber pressures, flow dynamics, and will result in error in the volume of the cavity and the resul-
the integrity of the pericardium. This additional information tant TAC.
makes these techniques much more valuable for patient evalua- Using this approach in ECG gated SPECT studies, normal
tion and management. value ranges were developed for PFR (2.62 ± 0.46 and −2 SD
Other studies have brought into question the value of measur- <1.71 EDV/s) and TPFR (164.6 ± 21.7 and −2 SD >216.7 msec)
ing relaxation rates and time intervals. Studies have shown that in 90 patients without CAD or hypertension. PFR had significant
despite the improvement in these parameters with the use of correlations with age, EDV, and EF, but TPFR did not. This sug-
calcium channel blockers, there may be an increase in LV end gests that TPFR may be a more robust measurement by this
diastolic pressure as well as an overall prolongation of the time technique, as it is independent of these other factors that influ-
constant of relaxation.2 ence PFR.
These normal ranges were then applied to a validation set
of patients and showed similar results. From the combined
FUTURE RESEARCH populations, normal threshold values for PFR of greater
than 1.70 EDV/sec and for TPFR under 208 msec were
Given the widespread use of ECG gated SPECT perfusion established.3 These results need to be validated in a larger
imaging and the relative lack of utilization of ERNA and FPRNA, population.
the ability to assess diastolic function analysis from perfusion data
would allow screening of diastolic dysfunction in a larger patient
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newer camera/workstation systems allow multiple acquisition nuclide angiography. Circulation 1981;64:315–323.
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1981;63:1228–1237.
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 CHRISTOPHER P. APPLETON, MD
10
Evaluation of Diastolic
Function by Two-
Dimensional and Doppler
Assessment of Left
Ventricular Filling
Including Pulmonary
Venous Flow
INTRODUCTION PULMONARY VENOUS FLOW VELOCITY
Relation of Mitral to Pulmonary Venous
LEFT VENTRICULAR FILLING: A HISTORICAL
A-Wave Duration
PERSPECTIVE
CLINICAL APPLICATIONS: INTERPRETATION
RELATION BETWEEN DIASTOLIC PROPERTIES
OF INDIVIDUAL MITRAL FLOW VELOCITY
AND LEFT VENTRICULAR FILLING PATTERNS
VARIABLES
EXERCISE AND LEFT VENTRICULAR Left Ventricular Isovolumic Relaxation
DIASTOLIC FUNCTION Time
Left Ventricular Intracavitary Flow During
DOPPLER MITRAL FLOW VELOCITY
Isovolumic Relaxation Time
PATTERNS
Mitral Time-Velocity Integral
Changes in Mitral Flow Velocity Patterns
Peak Mitral E-Wave Velocity
with Aging and Disease States
Mitral Deceleration Time
Left Ventricular Filling and Changing Cardiac
Mitral Flow Velocity at the Start of Atrial
Loading Conditions
Contraction
Grading the Degree of Left Ventricular
Peak Mitral A-Wave Velocity
Diastolic Dysfunction by Mitral Flow
Mitral A-Wave Duration
Velocity Alone
Mitral Peak E/A Wave Velocity
Grading the Degree of Left Ventricular
Ratio
Diastolic Dysfunction in Epidemiology
Studies
115
116 Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling

ANCILLARY DATA THAT HELP THE Mitral Regurgitation and Stenosis

INTERPRETATION OF MITRAL FLOW Sinus Tachycardia: Effect on Left Ventricular
VELOCITY PATTERNS Filling
M-Mode and Two-Dimensional Uncommon Mitral Valve Velocity Patterns
Echocardiography Increased Mitral Respiratory Flow Velocity
Tricuspid Flow Velocity Variation
Mitral Annular Velocities in Tissue Doppler Atrial Flutter and Fibrillation
Imaging and Relation to Left Ventricular Diastolic Mitral and Tricuspid
Filling Regurgitation
Pulmonary Artery Pressures
RIGHT VENTRICULAR DIASTOLIC FUNCTION
PERFORMING AN ECHO-DOPPLER
USING LEFT VENTRICULAR FILLING
EVALUATION OF LEFT VENTRICULAR
PATTERNS FOR PATIENT MANAGEMENT
DIASTOLIC FUNCTION
FUTURE RESEARCH
MITRAL FLOW VELOCITY PATTERNS:
INTERPRETIVE CHALLENGES
Mitral E/A Ratio Less Than 1

INTRODUCTION (CT) angiographic and magnetic resonance imaging (MRI) tech-

niques, cardiac ultrasound is currently the method of choice
The cardiac cycle is continuous. The filling of the ventricle (dias- because of its noninvasive and portable nature. Evaluating LV
tole) is followed by ventricular contraction (systole) to provide an filling by two-dimensional anatomic findings, Doppler flow, and
adequate cardiac output during both rest and exercise to meet the tissue Doppler imaging (TDI) have emerged as powerful clinical
body’s metabolic demands. Systole and diastole affect each other techniques to predict adverse cardiovascular events such as new-
in an intimate manner to accomplish this goal. The normal elastic onset atrial fibrillation and heart failure, as well as mortality
recoil after left ventricular (LV) contraction aids early filling of regardless of LVEF. The purpose of this chapter will be to describe
the ventricle, with the late diastolic atrial contraction ensuring the various LV filling patterns encountered in clinical practice,
that the myocardial sarcomeres are adequately stretched to opti- and what these patterns and their measurable variables reveal
mize contractile force. Exercise tests the health of this integrated about LV diastolic function. In cases of possible ambiguity, ancil-
system by shortening the time for filling and myocardial perfu- lary variables such as left atrial (LA) volume, pulmonary venous
sion, and a normally functioning cardiac electrical system is also (PV) flow velocity, and TDI that help in interpreting mitral flow
needed for optimal performance. velocity patterns will be discussed.
The “new” epidemiology of LV diastolic dysfunction has been
discussed in Chapter 6 of this volume. Diastolic heart failure is
now recognized as a major national health problem, especially in LEFT VENTRICULAR FILLING:
the elderly, who have a high incidence of LV hypertrophy (LVH). A HISTORICAL PERSPECTIVE
These patients present with symptomatic heart failure despite a
normal LV ejection fraction (LVEF) and have morbidity and In 100 bc, Galen proposed that the heart is filled by dilation of
mortality that is nearly equal to that of patients with reduced the right ventricle. Sixteen hundred years later, in 1628,
systolic function. Diastolic heart failure patients are also at risk William Harvey described the heart as a central pump in a circu-
for first-onset atrial fibrillation and a higher incidence of stroke. latory system with both arteries and veins. Logically, most cases
Although LVEF is normal in diastolic heart failure, ventricular of heart failure were ascribed to damage or weakening of the heart
contractile mechanics have been altered in a way that lengthens muscle and a decrease in pumping function. Diastole was consid-
the isovolumic contraction and relaxation period so that the ered simply the interval in which the cardiac chambers filled pas-
period for diastolic filling becomes shorter and may be inadequate. sively between each pumping cycle and therefore was largely
In both systolic and diastolic heart failure, the degree of diastolic ignored.
dysfunction is a powerful predictor of prognosis. Gradually, evidence emerged that abnormalities of ventricular
Despite this new appreciation of the importance of both systole filling could cause symptoms and that diastolic and systolic
and diastole in maintaining normal cardiovascular physiology, the functions were interrelated. About 1915, Wiggers described the
role of LV diastolic function in health and disease is incompletely phases of the entire cardiac cycle, and the Frank-Starling mecha-
understood and underappreciated by many primary care physi- nism was described, whereby LV end diastolic volume helps regu-
cians and cardiologists. As discussed in Chapter 2, diastole is a late forward stroke volume on a beat-to-beat basis. In 1930, Katz
complex phenomenon with many determinants that are difficult recognized the role of LV relaxation in the filling of the ventricle,
to study individually and several phases that encompass both the suggesting that the normal heart acts like a “suction” pump, a
relaxation and the filling of the ventricle. Physical examination, concept proven 60 years later.1 A limitation in cardiac filling, not
echocardiography (ECG), chest radiographs, and laboratory pumping function, with resultant reduced cardiac output was rec-
studies are unreliable in diagnosing diastolic heart failure in most ognized as the cardinal feature of constrictive pericarditis, further
individuals, and invasive measurements of LV diastolic properties emphasizing that disorders of filling could also cause cardiac
and pressures are impractical in clinical practice. Therefore, at symptoms and disease.
present, assessing the type and degree of LV diastolic dysfunction In the 1960s, the study of ventricular biomechanics accelerated.
relies on evaluating the pattern of LV filling. Although this can Although most research continued to focus on LV contractile
be accomplished by radionuclide and computed tomography function, cardiac diseases with thickened and noncompliant
 Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling 117

ventricles with good pumping function, such as restrictive2 and Transmitral

hypertrophic3 cardiomyopathies, were described. Angiographic pressure gradient
differences in LV filling patterns between normals and patients
with various heart diseases were reported even when the LVEFs LV
were similar,4 and these phenomena were subsequently studied by
M-mode echocardiography.5,6 At the same time, the importance TMPG
of LV systolic function in determining diastolic restoring forces LA
Elastic recoil
and rate of LV relaxation was appreciated. Our current view that LV relaxation
systole and diastole are an intertwined continuum, with each part LV-LA compliance
affecting all others, gradually began to emerge. Mitral valve LA pressure
Viscoelasticity
In the mid-1980s, echocardiographic studies showed that 20% LV-RV interaction LV pressure
to 40% of elderly patients with heart failure had a normal LVEF Atrial contractility
and, therefore, presumably “isolated” diastolic dysfunction.7,8 Electrical system
LV filling
However, difficulties in quantitating individual LV diastolic prop- Pericardial constraint
erties9 caused the clinical study of LV diastolic dysfunction to

Mitral flow velocity

proceed slowly. LV filling patterns were analyzed by digitized
M-mode,10 angiographic,11 and radionuclide12 methods. In 1982,
pulsed wave (PW) Doppler study of mitral flow velocities to
study LV filling was first reported.13,14 Doppler ultrasound, a
noninvasive technique that could determine dynamic changes in
LV filling after interventions and over time, revolutionized the
study of LV diastolic function. Age-related changes in LV filling
were quickly described,15–18 followed by the description of three Figure 10-1 Determinants of LV filling. In sum, they affect the transmitral
basic abnormal mitral flow filling patterns that were correlated to pressure gradient, which determines the LV filling pattern. When LV pres-
LV diastolic variables and filling pressures.19 The three abnormal sure falls below LA pressure, a positive pressure gradient occurs and early
mitral filling patterns were found to be independent of disease diastolic filling begins (hatching). Pressure in the ventricle rises and then
type19 and to have clinical significance and prognostic value briefly exceeds LA pressure, which decelerates mitral flow velocity. A posi-
tive pressure gradient occurs again at atrial contraction and results in flow
regardless of cardiac disease type,20–23 suggesting that different in late diastole, just before systole begins. (Modified from Appleton CP et al:
pathology altered the same basic diastolic properties. PV flow The echo-Doppler evaluation of left ventricular diastolic function. A current
velocity helped assess the filling of the left atrium, and variables perspective. Cardiol Clin 2000;18:513–46, ix.)
were found to aid the interpretation of LV filling patterns and
pressures.24–27 Using the two flow velocities, a “natural history” of
LV filling in normals and with disease patterns was described.24–27
Manipulation of preload and afterload demonstrated the dynamic ultimately determines mitral inflow and the LV filling pattern, as
nature of LV filling patterns in response to changes in loading shown in Figure 10-1.49 Positive gradients in diastole result in
conditions,28–30 and these changes also had prognostic significance flow across the mitral valve, while negative gradients decelerate or
in patients with cardiac disease.31,32 Additional Doppler methods stop flow.52–54
followed, such as TDI of mitral annular motion (MAM) and the The different LA and LV pressures that are determined by LV
rate of color Doppler mitral inflow propagation (Vp), and model- diastolic properties and filling are shown in Figure 10-2. Under-
based image processing continued to improve diagnostic accuracy standing that LV end diastolic pressure (LVEDP) can be elevated
and advance the new field of “diastology.”33–46 These continue to before mean LA pressure is increased is essential to understand-
enhance our basic knowledge regarding clinical observations. ing and interpreting diastolic function. Two key diastolic proper-
Although all echo-Doppler variables have limitations in inter- ties, the rate of LV relaxation (diastolic pressure fall) and of LV
preting diastolic function, the aggregate sum of the two- compliance (throughout all of diastole), are especially important
dimensional echo and Doppler findings provides us a powerful in understanding pressures and LV filling.55 Normal LV contrac-
and practical way to noninvasively assess LV diastolic function tion and relaxation are vigorous and rapid, resulting in diastolic
and to objectively follow serial changes after medical intervention elastic recoil that augments early diastolic filling through a suction
or with disease progression.47–49 These methods are powerful effect (chamber volume increasing while pressure is initially still
prognostic tools in asymptomatic50 as well as symptomatic decreasing).38,56,57 This promotes an early mitral valve opening and
patients with various diseases, like dilated21,51 and restrictive31 helps maximize the diastolic filling period and myocardial perfu-
cardiomyopathies. As a result, the clinical syndrome of diastolic sion. Rapid ejection and a predominance of early diastolic filling
heart failure is now more readily recognized, and studies on leaves a period of diastasis before atrial contraction as a reserve
improved diagnosis and the best treatment strategies for such that can help maintain adequate filling when exercise shortens
patients are under way. cardiac cycle length.
The first hemodynamic abnormality seen in nearly all cardiac
diseases is a slower rate of LV relaxation.14,52,55,58,59 This is
RELATION BETWEEN DIASTOLIC PROPERTIES commonly associated with hypertension or LVH.60 Both systole
AND LEFT VENTRICULAR FILLING PATTERNS and diastole are affected, even if the LVEF remains normal.
In systole, the LV isovolumic contraction and ejection times
The numerous factors that affect LV diastolic properties and the become prolonged. In diastole, the slower fall in LV pressure
filling of the left ventricle are described in Chapter 5 of this causes the mitral valve to open later and the early diastolic
volume. Although the interaction of these factors is complex, their transmitral pressure gradient and proportion of filling to
sum reflects the diastolic transmitral pressure gradient, which decline.55 The diastasis period often disappears, and a greater
118 Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling

LV LA LV + LA

LV
LV
V-wave A-wave

LV A-wave LA Mean LAP LA

LV EDP
TMPG

LV pre-A
LV RFW
LVmin
A B C
Figure 10-2 The left atrial (LA) and left ventricular (LV) pressures that are influenced by LV diastolic properties are shown. The transmitral pressure gradient
(TMPG, C) determines the LV filling pattern, while other hemodynamic variables relate to mitral and other echo-Doppler flow velocity variables. LV pressure
falls after aortic valve closure, and its rate of decline and minimum LV pressure (LVmin, A) reflects the rate of LV relaxation and elastic recoil. As blood fills
the left ventricle, there is a rapid increase in pressure from the rapid filling wave (RFW), which decelerates blood inflow. Low-level filling causes pressure
to increase slowly in mid-diastole, and then an increase in pressure is seen in both chambers with atrial contraction (A wave).
The first diastolic abnormality seen in nearly all cardiac diseases is a slower rate of LV relaxation. As LV compliance decreases, an abnormal increase in
LV pressure is initially confined to late diastole and is seen as an increased LV A-wave pressure rise and LV end diastolic pressure (LV EDP). When LV compli-
ance is further reduced, filling of the ventricle causes an increase in pressure throughout the diastolic filling period, which is manifest as an increase in
mean LA pressure (B) and its surrogate LV preA pressure. In these cases, LV EDP is obligatorily elevated. (From Appleton CP et al: The echo-Doppler evaluation
of left ventricular diastolic function. A current perspective. Cardiol Clin 2000;18:513–546, ix.)

proportion of filling at atrial contraction is needed to reach reduced atrial contribution indicates that LA systolic failure is
an optimal end diastolic volume. These changes can markedly present due to the chronic pressure overload. Patients with this
alter the length of the diastolic filling period and resting LV pattern are markedly symptomatic, demonstrate a severe func-
filling pattern, as shown in the two individuals in Figure 10-3. tional impairment, and have a poor prognosis.21,31,51
One is normal and one has hypertensive heart disease with Because both the rate of LV relaxation and LA pressures may
LVH. Both have identical heart rates and LVEFs. At this have many different values that are not necessarily related, many
stage, if LV compliance is reduced, the abnormal increase in different transmitral gradient profiles and LV filling patterns are
pressure is seen initially only in late diastole at the time of possible.49,67 As a result, a similar-appearing LV filling pattern
atrial contraction, and mean LA pressure remains normal, so may occur with different combinations of these two key diastolic
that patients are usually asymptomatic.47,49,61,62 A comparison properties, with clinically significant differences in LV filling pres-
of the durations of mitral and PV flow velocities at atrial sures. In these instances, the degree of abnormality of LV relax-
contraction indicates this earliest abnormality of ventricular ation and compliance is indicated by anatomic abnormalities such
compliance and hemodynamics.63–66 as reduced LVEF, LVH, LA enlargement or altered PV flow, and
With more advanced disease, LV relaxation remains abnormal, annular TDI velocities.49
but a decrease in LV compliance occurs throughout diastole,
which increases mean LA pressure and size and begins to result
in symptomatic heart failure. The increased LA pressure will EXERCISE AND LEFT VENTRICULAR
oppose the effect of a slower rate of LV relaxation, causing an DIASTOLIC FUNCTION
earlier mitral valve opening and a higher transmitral pressure
gradient,52,67 so that the LV filling pattern appears more “normal.” An increase in heart rate, as with exercise, is the heart’s diastolic
However, in this case the increase in early diastolic LV filling is “stress test.” As heart rate increases, diastolic filling time shortens.
caused by increased driving pressure rather than suction created In normal individuals, several adaptations help keep early and late
by normal ventricular elastic recoil. Patients with this “pseudonor- diastolic filling separated, a coordination of the electrical and
mal” LV filling19 begin to have heart failure symptoms and show mechanical systems that provide for increased filling and cardiac
moderate functional limitation.48,49,68,69 output without an elevation of diastolic pressures.71,72 Most
With a severe decrease in LV compliance, the marked elevation importantly the P-R interval shortens.73 At the same time, faster
in LA pressure causes early diastolic filling to predominate, while heart rates trigger the Treppe (or “staircase”) effect, which increases
the left atrium fails and provides little additional late diastolic LV contractility and rate of relaxation. LVEF increases and LV
filling. This third and most abnormal LV filling pattern is termed end systolic volume decreases. The overall effect is an earlier
“restrictive.”70 Patients with restrictive filling patterns also have mitral valve opening, increased elastic recoil, and a larger early
impaired LV relaxation, but the severe decrease in LV compliance diastolic transmitral pressure gradient.71 LV contractility is also
results in a marked elevation of LA pressure, which promotes a increased by sympathetic tone, while systemic vascular resistance
rapid initial flow of blood into the ventricle in early diastole. falls with muscular vasodilation.
However, the increased proportion of early filling has an abrupt, Impaired relaxation may reduce the cardiac output achieved by
premature termination due to a rapid increase in LV pressure reducing the diastolic filling time below that needed for optimal
with only minimal filling occurring at atrial contraction. The LV filling74 and myocardial perfusion. A premature fusion of early
 Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling 119

NORMAL IMPAIRED LV RELAXATION

LV filling LV filling
pattern pattern

Figure 10-3 The effect of impaired left ventricular HR 75 HR 75

(LV) relaxation on LV diastolic filling time (DFT) and
LV filling patterns. A, Echocardiography (ECG), pulsed
wave (PW) Doppler of mitral flow velocity and high-
fidelity LV pressure recordings are shown in two indi-
viduals at rest. Both individuals have heart rates of
75 bpm and a normal LV ejection fraction. In the
normal subject (left), LV pressure increases and DFT SYS DFT SYS
decreases rapidly so that the diastolic filling time A
(DFT) is longer than systole (SYS), with a period of HR 75 HR 125 HR 75 HR 125
diastasis in mid-diastole. In contrast, with impaired
LV relaxation (right), longer isovolumic contraction
and relaxation times result in the DFT being longer
than systole. As a result, the LV filling pattern is mark- LVP
edly altered to reach the same end diastolic volume,
with less filling in early diastole, the disappearance
of a diastasis period, and a larger contribution of
filling at atrial contraction. B, The effect of increased
heart rates on diastolic filling time. LV pressure (LVP)
is shown in the same two individuals at rest and with
exercise. At a heart rate of 125 bpm compared with
the normal subject (left), the DFT with impaired LV
relaxation (right) is markedly abbreviated, and only
25% as long as systole, making it difficult to maintain DFT DFT DFT DFT
adequate LV filling. The result is a reduced LV end
diastolic volume, blunted cardiac output, and Exercise Exercise
reduced functional aerobic capacity. B

and late diastolic filling often occurs (see Fig. 10-3) with an inabil- before atrial contraction.73 In these cases, the E/A wave ratio may
ity to increase LV end diastolic volume.72,74 LV and LA filling and be reduced compared with values obtained at a slower heart rate,
PV flow increase with atrial contraction of an incompletely so that more reliance on other echo-Doppler variables is needed
relaxed left ventricle. Patients are affected by reduced aerobic when interpreting the “fused” LV filling pattern.
capacity and may complain of abnormal exertional dyspnea.
Those with pseudonormal and restrictive filling patterns have a Changes in Mitral Flow Velocity Patterns with
significant decrease in exercise capacity. However, in these indi-
Aging and Disease States
viduals, it is the increase in mean LA pressure and pulmonary
congestion due to reduced LV compliance that limits exercise Elastic recoil and rapid LV relaxation in adolescents and young
rather than a blunted increase in LV end diastolic volume. adults result in a predominance of early diastolic filling (E wave)
with much less filling (10%–15%) due to atrial contraction. With
normal aging, LVEF changes little, but LV relaxation slows in
DOPPLER MITRAL FLOW VELOCITY PATTERNS most individuals. The slower relaxation appears to be due largely
to a gradual increase in systolic blood pressure and LV mass
Because of their noninvasive nature and ease of use, echo-Doppler (hypertrophy). The result is reduced LV filling in early diastole
techniques have become the accepted clinical standard for assess- and increased filling at atrial contraction.16–18 In most individuals,
ing LV diastolic function. LV filling is assessed with both continu- the peak E- and A-wave velocities become approximately equal
ous wave (CW) and PW Doppler techniques. Figure 10-4 shows during the sixth and seventh decade of life, with atrial filling
mitral flow velocity obtained with the PW Doppler technique contributing up to 35% to 40% of LV diastolic stroke volume. In
and the variables that are measured.75 These include: LV isovolu- individuals who maintain lower blood pressures and have no
mic relaxation time (IVRT); peak mitral flow velocity in early increase in LV mass, the age-related changes of decreasing
diastole (E wave) and at atrial contraction (A wave); the mitral E/A ratio in asymptomatic “normal” patients used in most
deceleration time (DT); the E-wave velocity just before atrial reference studies are less pronounced, and normal E-wave pre-
contraction (E at A), also sometimes referred to as preA velocity; dominance can occasionally be seen into the seventh decade of
and the duration of mitral A-wave velocity (Adur). An E-at-A life. In these individuals, normal two-dimensional findings, LA
wave velocity of more than 20 cm/sec results in a peak A-wave size, and annular TDI variables confirm that diastolic function is
velocity that is larger than it would have been at a slower heart normal. Normal age-related values for mitral variables are listed
rate, when mitral flow velocity has time to drop to a lower level in Table 10-1.
120 Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling

E E
A
LV A
RV
Sample
volume

Ac
RA E at A Ac
LA
0

LV Mdt Adur Mdt LV Adur

IVRT IVRT
Figure 10-4 Mitral flow velocity variables. These are obtained with PW Doppler by placing a 1–2 mm sample volume between the mitral leaflet tips as
shown. Variables measured include peak E- and A-wave velocities, as well as the E-wave velocity just prior to atrial contraction (E-at-A velocity). The left
ventricular (LV) isovolumic relaxation time (IVRT) is the time interval from aortic valve closure (Ac) to mitral valve opening. Mitral deceleration time (Mdt)
is from peak E-wave velocity to a line extrapolated down the decreasing velocity to the zero baseline. The duration of mitral A wave (Adur) is from the
E-at-A (preA) velocity to the time the A wave returns to the zero baseline. (From Appleton CP et al: The echo-Doppler evaluation of left ventricular diastolic
function. A current perspective. Cardiol Clin 2000;18:513–46, ix.)

TABLE 10-1
MITRAL FLOW VELOCITY IN NORMALS: AGE-RELATED CHANGES
AGE (yr) n IVRT (msec) E (mmHg) A (mmHg) MDT (msec) ADUR (msec)

2–20 46 50 ± 9 88 ± 14 49 ± 12 142 ± 19 113 ± 17

21–40 51 67 ± 8 75 ± 13 51 ± 11 166 ± 14 127 ± 13
41–60 33 74 ± 7 71 ± 13 57 ± 13 181 ± 19 133 ± 13
>60 10 87 ± 7 71 ± 11 75 ± 12 200 ± 29 138 ± 19

Normal age-related values for mitral E- and A-wave velocities, and mitral E/A wave ratios are shown ± SD. All individuals were free of cardiac disease and had a normal blood
pressure, physical exam, and electrocardiography. Left ventricular hypertrophy was excluded, and all E-at-A velocities were <20 cm/sec, so that the peak A-wave velocity was not
increased above that expected for the aging process.
IVRT = isovolumic relaxation time; Mdt = mitral deceleration time; Adur = duration of mitral A wave.
From Hatle LH; unpublished, with permission.

LV FILLING PATTERNS

A
IVRT
Figure 10-5 Normal and abnormal LV
filling patterns and their associated LV
Normal Impaired Pseudonormal Restrictive
diastolic abnormalities. The degree of
relaxation
abnormality increases from left to right.
Diastolic Abnormal Abnormal Abnormal The arrows indicate their dynamic
abnormalities: relaxation relaxation relaxation nature in response to loading condi-
+ ↓ compliance ↓↓ compliance tions and other variables. IVRT, isovolu-
Normal + + mic relaxation time; LA, left atrial; LAP,
LA pressure ↑ LAP ↑ LAP LA pressure; RFW, LV rapid filling wave
↑ LV RFW ↑ LV RFW in early diastole.

The three basic abnormalities of LV filling patterns were dis- present in all patterns, the difference being that with pseudonor-
cussed previously and are shown in Figure 10-5, where the arrows mal and restrictive filling, progressively reduced LV compliance
indicate that abnormal mitral filling patterns are a dynamic con- raises mean LA pressure to levels that mask their effects on the
tinuum and may worsen or become more normal with changes in transmitral pressure gradient and filling.
loading conditions. Common usage describes the three abnormal The changes in LV filling with normal aging and with cardiac
filling patterns as “impaired,” “pseudonormal,” and “restrictive” disease states can be combined into a “natural history of LV
relaxation. The diastolic property of impaired LV relaxation is filling,” which is shown together with their corresponding PV
 Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling 121

THE NATURAL HISTORY OF LV FILLING

Impaired LV relaxation

Normal Decrease in LV compliance

Young Middle age Older Mild Moderate Severe

m/sec
E
1
A
IVRT
0

PVs PVd
0.5

0
PVa
Figure 10-6 The “natural history” of left ventricular (LV) filling patterns with normal aging and with progressive diastolic dysfunction, as assessed by PW
Doppler mitral and pulmonary venous flow velocity recordings. Several abnormal LV filling patterns have E/A wave velocity ratios that are similar to those
seen in normal individuals. This can occur because different combinations of LV relaxation and left atrial (LA) pressures may result in the same early diastolic
transmitral pressure gradient and hence a similar mitral flow velocity pattern. For this reason, additional data, such as pulmonary venous flow velocity, is
often helpful in distinguishing normal from abnormal mitral filling patterns, especially of the pseudonormal type. The dashed lines in pulmonary venous
flow represent common variations. A, peak mitral flow velocity at atrial contraction; E, peak mitral flow velocity in early diastole; IVRT, LV isovolumic relax-
ation time; PVa, reverse pulmonary venous flow at atrial contraction; PVd, pulmonary venous flow velocity in diastole; PVs, pulmonary venous flow velocity
in systole. (Modified from Appleton CP: The natural history of left ventricular filling abnormalities: Assessment by two-dimensional and Doppler echocardiography.
Echocardiography 1992;9:437–457.)

flow velocities in Figure 10-6. Although theoretical when pro- pressure is normal, so that with preload reduction, the whole
posed in 1992,24 the progression of abnormalities in LV filling diastolic transmitral pressure gradient decreases and both E- and
patterns with disease states (from impaired relaxation to pseudo- A-wave velocities decrease. In patients with reduced systolic func-
normal to restrictive), together with changes in LV relaxation and tion and an impaired relaxation pattern, increasing preload by leg
compliance, has been documented in experimental models of con- raising may result in no change in the filling pattern. However, if
gestive heart failure76 and clinically observed in patients with a pseudonormal mitral flow velocity pattern results, it indicates a
restrictive cardiomyopathies.20 Many variations of LV filling pat- higher cardiovascular morbidity than if their E/A ratio remains
terns that do not exactly match the three “classical” abnormal less than 1.28
patterns are common because of the multiple combinations of the With pseudonormal mitral flow patterns, the Valsalva strain
rate of LV relaxation and compliance. However, the abnormal LV lowers the elevated LA pressure and “unmasks” the underlying
filling patterns remain specific to the alterations in diastolic prop- impaired LV relaxation.29 A notable feature of this change is the
erties rather than to the type of cardiac disease, with all three increase in mitral A-wave velocity and duration as the left atrium
patterns, depending on disease stage, being seen in disorders as ejects into a ventricle that has a lower pressure. Preload-sensitive
diverse as restrictive and dilated cardiomyopathies. patients with restrictive filling patterns will revert to a pseudonor-
This “natural history” of LV filling explains how both young mal filling pattern. In individuals who perform an adequate Val-
normal individuals and patients with severe disease and a salva and yet remain restrictive, LV stiffness is markedly increased,
restrictive filling pattern can have a high proportion of filling in even at the more normal filling pressures. These patients have a
early diastole and an audible S3 gallop.77 It also shows that PV poor prognosis.32
flow velocity has its own changes that occur with normal aging
and in cardiac disease states (discussed below) and that these
associated PV filling patterns are more distinctive than some
Grading the Degree of Left Ventricular Diastolic
similar-appearing normal and abnormal mitral flow velocity Dysfunction by Mitral Flow Velocity Alone
patterns.26 A simplified grading system for diastolic function based on the
three abnormal mitral flow velocity patterns alone is shown in
Figure 10-848 and has been found to be useful in many patients.
Left Ventricular Filling and Changing Cardiac
Grades Ia and Ib represent an impaired relaxation filling pattern
Loading Conditions with normal mean LA pressure and LA size. The difference is
Simple maneuvers in the echo laboratory to reduce (Valsalva) or whether all LV filling pressures are normal (Ia) or whether LV
increase (leg raising) preload demonstrate that mitral flow veloc- pressure increase with atrial contraction is abnormal and increases
ity patterns are a dynamic continuum.28–30 Plotting the changes LVEDP (Ib). This is important because an increase in LVEDP
in E-wave velocity and mitral DT in individuals after altering is the first hemodynamic abnormality of diastolic dysfunction
loading conditions has even been proposed as a load-independent (see Fig. 10-2). Grade II indicates pseudonormal filling with
index of normal and abnormal diastolic filling.78 increased mean LA pressure, and grade III is a restrictive LV
During the strain phase of a Valsalva maneuver, preload (mean filling pattern. Grade IV is restrictive filling that does not revert
LA pressure) is reduced, and in normals peak mitral E-wave to pseudonormal with preload reduction, indicating the most
velocity decreases by at least 20% during maximum strain with a advanced LV diastolic dysfunction and the worst prognosis.
smaller decrease in peak A-wave velocity (Fig. 10-7). Similarly, in Although grading LV diastolic dysfunction by mitral flow
patients with an impaired relaxation filling pattern, mean LA velocity pattern alone can be helpful, many patients (especially the
122 Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling

LV FILLING PATTERNS: RESPONSE TO PRELOAD REDUCTION (VALSALVA)

Normal Pseudonormal Pattern Baseline Maximum Interpretation

Normal Normal

Impaired Normal
relaxation pressures

Impaired ↑ LV A wave,
relaxation ↑ EDP
Valsalva Valsalva
Pseudonormal Pseudonormal

Preload sensitive
Restrictive
partially reversible

Restrictive Fixed restrictive

A B
Figure 10-7 Changes in mitral flow velocity patterns to preload reduction using the Valsalva maneuver. A, PW Doppler mitral flow velocity recordings
from a normal individual and a patient with pseudonormal left ventricular (LV) filling. After Valsalva, the normal has both E- and A-wave velocity decrease
with little change in E/A ratio, while the lowering of left atrial (LA) pressure in the pseudonormal patient “unmasks” an impaired LV relaxation filling pattern.
B, In tabular form the different responses seen in mitral LV filling patterns with a Valsalva maneuver after approximately 10 seconds of strain. In all but
fixed restrictive, the E-wave velocity should decrease at least 20%. When mean LA pressure is normal, the mitral A-wave velocity also decreases. No A-wave
change with an impaired relaxation filling pattern suggests an elevated LV end diastolic pressure (EDP). With mean LA pressure increased, pseudonormal
filling reverts to impaired relaxation filling, and most restrictive patterns to pseudonormal. The exception is irreversibly restrictive, where advanced disease
results in no change in filling, even with a moderate decrease in mean LA pressure. (A, From Dumesnil JG et al: Use of Valsalva maneuver to unmask left ven-
tricular diastolic function abnormalities by Doppler echocardiography in patients with coronary artery disease or systemic hypertension. Am J Cardiol 1991;68:515–
519. B, From Appleton CP: The echo-Doppler evaluation of left ventricular diastolic function. A current perspective. Cardiol Clin 2000;18:513–546, ix.)

SIMPLIFIED LV DIASTOLIC FUNCTION CLASSIFICATION

Normal IR IR+ PN Restrictive

Grade DHF Ia Ib II III IV*

*No change with Valsalva

Figure 10-8 A simplified grading system for diastolic dysfunction is shown that assigns each abnormal mitral flow velocity pattern to a progressively more
advanced grade of diastolic heart failure. Impaired relaxation Ia has normal filling pressures, while IR + Ib has an increase in left ventricular (LV) end diastolic
pressure, the first hemodynamic abnormality that occurs in diastolic dysfunction. Grade III is restrictive, which will revert to a pseudonormal pattern with
Valsalva maneuver and left atrial pressure (preload) reduction, while grade IV diastolic heart failure will not, an ominous prognostic sign. (From Oh JK
et al: Diastolic heart failure can be diagnosed by comprehensive two-dimensional and Doppler echocardiography. J Am Coll Cardiol 2006;47:500–506.)

elderly) may be misclassified. The rate of LV relaxation and LV giving similar mitral E/A wave ratios of approximately 2, yet the
compliance and filling pressures are a continuum, and similar LV mean LA pressure varies threefold because of the markedly dif-
filling patterns are possible with different combinations of these ferent rates of LV relaxation.59 In these cases, ancillary data such
diastolic properties.48,49 A major area of misinterpretation con- as two-dimensional anatomic abnormalities, LVEF reduction,
cerns patients with markedly impaired LV relaxation where LA LVH, LA enlargement, or altered PV flow or annular TDI veloci-
pressures are elevated with an increase in the E-wave velocity, yet ties are indicators that abnormal diastolic function and pressures
the filling pattern appears to be impaired (E/A ratio <1) because are present.47–49,79 Also some mitral filling patterns are “atypical,”
of partial fusion of early and late diastole (see Fig. 10-3) or because meaning that a biphasic mitral DT, a mid-diastolic filling “hump,”
LV relaxation is so abnormally slow that only marked increases or some other unusual feature is present. These less common LV
in mean LA pressure will result in pseudonormal filling. Figure filling patterns do not fit well into a grading scheme for diastolic
10-9 shows an example of this latter phenomenon. In this case, dysfunction that uses only the mitral flow velocity pattern and are
three patients with hypertrophic cardiomyopathy have different best understood by evaluating the abnormal diastolic properties
combinations of the speed of LV relaxation and LA pressure, and physiology that the altered LV filling reflects.
 Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling 123

LV
relaxation

Figure 10-9 An illustration of how dif- LV

ferent combinations of impaired left pressure
ventricular (LV) relaxation and left atrial
(LA) pressure can result in mitral flow 7
velocity patterns with similar E/A ratios
but markedly different filling pressures. All combinations = 7
The pulsed wave (PW) mitral recordings (i.e., LV relaxation + LV pressure = the same filling pattern)
shown are from three patients with
hypertrophic cardiomyopathy. The E
patient on the left is the most normal,
with the least impaired LV relaxation 150 mmHg
E E 0.2 m/sec
and a normal mean LA pressure. The
150 mmHg
patient on the right has a similar LV A
filling pattern but marked diastolic A LV LV
100 mmHg
dysfunction, with severely impaired LV A
relaxation and a mean LA pressure of
30 mmHg. In these cases, the grading
system of diastolic dysfunction in Figure
10-8 would not work well, and other
ancillary variables indicate the true
degree of diastolic dysfunction present. LA
(From Nishimura RA et al: Noninvasive LA
0 mmHg
Doppler echocardiographic evaluation of 0 mmHg 0 mmHg
left ventricular filling pressures in patients
with cardiomyopathies: A simultaneous
LV relaxation
Doppler echocardiographic and cardiac
catheterization study. J Am Coll Cardiol LA pressure 9 14 30 mmHg
1996;28:1226–1233.)

Grading the Degree of Left Ventricular Diastolic While there are now several additional echo-Doppler variables to
Dysfunction in Epidemiologic Studies help identify pseudonormal filling (LA size, color M-mode [CMM]
inflow propagation velocity, mitral annular TDI), PV flow velocity
Recent landmark studies show that many asymptomatic individuals analysis remains unique and indispensable to identifying an abnor-
with a normal LVEF have abnormal diastolic function that is a risk mal increase in LV pressure at atrial contraction.
factor for future development of adverse cardiovascular events such The various components of PV flow velocity change with age,
as new-onset heart failure, a first episode of atrial fibrillation or mitral flow velocity, and disease states and can be matched to their
stroke, and death.50,80 In an effort to improve predictive value beyond corresponding mitral Doppler patterns (see Fig. 10-6). The hemo-
that of analyzing mitral flow velocity alone, the classification of the dynamic determinants of PV flow velocity have been studied in
degree of LV diastolic abnormality in these studies included mitral vivo81–84 and clinically26,85–87 and related to individual variables (Fig.
inflow velocity variables (especially the E/A wave ratio), their 10-11). These include peak forward flow velocity in early systole
response to the Valsalva maneuver, PV flow velocity, and TDI of the (PVs1), late systole (PVs2), and early diastole (PVd) and peak
mitral annulus. Figure 10-10 shows the multiple echo-Doppler cri- reverse flow velocity at atrial contraction (PVa) and its duration
teria for grading diastolic dysfunction in these epidemiologic studies (PVa dur). A dip or “notch” between PVs1 and PVs2 in early
and provides a preview of the ancillary variables that aid in this LV systole represents the C wave seen in LA pressure recordings
interpretation (discussed later in this chapter). at the time of mitral valve closure. PVs1 blends with PVs2
velocity, and this “notch” is not distinctly seen in most (about 70%)
transthoracic flow velocity recordings75 but is observed more often
PULMONARY VENOUS FLOW VELOCITY with a first-degree atrioventricular (AV) block and in virtually
all transesophageal-echo (TEE) recordings in patients in sinus
PV velocity, usually obtained with PW Doppler from the right rhythm.86
upper pulmonary vein during transthoracic apical imaging, reflects PVs1 occurs in early ventricular systole as a result of LA relax-
the filling dynamics of the left atrium. With experience, high-quality ation and a decrease in downstream LA pressure at a time when
PW Doppler transthoracic recordings can be obtained in approxi- PV pressure is relatively constant. PVs2 peaks later in systole and
mately 85% to 90% of patients.75 Within a short time after mitral is due to the increase in PV flow and pressure that results from
flow velocity patterns were correlated with hemodynamics, it systolic right ventricular (RV) stroke volume. Maximal PVs2
became apparent that PV flow velocity could be of additional help velocity, its time-velocity integral (TVI), and deceleration of flow
in assessing LV filling patterns,26 especially impaired relaxation reflect the pressure difference between PV and downstream LA
filling with increased LVEDP and pseudonormal LV filling.64–66 pressure as blood fills both vascular systems. The descent of the
124 Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling

Severe diastolic dysfunction

Mild diastolic
Moderate diastolic
Normal diastolic dysfunction Reversible Fixed
dysfunction
function Impaired restrictive restrictive
Pseudonormal
relaxation
0.75 < E/A < 1.5 0.75 < E/A < 1.5 E/A >1.5 E/A >1.5
Velocity (m/sec) DT >140 msec E/A < 0.75 DT > 140 msec DT< 140 msec DT < 140 msec
2.0
E
Mitral inflow A

0
Adur
ΔE/A < 0.5 ΔE/A < 0.5 ΔE/A ≥ 0.5 ΔE/A ≥ 0.5 ΔE/A < 0.5
Velocity (m/sec) Velocity (m/sec)

2.0
Mitral inflow at
peak Valsalva E
A
maneuver
0

E/E′ < 10 E/E′ < 10 E/E′ ≥ 10 E/E′ ≥ 10 E/E′ ≥ 10

Doppler tissue 0
imaging of mitral
annular motion 0.15 A′
E′
S≥D S>D S < D or S < D or S < D or
ARdur < Adur ARdur < Adur ARdur > Adur + 30 msec ARdur > Adur + 30 msec ARdur > Adur + 30 msec
Velocity (m/sec)

1.0 S D
Pulmonary
ARdur
venous flow
0
AR
Time (msec) Time (msec) Time (msec) Time (msec) Time (msec)
Left ventricular relaxation Normal Impaired Impaired Impaired Impaired
Left ventricular compliance Normal Normal to ↓ ↓↓ ↓↓↓ ↓↓↓↓
Atrial pressure Normal Normal ↑↑ ↑↑↑ ↑↑↑↑
Figure 10-10 A more complicated grading system for left ventricular (LV) diastolic dysfunction that incorporates multiple mitral flow velocity variables,
their response to Valsalva maneuver, pulmonary venous flow velocity variables and tissue Doppler imaging of the septal mitral annulus. These criteria have
been used in epidemiologic studies to assess the asymptomatic prevalence of diastolic dysfunction in the community and also how LV diastolic dysfunc-
tion increases the risk for future adverse cardiac events. (From Redfield MM et al: Burden of systolic and diastolic ventricular dysfunction in the community:
Appreciating the scope of the heart failure epidemic. JAMA 2003;289:194–202.)

AV rings with ventricular systole increases LA size and compli- (<40%) indicates LA systolic dysfunction (decline in PVs1) and
ance while helping decrease the downstream LA pressure. PV has a high specificity for a pseudonormal LV filling pattern and
diastolic flow velocity (PVd) initially follows early diastolic mitral increased mean LA pressure (see Fig. 10-12).28,87 The PV A wave
flow velocity; but in mid-diastole, LV filling slows while PVd flow and its relation to mitral A-wave duration are of special impor-
continues with ongoing LA enlargement and appendage filling. tance and are discussed in detail below.
PV flow reversal due to atrial contraction (PVa) is determined by
LA contractility and LV compliance, with more and longer reverse
flow seen as LV compliance decreases. Relation of Mitral to Pulmonary Venous
Changes in PV flow velocity and their relation to LV compli- A-Wave Duration
ance and LA pressures are shown in Figure 10-12. In patients
As shown in Figure 10-13, when both A-wave flow velocity dura-
with impaired relaxation filling, decreased LV compliance, and
tions are accurately recorded, this relation is an important indica-
normal mean LA pressure, early diastolic filling (mitral E wave)
tion of LV A-wave pressure increase and LV end diastolic
is reduced. In these cases, LA hypertrophy (LAH) provides a
pressure,64–66,88,89 even in the pediatric age group.90 Laboratories
sufficient atrial “kick” to fill the left ventricle to its optimal end
that do not routinely record PV flow velocity will miss the unique
diastolic volume. An important benefit of LAH is that it confines
aspects of this derived variable. Unlike other Doppler variables,
the abnormal pressure rise in the atrium, ventricle, and pulmonary
the relation is independent of age, meaning that mitral A-wave
veins to the short period associated with atrial contraction so that
duration remains equal to or longer than PV A-wave duration
mean LA pressure remains normal (see Fig. 10-2). PVs1 is
throughout life in normal individuals. Secondly, the relation of
increased so that the PV systolic-to-diastolic flow velocity ratio
the two A-wave durations is our only echo-Doppler variable that
remains above 50%. If LV compliance decreases further, the
directly relates to the rise in LV pressure at atrial contraction,
atrium may begin to decompensate, enlarge, and have contractile
thereby separating patients with impaired relaxation who have
dysfunction. A reduced systolic fraction of PV antegrade flow
normal filling pressures from those who have an increased LVEDP
 Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling 125

PVs2

PVd
PVs1
ECG
PVs2 PVd

PVs1

0
Figure 10-11 A, Pulmonary venous (PV) vari-
ables obtained with the pulsed wave Doppler
technique include peak flow velocity and early PVa PVa
systole (PVs1), late systole (PVs2), and early dias- PVa dur
tole (PVd) and peak reverse flow velocity (PVa) A
and its duration (PVa dur) at atrial contraction.
B, Panel 1 shows simultaneously recording of PV
flow velocity together with PV and left atrial (LA)
pressures. Panel 2 is a schematic drawing of PV 80 PVd 200 msec
PV velocity (cm/sec)

and left atrial (LA) pressures showing the differ- 8

ent hemodynamic pressure gradients (hatched PVs2
areas) that determine the four individual PV flow PVs2 PV
PVa
velocity components. These components are 40 PV

mmHg
described in the text. (A, From Appleton CP et al: LA 6 LA PVd
The echo-Doppler evaluation of left ventricular PVs1
PVs1
diastolic function. A current perspective. Cardiol 0
Clin 2000;18:513–546, ix. B, From Appleton CP: PVa dur
Hemodynamic determinants of Doppler pulmo- –20
PVa 4
nary venous flow velocity components: New
PVa dur
insights from studies in lightly sedated normal
dogs. J Am Coll Cardiol 1997;30:1562–74.) B

PULMONARY VENOUS FLOW VELOCITY

PVs PVd

PVa
Normal ↓ LV ↓ LV
Impaired
compliance compliance
relaxation
↑ LAP ↑↑ LAP

40 1 m/sec
PWP (mmHg)

30
0.4
20

10 0

0
0 20 40 60 80 100
0.4
PV systolic fraction (%)
B C
Figure 10-12 A, Schematic drawing of pulmonary venous (PV) flow velocity patterns obtained with PW Doppler from normal to most abnormal (left to
right). With impaired relaxation, the proportion of PV systolic flow (PVs) increases as PV diastolic flow (PVd) decreases, paralleling the decrease in mitral
E-wave velocity. Reverse flow back into the pulmonary veins with atrial contraction (PVa) is variable, being increased in velocity (>35 cm/sec) and duration
(>30 msec greater than mitral A-wave duration) if left ventricular (LV) end diastolic pressure is elevated. As LV compliance decreases, and left atrial pressure
(LAP) increases, the proportion of PVs flow decreases. At the same time, PVd and E-wave velocity increase with pseudonormal and restrictive LV filling
being seen. All mitral and their corresponding PV patterns are shown together in Figure 10-6. B, The relation of PV systolic fraction (in % of total forward
flow) to pulmonary wedge pressure (PWP). When PVs is <40% in a patient with heart disease, PWP is elevated. C, PW Doppler mitral and PV flow velocity
in a patient with pseudonormal to restrictive filling who has an enlarged left atrium and whose contractile function is failing. PVs is decreased with a systolic
fraction <40%, PVd is increased, and the velocity and duration of PVa exceed those of the mitral A-wave (vertical lines). This indicates that mean LA pres-
sure, LV A-wave pressure rise, and LV end diastolic pressure are all increased. (B, From Kuecherer HF et al: Pulmonary venous flow patterns by transesophageal
pulsed Doppler echocardiography: Relation to parameters of left ventricular systolic and diastolic function. Am Heart J 1991;122:1683–1693.)
126 Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling

MITRAL VS. PULMONARY VENOUS A - WAVE DURATION:

RELATION TO LVEDP

–30
40
S
Velocity

D
30

LVEDP
PVa-d
Svti Dvti
20
PVa-vti
Ddt
PVa 10

A 0
E
–100 –50 0 50 100
Velocity

MVA dur – PVa dur

B
Pulmonary venous
Mitral
Edt Adur

1– 0.5–

EDP m/sec
Pressure

0
LVa
Pre-a
0 0.5–
PVa
Adur 121 msec Adur 200 msec
A C
Figure 10-13 A, Schematic diagram of the relation of pulmonary venous (PVa-d) and mitral flow velocity A-wave duration (Adur), which relates to the left
ventricular (LV) pressure rise at atrial contraction (LVa). The graph combines Doppler data from three separate studies (from references 64–66) and shows
that when the reverse duration of PV compared with mitral A-wave flow exceeds 30 msec, LV end diastolic pressure (LVEDP) is usually >15 mmHg. C, PW
Doppler mitral and PV flow velocity from a patient with LV hypertrophy and impaired relaxation filling. The mitral A-wave duration is 121 msec and PV A-
wave duration 200 msec, so that flow backward into the pulmonary vein continues for 80 msec after flow into the left ventricle stops. This indicates that
LV A-wave pressure increases and LV end diastolic pressure is elevated. (A, From Kuecherer HF et al: Pulmonary venous flow patterns by transesophageal pulsed
Doppler echocardiography: Relation to parameters of left ventricular systolic and diastolic function. Am Heart J 1991;122:1683–1693.)

(>12 mmHg), the first hemodynamic abnormality seen with dia- shorter because it starts above the conventional measuring point
stolic dysfunction. of the zero velocity baseline.
Under normal circumstances when the left atrium contracts,
the net volume and duration of flow should be greater forward
CLINICAL APPLICATIONS:
into the left ventricle than backward into the pulmonary veins. If
INTERPRETATION OF INDIVIDUAL MITRAL
the PV A wave is increased in either velocity (>35 cm/sec) or
FLOW VELOCITY VARIABLES
duration (>30 msec longer than mitral A wave), LV A-wave pres-
sure is increased and LVEDP is elevated (see Fig. 10-13). Even
Studying the factors that influence individual mitral flow velocity
in cases where the atrium is enlarged, markedly hypokinetic, and
variables is often useful in interpreting LV filling patterns in dif-
failing, the PV A-wave duration of reverse flow continues to be
ficult or uncommon cases. It is also a powerful tool for deciding
more than 30 msec longer than the abbreviated mitral A-wave
which diastolic property is most abnormal, which helps in the
inflow duration. If the PV A-wave duration is difficult to measure
planning of possible clinical interventions in individual patients.
due to a suboptimal recording, referencing the end of both A-wave
flows to the QRS complex is helpful, as PV flow duration is
abnormal if it exceeds that of the mitral A wave. A detailed guide Left Ventricular Isovolumic Relaxation Time
to obtaining high-quality PW Doppler PV flow velocity record- LV IVRT is the interval from aortic valve closure to mitral valve
ings has been published.75 opening and the start of mitral inflow (see Fig. 10-4). This interval
The interpretation of mitral versus PV A-wave duration may can be a powerful tool for physicians in helping to evaluate dia-
not be reliable if the mitral velocity at the start of atrial contrac- stolic dysfunction and filling pressures, especially when the mitral
tion is greater than 20 cm/sec,88 or if atrial contraction occurs E wave is increased or atrial fibrillation is present. We suggest it
before PVd has reached the zero velocity baseline.49 In the first be measured on all echo-Doppler studies.91
case, the peak mitral A-wave velocity, TVI, and A-wave duration In normal patients, IVRT varies with age, being shorter in the
are longer than normal to accommodate the increased atrial stroke young, who have rapid LV relaxation that results in an earlier
volume that is present; and in the second case, the PV Adur is mitral valve opening, and then becoming lengthened as relaxation
 Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling 127

slows with age.17 Figure 10-14 compares the effect of changes in A common instance when IVRT duration can be very helpful
the rate of LV relaxation and LA pressure on the IVRT interval, is when heavy mitral annular calcification is present and there is
timing of the mitral valve opening, and LV filling pattern using a a question of mild calcific mitral stenosis versus LV diastolic
normal subject and a patient with impaired LV relaxation. dysfunction. The mitral annular narrowing may increase E-wave
The IVRT interval is most helpful when it is at its extremes, velocity, the E/A wave velocity ratio, and LA size, making the
meaning farthest from expected norms, being either short assessment of LV diastolic dysfunction difficult. If the pressure
(<60 msec) or long (>110 msec). It is less useful in-between these half-time is normal or borderline but the IVRT is short (20 msec
values. A normal IVRT for a middle-aged adult is approximately less than expected for age), LA pressure is likely elevated due to
80 msec. A short IVRT (<60 msec) indicates an early mitral valve a noncompliant left ventricle. Conversely, if E-wave velocity is
opening; a long IVRT (>100 msec), a delayed LV relaxation and increased but the IVRT is normal, mild annular narrowing is
a late valve opening. In patients with impaired relaxation filling likely the cause for the increased velocity. A markedly prolonged
and normal pressures, a prolonged IVRT is an early indicator of pressure half-time indicates calcific mitral stenosis, in which case
LV diastolic dysfunction.60,92 If mean LA pressures remain a short IVRT would also indicate increased mean LA pressure,
normal, extremely slow LV relaxation can result in IVRT values similar to the auscultatory findings of a short opening snap
that approach 200 msec. The higher filling pressure in pseudo- interval.
normal filling patterns causes the mitral valve to open earlier, so
the IVRT shortens. More normal values of 60 to 100 msec are Left Ventricular Intracavitary Flow During
usually seen, and the IVRT value is less useful. A short IVRT of
40 to 60 msec can be seen in young, healthy, normal individuals Isovolumic Relaxation Time
or in patients with very high mean LA pressure and restrictive LV IVRT flow is usually apically directed, from one part of the
filling. This clinical distinction is easily made by normal versus ventricle to another, occurring when both aortic and mitral valves
abnormal two-dimensional anatomic findings, especially of LA are closed during IVRT.93 The importance of recognizing IVRT
size and contractile function. flow is twofold; it indicates that abnormal, dyssynchronous LV

Effect of the speed of

LV relaxation on
TMPG and LV IVRT
LV pressure
Mitral flow
velocity
Abnormal
LV relaxation

Ac

LAP
Abnormal
LV IVRT relaxation
A C
Effect of LAP on
TMPG and LV IVRT

Mitral flow velocity

Ao
Ao
1 m/sec
LV
LV c m/sec
–50
LV
Ac
LAP
Normal Abnormal
LV IVRT relaxation relaxation
B D
Figure 10-14 The left ventricular (LV) isovolumic relaxation time (IVRT). A, The effect of the speed of LV relaxation on early diastolic (E-wave) transmitral
pressure gradient (TMPG) and IVRT with constant left atrial (LA) pressure. The slower the LV relaxation, the longer the IVRT interval and the smaller the
TMPG (E wave). B, The effect of different LA pressures (LAP) on LV IVRT with a constant rate of LV relaxation. The higher the LAP, the shorter the IVRT and
the earlier the mitral valve opening. C, D, Schematic of LV pressure and mitral flow velocity (top) and PW Doppler mitral flow velocity recordings in two
subjects (bottom), illustrating the principles in the left panel. The normal subject shows rapid relaxation, a normal LV filling pattern, and normal IVRT of
70 msec (small vertical arrows). The patient on the left has hypertension and slower LV relaxation. With a normal mean LAP, this results in a longer IVRT
(110 msec), lower E-wave, increased A-wave velocity, and the familiar impaired LV relaxation filling pattern. (C, D, From Hatle LK et al: Differentiation of con-
strictive pericarditis and restrictive cardiomyopathy by Doppler echocardiography. Circulation 1989;79:357–370.)
128 Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling

relaxation is present between apex and base and that its peak stroke volume. Cardiac output is this stroke volume times the
velocity should not be confused with the mitral E-wave velocity heart rate. Since the mitral orifice is larger than the aortic annulus,
that immediately follows it. In the normal situation, no significant the mitral TVI should be smaller than the LV outflow tract
LV flow is detected during the IVRT period. When present, (LVOT) TVI, typically by about 30%.
IVRT flow is most easily detected from an apical transducer posi- If cardiac output is either elevated or decreased, the mitral-to-
tion with CW or CMM Doppler because both techniques scan LVOT TVI ratio should remain normal. With significant mitral
the long axis of the ventricle. PW Doppler can then be used for regurgitation (MR) or mitral stenosis (MS), the mitral TVI will
better velocity definition. When present, IVRT flow is usually 20 increase and be as large or larger than the LVOT TVI. With
to 60 cm/sec but can occasionally be as high as 1 to 2 m/sec, as isolated aortic regurgitation, the reverse relation may exist,
seen in Figure 10-15. increasing the difference from aortic to mitral TVI. As early and
When IVRT flow is present, the most common cause is sys- late diastolic mitral TVIs represent the sum of LV filling, an
tolic LV narrowing at the papillary muscle level, due to either inverse relation exists. A large early diastolic mitral TVI will be
LVH or hyperdynamic systolic function, which increases late sys- associated with a smaller TVI at atrial contraction. Conversely,
tolic flow velocities. The increased mid- or late systolic load placed when the E-wave TVI is decreased, the ventricle can reach a
on the LV apical segments causes the apex to relax prematurely normal end diastolic volume only if there is a corresponding
before the basal myocardial segments, with blood flow moving increase in A-wave TVI. If mitral E and A waves are partially
toward the lower pressure in the apex before the mitral valve fused at rest, a low proportion of E-wave versus A-wave TVIs
opens. “Bidirectional” IVRT flow is occasionally seen when apical may be present. Patients often have a reduced functional aerobic
directed flow “turns around,” flowing back toward the annulus as capacity because of an inability to increase LV diastolic volume
basilar relaxation reduces pressure below that in the apex. IVRT adequately with exercise.72
flow can also be observed in the left ventricle with dyssynchro-
nous LV relaxation due to coronary artery disease (CAD) with a
left bundle branch block (LBBB) and in the RV apex when it is Peak Mitral E-Wave Velocity
hyperdynamic and exhibits systolic cavity obliteration. The early diastolic transmitral pressure gradient52 (see Fig. 10-1)
determines peak mitral E-wave velocity, whose values in normals
of various ages have been published but have wide confidence
Mitral Time-Velocity Integral limits.16–18 These studies were performed before additional vari-
Though rarely considered when discussing the assessment of LV ables such as LA volume or TDI annular velocities were routinely
diastolic function, the absolute value of the mitral TVI is often performed, which would verify that normal cardiac physiology
helpful in interpreting mitral flow velocity patterns. In the absence was present. Table 10-1 lists E-wave velocities in individuals of
of significant mitral or aortic regurgitation, mitral TVI multiplied various ages without histories of cardiac disease, in whom these
by the mitral valve cross-sectional orifice area represents the LV newer variables were included, and who also had normal blood

CMM DOPPLER

IVRT flow

PW DOPPLER MID-LV CAVITY

IVRT flow 1.5 m/sec

E
Sys A
Figure 10-15 Isovolumic relaxation time
1.0 (IVRT) flow in the mid–left ventricular (LV)
E cavity in a patient with LV hypertrophy
A and near systolic cavity obliteration. All
1.0 1.5 recordings are from an apical transducer
0.5 position. The color M-mode (CMM, top
left) is directed through the mitral valve.
CW DOPPLER Sys Midcavity systolic flow (Sys) is followed by
bidirectional IVRT flow, first toward the
IVRT [m/sec] apex (orange) and then a shorter period
E flow toward the base (blue, arrows). This is
followed by mitral E and A waves. CW
Doppler shows the apically directed IVRT
–0.5 flow, followed by mitral E-wave and mild
mitral regurgitation. PW Doppler at the
83 mid-LV cavity shows late peaking systolic
1.0 1.5 2.0 flow acceleration at the area of LV narrow-
100 mm/sec HR
MR ing (papillary muscle level), and then very
prominent IVRT flow first toward the apex
(1.6 m/sec, arrow above baseline) and then
lower velocity toward the base (0.3 m/sec,
arrow below baseline).
 Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling 129

pressure, ECG, and echo-derived LV mass. Therefore, although the shorter the mitral DT and the more “restrictive” the LV filling
sample sizes are much smaller in terms of absolute patient pattern, the higher the mortality.
numbers, the confidence limits are smaller and the results more The acceleration of E-wave mitral flow velocity is related to the
likely to represent true normal values. maximum early diastolic transmitral pressure gradient. The decel-
Since E-wave and LVOT velocities are related to stroke volume eration of this flow, the mitral DT, is related to how fast (or slow)
and orifice area, a predictable ratio between these variables exists LV pressure increases in early diastole as volume enters the ven-
in normals regardless of heart rate and cardiac output. The normal tricle (the rapid filling wave as shown in Figs. 10-1 and 10-2). As
LVOT velocity is approximately 1 m/sec. Table 10-1 shows that with other mitral flow velocity variables, mitral DT changes with
the mitral/LVOT velocity ratio is about 80% in younger individ- age, lengthening as the rate of LV relaxation slows and less volume
uals, decreasing to 70% in middle age and 60% in the elderly as is transferred to the ventricle in early diastole (see Table 10-1). A
LV relaxation slows slightly and E-wave velocity decreases. Rou- short mitral DT (140–160 msec) is normal in healthy, young
tinely checking this E-wave/LVOT velocity ratio improves the individuals due to the high proportion of filling in early diastole
assessment of LV filling patterns and diastolic function. An E- that occurs because of LV elastic recoil. As E-wave velocity and
wave/LVOT velocity ratio lower than expected indicates impaired the proportion of early diastolic filling declines with age, mitral
LV relaxation and normal mean LA pressure. A normal ratio with DT increases to about 200 msec by age 65 (see Table 10-1).
increased or decreased E- and A-wave velocities is seen with With impaired LV relaxation and normal mean LA pressure,
reduced or increased cardiac output. Higher than expected ratios early diastolic filling is reduced (E/A wave ratio <1) and mitral
indicate that peak E-wave velocity is elevated, which may occur DT is prolonged roughly in proportion to the slowing in the rate
for several reasons. These include MS, MR, or increased mean of LV relaxation.97 With pseudonormal mitral filling, the elevated
LA pressure. mean LA pressure increases filling in early diastole into the non-
Patients with MS or MR have increased E-wave velocities that compliant ventricle, and the rapid filling wave shortens the DT,
may not reflect diastolic dysfunction. Mean transvalvular gradient with values that appear more normal for age. More advanced
and pressure half-times help assess the severity of MS, while disease and further decreases in LV compliance cause such high
IVRT reflects mean LA pressure. Significant MR increases E- LA pressure that blood is forced rapidly into a stiff ventricle in
wave velocity due to the regurgitant volume recrossing the mitral early diastole, which causes a very rapid, abnormal rise in LV
valve in early diastole. Normally the ventricle and left atrium pressure.19 A short mitral DT (<140 msec) characterizes this
become more compliant as they undergo chamber enlargement restrictive filling, which is most commonly seen in advanced
and eccentric hypertrophy through a rightward shift in the dilated or restrictive cardiomyopathies. In these cases, and despite
pressure-volume relation. Mitral DT and PA pressures remaining the widely variable LVEFs, mitral DT is strongly related to both
normal despite the volume overload reflect this normal adapta- the elevated filling pressures51 and survival.21,94
tion. A shortening of mitral DT or increased pulmonary artery Mitral DT is dynamic and will change with alterations in
pressures suggest acute MR or an abnormal decrease in LV com- preload and afterload that change the transmitral pressure gradi-
pliance due to additional pathology. ent. Patients who are volume overloaded may lengthen their DT
Many elderly patients with hypertension and LVH have an with diuresis. Similarly, mitral DT may lengthen and become less
elevated E-wave velocity of 1 m/sec or greater with a mitral E/A restrictive in response to a Valsalva maneuver (see Fig. 10-7) that
wave ratio of less than 1. Using a diastolic function assessment by lowers preload.30 Persistence of a restrictive LV filling pattern in
mitral filling pattern alone frequently labels these patients as a cardiomyopathy despite a Valsalva maneuver or after maximum
having “impaired LV relaxation,” suggesting that mean LA pres- medical therapy is the most severe form of diastolic dysfunction
sure is normal when in fact the increased E-wave velocity is due (grade IV; Figs. 10-7, 10-8, and 10-10), an ominous prognostic
to increased mean LA pressure. The higher A-wave velocity sign that indicates a very high mortality.32
reflects LAH or partial fusion of E- and A-wave velocities due to Mitral DT is also useful in patients with MR, where the well-
a relatively fast heart rate or first-degree AV block. Clues that adapted ventricle will retain a normal DT. Shortening of the
patients with an impaired relaxation pattern actually have moder- mitral DT from expected normal values for age indicates increased
ate diastolic dysfunction and elevated mean LA pressure equiva- ventricular stiffness and is a better indicator of myocardial pathol-
lent to pseudonormal filling are: marked LVH, LA enlargement, ogy than is peak E-wave velocity (see Fig. 10-16).
and a preA velocity greater than 20 cm/sec.
The differentiation between a normal and a pseudonormal Mitral Flow Velocity at the Start of
filling pattern can be made by two-dimensional findings (vigorous
LV and RV contraction, normal LA size) or other ancillary Atrial Contraction
variables, such as PV systolic fraction, CMM mitral inflow pro- Although rarely measured, or even considered, mitral flow veloc-
pagation velocity, and mitral annular TDI. The change to a less ity at the start of atrial contraction (see Fig. 10-4) is important
abnormal LV filling pattern with a Valsalva maneuver (see Fig. because it affects peak mitral A-wave velocity, the mitral E/A
10-7) reveals the preload sensitivity of the abnormal diastolic wave ratio, and the mitral A-wave duration. Therefore, we encour-
function. Figure 10-16 shows increased E-wave velocities from age its routine measurement along with those of the other mitral
expected values in several patients, illustrating the concepts we flow velocity variables to improve the accuracy of assessing LV
have discussed. diastolic function.
In normal individuals, the heart rate at rest is slow enough to
keep this velocity at under 20 cm/sec. This maximizes early and
Mitral Deceleration Time mid-diastolic ventricular filling and minimizes the proportion of
Mitral DT is arguably the most important mitral variable for filling associated with the booster pump function of atrial con-
prognosis when heart disease is present, regardless of LVEF.21,32,94,95 traction. With exercise, fusion of early and late diastolic filling will
In cardiac patients, mitral DT relates to LV chamber stiffness96; occur, but only at relatively rapid heart rates because of the effects
130 Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling

m/sec
2.0

1.5

1.0

0.5

0
NI IR PN PN-V RST MR MS
Figure 10-16 PW Doppler recordings of mitral flow velocity in seven individuals (left to right panels), illustrating how different E-wave velocities compared
with expected values aid in the interpretation of left ventricular (LV) filling patterns, some of which might be misdiagnosed by a scheme of grading diastolic
dysfunction by E/A wave ratio alone. All individuals had a left ventricular outflow tract (LVOT) velocity of approximately 1 m/sec. The last two subjects
have mitral valve disease. The 35-year-old normal (NI) has a mitral E-wave/LVOT velocity ratio of 85%. This ratio is reduced to 50% in the second patient,
who has impaired LV relaxation. The patient with pseudonormal filling has a normal-appearing E/A wave ratio, but the E-wave velocity of 1.2 m/sec is 20%
higher than LVOT velocity, indicating the increase in mean LA pressure. The next patient appears to have an impaired relaxation filling pattern with an E/A
wave ratio <1 but really has a pseudonormal pattern variant (PN-V) caused by the partial fusion of early and late diastolic filling. Pseudonormal abnormali-
ties present include an E-wave velocity elevated at 1 m/sec and an A-wave that would be much smaller (with a higher E/A ratio) if the heart rate were
slower and atrial contraction had occurred after the mitral flow velocity had fallen below 20 cm/sec. The next patient has a dilated cardiomyopathy and
restrictive (RST) filling with a short mitral DT (130 msec) and diminished atrial filling contribution.
The last two patients have an increased E-wave velocity due to mitral valve disease. The patient with severe mitral regurgitation (MR) has an E-wave
velocity of 1.4 m/sec, 40% higher than LVOT velocity. A shorter than expected mitral DT (170 msec) indicates reduced LV compliance, in this case from
coronary artery disease and diabetes. The last patient has rheumatic mitral stenosis (MS), a high E-wave velocity, increased mean gradient, and prolonged
pressure half-time.

of shortening of the P-R interval and faster LV relaxation (see 60 years (see Table 10-1). In patients with impaired relaxation
Fig. 10-3). filling and reduced E-wave velocity, an increased A-wave velocity
If mitral flow velocity does not have sufficient time to fall below and TVI are expected and necessary to maintain a normal LV end
20 cm/sec before atrial contraction, early and late diastolic filling diastolic volume and cardiac output. When LV relaxation is
(E and A waves) begin to merge, as shown in Figure 10-17. This slowed, the reduced filling in early diastole results in less LV pres-
decreases fluid dynamic and filling efficiency and may increase the sure increase after LV minimum pressure, so that the atrium
workload and size of the left atrium. The fusion of early and late contracts into a relatively low pressure, compliant chamber. By
diastolic filling most often occurs when the heart rate is too fast two-dimensional echo, the left atrium is usually normal in size
for a diastolic filling period that is shortened by impaired LV and appears “hypercontractile,” with exaggerated annular move-
relaxation from LVH, an LBBB, or CAD. A first-degree AV block ment superiorly toward the pulmonary veins. The A-wave peak
may also cause mitral E- and A-wave fusion due to atrial contrac- velocity is increased, A-wave TVI is relatively large, and the flow
tion occurring only shortly after mitral valve opening instead of duration is increased, usually to more than 140 msec. An A-wave
later in diastole. Depending on the physiology present, fusion can velocity below 1 m/sec or atrial DT that is unusually short
occur at heart rates as low as 70 to 80 bpm. In both cases, the A (<110 msec) may indicate a decrease in late diastolic LV chamber
velocity is higher than if no fusion were present, and the E/A ratio compliance and an increase in LV A-wave and end diastolic
is reduced compared with early and late diastolic filling that are pressures.
separated.
The consequences of resting or premature fusion of early and
late diastolic filling are frequently seen in a “limited” ability to
Mitral A-Wave Duration
increase mitral TVI (the LV stroke volume) and LV end diastolic The importance of mitral A-wave duration is in what it reveals
volume during exercise, with associated decrease in exercise capac- about late diastolic LV compliance. It is best used in conjunction
ity.72,74 The ability to see if the resting heart rate is well matched with PV A-wave duration, as discussed previously. Like all mitral
to the cardiac physiology present in individual patients by observ- variables, A-wave duration varies with age in normals, being about
ing the LV filling pattern is one of the great strengths of the 120 msec in the young and 140 msec in individuals over 60 (see
echo-Doppler technique that cannot be determined by physical Table 10-1). In general, when viewed in patients with cardiovas-
exam. If possible, altering the heart rate to restore a normal sepa- cular disease, the longer the mitral A-wave duration, the more
ration between early and late diastolic filling frequently improves likely filling pressures are normal, while a shortened A-wave dura-
patient symptoms and exercise capacity. tion indicates increased LVEDP.
Mitral A-wave duration, like peak A-wave velocity, is deter-
mined by the transmitral pressure gradient at atrial contraction
Peak Mitral A-Wave Velocity (see Fig. 10-1). Under normal circumstances, the pressure increase
The mitral A-wave velocity is determined by the late diastolic in the atrium is larger than that in the ventricle. In pseudonormal
transmitral pressure gradient (see Fig. 10-1) and varies from or restricted LV filling patterns, the mitral A-wave duration
50 cm/sec in younger individuals to 75 cm/sec in normals over is shortened because the reduced LV compliance results in an
 Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling 131

P wave
HR 70
preA 15 cm/sec

A
E
HR 82
preA 70 cm/sec

E A
HR 74
1° AVB LBBB
preA 90 cm/sec

A
HR 105
1° AVB
A wave only

E
E A A
HR 78 PR 276
LBBB
preA 1 m/sec
followed by PVC

PVC

Figure 10-17 Variable mitral E-wave velocity at the start of atrial contraction (preA velocity, dotted vertical line) and how it affects the left ventricular (LV)
filling pattern and especially E/A wave ratio and A-wave duration. PW Doppler recordings of mitral flow velocity in five separate patients are shown, and
referred to from top to bottom. The echocardiography at the bottom relates to the bottom-most patient only. These fused LV filling patterns make assess-
ment of diastolic dysfunction more challenging but are important because these patients are frequently symptomatic. For reference, the vertical dashed
line (p wave) is aligned to the start of atrial contraction in all recordings. Only the top patient with an impaired relaxation mitral pattern has a preA velocity
<20 cm/sec, the cutoff value at which E/A ratio, peak A velocity, and A-wave duration are unaffected by partial “fusion” of early and late diastolic LV filling.
Patients 2 and 3 are in their 70s and have histories of hypertension. They have higher E-wave velocities than expected for age, yet the high preA velocity
increases the peak A-wave velocity and makes the E/A ratio <1. Since the mitral time-velocity integral (TVI) represents LV filling volume, the higher pre-A
velocity reduces E-wave TVI, which results in a larger A-wave TVI and A-wave duration. Slower heart rates would decrease peak A-wave velocity and increase
the E/A wave ratio.
Patient 4 has sinus tachycardia so that only an A wave is present. The A-wave velocity is high (1.6 m/sec) because all LV filling must occur during the P-R
interval. Finally, patient 5 shows how after a premature ventricular contraction (PVC) and compensatory pause, the longer R-R interval markedly changes
the E/A ratio and LV filling pattern. 1º AVB, first-degree atrioventricular block; LBBB, left bundle branch block. (From Hatle LK: Differentiation of constrictive
pericarditis and restrictive cardiomyopathy by Doppler echocardiography. Circulation 1989;79:357–370.)

excessive rise in LV pressure with atrial contraction, which increase, so that when the atrium finally contracts, A-wave dura-
abruptly terminates transmitral flow (Fig. 10-18).98 The reduced tion and velocity integral are reduced. Conversely, shorter R-R
time of a positive transmitral pressure gradient is indicated by a intervals result in longer A-wave durations. A short P-R interval
shorter mitral A-wave duration whose DT is shorter than its accel- (<120 msec) will have a reduced A-wave duration because the rise
eration time.99 in LV pressure soon after atrial contraction will result in mitral
Observing changes in A-wave duration over time (or after valve closure and abrupt termination of A-wave flow. Advanced
changes in loading conditions or medical therapy [see Fig. 10-18]) degrees of heart block continually change the relation between
may confirm that LV diastolic function is improving more easily early and late diastolic filling so that virtually every A wave has a
than examining other Doppler variables. For instance, in patients different velocity and duration.
with hypertensive heart disease and an impaired LV relaxation
filling pattern, a lengthening of A-wave duration after medical
therapy is helpful in confirming if an increase in peak E-wave Mitral Peak E/A Wave Velocity Ratio
velocity represents improved LV relaxation and not increased LA Peak E/A ratio has been the single most important variable
pressure.100 used to help characterize the overall mitral flow velocity
Conditions that affect mitral A-wave duration and make it pattern47–49,79,102–105 and define diastolic function in patient groups
more difficult for use in assisting the evaluation of LV diastolic in previous research studies (see Figs. 10-8 and 10-10).80,106 In
function include partial fusion of early and late diastolic filling101 patients with systolic heart failure, the E/A ratio is related to
(see Fig. 10-17), variation in cardiac cycle length due to sinus filling pressures and prognosis. While the diastolic function eval-
arrhythmia, premature atrial or ventricular beats, second- or uation by E/A wave ratio “pattern recognition” is quick, using it
third-degree AV block, and a short (<120 msec) P-R interval. without consideration of the individual variables for mitral veloci-
Longer cycles result in more mid-diastolic LV filling and pressure ties previously described, other two-dimensional findings, and
132 Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling

LA-LV pressure gradient

LV
mmHg

20 20 LA
20

10

A wave
140 msec 90 msec 75 msec
(+) TMPG
A
Nitroglycerin
Angina at rest
1 min 5 min

1 m/sec

Mitral DT 120 msec 140 msec 160 msec

A duration 80 msec 100 msec 140 msec
B
Figure 10-18 The hemodynamic determinants of mitral A-wave peak velocity and duration (top), and an example of their dynamic variation in a patient
with rest angina treated with sublingual nitroglycerin (bottom). A, High-fidelity recordings of left ventricular (LV) and left atrial (LA) pressure show the
positive late diastolic transmitral pressure gradient (TMPG) associated with LA contraction (dotted lines) in three individuals. In the normal subject (left),
LA pressure rise at atrial contraction exceeds that seen in the ventricle, so that the positive (+) A-wave TMPG goes on until LA pressure falls below LV pres-
sure during atrial relaxation. The patient in the middle panel has a decrease in LV compliance. The maximal LA-LV pressure gradient at atrial contraction
is approximately the same, but the rise in LV pressure exceeds LA pressure at 90 msec, shortening the (+) A-wave TMPG and A-wave duration but not its
peak velocity. The patient on the right has a marked decrease in LV compliance. LV pressure increases rapidly after LA contraction, so the maximum (+)
TMPG and duration is further shortened, resulting in a lower peak A-wave velocity with a shorter duration. B, Patient with angina at rest. The pulsed wave
mitral flow velocity shows a high E-wave velocity, a short, “restrictive” like mitral DT, and a low A-wave velocity and duration, which are partially “masked”
by some fusion of early and late diastolic filling (velocity at the start of atrial contraction >20 cm/sec). One minute after taking sublingual nitroglycerin,
LV hemodynamics are improving, as evidenced by a longer diastolic filling period, lower E-wave velocity, longer mitral deceleration (DT), and wider A-wave
duration. By 5 minutes, the improvement in mitral filling variables are even more obvious. (A, From Matsuda Y et al: Change of left atrial systolic pressure
waveform in relation to left ventricular end-diastolic pressure. Circulation 1990;82:1659–67. B, From Hatle LK et al: Differentiation of constrictive pericarditis and
restrictive cardiomyopathy by Doppler echocardiography. Circulation 1989;79:357–370.)

ancillary Doppler variables will lead to a certain number of that additional ancillary data are available to further document
patients being misclassified. The E/A ratio is most helpful when the cardiac abnormalities present for both diagnosis and
the mitral DT is linear and preA velocity is below 20 cm/sec. If treatment.49
mitral DT is curved or biphasic or if there is partial fusion of E-
and A-wave velocities, then the LV filling pattern needs a careful
assessment in relation to the other echo-Doppler findings. M-Mode and Two-Dimensional Echocardiography
There is considerable information about LV diastolic function
and filling pressures available from M-mode and two-dimensional
ANCILLARY DATA THAT HELP THE cardiac ultrasound recordings to complement Doppler vari-
INTERPRETATION OF MITRAL FLOW ables.5,49,114 With practice, the visual interpretation of these
VELOCITY PATTERNS anatomic findings usually will suggest what Doppler LV filling
patterns are present. From the parasternal long axis view, observ-
A criticism of the assessment of LV diastolic dysfunction by ing the movement at the AV groove helps identify the cardiac
mitral flow velocity variables and LV filling pattern is that they rhythm, LA size, and contractility. In the parasternal short axis,
are affected by multiple confounding variables and therefore are the normal left atrium appears approximately the same size or
unsuitable for determining LV diastolic properties,107 and by slightly larger than the aorta. From apical views, the sizes of both
implication LV diastolic dysfunction. This discounts the large atria in relation to their respective ventricles can be determined,
body of evidence now accumulated on the predictive value of as well as comparisons made of their respective sizes and contrac-
these variables in clinical medicine21,28,31,32,80,94,108–113 and the fact tilities. Differences are usually obvious. A normal-sized left atrium
 Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling 133

that appears “hypercontractile” indicates reduced LV filling in those seen on the left side of the heart. Since the tricuspid leaflet
early diastole, increased filling at atrial contraction, and an orifice is larger, tricuspid velocities are slightly lower. Tricuspid
impaired relaxation pattern. LA enlargement and reduced con- flow velocity increases significantly with respiration, which differs
tractility are often associated with elevated pressures and pseudo- from left heart filling (this aspect will be discussed in the section
normal or restrictive mitral filling patterns as long as there have on assessing RV diastolic function).
been no recent atrial arrhythmias. At the same time, noting asym- Differences between mitral and tricuspid filling patterns usually
metry in the rate of LV and RV contractility and relaxation, and reflect cardiac pathology. Since most cardiac diseases affect the left
the excursion of AV longitudinal plane movement, often indicates heart, the more abnormal filling pattern is usually seen in LV
the abnormalities of ventricular diastolic filling that will be seen filling, although the right heart is also affected through the involve-
on Doppler exam. ment of the intraventricular septum. For instance, in an individual
LVH slows LV relaxation independent of other cardiac abnor- with an ischemic cardiomyopathy who has a pseudonormal LV
malities and results in an impaired relaxation that is often obvious filling pattern, tricuspid filling often “lags behind,” showing an
in M-mode LV recordings (Fig. 10-19). In the absence of MR, impaired relaxation pattern.49
arrhythmias, or cardiac conduction system disease, LA enlarge-
ment usually indicates an elevated mean LA pressure associated Mitral Annular Velocities in Tissue Doppler
with pseudonormal and restrictive mitral flow velocity pat-
terns.86,106,115 Because maximal LA volume is strongly associated Imaging and Relation to Left Ventricular Filling
with adverse cardiac events such as new-onset atrial fibrillation, The recently developed TDI ultrasound modality (discussed in
congestive heart failure, and stroke,106,115,116 we agree that it should detail in Chapter 12 of this volume) has underlying physics and
be measured according to the guidelines of the American Society principles similar to those of conventional PW spectral Doppler.
of Echocardiography and the European Society of Cardiology117 From the apical views, the velocities are related to LV contraction
in all patients. Conversely, normal LA size suggests that mean LA and relaxation. In interpreting LV filling patterns, TDI of myo-
pressure is normal. Left atrial minimum volume is related to pul- cardial velocities has its greatest use in distinguishing normal
monary wedge pressure with a correlation coefficient equal to that and pseudonormal LV filling.39 The ratio of peak mitral E-wave
of most other Doppler variables.89 velocity to myocardial E′ velocity is used to estimate mean LA
pressure.64,118–120
The normal diastolic velocity pattern of myocardial velocities
Tricuspid Flow Velocity obtained from TDI is similar to that of transmitral flow in patients
Tricuspid and mitral flow velocity patterns are normally qualita- in sinus rhythm, except inverted.39,121–127 There is positive (above
tively similar, and in RV pathology the alterations are similar to the zero velocity baseline) movement toward the apex with

LV DIASTOLIC FUNCTION

1 m/sec
1 m/sec

IVRT - 70 msec IVRT - 110 msec IVRT - 95 msec

Normal LVH abnormal relaxation LVH ↑ LVEDP
A B C
Figure 10-19 Pulsed wave mitral flow velocity together with M-mode recordings of the left ventricular (LV) cavity in three individuals, illustrating how
the diastolic wall motion pattern helps in interpreting the LV filling pattern. Compared with the normal subject (A), the patient in B with LV hypertrophy
(LVH) has impaired relaxation filling. Their longer isovolumic relaxation time (IVRT) and reduced E-wave velocity matches the slower rate of early diastolic
LV filling seen in the LV posterior wall (arrow). The patient in C has a mitral pattern that may appear similar to the normal so as to be difficult to interpret
without additional data. However, the M-mode recording shows marked LVH, very delayed early diastolic filling with relaxation, and mid-diastolic LV cavity
expansion continuing to occur up to the time of atrial contraction. These findings, along with the increased E-wave velocity (1 m/sec), indicate pseudo-
normal LV filling and moderate diastolic dysfunction. Small vertical arrows indicate LV IVRT period and mitral A-wave duration for comparison. (From Hatle
LK et al: Differentiation of constrictive pericarditis and restrictive cardiomyopathy by Doppler echocardiography. Circulation 1989;79:357–370.)
134 Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling

systolic contraction and negative movement back toward the pul- As shown in Figure 10-3 and discussed (see the section “Exer-
monary veins with LV filling in early (E′) and late diastole (A′). cise and Left Ventricular Diastolic Function”), impaired relaxation
In patients with normal ventricular diastolic function, the E′/A′ reduces the time available for diastolic filling and myocardial per-
and mitral E/A flow velocity wave ratios are similar. Patients with fusion and sets in motion a process that leads to limitation in
impaired relaxation filling have a myocardial velocity E′/A′ ratio cardiac output (Fig. 10-21).72,74 In patients presenting with exer-
of under 1, again mirroring the findings seen with mitral flow tional dyspnea, examining changes in the ratio of mitral E-wave
velocity. However, in pseudonormal mitral flow velocity patterns, and TDI E′ velocity at rest and exercise has been proposed as a
a myocardial velocity E′/A′ ratio of less than 1, rather than higher diastolic stress.128 Using supine bicycle exercise and classifying
than 1, is present, reflecting the impaired LV relaxation that points by E/E’ of more than 10, exercise duration was significantly
separates these patients from true normals. This is similar to the longer in patients whose E/E′ ratios were equal to or greater than
relaxation abnormality seen in the myocardial M-mode in Figure 10 and did not increase with exercise. These preliminary results
10-19, despite the “normal”-appearing Doppler LV filling pattern. suggest that the hemodynamic consequences of exercise-induced
With restrictive LV filling, the E′/A′ ratio frequently is greater increase in diastolic filling pressure may be possible noninvasively
than 1 because the majority of filling occurs in early diastole, with with exercise Doppler ECG (see Chapter 17).
little contribution from atrial contraction. Figure 10-20 shows a
schematic diagram of normal and abnormal mitral LV filling pat-
terns together with LV pressure, TDI myocardial velocity, and Pulmonary Artery Pressures
PV flow velocity for reference. The estimation of PA systolic and diastolic pressures is a valuable
The interpretation of TDI myocardial velocities is enhanced by adjunct to assessing LV filling patterns. Using the modified
an awareness of the factors that influence these annular move- Bernoulli equation, this can be accomplished in a high percentage
ments. The E′/A′ ratio is higher in the lateral as compared with of patients with right-sided valvular regurgitation. The velocity of
the septal annulus because the septal is tethered to the right ven- pulmonary regurgitation at end diastole together with an estimate
tricle and other structures in the middle of the heart. The E′ dia- of central venous pressure (physical exam, size of inferior vena
stolic annular movement predominates in normals because LV cava, and degree of respiratory collapse) is used to estimate PA
longitudinal movement at the base in both systole and diastole is diastolic pressure. In the absence of pulmonary vascular disease,
greater than displacement in a radial direction. In patients with a this is a surrogate estimate of mean LA pressure. Similarly, peak
normal LVEF and pseudonormal filling, a reduced E′ is present velocity of tricuspid regurgitation (TR) together with central
because LVH causes an increase in systolic radial movement that venous pressure helps estimate PA systolic pressure.
is reversed (outward LV motion) in early diastole. The E′/A′ ratio Patients with impaired relaxation in LV filling are expected to
will be less abnormal if there is another reason for the reduced have normal or at worst borderline increases in PA pressure in
LV compliance than LVH or if the LVEF is decreased. Regardless the absence of pulmonary parenchymal or vascular disease.
of LVH, a large volume of blood flow across the mitral valve in Pseudonormal filling is associated with elevated mean LA pres-
early diastole due to MR will fill the ventricle and increase upward sure, and so PA pressures are passively elevated. With the higher
annular movement and E′ velocity so that the E′/A′ ratio will left heart pressures seen in restrictive filling, PA systolic pressure
appear more normal. can be quite elevated, in the 50–70 mmHg range.

LV FILLING PATTERNS

Decrease in compliance
Abnormal
Normal relaxation Moderate Marked Irreversible

LV
pressure

Mitral flow
velocity

Tissue
Doppler

Pulmonary
vein

Normal IR PN RST Irreversible RST

Figure 10-20 Schematic diagram showing the correlation of pulsed wave tissue Doppler imaging (TDI) recordings of the mitral annulus with normal and
abnormal left ventricular (LV) filling patterns, LV pressures, and pulmonary venous (PV) flow velocity; IR, impaired relaxation; PN, pseudonormal; RST,
restrictive. TDI is especially helpful in distinguishing normal from PN LV filling in most circumstances. Note that in normal and IR filling, the mitral and TDI
patterns are inverted but similar in terms of early and late diastolic ratios. In contrast, PN filling has a markedly disparate TDI with reduced longitudinal
movement in early diastole and increased movement at atrial contraction, a pattern that reflects the impaired LV relaxation. The TDI patterns in RST filling
can be variable depending on disease process and LV ejection fraction, with the most typical shown. The dashed lines and arrows in impaired relaxation
filling in LV pressure and PV A-wave refer to patients with decreased LV compliance in late diastole who have an increase in LV end diastolic pressure.
 Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling 135

HOCM 68F s/p myectomy

HR 57 TVI-16 CO 4.4 L/min

B

Reduced FAC

Pulmonary wedge pressure (mmHg)

30 Normal subjects
Peak
A exercise

20

10 Peak
exercise
Rest

0
60 100 140
HR 87 TVI-17 CO 6.7 L/min LV end-diastolic volume (ml)
C D
Figure 10-21 Reduced functional aerobic capacity in a patient due to left ventricular (LV) diastolic rather than systolic dysfunction. The patient has hyper-
trophic obstructive cardiomyopathy (HOCM) (A) and is status postsurgical septal myectomy with resultant gradient reduction but also a left bundle branch
block (LBBB). At rest, an impaired relaxation pattern is present (B). With exercise, (C) an increase in heart rate (HR) to 87 bpm, a premature fusion of early
and late diastolic filling is seen with only a small increase in mitral time-velocity integral (TVI), which represents LV filling. Therefore, the cardiac output
increase is mostly from the increase in heart rate. As shown in the graph (D), the inadequate diastolic filling blunts the normal increase in end diastolic
volume, reducing cardiac output while also causing an increase in pulmonary pressures and venous congestion. (B, From Kitzman DW et al: Exercise intoler-
ance in patients with heart failure and preserved left ventricular systolic function: failure of the Frank-Starling mechanism. J Am Coll Cardiol 1991;17:
1065–1072.)

PERFORMING AN ECHO-DOPPLER EVALUATION After the two-dimensional exam is finished, an apical four-
OF LEFT VENTRICULAR DIASTOLIC FUNCTION chamber color Doppler screen is performed to check for signifi-
cant valvular regurgitation. CMM of mitral inflow and LV outflow
The assessment of LV diastolic function requires high-quality is then used to preview the LV filling pattern and mitral E-wave
two-dimensional images and Doppler recordings of mitral, PV, flow velocity propagation, as well as whether systolic LV intracavi-
and TDI flow velocities. Guides are available for optimizing these tary gradients or IVRT flow is present. CW Doppler is activated
recordings and avoiding pitfalls, with many examples.91 Tech- to profile the LV filling and ejection velocities throughout the
niques for optimizing CMM mitral inflow velocity propagation ventricle. CW technique is used before PW Doppler because CW
and TDI of the mitral annulus are covered in Chapter 18 of this profiles the mitral inflow pattern, provides a reference for the peak
volume. E- and A-wave velocities that will be obtained during the subse-
Organizing an echo-Doppler assessment of LV diastolic func- quent PW Doppler interrogation, and displays IVRT flow and
tion into a standard routine helps both the sonographer (Chapter the magnitude of any systolic intracavitary gradients. PW Doppler
17) and the physician improve their technical and interpretive mitral inflow velocity, mitral velocity response to Valsalva maneu-
skills.61,69,129 We recommend starting with M-mode and two- ver, and PW Doppler of PV flow is then performed. If confusion
dimensional anatomic imaging to obtain measurements of still exists regarding the normalcy of the LV filling pattern, TDI
chamber sizes, maximal LA volume, and LV diastolic and systolic spectral Doppler of mitral annular motion (lateral, medial, or
volumes. LV mass, relative wall thickness,130 and LVEF are then both) will usually help make this distinction, and together with
calculated. Variables of special importance include absolute LV peak mitral E-wave velocity may indicate whether normal or
mass and LV relative wall thickness (normal <42%) and maximal increased mean LA pressure is present. Before leaving the left side
LA size (normal <32 ml/m2). of the heart, any LV intracavitary gradients or IVRT flow seen on
136 Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling

the CMM screen are located and quantified by PW Doppler. The the mitral E-wave velocity. LA size and the mitral E-wave/LVOT
transducer is then moved medially toward the sternum, and PW velocity ratio will both be increased. However, LV diastolic dys-
Doppler of tricuspid inflow along with estimation of PA systolic function and filling pressures are not necessarily abnormal since
pressures using peak TR velocity by CW Doppler is performed. the normal adaptation of the left atrium and ventricle to chronic
Finally, PW analysis of Doppler hepatic veins and superior vena volume overload is a rightward shift in the pressure-volume rela-
caval flow throughout respiration is recorded.131 tion, which makes both chambers more compliant. A normal
With practice and performing a complete diastolic function mitral DT is the best indicator of a healthy adaptation to the
exam on every patient, the components we have listed can be chronic volume overload of MR. Conversely, a shortened mitral
completed with only an additional 5 to 10 minutes of scanning DT indicates an abnormal rise in early diastolic LV pressure from
time. The information derived not only helps assess LV diastolic reduced LV chamber compliance. This finding is expected in acute
function, filling pressures, and future possible adverse cardiovas- MR because of a lack of time for the ventricle to adapt, but in
cular events, but also aids patient management decisions. chronic regurgitation it signifies an increase in myocardial stiff-
ness from a process unrelated to the valve disease. A shortened
mitral IVRT, decrease in PV systolic fraction, and increase in
MITRAL FLOW VELOCITY PATTERNS: TR velocity are other indicators of increased left heart filling
INTERPRETIVE CHALLENGES pressures.
MS increases E-wave velocity by reducing orifice size and is
Mitral E/A Ratio Below 1 associated with a prolonged mitral pressure half-time as well as
The most common mitral filling pattern is also the one most fre- LA enlargement. Impaired LV relaxation may prolong the mitral
quently misinterpreted and therefore deserves special mention. DT, while reduced LV myocardial compliance may shorten it
The “true” impaired relaxation filling pattern is due to slow independent of valve area. When MS is present, a clinically useful
LV relaxation with normal mean LA pressure (see Fig. 10-14). approach is to measure the LV IVRT (whose shortening indicates
Criteria include normal LA volume, with “hypercontractile”- the degree of mean LA pressure elevation), calculate the mean
appearing LA systolic function (especially in the parasternal long mitral gradient while noting the heart rate, estimate the mitral
axis view) due to ejection into a ventricle with a lower than normal valve area by the pressure half-time method, and estimate the PA
preA pressure. Compared with normal age-related values, the LV pressure by TR velocity. If mitral preA velocity is greater than
IVRT and mitral DT should be prolonged, mitral E-wave veloc- 20 cm/sec, slowing the heart rate may improve the hemodynamic
ity should be lower than expected for age and LVOT velocity, and abnormalities and patient symptoms. In patients with mixed MS
the preA velocity should be below 20 cm/sec. If the analysis stops and MR, the focus is on the valve disease and its consequences
here, the interpretation is incomplete, for it has not been deter- rather than LV diastolic dysfunction. The LV IVRT, mitral valve
mined whether LV end diastolic compliance and pressure are area, and PA pressures become important objective data to relate
normal or abnormal, the latter being the first indication of ele- to patient symptoms.
vated LV filling pressures (see Fig. 10-2). This can be determined
only by comparing the duration of mitral and PV flow velocity A
waves, as previously described. If PVa duration is more than Sinus Tachycardia: Effect on
30 msec longer than mitral A-wave duration, LVED pressure is
Left Ventricular Filling
elevated and LV compliance is reduced, indicating that early dia-
stolic dysfunction is present (see Fig. 10-13). Previous animal studies link the normal cardiac pathophysiology
There are two common instances where the E/A wave velocity that occurs as heart rate increases with changes in mitral flow
ratio is less than 1, implying an impaired relaxation filling pattern, velocity (see Fig. 10-14). The method by which heart rate is
and yet the diastolic abnormalities are more severe and closer to increased (withdrawal of parasympathetic tone, increase in
pseudonormal with decreased LV compliance and increased mean sympathetic tone or exercise) markedly affects when mitral E
LA pressure. The first occurs when the mitral velocity at atrial and A waves begin to fuse and when complete fusion (A-wave
contraction is above 20 cm/sec and there is fusion of early and flow only) occurs. In normal dogs, withdrawal of parasympathetic
late diastolic LV filling (see Figs. 10-16, 10-17, and 10-21). In this tone with atropine administration results in complete fusion of E
case, the A-wave velocity is higher than it would be at a slower and A waves at 160 bpm, while with isoproterenol infusion this
heart rate or shorter P-R interval, which reduces the E/A wave is not observed until a heart rate of 220 bpm. These differences
ratio to below 1. A premature beat or slower heart rate will reveal relate to the effect of each intervention on LV contractility and
the pseudonormal filling pattern. An E/A ratio of less than 1 with the degree of shortening of the P-R interval. Increased contractil-
increased filling pressures can also be seen in patients with marked ity shortens the LV isovolumic contraction, ejection, and relax-
LVH and severely impaired LV relaxation. In these cases, a mark- ation times so that diastolic filling time is maximized, while
edly elevated LA pressure may be needed before the filling pattern shortening of the P-R interval provides for more diastolic filling
appears pseudonormal (see Fig. 10-9). In both instances, the pres- before atrial contraction. With exercise, increased venous return
ence of moderate or severe LVH, increased LA volume, E-wave and LA pressure also result in an earlier mitral valve opening,
velocity that approaches or exceeds LVOT velocity, and increased which also helps keep early and late diastolic filling separated.
E/E′ ratio are all clues that despite the E/A wave ratio of below LVH, systolic dysfunction, increased wall stress, and cardiac
1, mean LA pressure is elevated. conduction system disease (first-degree or LBBB) prolong
systolic periods and shorten the diastolic filling time so that E-
and A-wave fusion occur at lower heart rates (see Fig. 10-3). This
Mitral Regurgitation and Stenosis may limit LV filling and result in a reduced exertional cardiac
Hemodynamically significant MR will increase the volume output and functional aerobic capacity, as previously discussed
returning through the mitral valve in early diastole and increase (see Fig. 10-21).
 Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling 137

Uncommon Mitral Valve Velocity Patterns mality present is markedly impaired LV relaxation, which causes
a severe decrease in LV compliance (the short initial mitral DT)
Variations in LV filling patterns are seen where impaired LV but is confined to early diastole, perhaps because of delayed actin-
relaxation persists into mid-diastole, or altered compliance is myosin cross-bridge detachment. In mid-diastole there is contin-
present only in early diastole rather than throughout the diastolic ued LV relaxation and a fall in pressure so that the mitral DT
filling period. This physiology is most commonly present with markedly slows and becomes nonlinear, or a mid-diastolic filling
marked LVH, especially in the elderly with severe and long- hump is seen. The width of the A wave is variable depending on
standing hypertension132 or in patients with hypertrophic cardio- the end diastolic compliance of the ventricle. Because of the pro-
myopathy. Figure 10-22 shows examples of uncommon mitral LV found relaxation abnormality, these patients often do well with
filling patterns in five such patients. Most typically the initial very slow (40–55 bpm) resting heart rates, while faster heart rates
mitral E-wave velocity is increased compared with LVOT veloc- result in inadequate LV filling, exercise intolerance, and pulmo-
ity, and there is a short initial mitral DT. The predominant abnor- nary congestion.

m/sec
1.0

0.5

0
A B C

LV pressure

60 cm/sec

D E
Figure 10-22 Five patients (A to E) with markedly impaired left ventricular (LV) relaxation that results in unusual PW Doppler mitral flow velocity record-
ings that do not fit conventional LV filling patterns of diastolic dysfunction. All patients are in normal sinus rhythm. Each peak E-wave velocity is followed
by an initial restrictive-like mitral DT and then variable degrees of additional filling in mid-diastole and with atrial contraction, indicating profound myo-
cardial relaxation abnormalities and dynamic changes in LV compliance throughout diastole.
Patient A has marked LV hypertrophy (LVH) from long-standing hypertension and a normal LV ejection fraction (LVEF). The initial mitral deceleration
time (DT) is 100 msec, which then dramatically changes slope to 280 msec in mid-diastole with A-wave duration of 100 msec. LV posterior wall M-mode
motion showed continuous filling throughout mid-diastole, indicating ongoing LV relaxation. Patient B is a 35-year-old on dialysis with LVH and normal
LVEF. Without the abnormal mid-diastolic filling “hump,” the mitral pattern might be mistaken for normal. Patient C is elderly with hypertension and slight
sinus arrhythmia. With a slower heart rate, the filling pattern would be similar to B, but the slightly faster heart rate results in the mid-diastolic filling
blending into the A wave, making its true duration difficult to measure except on the first beat. Patient D has a 50-year history of nonobstructive hyper-
trophic cardiomyopathy with a giant left atrium. The initial mitral DT is only 80 msec, with over two thirds of LV filling occurring in mid-diastole (middle
hump) and then with atrial contraction. The patient reports feeling best with a resting heart rate of 40–45 bpm. Functional aerobic capacity is severely
reduced with any increase in heart rate.
Patient E has a mitral flow velocity somewhat similar to patient D. Patient E’s LV pressure recording shows an initial rapid filling wave correlating with
the restrictive early diastolic mitral DT, but then LV pressure declines in mid-diastole with reestablishment of transmitral flow. The cellular mechanisms
that result in these marked derangements of LV relaxation and early diastolic restrictive physiology, which are transient rather than fixed, are under
investigation.
138 Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling

Increased Mitral Respiratory Flow mitral E-wave velocity equal to LVOT velocity, short mitral DT
Velocity Variation (<160 msec), and reduced (<25%) PV systolic fraction and
increased E/E′ ratio all suggest reduced LV compliance and
The diagnosis of a number of important conditions is dependent increased filling pressures. A mitral DT under 140 msec has been
on a measure of increased variations in mitral respiratory flow shown to have the same unfavorable prognosis as for patients in
velocity. The presence of these conditions would be missed in sinus rhythm.95
laboratories that do not record mitral flow velocity initially at the When recording atrial fibrillation, CW technique is again sug-
slower sweep speed of 50 cm/sec to observe whether increased gested first to display the maximum velocities and measure the
respiratory variation is present. Although respiratory variation in LV IVRT. PW Doppler is used for mitral DT, and five beats are
tricuspid E-wave flow velocity is expected to be 15% to 25%, the averaged to assess mitral variables. Beats with short R-R intervals
respiratory change in mitral E-wave velocity in normals is less should be excluded, especially if systole causes an abrupt cessation
than 5%.133 Increased changes in both mitral and tricuspid inflow of mitral inflow. Examples of mitral flow velocity in atrial flutter
velocities with respiration can be seen in patients with acute or and atrial fibrillation are shown in Figure 10-23.
chronic pulmonary disease134 or pericardial abnormalities, includ-
ing tamponade,135,136 constriction,133,134,137 and pericardial restraint
due to acute cardiac dilation from RV infarction, pulmonary Diastolic Mitral and Tricuspid Regurgitation
embolus, or acute valvular regurgitation. Regurgitation occurs when there is a reverse diastolic transmitral
So that abnormal respiratory mitral changes are not overlooked, pressure gradient where LV pressure exceeds LA pressure in dias-
we recommend recording mitral flow velocity using CW Doppler tole. Although the magnitude of the reverse transmitral pressure
from the apical transducer position at a sweep speed of 50 mm/ gradient can exceed the normal forward-flow gradient, the amount
sec. Any variation greater than 10% with a regular heart rate is of regurgitation is hemodynamically insignificant because it is
considered abnormal. Accompanying changes in the LV IVRT limited by a small AV valve orifice area.138
verify that the alterations in velocity are due to alterations in LA There are several situations in which diastolic MR and aortic
pressure and the timing of mitral valve opening. A PW Doppler regurgitation can be seen. By far the most common is with first-,
exam of mitral flow velocity with a respirometer is then performed. second-, or third-degree AV block,139 or with atrial flutter and
The clinical history and characteristic two-dimensional findings greater than 2 : 1 AV block (see Fig. 10-23). In these cases, the
(such as an inspiratory septal shift) are noted, along with the exact atrium contracts, and atrial and ventricular pressures both
timing of the flow velocity changes. This will help determine increase. However, in the absence of a normal P-R interval and
whether pulmonary or pericardial disease is present. The hepatic properly timed ventricular systole, atrial relaxation causes its pres-
venous Doppler is especially important and should always be sure to fall below ventricular pressure, and diastolic regurgitation
recorded because in primary pericardial disease the heart has dif- occurs. Diastolic MR due to first-degree AV block is usually not
ficulty filling normally (low velocities), while with pulmonary seen until the P-R interval exceeds 280 msec. The Doppler find-
disease the heart overfills due to the excessive swings in intratho- ings of first-degree AV block are worth noting, especially if it is
racic pressure and RV minimum pressure.134 causing partial fusion of early and late diastolic filling.
Diastolic MR is more pathologic when associated with
advanced restrictive LV filling. After filling in mid-diastole or
Atrial Flutter and Fibrillation after atrial contraction, there is a marked increase in LV pressure
Regardless of whether there is 2 : 1 or higher-degree AV block, that not only decelerates, but transiently reverses transmitral flow
almost no assessment of LV diastolic function can be made from in mid-diastole or after atrial contraction. Aortic regurgitation
mitral flow velocity when atrial flutter is present. All LV filling is with marked bradycardia or atrial fibrillation and a very slow
due to atrial contractions, so that no E velocity, E/A wave ratio, ventricular rate is an additional uncommon etiology.
or mitral DT is available for measurement. If 3 : 1 or 4 : 1 AV
block is present, multiple filling waves are seen with diastolic MR
interspersed between each. PA pressure calculated from peak TR RIGHT VENTRICULAR DIASTOLIC FUNCTION
velocity may be the best indicator of increased left heart filling
pressures if no lung disease is present. The same Doppler analysis and variables used for mitral flow
New-onset “coarse” atrial fibrillation may resemble atrial flutter velocity can be applied to tricuspid inflow and RV filling (see
in that multiple pulses of blood flowing from atrial contraction Chapter 14 in this volume).91,140 Because inspiration increases RV
enter the ventricle in diastole. This makes the interpretation of filling, changes in tricuspid flow velocity are seen throughout the
peak E-wave velocity and mitral DT difficult to relate to LV dia- respiratory cycle, while on the left side of the heart, Doppler
stolic properties. Chronic atrial fibrillation, when LA mechanical mitral variables vary only about 5%.133 This increase in inspiratory
function is negligible and the rate is <100 bpm, is easier to inter- RV filling can be used, in conjunction with hepatic and superior
pret. In patients with heart disease, the mitral E wave to TDI E′ vena cava flow velocities, to assess the diastolic properties of the
ratio119 or LV IVRT is a good indicator of whether filling pres- right ventricle.
sures are elevated. Since all LV filling must occur without an atrial PW Doppler tricuspid DT is about 25 msec longer than its
booster pump, mean LA pressure and peak E-wave velocity are mitral counterpart. With normal RV diastolic function, this value
usually slightly higher than normal for age, except in young changes little with the increased flow during inspiration, and
patients with lone atrial fibrillation and vigorous elastic recoil. hepatic A-wave reversals decrease in velocity and duration. With
Mitral DT is generally about 20 msec shorter than in normal a decrease in late diastolic RV compliance, hepatic venous A-wave
sinus rhythm, and PV flow should have a reduced but not absent velocity and duration increase with inspiration. An inspiratory
systolic fraction, since the S1 component due to atrial relaxation shortening of tricuspid DT, diastolic predominance of hepatic
is absent. In adult cardiac patients, a short LV IVRT (<60 msec), venous flow with prominent V- and A-wave reversals are signs of
 Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling 139

ATRIAL FIBRILLATION

Mitral Pulmonary vein

Figure 10-23 PW Doppler mitral flow
velocity in a patient with atrial flutter
Atrial flutter
and atrial fibrillation. In atrial flutter, left
ventricular (LV) filling is a regular pulsa- E
tion of A waves (arrows), often with mild PVd
diastolic mitral regurgitation (dMR) A
during atrial relaxation. Left atrial (LA)
size is often enlarged from the arrhyth- A
mia, the isovolumic relaxation time
(IVRT) is affected by the atrial contrac- A Af
Af PVs
tions, and there is no E wave or mitral
deceleration (DT) to measure, making
the assessment of diastolic function
problematic. In atrial fibrillation (Af ),
peak E-wave velocity and mitral DT can
be measured but can also be affected
by the fibrillatory contractions of the
atrium (Af flow = arrows). It is likely that –3 –2
this patient does have an increase in 2
dMR
mean LA pressure because the LV IVRT
is short (50 msec) and pulmonary
venous systolic (PVs) filling is negligible, 1
a sign of reduced LA compliance.

a marked decrease in RV compliance and increased diastolic notable. Better diastolic than systolic function suggests a well-
filling pressures.140 The early diastolic slope and A-wave decrease adapted, compliant ventricle. Such individuals often have a good
in velocity in pulmonary regurgitation Doppler signals can also functional capacity and a favorable prognosis.28 Conversely, a
be used to assess early and late diastolic RV compliance. The pseudonormal or restrictive mitral filling pattern with mild sys-
assessment of right heart pressures from inferior vena cava size141 tolic function suggests volume overload (easily detected by imaging
and systemic venous flow (hepatic vein and superior vena cava) of the inferior vena cava) or pathology, which increases myocardial
has also been described.142,143 stiffness. Why patients with LV systolic dysfunction have such
variability in LV compliance remains a key enigma that requires
further investigation.
USING LEFT VENTRICULAR FILLING PATTERNS In patients with normal LV systolic function and diastolic
FOR PATIENT MANAGEMENT heart failure, questions to be answered include whether abnor-
malities of LV relaxation or compliance predominate, and during
If the only information available from examining LV filling what part(s) of diastole are the abnormalities present. This gives
patterns is whether the patient has elevated LA pressure, this can an idea of the best approach for short-term therapy and whether
be usually ascertained from the patient’s history, physical exami- altering the heart rate is likely to improve the patient’s symptoms.
nation, chest x-ray, and brain natriuretic peptide level (see Chapter Although classifying patients as having one of the three abnormal
32). Unique information available from an echo-Doppler study is filling patterns is often useful for this purpose, enough variations
the identification of early diastolic dysfunction (impaired relax- in LV filling patterns and combinations of LA pressure and rates
ation filling pattern with elevated LVEDP), with the relation of of LV relaxation exist that the choice of treatments to benefit the
LV systolic to diastolic function identifying which diastolic prop- patient are still best determined by carefully examining the mitral
erty (relaxation or compliance) is most abnormal and which parts flow velocity pattern and its individual Doppler variables, as in
of diastole are most affected by these abnormalities. In addition, the patients in Figures 10-15 through 10-19 and Figures 10-21
seeing whether the patient’s heart rate at rest is well matched to and 10-22.
the cardiac physiology present is a great strength of the echo-
Doppler technique that cannot be done reliably by physical exam.
Using this information is a powerful tool for intervening to
prevent progression of diastolic abnormalities and for treating FUTURE RESEARCH
patients with symptoms of diastolic heart failure to improve their
functional status and prognosis. The greatest limitation to the echo-Doppler assessment of LV
After the echo-Doppler study is completed, the first question diastolic dysfunction is the experience to discern from the infor-
is, What is the main cardiac abnormality present: systolic dys- mation available which of the key diastolic properties (LV relax-
function, diastolic dysfunction, or valvular heart disease? In ation or compliance) is most abnormal, how these are related to
patients with a reduced LVEF, diastolic dysfunction is expected LV systolic function, and how both interact to affect the overall
and is usually “matched” to the reduction in LVEF. For example, LV filling pattern. When first learning to interpret LV diastolic
patients with a moderate reduction in LVEF (30%–35%) often function, there is a tendency to try to make all variables fit into
have a pseudonormal mitral filling pattern, while patients with one abnormal LV filling pattern or another, when in reality there
severe reduction in LVEF (<20%) commonly demonstrate restric- are nearly endless variations and exceptions to defined “criteria.”
tive filling. A “mismatch” between these expected relations is This is why we believe that examining the mitral filling pattern
140 Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling

together with all available two-dimensional and Doppler infor- PN: pseudonormal (LV filling)
mation is most helpful for patient management. This approach PV: pulmonary venous
acknowledges that the variables used are imperfect indicators of PVs1: PV flow velocity in early systole
individual diastolic filling properties or pressures and can some- PVs2: PV flow velocity in middle and late systole
times appear contradictory, but in aggregate they usually provide PVa: flow pulmonary venous flow
sufficient information to be clinically useful in the great majority PV Adur: reverse PV flow velocity at atrial contraction
of patients. PW Doppler: pulsed wave Doppler (technique)
Another common limitation is the lack of technical experience RST: restrictive (LV filling)
in acquiring high-quality Doppler recordings so that all variables RV: right ventricular
are accurately measured. It can be expected that even when SHF: systolic heart failure
performing a routine diastolic-function examination on every TDI: tissue Doppler imaging
patient undergoing ECG, it could take at least 6 months for TMPG: transmitral pressure gradient
sonographers and physicians to master these skills. With the TR: tricuspid regurgitation
advent of Doppler annular TDI recordings and measurement of
LA volume, the problem of identifying patients with pseudonor-
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 L. LEONARDO RODRIGUEZ, MD
11
Evaluation of
Diastolic Function by
Color M-Mode Doppler
INTRODUCTION CLINICAL RELEVANCE
Pseudonormal Filling Patterns
BACKGROUND
Estimation of Left Atrial Pressures
Obtaining and Measuring Flow Propagation
Use of Color M-Mode in Clinical Settings
Color M-Mode Intraventricular Pressure
Limitations of Color M-Mode Indices
Gradients
Pathophysiology FUTURE RESEARCH
COLOR M-MODE DOPPLER AND
DIASTOLIC FUNCTION

INTRODUCTION tracing, and clinical situations in which this technique may be

applied. We will also describe its application in the calculation of
Pulsed-wave Doppler velocities of mitral inflow are the most intraventricular pressure gradients (IVPGs).
commonly used indices of diastolic function. Their application is
nevertheless limited by their load dependency. Flow propagation
(Vp) using Doppler color M-mode (CMM) has been proposed BACKGROUND
as a complementary technique to evaluate left ventricular (LV)
relaxation. It is now well recognized that in early diastole small but significant
Color Doppler M-mode echocardiography provides a spatio- intraventricular mitral-to-apex pressure gradients are gener-
temporal map of blood distribution (v(s,t)) within the heart, with ated.10,11 These IVPGs are related to elastic recoil12–14 and apical
a typical temporal resolution of 5 ms, a spatial resolution of 300 untwisting. They represent one of the driving forces of the blood
microns, and a velocity resolution of 3 cm/s. By aligning the entering the left ventricle (ventricular “suction”). As a result, when
cursor parallel to the streamlines of flow, we can observe the the mitral valve opens, a column of blood accelerates from the
propagation of flow from the mitral valve to the apex (Fig. 11-1). atrium toward the ventricular apex. In normal ventricles, flow
Assessment of diastolic flow propagation has offered novel infor- propagates very rapidly, while in dilated, poorly contracted ven-
mation about LV filling dynamics and has been applied in a tricles it occurs comparatively slowly (Fig. 11-2, right).2
variety of clinical conditions. Since the initial descriptions by Mitral inflow propagation displayed by CMM has a complex
Jacobs1 and later Brun,2 computer simulation,3 in vitro modeling,4 pattern. The earliest CMM velocities often occur during isovolu-
and animal5,6 and clinical studies2,5–8 have improved our under- mic relaxation. After the mitral valve opens, there is a rapid initial
standing of the determinant of Vp but also have shown the com- component (phase I), often followed by a slower component
plexity of this index. Vp appears to be relatively independent of (phase II). Finally, the last component in late diastole is associated
loading conditions and therefore may overcome one of the main with atrial contraction (see Fig. 11-1). Computer and in vitro
limitations of Doppler-based techniques.2,5,7,9 modeling have studied the phenomenon of flow propagation.
In this chapter we will review the current understanding of During phase I, blood moves almost simultaneously in the whole
how flow propagates from the base to the apex of the left ventricle, left ventricle, behaving as an incompressible fluid column (colum-
its major determinants, how to properly obtain a color M-mode nar flow).3,4 Phase II is a flow wave thought to be caused by
145
146 Chapter 11 • Evaluation of Diastolic Function by Color M-Mode Doppler

propagation of a ring vortex formed at the ventricular base.3,4,15,16 tion of flow, maximizing the distance from mitral tips to apex. At
Vortices are formed during the acceleration phases of the early least 4 cm of CMM depth should be obtained and displayed at
and atrial filling waves. During the deceleration phases, the vorti- 100 cm/sec sweep speed. In the initial description by Brun,2
ces are amplified and convected into the ventricle (Figs. 11-3 and CMM flow propagation was measured as the slope of color-
11-4).3 The formation of a vortex is affected by the size of the noncolor interface. The use of the slope of the color-noncolor
inlet (mitral orifice)4 and the geometry and size of the receiving interface is limited by its interference with isovolumic flow. Since
chamber. In small, tubular ventricles there is predominant colum- then, several other methods have been proposed. This constitutes
nar flow with no space from the mitral leaflets to the ventricular one of the main limitations of this technique, as it is difficult to
wall for vortex formation. In dilated ventricles with decreased compare studies among different authors. The slope of the first
ratio of mitral valve orifice to ventricular diameter, there would aliasing velocity has also been used by several authors, setting the
be predominant vortex formation and propagation.4 In this cir- aliasing velocity at a percentage (40%–70%) of the maximal
cumstance, flow velocities at the mitral tips can be relatively high, inflow velocity (see Fig. 11-2).5,17 An aliasing velocity of 40% of
but the velocity of the front wave propagation remains slow. This the peak E-wave velocity appears to be more reproducible and to
explains why patients with a restrictive filling pattern can have a better reflect the velocity of propagation.17 There are no consensus
peak E-wave velocity greater than 1 m/sec at the level of the guidelines as to whether phase I or phase II should be measured.
mitral level tips and at the same time a flow velocity propagation Garcia et al. proposed the use of phase II when present.18
of 40 cm/sec or less. In in vitro modeling, the ratio of flow velocity Stugaard et al. used a computer algorithm to detect the maximal
to vortex propagation is around 2 : 1.4 velocities along the center of the flow propagation wave and mea-
sured the time delay between the velocity at mitral tips and apex.8
This method is attractive, for it appears to be more objective, but
Obtaining and Measuring Flow Propagation it is not widely available. An automated way to measure the slope
CMM flow propagation is usually measured from the apical four- of Vp has been described.19 Normal values depend on the meth-
chamber view. The M-mode cursor is carefully aligned with direc- odology used. With the slope of first aliasing (40%–50% of peak
E velocity), values greater than 45 cm/sec are considered normal.
The interobserver variability of Vp measurements has been
.45
reported to be around 12%20 but can be as high as 20%.15

.75
Late (A Wave) Color M-Mode Flow Propagation
Cal = 10mm I II
Most of the studies have focused in the propagation of early
22 mitral inflow. There are limited data about the importance and
clinical significance of the propagation of flow during atrial con-
IVF traction. There is a fundamental difference between early and late
AC
flow propagation. During early propagation, blood is pulled into
the ventricle, while during late propagation, it is pushed (atrial
contraction). A ratio of early to late flow propagation has been
reported in patients with pseudonormal filling patterns,21 although
the advantage of this over early Vp alone or E/Vp is unclear.
133

Figure 11-1 Color M-mode of mitral inflow obtained from the apical Color M-Mode Intraventricular Pressure Gradients
window. Several components can be appreciated from this tracing. Phase
I is faster, followed by the slower phase II (vortex) component. A short flow Given the complexity of CMM inflow patterns and the variability
during isovolumic relaxation (IVF) is also seen, as well as late flow during of the measurements of flow propagation, a more objective analy-
atrial contraction (AC). sis of LV filling is desirable. It is well known that the presence of

Figure 11-2 Example of a young

normal individual (left) and a patient
with delayed relaxation (right). Note the
difference in Vp slope between the
two.
 Chapter 11 • Evaluation of Diastolic Function by Color M-Mode Doppler 147

Figure 11-3 Computer simulation of

vortex formation, flow patterns, and cal-
culated 2D color Doppler echocardio-
grams at six different points in time
during filling. Note that the vortex is
amplified during the deceleration phase
of the early filling wave and moves into
the left ventricle toward the apex. (From
Vierendeels JA et al: Hydrodynamics
of color M-mode Doppler flow wave
propagation velocity V(p): A computer
study. J Am Soc Echocardiogr 2002;15:
219–224.)

Figure 11-4 In vitro model of diastolic

flow obtained by injecting liquid dye of
the same density as water from two
opposing thin needles placed at the top
and bottom of the orifice. This model pro-
duced a succession of vortex rings. The
driving waveforms resulted in trailing
vortex rings in addition to a primary ring.
(From Cooke J et al: Characterizing vortex
ring behavior during ventricular filling with
Doppler echocardiography: An in vitro study.
Ann Biomed Eng 2004;32:245–256.)

regional pressure differences in the left ventricle is related to LV apex

∂p
relaxation and suction. Ling et al. demonstrated in a canine model
the presence of regional diastolic IVPGs between the base and
ΔPIV (t ) = ∫ ∂s
ds
base
the apex of the left ventricle. These gradients resulted in the active
filling of the ventricle. Courtois et al.11,22 validated these findings where ΔPIV(t) represents IVPG.25
and later demonstrated a reduction in IVPG during myocardial This methodology has been reproduced by others26 and opens
ischemia in an animal model. These IVPGs are related to elastic the possibility of evaluating diastole in a more fundamental way
recoil and to apical untwisting.23 Greenberg and Thomas24 used by measuring one of the driving forces of early filling.
the Euler equation to calculate local pressure gradients,
∂p ⎡ ∂v ∂v ⎤ Pathophysiology
= −ρ ⎢ + ν ⎥ ,
∂s ⎣ ∂t ∂s ⎦ In abnormal ventricles, IVPGs are blunted22 or even reversed—
where p, s, t, and v are pressure, distance, time, and velocity, the initial, faster phase is then lost; vortex formation predomi-
respectively. Integrating the Euler equation from the LV base to nates, slowing the progression of the wavefront toward the apex
apex IVPG can be estimated by (see Fig. 11-2). Factors that can affect the formation of IVPGs
148 Chapter 11 • Evaluation of Diastolic Function by Color M-Mode Doppler

include regional wall motion abnormalities, increased end systolic This method has been investigated in patients under several
volume, and dyssynchrony of relaxation.15 The magnitude of pres- conditions, in sinus rhythm and atrial fibrillation.39 Garcia et al.
sure gradient formation also depends on ventricular size. In small studied 45 patients and found a robust correlation of E/Vp with
ventricles, intraventricular gradient formation is enhanced. Vortex PCWP (r = 0.80) with a regression equation:
formation and propagation require that the ventricular diameter
PCWP = 5.27 × [E/Vp] + 4.6.
exceed the mitral diameter.4 In dilated, spherical ventricles, the
difference in axial velocity between the blood already in the ven- The limitations of this method to calculate a numerical value
tricle and blood coming through the mitral valve creates a larger for LA pressure lie in the difficulty in measuring a reliable and
vortex.4 reproducible slope of the CMM. As an example, the same group
published the relation of CWP and Vp in normal subjects. The
regression equation in this group was:
COLOR M-MODE DOPPLER AND
DIASTOLIC FUNCTION PCWP = 25.6 × Vp − 26.1 (r = 0.81).
Adding isovolumic relaxation time (IVRT) to the calculation
Human and animal studies have shown that flow propagation appears to improve the correlation with CWP. Gonzales-Vilchez
velocity of early transmitral flow (Vp) correlates well with the and Ares40 modified the Weiss equation to derive:
time constant of isovolumic relaxation (Tau, τ).2,5,6,27 This correla-
tion is maintained under a variety of loading and inotropic5 condi- PCWP = (0.9 × SBP) × e−IVRT×Vp,
tions and also in children.28 The strength of the correlation varies where SBP is systolic blood pressure. Using this equation, they
according to the technique used to measure Vp, with r values found an improved correlation compared with the E/Vp ratio
ranging from 0.5 to 0.9.5,6,27,28 Vp is also related to −dP/dt and alone (r = 0.80 vs. 0.55).40
minimal LV diastolic pressure.27 Vp appears to be a more complex Another approach is to use the ratio of E/Vp to identify
parameter than a simple index of ventricular relaxation.29,30 Vp is patients with normal versus elevated PCWP. An E/Vp of less
influenced not only by the rate of LV relaxation, but also by ven- than 1.4 or 1.5 appears to have high sensitivity and reasonable
tricular geometry,31 the ratio between mitral orifice size and LV specificity to identify PCWP under 15 mmHg in patients in
cavity size, and dyssynchrony of relaxation.4,30,32 sinus rhythm or even in atrial fibrillation.39 Other authors have
Because Vp correlates well with tau, which is preload indepen- used a ratio of 2.540 to predict elevated CWP, once again reflecting
dent, CMM flow propagation has been proposed as a load- variability in measuring the slope of Vp.
insensitive method of assessing LV relaxation.5,7 Although most
clinical studies have found that Vp is relatively load independent,
there is still some controversy, particularly regarding patients with Use of Color M-Mode in Clinical Settings
normal systolic function and hypertrophy.30,33–36 In this group of Abnormalities in Vp have been described in ischemic heart
patients, LV geometry may play a predominant role. It has also disease,6,8,38,41,42 before cardiac resynchronization43 and constric-
been reported that in patients with congestive heart failure, Vp tive pericarditis,44 and in dilated,1,21 hypertrophic,45 and restrictive
may decrease after medical treatment and is correlated with cardiomyopathies.46,47 In all clinical conditions with abnormal
changes in pulmonary capillary wedge pressure (PCWP).37 relaxation, the velocity of propagation is diminished. In patients
with isolated constrictive physiology, where the intrinsic proper-
ties of the myocardium are normal and the left ventricle has small
CLINICAL RELEVANCE end systolic volume, Vp is normal or even augmented despite
elevated filling pressures.44
Pseudonormal Filling Pattern The prognostic value of Vp has been investigated in patients
In patients with elevated left atrial (LA) pressure, the mitral after their initial myocardial infarction. Patients with a pseudo-
inflow Doppler pattern can be indistinguishable from normal normal pattern, defined by normal E/A ratio and slow Vp, had
diastolic function. This important limitation of pulsed Doppler an adverse prognosis.38 The researchers found that an E/Vp
regarding mitral inflow has led to a search for other techniques. greater than 1.5 was a strong predictor of in-hospital heart failure
One of the early applications of CMM was to differentiate normal in patients with acute myocardial infarction (Fig. 11-5).48
from pseudonormal filling patterns. The Vp has been studied in patients with congestive heart
In patients with a pseudonormal mitral filling pattern, CMM failure. The E/Vp ratio has a modest correlation with brain natri-
will show slow flow propagation.27,38 Takatsuji et al. studied uretic peptide (BNP) levels.49 In patients with hypertensive heart
patients with decreased ejection fractions and mitral E/A ratios disease and normal function who present with dyspnea to the
less than 1 and equal to or greater than 1 and compared them emergency room, E/Vp has a sensitivity of 73%, a specificity of
with a group with normal ejection fractions. The rate of velocity 75%, and an accuracy of 74.3% for diagnosis of heart failure for
propagation of CMM was significantly lower in patients with low the optimal cutoff of 1.5.50 Others have found that an E/Vp of
ejection fractions, regardless of the mitral inflow pattern.27 1.8 has a sensitivity of 83% and a specificity of 86% to predict
pulmonary congestion in patients with normal or low ejection
fraction and correlated with LV end diastolic pressure (r = 0.73).51
Estimation of Left Atrial Pressures As mentioned previously, in patients with heart failure, Vp may
The main determinants of Doppler peak E-wave velocity (E) are show some dependency on loading conditions,37,52 and Vp can be
LA pressure (LAP) and relaxation. By using 1/Vp as a surrogate lower after heart failure treatment. This may limit the application
for relaxation, it is in theory possible to estimate LA pressure, by of Vp for assessing therapy in patients with congestive heart
substituting Vp α 1/τ in E α LAP/τ to yield E α LAP × Vp, failure. In this situation, E/Vp appears to be still useful, as E
which is then rearranged LAP α E/Vp. decreases more than Vp, and therefore the ratio diminishes in the
 Chapter 11 • Evaluation of Diastolic Function by Color M-Mode Doppler 149

100
E/Vp < 1.5
90
80

Cumulative survival (%)

70
60
E/Vp > 1.5
50
40
30
Figure 11-5 Kaplan-Meier curves showing the effect of the ratio 20
of peak E-wave velocity and flow propagation velocity (E/Vp) on
cardiac survival in patients after first myocardial infarction. (From 10 Log rank 28; p < 0.00001
Moller JE et al: Ratio of left ventricular peak E-wave velocity to flow 0
propagation velocity assessed by color M-mode Doppler echocar- 0 3 6 9 12 15 18 21 24 27 30 33
diography in first myocardial infarction: Prognostic and clinical impli-
cations. J Am Coll Cardiol 2000;35:363–370.) Days

direction of hemodynamic improvement. Further research in this

IVPG = 3.5 – 0.056*t0 + 0.11*PCW
area is necessary. In patients with systolic heart failure, E/Vp p < 0.001
greater than 2.7 independently predicts the composite end point r = 0.58
of death, transplantation, or hospitalization.52
The calculation of IVPG using CMM has yielded important 4

IVPG (mmHg)
information in patients with hypertrophic cardiomyopathy and
has been used as a tool to study basic physiologic changes of
aging25 and exercise.23,25,53 Rovner et al.53 found that exercise
capacity and its maximum oxygen use, VO2 max, have a tight 2
relationship with changes in IVPG with exercise. Notably, basal
IVPG was not related to exercise capacity. Normal aging impairs
the relationship between IVPGs and preload, probably through
age-dependent decline in relaxation, and is independent of
changes in ventricular compliance.25 IVPGs appear to be influ- 80
enced by τ and preload (Fig. 11-6).25,51 More recently, a close 60
relation between IVPGs and velocity of apical untwisting has
been shown at rest and with exercise.23 The increase in IVPGs 40 24
τ0

20
(m

during exercise appears to be an essential mechanism to augment 16

s)

stroke volume during this condition. 12

20 8 Hg)
The precise relationship between CMM-derived IVPGs and 4 P (mm
Vp has not yet been well characterized. This relationship is prob- 0 PCW
ably complex, involving not only the absolute pressure difference
Elderly sedentary
but also the temporal and spatial location of local pressure gradi- Young
ents. In an animal model of ischemia, time delay of Vp from base
to apex correlated closely with IVPGs (r = 0.94). Figure 11-6 Three-dimensional scatterplot that shows correlation
between time constant of ventricular relaxation (τ0, x-axis), pulmonary cap-
illary wedge pressure (PCWP) (y-axis), and intraventricular pressure gradi-
Limitations of Color M-Mode Indices ent (IVPG) (z-axis). Data are from both elderly (solid circles) and young (open
circles) subjects around the regression plane. A highly significant, moder-
The main limitation of Vp is its high variability in measuring the ately strong correlation of IVPG with relaxation and preload was observed.
slope of CMM. There is no agreement in how to measure it, and Note that separation of young and elderly subjects according to their IVPG
even if there were, the color display is often complex, bifurcated, values disappears when both τ0 and PCWP are taken into account. (From
Popovic ZB et al: Relationship among diastolic intraventricular pressure gradi-
and curvilinear. In some patients, prominent isovolumic flow ents, relaxation, and preload: Impact of age and fitness. Am J Physiol Heart
interferes with measurement of the slope. Circ Physiol 2006;290:H1454–H1459.)
Normal or increased Vp in patients in whom we expect delayed
relaxation has been described,34 a condition named by some
authors as pseudonormalization of Vp.15 This appears to be ring during isovolumic relaxation and early filling will allow
limited to small, hypertrophic ventricles with small end systolic development of more precise methods to quantitate flow propaga-
volumes. tion and may explain the discrepancies among studies—in par-
ticular, the load dependency of this technique. Further research
into the correlation of Vp with ventricular torsion in clinical situ-
FUTURE RESEARCH ations will greatly help us understand the determinants of Vp.23
The estimation of IVPG using CMM has been used only in
Automatic or semiautomatic methods are necessary to introduce limited clinical conditions but is a promising technique if calcula-
more objectivity into the measurements of Vp.19 A better under- tions can be automatized and widely available in different echo-
standing of the hydrodynamic and mechanical phenomena occur- cardiographic machines.
150 Chapter 11 • Evaluation of Diastolic Function by Color M-Mode Doppler

The issue of preload independence of CMM is not settled, and 22. Courtois M, Kovacs SJ, Ludbrook PA: Physiological early diastolic intraven-
further studies are necessary. Larger numbers of patients in dif- tricular pressure gradient is lost during acute myocardial ischemia. Circula-
tion 1990;81:1688–1696.
ferent clinical conditions and with a variety of LV volumes and 23. Notomi YM, Oryszak SJ, Shiota T, et al: Enhanced ventricular untwisting
ejection fractions need to be studied. The Vp and IVPG under during exercise: A mechanistic manifestation of elastic recoil described by
different loading conditions may be useful to our understanding Doppler tissue imaging. Circulation 2006;113:2524–2533.
of the discrepancies among studies. 24. Greenberg NL, Vandervoort PM, Firstenberg MS, et al: Estimation of dia-
stolic intraventricular pressure gradients by Doppler M-mode echocardiog-
raphy. Am J Physiol Heart Circ Physiol 2001;280:H2507–H2515.
25. Popovic ZB, Prasad A, Garcia MJ, et al. Relationship among diastolic intra-
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 Chapter 11 • Evaluation of Diastolic Function by Color M-Mode Doppler 151
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 MARIO J. GARCIA, MD
12
Evaluation of Diastolic
Function by Tissue
Doppler, Strain, and
Torsion Analysis
INTRODUCTION Ischemic Heart Disease
Dilated Cardiomyopathies
PATHOPHYSIOLOGY
Restrictive Cardiomyopathies
Tissue Doppler Velocities
Constrictive Pericarditis
Myocardial Strain and Strain Rate
Hypertrophy Cardiomyopathies
Left Ventricular Torsion
Transplant Rejection
CLINICAL APPLICATIONS Diabetes and Myocardial Disease
Assessment of Left Ventricular Relaxation Tissue Doppler Parameters and
Evaluation of Left Ventricular Filling Prognosis
Pressures
FUTURE RESEARCH

INTRODUCTION PATHOPHYSIOLOGY

Early Doppler echocardiographic indices of left ventricular (LV)

Tissue Doppler Velocities
diastolic function have studied the mechanics of left atrial (LA) In technical terms, tissue Doppler echocardiography (TDE)
and ventricular filling. These filling indices have been proven differs from standard Doppler by eliminating the highpass filter
to be useful, providing prognostic information in heart failure and using low gain amplification to display the velocities of the
patients.1–3 However, filling indices have limited accuracy predict- myocardium. TDE velocities may be displayed in spectral pulsed
ing intrinsic parameters of diastolic function due to the con- mode or in color-encoded two-dimensional maps superimposed
founding effects of extrinsic loading conditions and valvular on structural images (Figs. 12-1 and 12-2).4 The technical prin-
hemodynamic performance. Doppler ultrasound and more ciples and limitations of these modalities are similar to those
recently two-dimensional speckle tracking may be applied to encountered with standard Doppler flow systems. Myocardial
study LV myocardial mechanics. Since myocardial mechanical velocities may be obtained from multiple locations of the myocar-
events precede LA and LV filling, they may be potentially less dium. In a typical spectral display, the myocardial velocity is a
dependent on extrinsic variables and therefore more accurate in positive waveform representing ventricular systole (SM) and two
characterizing intrinsic myocardial properties. waves corresponding to early filling (EM) and atrial contraction
In this chapter, we will review the role of tissue Doppler and (AM). From the apical acoustic windows, the diastolic myocardial
two-dimensional particle tracking–derived myocardial velocities velocities obtained from any of the LV myocardial segments
and their derivatives for the assessment of LV diastolic appear as a mirror image of the mitral inflow early (E) and atrial
function. (A) filling velocities. In normal humans, the peak of EM precedes
153
154 Chapter 12 • Evaluation of Diastolic Function by Tissue Doppler, Strain, and Torsion Analysis

SM
1

3
AM Figure 12-1 Longitudinal axis tissue Doppler velocities
EM obtained using spectral Doppler from the basal lateral left
ventricular segment. AM, atrial contraction velocity; EM,
early diastolic velocity; SM, systolic velocity.

Figure 12-2 Color-encoded tissue

Doppler velocities obtained from the
A B four-chamber view during systole (A)
and diastole (B).

the peak of LV filling E velocity, suggesting that active relaxation

of the myocardium generates negative pressures in the LV cavity
that initiate LV filling. TDE velocities are affected not only by
regional LV mechanical events, but also by global translation and
rotation of the heart. SM
Accordingly, spectral TDE velocities are usually obtained from
the apical acoustic window, since LV longitudinal velocities are
less affected by translational motion (Figs. 12-3 and 12-4).5 Alter-
natively, translational motion may be corrected by offline analysis
from color-encoded TDE velocities. One method plots the veloc-
ity of each adjacent scan line from the distance of the epicardium
to the endocardium. From a parasternal color M-mode image, the
rates of circumferential fiber shortening and lengthening are pro-
portional to the slope of the velocity/distance regression line. The
value of this slope has been referred to as the myocardial velocity AM
gradient (MVG). EM

MYOCARDIAL STRAIN AND STRAIN RATE

Figure 12-3 Regional values derived from the color-encoded velocities
The change in length of the myocardial fiber (end diastolic length, obtained from different regions of the myocardium. Notice that velocities
that are obtained closer to the base have a higher magnitude, due to the
end systolic length/end diastolic length) is also known as myocar- added translation produced by the contraction and relaxation of middle
dial strain. The spiral architecture of the myocardial fiber bundles and apical segments. AM, atrial contraction velocity; EM, early diastolic
determines strain deformation in multiple directions. Thus, velocity; SM, systolic velocity.
 Chapter 12 • Evaluation of Diastolic Function by Tissue Doppler, Strain, and Torsion Analysis 155

changes in LV geometry during LV systole relate primarily to by: SR = (V1 − V2)/L0, where V1 and V2 are the tissue Doppler
radial (short axis), longitudinal (long axis), and meridional (LV velocities at each end of the segment (L0). Strain (ε) represents
torsion) strain (Fig. 12-5). Myocardial strain may be quantified the percent deformation for the given segment over its initial
noninvasively using magnetic resonance imaging (MRI), TDE, or value, and is obtained by integrating SR over the systolic (shorten-
high-frame-rate two-dimensional echocardiography with speckle ing) or diastolic interval (lengthening) of the cardiac cycle (Figs.
tracking. (Strain analysis using MRI is described in detail in a 12-6 and 12-7). Recent studies have demonstrated a closed cor-
separate chapter.) TDE-derived strain quantifies tissue deforma- relation between SR and indices of LV contractility and between
tion based on Doppler velocity shifts. Unlike tissue Doppler ε and LV stroke volume.6,7 Unfortunately, Doppler-derived strain
velocities, tissue strain is less affected by segmental tethering and is limited to interrogating segments aligned in parallel with the
translational motion; therefore, it reflects primarily the intrinsic Doppler angle of incidence. More recently, strain analysis derived
deformation of the myocardial segment within the sample region. from two-dimensional speckle tracking has become available. This
The strain rate (SR) of a segment of a given length (L0) is given method promises to be more robust than Doppler-derived strain,

SM

εl

εl : Longitudinal strain
εr
εr : Radial strain

εc
εc : Circumferential strain
EM

AM

Figure 12-4 Regional values derived from the color-encoded velocities

obtained from different regions of the myocardium from a patient with
abnormal relaxation. AM, atrial contraction velocity; EM, early diastolic veloc- Figure 12-5 Diagram indicating the direction of different myocardial
ity; SM, systolic velocity. strain vectors.

Velocity
Strain rate

V2

V1

Strain rate = (V2−V1)/d

Strain rate Strain

Systolic strain rate Systolic strain

Diastolic strain rate Diastolic strain

Figure 12-6 Diagram indicating the

mathematical steps used to derive
strain rate and strain from tissue veloci- ∫ (Strain rate) δ time = strain
ties. d, distance; V, velocity.
156 Chapter 12 • Evaluation of Diastolic Function by Tissue Doppler, Strain, and Torsion Analysis

Time
+

Figure 12-7 Curved M-mode display of

AL the strain rate derived from different
BL myocardial segments. The vertical axis
AS
ML indicates the spatial location. The hori-
ML zontal axis represents time, according to
AL the electrocardiographic tracing above.
MS
The colors represent the magnitude of
BL tissue deformation: Red corresponds to
AS systolic contraction, blue corresponds
BS
to diastolic expansion, and green indi-
MS
cates absence of deformation. BS, basal
septum; MS, midseptum; AS, apical
BS
– septum; AL, apical lateral; ML, midlat-
SRI M-mode/curved M-mode eral; BL, basal lateral.

Figure 12-8 Diagram indicating the

vectors of apical counterclockwise and
basal clockwise twist. Torsion is the sum
of both components. (From Notomi Y
et al. Measurement of ventricular torsion
by two-dimensional ultrasound speckle
tracking imaging. J Am Coll Cardiol
2005;45:2034–2041.)

and may provide strain analysis in multiple directions, from virtu- do those in the inner layers. The process can be viewed as a global
ally any echocardiographic image. LV spring between the epicardium and endocardium that is
stretched during systole, storing potential energy for release in
early diastole. Accordingly, LV myocardial contraction and relax-
LEFT VENTRICULAR TORSION ation are tightly interconnected: The potential energy stored
during systole is converted to kinetic energy during diastole, thus
In addition to radial and longitudinal deformation, there is tor- effectively bridging the two periods. Peak LV untwisting velocity
sional deformation of the left ventricle during the cardiac cycle occurs approximately 60 msec earlier than long-axis lengthening
due to the helical orientation of the myocardial fibers.8–15 During and short-axis expansion18 and may be accentuated by catechol-
systole, the basal segments of the LV myocardium rotate or twist amine infusion. Left ventrical untwisting is 40% to 50% com-
in counterclockwise direction, whereas the apical segments twist pleted by the time of mitral valve opening and continues during
in clockwise direction. During diastole, untwisting occurs in the early LV filling.14
opposite direction. Systolic torsion represents the net effect of
basal and apical twist. Apical twisting is the main component of
global LV systolic torsion, and in the next diastole, the apical CLINICAL APPLICATIONS
untwisting also plays the dominant role, whereas basal rotation
is of less importance. Torsional deformation may be quantified Doppler myocardial velocities and, to a lesser extent, strain analy-
by MRI or by either TDE velocities or high-frame-rate two- sis have been used to evaluate myocardial relaxation in a variety
dimensional echocardiography with speckle tracking (Fig. 12-8). of cardiac diseases associated with LV diastolic dysfunction. In
Systolic LV torsion tends to equalize sarcomere shortening addition, TDE combined with LV filling Doppler indices has
between endocardial and epicardial layers of the left ventricle and been used to evaluate LV filling pressures.
is a possible mechanism by which potential energy can be stored
during ejection and then released during early diastole to generate
suction and rapid filling by “elastic recoil.” Assessment of Left Ventricular Relaxation
LV untwisting has been shown to be dissociated from filling Several studies have shown an inverse relationship between EM
and accentuated by catecholamines, with the untwisting rate and LV relaxation (τ)19,20 in patients with both normal and ele-
related to LV pressure decay. The magnitude of the restoring force vated preload. Tissue Doppler EM has been shown to be less
appears to be inversely related to end systolic volume.16,17 Epicar- influenced by preload alterations than standard Doppler LV
dial contraction dominates the direction of torsion because these filling indices, particularly in the presence of slow ventricular
fibers are at larger radii and therefore produce greater torque than relaxation.21 Clinical studies suggest that EM is a better discrimi-
 Chapter 12 • Evaluation of Diastolic Function by Tissue Doppler, Strain, and Torsion Analysis 157

nator between diastolic dysfunction and normal patients, com-

Exercise performance
p < 0.001
pared with any other single or combined index of transmitral 20 n = 85
filling and pulmonary venous Doppler flows.22 LV torsion and 15

(METs)
untwisting also correlate well with the relaxation time constant15 n = 36
10
and with the early LV diastolic intraventricular pressure gradient
(IVPG) (that is, LV suction). Delayed LV untwisting has been 5
reported in patients with severe aortic stenosis and impaired LV
0
relaxation.13 Enhanced LV torsion during exercise is associated
< 10 ≥ 10
with increased IVPG.18 We have recently demonstrated that the
ability to increase IVPG during exercise is directly related to E/EM
aerobic capacity in normals and in heart failure patients.23 A

Exercise performance
p < 0.001
20 n = 44
Evaluation of Left Ventricular Filling Pressures n = 40*
15
Several investigators have studied the utility of Doppler ECG for

(METs)
n = 19† n = 18
the assessment of LV filling pressures.24–27 Previous studies have 10
demonstrated a relationship between mean LA pressure and pul- 5
monary venous systolic (S)/diastolic (D) ratio, mitral E/A ratio,
isovolumic relaxation time (IVRT), and deceleration time (DT). 0
All pulsed Doppler–based methods are accurate when applied to Normal Slow relaxation Pseudonormal/
groups of patients with homogeneously impaired LV relaxation restrictive
since they assume that reduction in IVRT, atrial filling fraction, *E/EM < 10 †E/E ≥ 10
M
pulmonary venous S/D ratio, and DT will occur solely as a con- B
sequence of elevated LA pressure. However, when these methods Figure 12-9 A, Exercise capacity in patients with normal or increased E/EM
are applied to younger patients and those with minimal structural (<10 vs. ≥10). Exercise capacity was greater by a mean of 5.0 METs in
heart disease with a normal ejection fraction (EF), they overesti- patients with E/EM ≥10. B, Exercise capacity in patients categorized by their
mate actual LV filling pressure since they cannot separate the mitral inflow pattern. Patients in slow relaxation group were subdivided
effect of LV relaxation and preload as confounding variables. into those with normal and increased E/Ea. Box plot shows median (center
line), first and third quartiles (top and bottom of box), and lowest and
TDE velocities used as an index of LV relaxation may be com- highest values (vertical lines) of exercise performance. (Modified from
bined with standard Doppler flow indices in order to separate Skaluba SJ, Litwin SE: Mechanisms of exercise intolerance: Insights from tissue
these confounding effects. Since pulsed Doppler E velocity is Doppler imaging. Circulation 2004;109:972–977.)
determined equally by both LA pressure and LV relaxation,
whereas TDE EM is related primarily to LV relaxation, the ratio to a pattern of impaired LV relaxation. Doppler LV filling pat-
of E/EM may be used to predict LA pressure. This concept has terns will vary according to the extent, duration, and severity of
been developed and validated in relatively heterogeneous groups ischemia. These patterns have been shown to carry important
of patients undergoing right heart catheterization.28 In subjects prognostic information after an acute myocardial infarction30 and
with normal LV relaxation and normal LA pressure, both E and in chronic ischemic heart disease.24 TDE myocardial velocities
EM are elevated. In subjects with impaired relaxation and normal and strain indices may identify myocardial ischemia and viability
LA pressure, both E and EM are decreased. In patients with during pharmacologic stress testing (Fig. 12-10).31 Strain rate
impaired relaxation and elevated LA pressure, E is elevated but imaging may be used to identify not only the magnitude but also
EM is reduced. An E/EM ratio greater than 15 is almost invariably the time of peak systolic myocardial contraction. Postsystolic
associated with a mean LA pressure greater than 15 mmHg. shortening is a sensitive marker of ischemia. In pigs subjected to
The combined E/EM ratio also appears to be an important acute myocardial ischemia during angioplasty balloon inflation,
independent predictor of exercise capacity. In 121 subjects who there is a strong direct correlation between the spatial distribu-
were studied with Doppler echocardiography before maximal tions of postsystolic shortening measured by strain rate imaging
exercise testing, exercise capacity was similar in the population and myocardium at risk.32 In patients with ischemic cardiomy-
with a normal mitral inflow pattern (E/A >1) and those with a opathy, an increase of peak systolic strain rate from rest to dobu-
slow relaxation pattern (E/A <1) only when E/Ea was less than tamine stimulation by more than −0.23 s−1 allowed accurate
10 (Fig. 12-9).29 However, those subjects with slow relaxation and discrimination of viable from nonviable myocardial segments, as
E/Ea less than 10 had reduced exercise tolerance. Compared with determined by 18-fluorodeoxyglucose positron emission tomog-
other echocardiographic and clinical parameters, E/Ea had the raphy with a sensitivity of 83% and a specificity of 84%. In this
best correlation with exercise capacity (r = 0.684, p < 0.001) and study, strain imaging was superior to TDE and two-dimensional
was the strongest independent predictor of exercise capacity less wall thickening subjective assessment.
than 7 metabolic equivalents (METs) by multivariate analysis.
Dilated Cardiomyopathies
Ischemic Heart Disease In many patients with dilated cardiomyopathies, conduction
Ischemia affects relaxation by limiting the availability of energy abnormalities result in the late activation and contraction of the
substrates in the form of adenosine triphosphate (ATP). The LV lateral wall. This ventricular dyssynchrony and associated
reabsorption of Ca++ ions by the sarcoplasmic reticulum is an mechanical abnormalities result in an inefficient global contrac-
energy-dependent process, which is required for the deactivation tion that in turn results in reduced stroke volume.33 Cardiac
of the troponin-tropomyosin complex. In the presence of normal resynchronization therapy (CRT), via biventricular pacing, can
systolic function at baseline, ischemia is manifested by a change restore electrical and mechanical synchrony. Clinical studies have
158 Chapter 12 • Evaluation of Diastolic Function by Tissue Doppler, Strain, and Torsion Analysis

Figure 12-10 Regional strain derived from speckle track-

ing in a patient with a lateral wall infarct. Notice the dys-
kinetic (+) systolic strain in the basal lateral wall.

shown that CRT may reduce symptoms, increase exercise capac- thickness and rigidity of the pericardium. Patients present with
ity, reduce hospitalizations for heart failure, induce ventricular signs and symptoms of right-sided heart failure, which are similar
reverse remodeling, and improve survival in symptomatic heart to those found in restrictive cardiomyopathy.41 Two-dimensional
failure patients.34–37 However, a significant proportion of eligible echocardiogrpahy does not always demonstrate increased pericar-
patients do not respond, some may experience increased event dial thickness and the typical interventricular septal bounce. Right
rates after CRT,38 and it appears that a significant number of ventricular (RV) and LV Doppler filling patterns may demon-
patients who have a wide QRS do not have significant mechanical strate respiratory variability. However, these findings are not
dyssynchrony. The mechanical delay or dyssynchrony is not always always present and are not specific. Acute respiratory illnesses can
evident by visual assessment of regional wall motion. TDE may increase intrathoracic pressure swings, increasing also respiratory
be used to determine mechanical dyssynchrony in heart failure flow variability. Excessive preload may attenuate the effect of intra-
patients who are being evaluated for CRT. An intraventricular thoracic pressure swings and decrease respiratory variability,
delay of greater than 65 msec measured by TDE before CRT whereas low preload can decrease the constraining effect of the
identifies patients who experience superior outcomes, including pericardium, also masking the characteristic Doppler signs of
improved 6-minute walk time and greater reduction in LV end constriction. Tissue Doppler myocardial velocities are useful in
systolic volume. Changes in LV end systolic volume after CRT differentiating restrictive cardiomyopathy from constrictive peri-
are strong predictors of long-term survival and heart failure events carditis. In restrictive cardiomyopathy patients, both relaxation
in these patients.39 and stiffness are abnormal. On the other hand, relaxation is pre-
served in pure constrictive pericarditis, in the absence of other
myocardial disease. Patients with constrictive pericarditis and
Restrictive Cardiomyopathies normal systolic function have normal or elevated EM velocities
The restrictive cardiomyopathies are a group of primary and sec- (>8 cm/sec), probably reflecting their preserved ventricular relax-
ondary myocardial diseases characterized by small LV cavity size, ation.5 In a study that included 30 consecutive patients with
abnormal LV relaxation, and increased LV stiffness. Commonly, suspected pericardial constriction versus restrictive myocardial
in restrictive cardiomyopathies, LV wall thickness is normal or disease, an EM greater than 8.0 cm/sec differentiated patients with
increased due to infiltration or fibrosis. Systolic function is abnor- constriction from restriction with 89% sensitivity and 100% speci-
mal only in advanced stages of disease. Pulsed Doppler LV filling ficity (Fig. 12-11).42
patterns vary according to the severity of the disease. Initially, a
pattern of delayed relaxation is seen, progressing to pseudonormal
and finally to restrictive filling patterns in advanced disease. Hypertrophy Cardiomyopathies
Therefore, early diagnosis by conventional echocardiography is The most common form of hypertrophic cardiomyopathy is char-
often difficult. Tissue Doppler early diastolic myocardial velocity acterized by prominent increase in global or segmental LV wall
(EM) is abnormally reduced in patients with restrictive cardiomy- thickness and histologically by myocardial fiber disarray.43 Dia-
opathies.5 A recent study also demonstrated reduced myocardial stolic function is characterized by increased LV chamber stiffness
systolic strain in patients with amyloidosis, even before the devel- and decreased relaxation of variable severity due to the asynchro-
opment of congestive heart failure symptoms.40 nous deactivation of the muscle fibers.44,45 Patients with hypertro-
phic cardiomyopathies can have symptoms even in the absence of
systolic obstruction of the LV outflow tract (LVOT), although
Constrictive Pericarditis recent studies suggest that relief of the LVOT gradient after
Diastolic dysfunction in constrictive pericarditis results from alcohol embolization may be accompanied by an improvement in
increased pericardial constraint on the LV that is related to the LV relaxation.46,47 Pulsed Doppler LV filling usually shows
 Chapter 12 • Evaluation of Diastolic Function by Tissue Doppler, Strain, and Torsion Analysis 159

impaired relaxation or pseudonormal patterns and rarely restric- These abnormalities can often be found in asymptomatic car-
tive patterns because of the markedly increased wall thickness and riers of genetic mutations, even in the absence of phenotypic
impaired relaxation. Two-dimensional echocardiography can expression (Fig. 12-13).50 In hypertrophic cardiomyopathy
establish the diagnosis in patients with either asymmetric hyper- patients with β-myosin heavy chain (β-MHC) mutation, geno-
trophy or LVOT obstruction. However, many patients with type (+) individuals with LVH and genotype (+) individuals
hypertrophic cardiomyopathies have concentric hypertrophy without LVH have lower EM than gender- and age-matched
without obstruction, which is indistinguishable from the physio- controls. Similar findings have been reported in Fabry’s disease,
logic hypertrophy seen in endurance athletes or in patients with a cardiomyopathy secondary to α-galactosidase A deficiency.
hypertensive heart disease. TDE velocities may help to differenti- Mutation-positive Fabry’s patients have significant reduction of
ate myocardial hypertrophy seen in athletes from hypertrophic EM and higher E/EM compared with normal control subjects, even
cardiomyopathy, where these velocities are abnormally decreased.48 before the development of LVH.51 TDE has been used to study
Tissue Doppler can also identify abnormal regional strain, pre- myocardial performance in patients with Friedreich’s ataxia, a
dominantly in areas of localized hypertrophy (Fig. 12-12).49 In
fact, it appears that the greater the extent of segmental wall thick-
ness, the greater the reduction in myocardial strain. 25

30

Averaged EM velocity (cm/sec)

20
25
*†
Peak EM (cm/sec)

20
15
*
15

10 Y = 8.0 cm/sec 10

0 5
CP RCM G+/LVH+ G+/LVH– Controls
Figure 12-11 Peak early longitudinal axial velocities (EM) in patients with Figure 12-13 Averaged EM velocity in two hypertrophic cardiomyopathy
constrictive pericarditis (CP) and restrictive cardiomyopathy (RCM). A value subgroups and normal control subjects. Mean values (䊉) and SD (vertical
of greater than 8.0 cm/sec differentiated patients with constrictive pericar- line) are indicated. *p < 0.0001 compared with control subjects; †p < 0.0001
ditis with 89% sensitivity and 100% specificity. (Modified from Rajogopalan compared with β-myosin gene (+) and left ventricular hypertrophy group
N et al: Comparison of new Doppler echocardiographic methods to differenti- (G+/LVH+). (Modified from Ho CY et al: Assessment of diastolic function with
ate constrictive pericardial heart disease and restrictive cardiomyopathy. Am Doppler tissue imaging to predict genotype in preclinical hypertrophic cardio-
J Cardiology 2001;87:86–94.) myopathy. Circulation 2002;105:2992–2997.)

Figure 12-12 Regional strain obtained

at the septum from a patient with
hypertrophic cardiomyopathy. The
thicker midseptal segment (blue line)
is dyskinetic (+ strain in systole).
(Modified from Yang H et al: Use of
strain imaging in detecting segmental
dysfunction in patients with hypertrophic
cardiomyopathy. J Am Soc Echocardiogr
2003;16:233–239.)
160 Chapter 12 • Evaluation of Diastolic Function by Tissue Doppler, Strain, and Torsion Analysis

neurodegenerative disorder associated with cardiomyopathy and Diabetes and Myocardial Disease
impaired glucose tolerance (Fig. 12-14). The genetic basis for this
inherited disease is a glucosidase acid alpha (GAA) trinucleotide Glycemic control in diabetic patients has been associated with
repeat expansion in the first intron of gene X25, which encodes a microvascular complications. Microvascular disease may lead to
210–amino acid protein, frataxin. It appears that the GAA expan- ischemia and subsequent impaired LV relaxation and increased
sion leads to reduced levels of frataxin, resulting in abnormalities myocardial stiffness. Advanced glycation end-products (AGEs)
of mitochondrial iron transport and antioxidant systems. Asymp- have been associated with microvascular complications of type
tomatic patients who are homozygous for the GAA expansion in 1 diabetes mellitus and may be a pathophysiologic mechanism
the Friedreich’s ataxia gene have reduced MVGs during systole for diastolic dysfunction in these patients. Advanced glycation
and in early diastole.52 There appears to be a strong relationship end-products may lead to early reversible glycation products, fol-
between age-corrected early diastolic MVG and the GAA expan- lowed by irreversible Amadori products and subsequent diabetic
sion in the smaller allele of the Friedreich’s ataxia gene, suggesting cardiomyopathy. We performed echocardiographic studies on 25
that TDE-derived MVGs may be used to determine the extent of patients with type 1 diabetes without clinical evidence of heart
genotypic expression. disease.56 Compared with 26 nondiabetic controls, type 1 diabetic
subjects had worse diastolic function with lower tissue Doppler
EM. Furthermore, glycosylated hemoglobin (HgbA1C) was corre-
Transplant Rejection lated with E/EM (r = 0.68, p = 0.0002). These results demonstrate
Heart transplant patients often receive serial echocardiography in that asymptomatic diastolic dysfunction is common in patients
an effort to detect abnormalities related to organ rejection. It has with type 1 diabetes mellitus and that its severity is correlated
been proposed that serial echocardiographic studies may help in with glycemic control. Furthermore, our data suggest that asymp-
reducing the frequency of surveillance biopsies. Transplant rejec- tomatic diabetic patients have increased LV filling pressure as
tion is associated with lymphocytic infiltration and edema, result- measured by E/EM, and a larger LA size.
ing in increased myocardial stiffness and abnormal relaxation.
Diastolic myocardial velocities measured by TDE may be reduced Tissue Doppler Parameters and Prognosis
in heart transplant patients with rejection and may return to
normal after successful treatment.53,54 One caution that has to be A reduced EM has been associated with reduced survival in patients
taken, however, when interpreting these results is that factors with cardiac disease. In a study that followed for 2 years 165
other than rejection may affect LV relaxation and EM in these normals and 353 patients with hypertension, ischemic heart
patients, such as the age of the donor heart and the time after disease, valvular heart disease, heart failure, diabetes, and obstruc-
transplantation. Thus lower velocities may not imply rejection if tive sleep apnea, a reduced EM was independently predictive of
the organ belonged to an older donor or if these velocities are cardiac death (Fig. 12-15).57 In another recent study, which fol-
obtained several years following transplantation. One way to cir- lowed 225 patients with symptomatic systolic heart failure, E/EM
cumvent this problem would be to compare the results of serial was associated with an increased risk of death or transplant
studies obtained in the same patient. In most circumstances, (p < 0.05) (Fig. 12-16).58 Those patients with an E/EM ratio
however, the diagnosis of rejection requires the integration of
clinical data in addition to the detection of several echocardio- 1.0
graphic markers, such as pericardial effusions, increased wall
thickness, and diastolic abnormalities.55

15 .9
Cum survival
MVG in early diastole (s–1),

r = –0.68
p < 0.001
age corrected

10

.8
5
Em > 5 cm/sec
3 < Em ≤ 5 cm/sec
Em ≤ 3 cm/sec
0
0 250 500 750 1000 1250 .7
GAA repeats on smaller frataxin allele 0 10 20 30 40
Figure 12-14 Relationship between size of GAA expansion in smaller
allele of Friedreich’s ataxia gene and myocardial velocity gradients in early Follow time (months)
diastole, corrected for age. (Modified from Dutka JP et al: Echocardiographic Figure 12-15 Cumulative cardiac death by tertiles of EM in patients with
characterization of cardiomyopathy in Friedreich’s ataxia with tissue Doppler cardiac disease. (Modified from Wang M et al: Peak early diastolic mitral
echocardiographically derived myocardial velocity gradients. Circulation annulus velocity by tissue Doppler imaging adds independent and incremen-
2000;102:1276–1282.) tal prognostic value. J Am Coll Cardiol 2003;41:820–826.)
 Chapter 12 • Evaluation of Diastolic Function by Tissue Doppler, Strain, and Torsion Analysis 161

1 1

Death or heart transplant

Death or heart transplant
E/Vp < 2.7 E/EM < 17
0.9 0.9

0.8 0.8
E/Vp > 2.7 E/EM > 17
Figure 12-16 Cumulative survival by the ratio of LV 0.7 0.7
filling pulsed Doppler E to color M-mode propagation
velocity (VP) and E to EM. (Modified from Troughton RW P < 0.01 P < 0.001
et al: Usefulness of tissue Doppler and color M-mode 0.6 0.6
indexes of left ventricular diastolic function in predicting 0 12 24 36 0 12 24 36
outcomes in systolic left ventricular heart failure (from
the ADEPT study). Am J Cardiol 2005;96:257–262.) Months Months

greater than 17 had a mortality of approximately 40% at 36 months 11. Ingels NB Jr, Hansen DE, Daughters GT 2nd, et al: Relation between
compared with 5% in those with an E/EM ratio of less than 17 longitudinal, circumferential, and oblique shortening and torsional deforma-
tion in the left ventricle of the transplanted human heart. Circ Res
(p < 0.001). In a study that included 250 nonselected patients who 1989;64:915–927.
had had an echocardiogram 1.6 days after a myocardial infarction 12. Rademakers FE, Buchalter MB, Rogers WJ, et al: Dissociation between left
followed up for a median of 13 months, the most powerful predic- ventricular untwisting and filling. Accentuation by catecholamines. Circula-
tor of survival was an E/EM ratio of greater than 15.59 In this study, tion 1992;85:1572–1581.
13. Stuber M, Scheidegger MB, Fischer SE, et al: Alterations in the local myo-
E/EM was a stronger predictor than other Doppler echocardio- cardial motion pattern in patients suffering from pressure overload due to
graphic indices, including the LV filling pulsed Doppler DT. aortic stenosis. Circulation 1999;100:361–368.
14. Bell SP, Nyland L, Tischler MD, et al: Alterations in the determinants of
diastolic suction during pacing tachycardia. Circ Res 2000;87:235–240.
FUTURE RESEARCH 15. Dong SJ, Hees PS, Siu CO, et al: MRI assessment of LV relaxation by
untwisting rate: A new isovolumic phase measure of tau. Am J Physiol Heart
Circ Physiol 2001;281:H2002–H2009.
The introduction of tissue Doppler techniques has led to signifi- 16. Nikolic S, Yellin EL, Tamura K, et al: Passive properties of canine left ventri-
cant advance in our understanding of cardiac physiology. However, cle: Diastolic stiffness and restoring forces. Circ Res 1988;62:1210–1222.
more studies are needed to help understand the relationship 17. Yellin EL, Hori M, Yoran C, et al: Left ventricular relaxation in the filling
between TDE indices and myocardial morphology and cellular and nonfilling intact canine heart. Am J Physiol 1986;250:H620–629.
18. Notomi Y, Martin-Miklovic MG, Oryszak SJ, et al: Enhanced ventricular
function. In addition, it will be important to better define how untwisting during exercise: A mechanistic manifestation of elastic recoil
these indices are related to exercise performance. We foresee that described by Doppler tissue imaging. Circulation 2006;113:2524–
TDE will become a valuable tool for the evaluation of novel 2533.
therapeutic interventions. 19. Sohn DW, Chai IH, Lee DJ, et al: Assessment of mitral annulus velocity by
tissue Doppler imaging in the evaluation of left ventricular diastolic func-
tion. J Am Coll Cardiol 1997;30:474–480.
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 SATOSHI NAKATANI, MD, PhD
13
Assessment of Left Atrial
Size and Function
INTRODUCTION diseases. For example, increased LA size is associated with atrial
fibrillation, stroke, and adverse cardiovascular outcomes.5,8,9–15 LA
PATHOPHYSIOLOGY size has also been known to correlate with overall mortality after
Quantification of Left Atrial Size myocardial infarction16,17 and risk of death and hospitalization in
Assessment of Left Atrial Function patients with dilated cardiomyopathy.18–21
CLINICAL RELEVANCE
Diastolic Dysfunction and Left Atrial Size
PATHOPHYSIOLOGY
FUTURE RESEARCH
Quantification of Left Atrial Size
Measurement of Left Atrial Diameter
LA size is usually measured at end systole, when the left atrium
is most dilated. Traditionally, it is measured at the parasternal
long-axis view using M-mode or B-mode echocardiography (Fig.
INTRODUCTION 13-1). When the M-mode technique is used, the cursor should
pass through the aortic valve. The largest anteroposterior diame-
The left atrium is an oval chamber with thin, muscular walls, ter is measured from the trailing edge of the posterior aortic wall
located between the aorta and the esophagus. Because of this to the leading edge of the posterior LA wall. Although the
location, it is easily recognized not only by transthoracic but also convention for M-mode is to measure from the leading edge to
by transesophageal echocardiography. The left atrium collects the leading edge, the trailing edge of the posterior aortic root is
blood from the pulmonary veins and ejects it into the left ventri- recommended by the American Society of Echocardiography,
cle. The left atrial (LA) chamber changes its size during a cardiac to avoid the variable extent of space between the left atrium and
cycle, being largest at ventricular systole and smallest at atrial the aortic root.22 When the M-mode cursor is not perpendicular
systole. This phasic change involves mainly the anteroposterior to the posterior aortic wall or the posterior LA wall, measurement
and supero-inferior diameters, while the mediolateral diameter based on B-mode echocardiography should be done.
does not change significantly. The left atrium has three functions
in a cardiac phase (see Chapter 4). During ventricular systole, the
Measurement of Left Atrial Area
left atrium functions as a reservoir that collects pulmonary venous
flow; and during early diastole, following passive atrial emptying, by Echocardiography
it functions as a conduit allowing the passage of stored blood from The left atrium can be observed at multiple views besides the
the left atrium to the left ventricle. During atrial contraction, the parasternal long axis. It can also be observed at apical two- and
left atrium acts as a contractile pump that delivers as much as four-chamber views and a parasternal short-axis view, and a diam-
one-third of the left ventricular (LV) filling.1 This atrial contrac- eter can be measured at each. Anteroposterior and supero-inferior
tion makes a significant contribution to maintaining cardiac diameters can be measured at the parasternal long-axis view.
output, especially in patients with LV dysfunction.2–4 Anteroposterior and mediolateral diameters can be measured
Because the left atrium is connected to the left ventricle, at the parasternal short-axis view, and supero-inferior and medio-
enlargement of LA size suggests the presence of elevated filling lateral diameters can be measured at the four-chamber view
pressure and diastolic dysfunction.5–7 Thus, LA size has been (Fig. 13-2). The normal values for each diameter are shown in
noted to be a good prognosticator in various cardiovascular Table 13-1.23
163
164 Chapter 13 • Assessment of Left Atrial Size and Function

Measurement of Left Atrial Volume obtained at the parasternal long- and short-axis views, respec-
by Echocardiography tively.30–32 The method based on diameter measurements is
dependent on selection of the location and direction of the minor-
Linear measurements have been reported to correlate with the axis diameters and has been shown to significantly underestimate
angiographically determined LA size.24,25 However, the left atrium LA volume.30 Alternatively, volume can be calculated using the
has an oval shape that changes asymmetrically according to disease biplane ellipsoid area-length method:
state and loading conditions. Therefore, it is not always the case
that the anteroposterior diameter represents LA size.26,27 For Volume = 8 (A1) (A2)/3π (L),
example, patients with mitral stenosis have an enlarged antero- where A1 and A2 represent the maximal LA area acquired from
posterior diameter, but patients with mitral regurgitation due to the apical four- and two-chamber views, respectively. L is the
mitral valve prolapse often have an enlarged supero-inferior diam- shortest LA long-axis diameter, determined as the distance of
eter. Thus, the measurement of LA anteroposterior diameter may the perpendicular line connecting the mitral annular plane and
be misleading, and LA volume, instead of diameter, should be the superior aspect of the left atrium at either the four-chamber
determined in both clinical practice and research. or the two-chamber view. The ellipsoid method assumes that the
LA volume can be calculated using either an ellipsoid method atrium can be represented by an ellipsoid. However, this assump-
or Simpson’s method.5,8,15,16,24–26,28–30 In the ellipsoid method, the tion often fails when the atrium is deformed by external compres-
left atrium is assumed to be represented as a prolate ellipse, and sion or ventricular distortion. On such occasions, Simpson’s
the volume can be calculated by method is more appropriate.
Volume = 4π/3 (L/2) (D1/2) (D2/2), Simpson’s method states that the volume of a large figure can
be calculated from the sum of the volumes of a series of smaller
where L is the LA long-axis diameter at the four-chamber view, figures of similar shape. Thus, the LA volume can be obtained as
and D1 and D2 are anteroposterior and mediolateral diameters the sum of the volumes of a series of smaller elliptic cylinders of
known height (h):
Volume = π/4 (h) Σ (D1) (D2),

TABLE 13-1
NORMAL VALUES FOR LEFT ATRIAL DIAMETER
0 MEAN ± SD (cm) RANGE (cm)

Parasternal long-axis view

Anteroposterior diameter 3.0 ± 0.3 2.3–3.8
Supero-inferior diameter 4.8 ± 0.8 3.1–6.8
Parasternal short-axis view
Anteroposterior diameter 2.9 ± 0.4 2.2–4.1
Mediolateral diameter 4.2 ± 0.6 3.1–6.0
Left atrial diameter
Apical 4-chamber view
Supero-inferior diameter 4.1 ± 0.6 2.9–5.3
Mediolateral diameter 3.8 ± 0.4 2.9–4.9
40
From Weyman AE: Normal cross-sectional echocardiographic measurements. In
Figure 13-1 Measurement of left atrial diameter by M-mode Weyman AE (ed): Principles and Practice of Echocardiography, 2nd ed. Philadelphia,
echocardiography. Lea & Febiger, 1994:1289–1298.

D1
D1
D3 D3
D2

D2

A B C

Figure 13-2 Left atrial diameter measures. A, In the parasternal long-axis view; B, in the parasternal short-axis view; and C, in the apical four-chamber
view. D1, anteroposterior diameter; D2, mediolateral diameter; D3, supero-inferior diameter.
 Chapter 13 • Assessment of Left Atrial Size and Function 165

where D1 and D2 are orthogonal minor and major axes of each Measurement of Left Atrial Volume by
cylinder (Fig. 13-3). For these calculations, the planimetered LA Other Methods
areas at the orthogonal views, such as apical four-chamber and
two-chamber, are required. The pulmonary veins and the LA LA volume has been determined by computed tomography,
appendage should be excluded, and the inferior border should be biplane contrast ventriculography, and magnetic resonance
represented by the mitral annular plane when the LA border is imaging.24,28,29,35,36 LA volume determined by echocardiography has
traced. Normal LA volume determined by echocardiography in a been shown to correlate well with or to underestimate measure-
number of studies is 22 ± 6 ml/m2.5,32–34 Table 13-2 shows refer- ments by these methods.24,28,29,36 In a dog model, LA volume can be
ence limits and partition values for LA measurements obtained estimated accurately with two pairs of sonomicrometers sewn into
from a Framingham Heart Study cohort.22 the anteroposterior and mediolateral walls of the left atrium.37
Because the entire left atrium cannot always fit into the image
sector when using the transesophageal approach, measurements
of LA volume cannot be reliably performed. However, LA diam-
Assessment of Left Atrial Function
eter can be estimated combining measurements from different The left atrium has several physiologic functions. During LV
imaging planes. systole, the left atrium collects and stores blood (a reservoir func-

TABLE 13-2
REFERENCE LIMITS AND PARTITION VALUES FOR LEFT ATRIAL DIMENSION AND VOLUME
WOMEN MEN

REFERENCE MILDLY MODERATELY SEVERELY REFERENCE MILDLY MODERATELY SEVERELY

RANGE ABNORMAL ABNORMAL ABNORMAL RANGE ABNORMAL ABNORMAL ABNORMAL

LA diameter, cm 2.7–3.8 3.9–4.2 4.3–4.6 ≥4.7 3.0–4.0 4.1–4.6 4.7–5.2 ≥5.2

LA diameter/BSA, 1.5–2.3 2.4–2.6 2.7–2.9 ≥3.0 1.5–2.3 2.4–2.6 2.7–2.9 ≥3.0
cm/m2
LA area ≤20 20–30 30–40 >40 ≤20 20–30 30–40 >40
LA volume, mL 22–52 53–62 63–72 ≥73 18–58 59–68 69–78 ≥79
LA volume/BSA, 22 ± 6 29–33 34–39 ≥40 22 ± 6 29–33 34–39 ≥40
ml/m2

LA, left atrial; BSA, body surface area. Bold italic values: Recommended and best validated.
From Lang RM et al: Recommendations for chamber quantification: A report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber
Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr
2005;18:1440–1463.

A B
Figure 13-3 Measurement of left atrial volume using modified Simpson’s method. Apical four-chamber view (left) and two-chamber view (right) are
obtained at end systole to obtain maximum left atrial size.
166 Chapter 13 • Assessment of Left Atrial Size and Function

tion). During LV early diastole, a part of the blood in the left reported to be 1.60 ± 0.41 ml/mmHg/m2, one-half to one-third
atrium flows into the left ventricle, helping rapid ventricular filling of LV compliance.39,40 LA compliance is an important determi-
(passive emptying); and from rapid filling to mid-diastolic slow nant of diastolic filling and atrial function. Hoit et al. showed that
filling, the left atrium helps the passage of blood from the pulmo- LA compliance was affected by the presence of the LA appendage
nary veins to the left ventricle (a conduit function). During atrial (see Chapter 4). They found that in a canine model, the diastolic
systole, the left atrium expels blood to the left ventricle against pressure-volume relation of the left atrium was shifted upward
LV diastolic pressure (a contractile function). To facilitate under- and leftward after appendectomy, suggesting that the LA append-
standing of LA function, the instantaneous changes in LA pres- age was more distensible than the LA body. Larger compliance of
sure and volume during a cardiac cycle are shown in Figure 13-4. the appendage may be beneficial when LV filling pressure is
LA volume increases during LV systole due to LA active relax- increased and atrial distensibility is decreased.41
ation just after atrial active contraction, LV shrinkage by LV It has been reported that blood volume ejected by atrial con-
contraction, and caudal movement of the inferior aspect of the traction has a linear relationship with LA volume just before atrial
left atrium. LA pressure decreases after mitral valve closure (“c”) contraction.42 This supports the presence of the Frank-Starling
and makes the “x” trough. Then, receiving blood from the right mechanism in the atrium. We have recently demonstrated a linear
heart, the left atrium is passively expanded, and both volume and relationship between LA peak change in pressure by time (dP/dt)
pressure increase, making the “v” wave in the pressure tracing. and LA pressure just before atrial contraction.43 The blood volume
With mitral valve opening, blood flows into the left ventricle ejected by atrial contraction is related to LV function. It is about
rapidly, and LA volume decreases (passive atrial emptying). 20% in normal subjects but is about 35% in patients with myo-
During this phase, LA pressure also decreases and makes the “y” cardial infarction.2 Thus, LA contractile function seems to com-
trough. During mid-diastole, blood from the pulmonary veins pensate the reduced LV stroke volume in LV dysfunction.
flows into the left ventricle (a conduit function). LA volume and However, when LV end diastolic pressure is very high, with sig-
pressure increases only a little at this phase in the normal compli- nificant LV dysfunction, much of the blood ejected by LA con-
ant heart. However, in the noncompliant heart, LA pressure traction goes back to the pulmonary veins, leading to an inefficient
increases rapidly. At late diastole, LA volume decreases and LA LA contraction.
pressure increases rapidly, making the “a” wave with atrial active
contraction. A part of the blood flows back into the pulmonary
veins. CLINICAL RELEVANCE
The atrial pressure-volume relationship has a “figure 8” shape
(Fig. 13-5). It has an “a-loop” during atrial contraction and a “v- Diastolic Dysfunction and Left Atrial Size
loop” during the other phase. The ascending limb of the v-loop It has been reported that about half of patients with chronic heart
corresponds to the period between the “x” trough and the peak of failure have preserved LV ejection fraction (diastolic heart
the “v” wave and represents LA passive expansion. There have failure).44–47 Hypertension, LV hypertrophy, ischemic heart
been some studies to calculate LA compliance by fitting the limb disease, aging, and other cardiovascular disease can potentially
to an exponential curve: cause diastolic dysfunction. Diastolic dysfunction elevates filling
P = beaV, pressures leading to atrial enlargement. Doppler parameters such
as transmitral flow and mitral annulus velocity, considered to be
where P is LA pressure, b is a constant, a is a chamber stiffness useful to assess diastolic function, reflect filling pressures at one
parameter, and V is LA volume.38–40 LA compliance can be deter- time and would be altered if loading conditions changed. In con-
mined as a reciprocal of a chamber stiffness parameter. It has been trast, an enlarged atrium may better reflect the cumulative effect
of elevated filling pressures over time. Thus, atrial size has been
suggested as a marker of the severity and duration of diastolic

17

ECG 15
a-loop
LA pressure (mmHg)

13 v-loop
LAV
11

v 7
a
d 5
y
LVP c
LAP
x 20 30 40 50 60 70 80
Figure 13-4 Echocardiography (ECG) shows instantaneous changes in left
LA volume (ml)
atrial pressure (LAP) and left atrial volume (LAV), along with left ventricular
pressure (LVP) during a cardiac cycle. Figure 13-5 Left atrial (LA) pressure-volume relationship.
 Chapter 13 • Assessment of Left Atrial Size and Function 167

dysfunction. There is a famous analogy: Serum glucose is used to incremental prognostic value beyond that provided by diastolic
assess transient diabetic control, and hemoglobin A1C is used as a dysfunction grade.49
long-term biomarker of average metabolic state. Similarly, LV The significance of LA enlargement in cardiovascular diseases
filling pressure is used to assess transient loading conditions, and has been demonstrated in many studies. LA enlargement has
LA size is used as a long-term biomarker of average LV diastolic been reported to be an early sign of hypertensive heart disease.50
pressure.48 In fact, Pritchett et al. have shown that LA volume LA size is associated with the outcomes in patients with myocar-
increased with worsening of diastolic dysfunction in a general dial infarction. Møller et al. found that an LA volume index of
population, as shown in Table 13-3.49 They found that the grade greater than 32 ml/m2 measured a median of one day after
of diastolic dysfunction was positively associated with the LA admission was a powerful and independent predictor of mortality
volume index. Thus, diastolic dysfunction has been considered to in patients with acute myocardial infarction.16 Moreover, LA
contribute to LA remodeling. volume of greater than 32 ml/m2 has been reported in another
LA size can be evaluated by diameter and volume. Which is study to be an independent predictor of 5-year mortality in
suitable for the assessment of diastolic dysfunction? Previous patients with acute myocardial infarction (Fig. 13-6).17 These
investigations used mainly LA diameter as an index of the size of results are well explained by the fact that LA size reflects chroni-
the left atrium.10,13,50–52 For example, Vaziri et al. demonstrated cally elevated filling pressure. A recent paper using stress echocar-
that there was a significant association between elevated systolic diography suggested that normal resting LA volume (≤28 ml/m2)
pressure and increased LA diameter in the Framingham Heart predicts a normal stress echocardiogram and identifies patients
Study.53 In contrast, recent studies have demonstrated that LA with low ischemic risk.58 This is an interesting observation and
volume may be more suitable to reflect morbid conditions.26,54 should be further assessed for its complementary role in stress
Tsang et al. followed 423 patients who had a general medical testing.
consultation for subsequent development of new atrial fibrilla-
tion, congestive heart failure, stroke, transient ischemic attack,
myocardial infarction, coronary revascularization, and cardiovas-
cular death. They found that LA volume was a more robust 100
marker of cardiovascular events than was LA diameter or area.55
LA volume has been related to the occurrence of atrial fibrilla-
tion54,56 and other cardiovascular events, such as myocardial 90
infarction, congestive heart failure, and stroke.8 It has been shown
that both body size and aging influence LA size.1,54,57 The influ-
Survival (%)

ence of body size on LA size is typically corrected by indexing to 80

body surface area.

70
Left Atrial Size and Prognosis
Since diastolic heart failure has a poor prognosis, similar to sys-
tolic heart failure, enlarged LA size may potentially indicate a 60
LA volume index < 32 ml/m2
worse outcome.55 Tsang et al. noted that LA volume was associ- LA volume index ≥ 32 ml/m2
ated with poor outcome in a community-based elderly popula-
tion.8 They found that an LA volume index of more than 32 ml/m2 50
was an independent predictor of cardiovascular events, including 0 1 2 3 4 5
congestive heart failure, myocardial infarction, and stroke. Time (years)
However, it has been suggested in another study that LA volume Figure 13-6 Kaplan-Meier survival curves of patients with acute myocar-
might not be a better predictor than diastolic dysfunction grade.49 dial infarction with left atrial (LA) volume index ≥32 ml/m2 and with
Pritchett et al. found that the LA volume index was highly sensi- <32 ml/m2. They were adjusted for age, gender, Killip class ≥2, primary
tive and specific for the detection of severe diastolic dysfunction reperfusion, diabetes, systemic hypertension, paroxysmal atrial fibrillation,
previous myocardial infarction, left ventricular ejection fraction, moderate
but was not a robust marker of mild or moderate diastolic dys- and severe mitral regurgitation, and left ventricular filling pattern. p = 0.02.
function. In addition, they found that although diastolic function (From Beinart R et al: Long-term prognostic significance of left atrial volume
grade had prognostic importance, the LA volume index added no in acute myocardial infarction. J Am Coll Cardiol 2004;44:327–334.)

TABLE 13-3
LEFT ATRIAL VOLUME INDEX ACCORDING TO DIASTOLIC FUNCTION GRADE
% MEETING CRITERIA FOR LEFT ATRIAL
DIASTOLIC GRADE n % OF COHORT LEFT ATRIAL VOLUME INDEX, ml/m2 ENLARGEMENT

Normal 1212 73 23 ± 6 9
Grade I 315 19 25 ± 8 17
Grade II 118 7 31 ± 8 48
Grade III to IV 12 1 48 ± 12 100

Left atrial enlargement, ≥30 ml/m2 in women or ≥33 ml/m2 in men.

From Pritchett AM et al: Diastolic dysfunction and left atrial volume: A population-based study. J Am Coll Cardiol 2005;45:87–92.
168 Chapter 13 • Assessment of Left Atrial Size and Function

S-v
S-sr
S-s

E-s

E-v
E-sr

A-v A-sr

A B C
Figure 13-7 A, Left atrial (LA) tissue velocity; B, LA strain; C, LA strain rate. These traces were obtained with a region of interest placed in the midseptum
at the four-chamber view. S-v, peak velocity in systole; E-v, peak velocity in early diastole; A-v, peak velocity in late diastole; S-s, peak strain in systole; E-s,
peak strain in early diastole; S-sr, peak strain rate in systole; E-sr, peak strain rate in early diastole; A-sr, peak strain rate in late diastole.

LA volume is also helpful to determine prognosis in patients ments of local velocities, it is affected by motion of the adjacent
with dilated cardiomyopathy having systolic dysfunction as well tissues and Doppler incident angle. Since strain and strain rate
as diastolic dysfunction. In the Studies Of Left Ventricular Dys- parameters are determined based on spatial differences in veloci-
function (SOLVD) population, a left atrium larger than 4.17 cm ties or moving distance between two different regions, they are
in diameter was closely associated with increased risk of death independent of cardiac translational motion and the tethering
and cardiovascular hospitalization.18 Rossi et al. showed that effect. Recently, these indexes could be obtained not only by tissue
determinants of LA volume in patients with dilated cardiomyopa- Doppler imaging but also by speckle tracking imaging, which is
thy include LV volume, ejection fraction, the degree of mitral independent of Doppler incident angle.
regurgitation, and diastolic dysfunction.19 These parameters all LA strain and strain rate can be obtained by placing a region
related to the outcome. However, compared with all of these of interest on the midsegment of the LA walls at the apical views.
determinants, LA volume has an independent and incremental It has been reported that LA systolic and early diastolic strain
prognostic value. rates are correlated with age.60 Moreover, LA peak systolic
strain rate is significantly lower in patients with atrial fibrillation
than in age-matched control subjects. LA late diastolic strain
FUTURE RESEARCH rate, which corresponds to atrial contraction, is also lower in
patients with atrial fibrillation, and this increases gradually
Since LA size is closely linked to cardiac risk and prognosis, its after cardioversion.61 LA strain and strain rate have been reduced
evaluation, that is, LA volume indexed to body surface area, in various conditions, such as amyloidosis62 and postsurgical
should be measured routinely in the echocardiographic labora- correction of atrial septal defect.63 They did not reduce when
tory. However, the measurement is still cumbersome and may be closure of the atrial septal defect was done with a catheter-based
affected by LA morphology. Sometimes the left atrium is com- device, suggesting that this was a less invasive procedure to the
pressed by a marked dilation of the aortic root or extracardiac left atrium. Strain and strain rate imaging is promising
masses, causing asymmetric atrial morphology. On these occa- because the parameters obtained may reflect subtle changes in
sions, the accuracy of measurements of LA size may be question- LA function that are not readily assessed with conventional
able. Recently, real-time three-dimensional echocardiography has echocardiography.
emerged as a tool for accurate volume measurements in clinical
assessment. Further development of three-dimensional echocar-
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measurements: A call for standardization. Am Heart J 2000;139:412– 62. Modesto KM, Dispenzieri A, Cauduro SA, et al: Left atrial myopathy in
422. cardiac amyloidosis: Implications of novel echocardiographic techniques.
58. Alsaileek AA, Osranek M, Fatema K, et al: Predictive value of normal left Eur Heart J 2005;26:173–179.
atrial volume in stress echocardiography. J Am Coll Cardiol 2006;47: 63. Di Salvo G, Drago M, Pacileo G, et al: Atrial function after surgical and
1024–1028. percutaneous closure of atrial septal defect: A strain rate imaging study.
59. Abhayaratna WP, Seward JB, Appleton CP, et al: Left atrial size: Physiologic J Am Soc Echocardiogr 2005;18:930–933.
determinants and clinical applications. J Am Coll Cardiol 2006;47:
2357–2363.
 SHERIF F. NAGUEH, MD
WILLIAM A. ZOGHBI, MD
14
Evaluation of
Right Ventricular
Diastolic Function

INTRODUCTION filling patterns and RV filling pressures reflect the net balance of
many variables. Active relaxation is among the important deter-
PATHOPHYSIOLOGY minants of RV diastolic function and is dependent on calcium
Right Atrial and Ventricular Dimensions uptake by the sarcoplasmic reticulum, intrinsic contractility, uni-
Inferior Vena Cava Diameter and Respiratory Collapse formity of relaxation, and the load-dependent properties of relax-
Tricuspid and Pulmonary Regurgitation Signals by ation. Ventricular suction and active myocardial relaxation in
Continuous Wave Doppler health lead to a small positive pressure gradient between the right
Tricuspid Inflow atrium and the right ventricle, hence the predominant RV filling
Hepatic Venous Flow in early diastole. In addition, recent animal studies with three-
Tissue Doppler Imaging dimensional real-time echocardiography have drawn attention to
FUTURE RESEARCH the presence of vortical motion during early diastolic RV filling,
which is reduced with chamber dilatation.1 This vortical motion
can facilitate RV filling by shunting kinetic energy that could
otherwise lead to increased convective deceleration and therefore
a reduced right atrial (RA) to RV pressure gradient.
INTRODUCTION With impaired RV relaxation, an increase in RA pressure is
needed to maintain adequate RV filling and stroke volume. Myo-
Assessment of right ventricular (RV) function is an important cardial stiffness, RV chamber geometry (dimensions and wall
component of the comprehensive evaluation of cardiac function thickness), and RA systolic function determine RV filling later in
in patients with known or suspected heart disease. RV function diastole. In particular, RA systolic function appears to play an
may be normal when left ventricular (LV) function is depressed, important compensatory role in preventing heart failure in the
and conversely, RV dysfunction may occur in the presence of presence of pulmonary hypertension.2 In addition, factors extrin-
normal LV function. Therefore, a careful evaluation of RV func- sic to the right ventricle determine RV filling, including pericar-
tion is essential irrespective of LV functional status. In this dial properties, LV filling, and extrinsic compression by medias-
chapter, we will discuss the assessment of RV diastolic function tinal masses or large pleural effusions. In turn, RV filling can
with echocardiographic and Doppler techniques. affect LV diastolic volume and pressure.3
It is possible to assess RV relaxation invasively by using high-
fidelity pressure catheters to measure peak negative pressure/time
PATHOPHYSIOLOGY change (dP/dt) and the time constant of pressure decay during
isovolumic relaxation (τ). Both measurements, however, are load
RV diastolic function is determined by a number of factors at the dependent,4,5 with an inverse linear relation to systolic load. There
cellular, myocardial, and cardiac chamber levels. Therefore, RV is a paucity of data with respect to human measurements that
171
172 Chapter 14 • Evaluation of Right Ventricular Diastolic Function

include small numbers of patients with coronary artery disease,6 equivocal findings in Doppler parameters. Although RA volumes
pulmonary hypertension,5 and hypertrophic cardiomyopathy.7 can be measured at any time during the cardiac cycle, maximal
RV chamber stiffness can also be quantified using the combina- RA volumes (Fig. 14-1) are most frequently measured before tri-
tion of RV diastolic pressures and volumes.4,8 In comparison with cuspid valve opening at end systole; RA minimum volume is
invasive measurements, echocardiography has the advantages of measured after tricuspid valve closure at end diastole. RA empty-
safety, versatility, and portability, and therefore is the modality ing fraction can be computed as the difference between RA
that is most frequently utilized to gain insight into RV diastolic maximum and minimum volumes/RA maximum volume. In
function and filling pressures (Table 14-1). patients with increased mean RA pressure, RA maximum and
minimum volumes are increased, whereas RA emptying fraction
is decreased.9 The correlation of RA volumes with RA pressure,
Right Atrial and Ventricular Dimensions however, is weak and is heavily modified by RA stiffness and
The assessment of RV diastolic function should begin with the contractility. In addition, RA volumes may be increased for
evaluation of RV dimensions and systolic function, as patients reasons other than diastolic dysfunction, such as atrial fibrillation
with reduced RV systolic performance have diastolic dysfunction. and tricuspid valve disorders.
RV systolic function is usually assessed in a qualitative manner
by paying attention to RV dimensions and fractional area change.
This is done utilizing two-dimensional echocardiography, with Inferior Vena Cava Diameter and
images acquired from the parasternal, apical, and subcostal views. Respiratory Collapse
Likewise, the presence of RV hypertrophy is associated with dia- Inferior vena cava (IVC) diameter and its change during inspira-
stolic dysfunction. tion are useful indicators of RA pressure. Previous studies have
RA volume is another useful parameter obtained with two- noted that the segment within 2 cm of the RA-IVC junction is
dimensional echocardiography. It is usually increased in patients the region most responsive to changes in respiratory effort.10,11 In
with RV diastolic dysfunction. RA volumes should be considered particular, IVC expiratory and inspiratory diameters as well as
when drawing conclusions about RA pressure in patients with percent collapse were reported to have significant relations with
RA pressure in patients with spontaneous respiration.9–11 Clini-
cally, IVC imaging is acquired in the subcostal view at rest and
with inspiratory effort, or a “sniff test.” The presence of at least
TABLE 14-1 50% collapse is usually seen with an RA pressure less than
10 mmHg, whereas patients with RA pressure greater than
ECHO DOPPLER INDICES FOR ASSESSMENT OF RIGHT 10 mmHg typically exhibit less than 50% IVC collapse.11 Figure
VENTRICULAR DIASTOLIC FUNCTION 14-2 is from a patient with an increased RA mean pressure
1. Right atrial volumes (maximum, minimum, and emptying (>20 mmHg) who exhibits a dilated IVC and minimal change in
fraction) IVC diameter with inspiration.
2. Inferior vena cava diameter and collapse index The limitations of this method occur in patients with dyspnea
3. Downslope of tricuspid regurgitation jet by continuous wave
(CW) Doppler
and those on mechanical ventilation. In patients on mechanical
4. Deceleration rate of pulmonary regurgitation jet by CW Doppler ventilation, IVC percent collapse relates poorly (Fig. 14-3) to
5. Tricuspid inflow velocities (E, A, E/A ratio, and deceleration time of mean RA pressure,9,12 whereas IVC diameter at expiration has a
E velocity) somewhat better correlation (r = .58). An IVC diameter no
6. Hepatic venous flow (systolic, diastolic, and atrial reversal greater than 12 mm appears highly accurate in identifying patients
velocities)
7. Tricuspid annulus early (Ea) and late (Aa) diastolic velocities by with an RA pressure less than 10 mmHg, whereas a diameter
tissue Doppler (TD) greater than 12 mm has no predictive value in this population.12
8. Isovolumic relaxation time by TD: time between end of systolic In addition, it is possible to image the left hepatic vein from
velocity and onset of Ea the same window. In one study, the transverse diameter of this
9. Early (SRe) and late (Sra) diastolic strain rate vein at expiration and inspiration, as well as end expiratory apnea,
was shown to relate significantly to mean RA pressure in a group

NORMAL RA VOLUME MARKEDLY ENLARGED RA

Figure 14-1 Right atrial (RA) end sys-

tolic volume from two patients: one
RA with normal RA volume at 26 ml (left)
RA and the other with pulmonary hyper-
tension, a dilated and hypertrophied
right ventricle, and a markedly enlarged
right atrium, with a maximum volume of
156 ml.
 Chapter 14 • Evaluation of Right Ventricular Diastolic Function 173

Expiration Inspiration

Normal
RAP

Figure 14-2 Examples of inferior vena cava

(IVC) diameter changes with inspiration
(between arrows) from a patient with normal
right atrial pressure (RAP) (upper panel) and Increased
another with increased RAP (lower panel). In RAP
the upper panel, there is complete collapse
of the IVC with inspiration, whereas in the
lower panel, the IVC is dilated with minimal
change in its diameter with inspiration. The
latter observation is consistent with an RAP
>20 mmHg.

30
Overall r = –0.63, y = 16.6 – 0.16x Tricuspid and Pulmonary Regurgitation Signals
n = 35, SEE = 4.4 mmHg by Continuous Wave Doppler
Mean right atrial pressure by catheter (mmHg)

25
The rate of rise and fall in tricuspid regurgitation (TR) jet velocity
by continuous wave (CW) Doppler parallels the corresponding
– vent
r = –0.76, SEE = 4.1 mmHg events in RV pressure, assuming minimal fluctuations of RA
+ vent pressure throughout the cardiac cycle. Therefore, it is possible to
20
r = 0.24, p = ns calculate RV peak positive and peak negative dP/dt by using the
TR jet and applying the modified Bernoulli equation to convert
the TR velocity to RV pressure. In one study,14 a strong correla-
15 tion was observed between the invasive measurement and the
noninvasive estimate of peak negative dP/dt. The limitations of
this approach include the need for a complete TR signal and the
10 underestimation of peak negative dP/dt in patients with an RA
“v” wave pressure of at least 10 mmHg. For clinical application,
one depends more on the shape of the signal (slow decay of the
5 peak velocity to baseline) than the actual measurement, as shown
in Figure 14-4.
A pulmonary regurgitation (PR) signal by CW Doppler can
0 be recorded in many patients, particularly in the presence of pul-
0 20 40 60 80 100 monary hypertension. In addition, it is possible to enhance the
IVC collapse index (%) signal by using intravenous contrast.15 Once an adequate signal is
recorded, its peak velocity can be used to estimate mean pulmo-
Figure 14-3 Relation between mean right atrial pressure and inferior vena
cava (IVC) percent collapse. Patients on mechanical ventilation are shown nary artery pressure, whereas its end diastolic velocity in conjunc-
as blue circles, whereas those with spontaneous breathing are shown as red tion with mean RA pressure can be used to estimate pulmonary
circles. A significant inverse correlation was present only in the group artery diastolic pressure.16 Discrepancies may occur if RV end
with spontaneous breathing. (From Nagueh SF et al: Relation of mean right diastolic pressure is significantly different than mean RA
atrial pressure to echocardiographic and Doppler parameters of right atrial
and right ventricular function. Circulation 1996;93:1160–1169.)
pressure.
In addition, in the absence of significant PR, the deceleration
slope and the pressure half-time of the PR jet by CW Doppler
can provide unique insight into RV diastolic function. Patients
of 32 patients presenting with acute myocardial infarction.13 with increased RV stiffness and rapidly rising RV diastolic pres-
Assessment of the left hepatic vein diameter could be helpful in sure have a rapid equalization of the pressure gradient between
patients where the IVC is not well visualized. However, there is the pulmonary artery and the right ventricle and therefore a short
a paucity of data on the clinical application of this approach in pressure half-time (Fig. 14-5). In one study, which used right
patients on mechanical ventilation. heart catheterization, a pressure half-time of no greater than
174 Chapter 14 • Evaluation of Right Ventricular Diastolic Function

NORMAL RV FUNCTION DEPRESSED RV FUNCTION

Figure 14-4 Example of tricuspid regur-

gitation jets by CW Doppler from two
patients: one with normal right ventricu-
lar (RV) function (left) and the other with
depressed RV function (right). Notice
the slow decay of the peak velocity to
the baseline from the patient with
depressed RV systolic function com-
pared with the normal, as indicated by
the slope of the yellow arrows.

Figure 14-5 Example of pulmonary

regurgitation jets by CW Doppler from
two patients: one with normal right
ventricular (RV) diastolic pressure (left)
and the other with highly increased RV
diastolic pressures (right). Notice the
very steep deceleration of pulmonary
regurgitation from the patient in the
right panel as indicated by slope of the
yellow arrows.

150 ms was the best predictor of RV involvement in patients Similar to mitral inflow, tricuspid inflow (Fig. 14-6) is analyzed
presenting with acute inferior wall myocardial infarction.17 The for peak early (E) and late (A) diastolic velocity, deceleration time
same investigators reported that this parameter was the only pre- (DT) of E velocity, duration of A velocity, and the fraction of RA
dictor of overall in-hospital clinical events in the same patient contribution to RV filling (the atrial filling fraction [AFF]). All
population.18 measurements except for the A duration are obtained from the
Doppler recordings at the level of the valve tips. The A duration
is measured from the recording at the level of the tricuspid
Tricuspid Inflow annulus. Because the tricuspid and pulmonary valves are in dif-
Pulsed-wave (PW) Doppler recording of tricuspid inflow is ferent planes, isovolumic relaxation time (IVRT) is measured by
essential for the assessment of RV filling. Care should be exer- Doppler using two time intervals, as the difference between the
cised to obtain the best alignment with the direction of blood duration from the QRS complex to onset of tricuspid inflow and
flow, which typically requires a medial movement of the trans- the interval from the QRS complex to end of pulmonic flow.
ducer from the conventional apical position.19 The recording is Alternatively, IVRT can be calculated by subtracting the time
obtained by placing a 1–2 mm sample volume at the valve annulus between the QRS complex and the end of pulmonic ejection from
and tips with filter and gain adjustments to obtain a clear signal. the duration of the TR jet.
Respiratory variability is an additional factor that needs to be Early diastolic RV filling is reduced with normal aging,20,21
considered with measurements taken at end expiratory apnea or which should be considered when drawing conclusions about RV
as the average of five to seven consecutive cardiac cycles. The latter diastolic function using tricuspid inflow velocities. In general,
approach has been shown to yield identical results to those patients with impaired RV relaxation have a reduced E/A ratio,
obtained at end expiratory apnea.20 a prolonged IVRT and DT, and an increased AFF. As RA pres-
 Chapter 14 • Evaluation of Right Ventricular Diastolic Function 175

sure increases, E/A ratio increases and DT shortens (Fig. 14-7). Quantitative measurements include the peak velocity, the dura-
However, the individual response is highly variable and depen- tion, and the time-velocity integral (TVI) of velocity at each of the
dent on the interplay between many hemodynamic parameters, phases (see Fig. 14-6), as well as the proportion of forward flow
such that the E/A ratio has a significant positive relation with during systole and diastole, using either peak velocity or TVI
mean RA pressure but with a wide scatter (Fig. 14-8). Neverthe- measurements. Such parameters can be used to assess mean RA
less, in patients with RV systolic dysfunction, a short DT is pressure in patients who are in sinus rhythm.9 This is based on the
usually associated with increased filling pressures.9 In addition, following premise: Systolic forward flow from the hepatic veins to
diastolic TR, when present and in the absence of atrioventricular the RA depends on RA relaxation, RV systolic function, and RA
(AV) block, indicates the presence of increased RV stiffness and pressure. In the presence of a normal RA pressure, predominant
highly increased RV filling pressures.22 flow occurs in systole (Fig. 14-9). As the RA pressure increases,
the pressure gradient between the hepatic veins and the right
atrium decreases, and correspondingly forward systolic flow
Hepatic Venous Flow decreases.9,25 This abnormal pattern of flow is most exaggerated in
The flow in the hepatic veins is largely determined by RA pressure patients with restrictive physiology with large atrial and venous
during the cardiac cycle. In normal subjects, antegrade flow from reversals.22 Systolic forward flow parameters, particularly systolic
the hepatic veins to the RA occurs in systole (S) and diastole (D). filling fraction (systolic flow/total antegrade flow), derived
With RA contraction, as well as in late ventricular systole (Vr), from either TVIs or maximal velocities, have been successfully
brief retrograde flow (Ar) occurs into the hepatic veins.23 It is applied to estimate RA pressure noninvasively in patients with a
feasible to record high-quality signals by transthoracic imaging variety of diseases, including those on mechanical ventilation
from the subcostal window. It is also possible to record them by (Fig. 14-10). Ar duration is also of value, as it has been shown to
transesophageal echocardiography (TEE) in the course of a
transesophageal examination.24 The sample volume (3–4 mm) is 30
placed 1–2 cm in the hepatic veins, close to their entrance into r = 0.66
the IVC. Similar to tricuspid inflow velocities, flow should be n = 35
Mean right atrial pressure by catheter (mmHg)
y = –1 + 9.6x
recorded for five to seven consecutive cardiac cycles or at end 25 SEE = 3.8 mmHg
expiratory apnea.

20
E
VAR
VVR
15
A

AR dur
10

VS
5
AT DT A wave
duration VD
Figure 14-6 Schematic diagram of tricuspid inflow (left) and hepatic 0
venous flow (right). E, peak early diastolic velocity; A, peak late diastolic 0 1 2 3
velocity; AT, acceleration time of E velocity; DT, deceleration time of E veloc-
ity; VS, peak systolic velocity; VD, peak diastolic velocity; VVR, midsystolic Tricuspid E/A ratio
reversal velocity; VAR, peak atrial reversal velocity; AR dur, duration of atrial Figure 14-8 Relation between tricuspid E/A ratio and mean right atrial
reversal velocity. (From Nagueh M et al: Relation of mean right atrial pressure pressure. (From Nagueh SF et al: Relation of mean right atrial pressure to
to echocardiographic and Doppler parameters of right atrial and right ven- echocardiographic and Doppler parameters of right atrial and right ventricu-
tricular function. Circulation 1996;93:1160–1169.) lar function. Circulation 1996;93:1160–1169.)

Figure 14-7 Examples of normal tricus-

pid inflow (left), impaired relaxation
(middle), and restrictive filling (right).
E, early velocity; A, velocity with atrial
contraction.
176 Chapter 14 • Evaluation of Right Ventricular Diastolic Function

Figure 14-9 Examples of hepatic

venous flow. In the example shown on
the left, forward flow occurs predomi-
nantly in systole, which corresponds
to a mean right atrial (RA) pressure
≤5 mmHg. In the example on the right,
the peak systolic and diastolic velocities
are similar, corresponding to mean RA
pressure of 5–10 mmHg.

SYSTOLIC FILLING FRACTION

30 30
r = –0.86 r = –0.85

Mean right atrial pressure by catheter (mmHg)

Mean right atrial pressure by catheter (mmHg)

n = 35 n = 35
25 y = 21.6 – 24x 25 y = 23 – 29x
SEE = 2.5 mmHg SEE = 3 mmHg

20 20

15 15

10 10

5 5

0 0
0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0
TVIS/(TVIS + TVID) VS/(VS + VD)
Figure 14-10 Correlation between mean right atrial pressure and right atrial systolic filling fraction calculated using the time-velocity integral (left) and
peak systolic velocity (right). (From Nagueh SF et al: Relation of mean right atrial pressure to echocardiographic and Doppler parameters of right atrial and right
ventricular function. Circulation 1996;93:1160–1169.)

relate to RA pressure9,26 and late diastolic RV pressures (Fig. dependent upon increased LV filling with expiration in the pres-
14-11). ence of a taut pericardium, which leads to reduced RV filling with
These principles are not applicable to patients in nonsinus RA contraction. Accordingly, RA contraction results in increased
rhythms or with cardiac transplants, tricuspid valve disease (sig- flow into the hepatic veins during expiration. Table 14-2 shows a
nificant stenosis or regurgitation and prosthetic valves), or peri- practical summary for estimating mean RA pressure using an
cardial compression syndromes (tamponade or constriction). IVC collapse index and hepatic venous flow.
However, hepatic venous flow may still be helpful in these condi-
tions. For example, patients with severe TR usually exhibit sys-
tolic flow reversal (Fig. 14-12) into the hepatic veins.27 Likewise, Tissue Doppler Imaging
hepatic venous flow can help differentiate pericardial constriction Tissue Doppler imaging (TDI) allows the recording of myocar-
from restrictive cardiomyopathy. In patients with constrictive dial velocity during the cardiac cycle, including velocities at the
physiology, a predominant systolic or biphasic flow pattern is fre- tricuspid annulus. In addition, using TDI or recently developed
quently recorded. In addition, respiratory flow variation presents speckle tracking technology, one can measure local rates of systolic
unique insight into RV and LV filling, where RA and RV filling compression and early and late diastolic expansion of the myocar-
increase with inspiration and the Vr and Ar velocities become dium (systolic and diastolic strain rates, respectively). For assess-
more prominent with expiration.28 The latter observation is ment of RV global diastolic function, tricuspid annulus velocities
 Chapter 14 • Evaluation of Right Ventricular Diastolic Function 177

Figure 14-13 Example of tissue Doppler recording of myocardial veloci-

ties from the right ventricular free wall in a normal subject. The inset shows
Figure 14-11 Hepatic venous flow from a patient with pulmonary hyper- the location of the sample volume at the right side of the tricuspid annulus.
tension and increased late diastolic right ventricular pressures and stiff- Notice the presence of an Sa peak velocity of 15 cm/s, a peak Ea velocity
ness. Notice the prominent AR (atrial reversal) velocity. of 18 cm/s, and an Ea/Aa ratio >1. IVRT, isovolumic relaxation time between
end of Sa and onset of Ea; Sa, systolic ejection velocity; Ea, early diastolic
velocity; Aa, late diastolic velocity.

examination of function of multiple segments simultaneously, in

the same beat; however, an estimate of mean myocardial velocities
is provided. The velocity measured by color TDI is therefore
lower than the maximal velocity measured by PW Doppler, which
should always be considered when normal values and results are
compared among different studies.
The following indices of diastolic function are measured by
TDI at the tricuspid annulus:
❒ Early diastolic velocity (Ea)
❒ Late diastolic velocity (Aa)
❒ Ea/Aa ratio
❒ RV regional IVRT (Fig. 14-13)
❒ Early diastolic strain rate
❒ Late diastolic strain rate
Figure 14-12 Hepatic venous flow from a patient with severe tricuspid A number of studies have evaluated the utility of Ea, Aa, and
regurgitation. Notice the presence of flow reversal during systole. the Ea/Aa ratio to assess RV diastolic function. Patients with RV
diastolic dysfunction usually have reduced Ea velocity and a
reduced Ea/Aa ratio. Aa velocity may be increased in the early
TABLE 14-2 course of diastolic dysfunction, whereas with increased RV late
diastolic pressures, it may decrease. Using these simple and repro-
SUMMARY OF RIGHT ATRIAL PRESSURE (RAP)
ducible velocity measurements, a number of investigators
ESTIMATION USING INFERIOR VENA CAVA (IVC)
have reported on RV diastolic function in several cardiac dis-
COLLAPSE INDEX AND HEPATIC VENOUS FLOW
orders. These included patients with coronary artery disease,29
MEAN RAP (mmHg) IVC % COLLAPSE HEPATIC VEINS inferior wall myocardial infarction and RV involvement,30
dilated cardiomyopathy,31 hypertrophic cardiomyopathy,32
0–5 ≥50 VS > VD obesity,33,34 congenital heart disease,35 and systemic36 and pulmo-
5–10 ≥50 VS = VD nary hypertension.37
10–15 <50 VS < VD
≥20 <50 Flow only with VD While the observations in this chapter support an important
clinical role for TDI-derived velocities, there have been no direct
VS = systolic velocity; VD = diastolic velocity.
validation studies in animals or humans against invasive measure-
ments of negative dP/dt or τ. Similar to early diastolic velocity at
the mitral annulus, tricuspid Ea is load dependent in normal
are recorded by placing the PW Doppler sample volume (4– ventricles.38 On the other hand, the tricuspid Ea/Aa ratio appears
5 mm) at the right border of the annulus. It is also possible to use unchanged with preload reduction.38 Notwithstanding, existing
color Doppler two-dimensional images to obtain a display of studies support the conclusion that tricuspid annulus Ea velocity
myocardial and annular velocities. The advantages of the PW is not positively affected by preload in patients with RV dysfunc-
approach include online beat-to-beat evaluation and the spectral tion, given the presence of an inverse correlation between Ea and
display of velocities. On the other hand, color TDI allows the mean RA pressure in cardiac patients.39 Accordingly, the ratio of
178 Chapter 14 • Evaluation of Right Ventricular Diastolic Function

tricuspid E velocity to annular Ea velocity has been applied to In cardiac transplant recipients, the ratio of E to Ea is also
predict RV filling pressures (Figs. 14-14 and 14-15), in an analo- useful (Fig. 14-16), where a ratio greater than 8 had a sensitivity
gous manner to the use of mitral velocities, in both animal40 and of 78% and a specificity of 85% for RA pressure of at least
human studies.39,41 In the human studies, different groups of 10 mmHg.41 Furthermore, Ea of the tricuspid annulus had no
patients were evaluated, and overall an E/Ea ratio greater than 6 significant relation to RA pressure and was not altered by pres-
had a sensitivity of 79% and a specificity of 73% for mean RA sure changes. Accordingly, the E/Ea ratio readily detected changes
pressure of at least 10 mmHg.39 The good correlation of tricuspid in mean RA pressure of at least 5 mmHg (Fig. 14-17) with a
E/Ea ratio to mean RA pressure was noted in patients with and sensitivity of 70% and a specificity of 75%.41 These observations
without RV systolic dysfunction, as well as in those on mechanical are in contrast to the limited role of hepatic venous flow in the
ventilation.39 transplant population as a result of mechanical dissociation
between the donor and recipient atria, which alters the systolic
and diastolic components of hepatic venous flow and renders their
interpretation more challenging.
TRICUSPID INFLOW A recent study reported on the clinical application of another
100 TDI-derived measurement, namely the time interval between the
80 end of tricuspid annular systolic velocity and the onset of annular
E Ea. The latter time interval had a significant inverse correlation
60 with mean RA pressure. In a study of 21 patients, a time interval
cm/sec

A of less than 59 ms had a sensitivity of 80% and a specificity of

40
88% in identifying patients with RA pressure greater than
20 8 mmHg.42
0
There are advantages to determining mean RA pressure by
using TDI. In the case of RV regional IVRT, this is a single
–20 measurement that is not affected by angulation. In addition, the
TISSUE DOPPLER tricuspid E/Ea ratio and the above time interval are particularly
20 helpful in patients without subcostal windows where there is
concomitant inability to image the IVC and acquire hepatic
Sa venous flow. However, these methods may not be accurate in the
presence of nonsinus rhythms and tricuspid valve disease.
cm/sec

Ea
FUTURE RESEARCH
Aa
Evaluation of RV diastolic function is important clinically. Echo-
–20 cardiography and Doppler provide several complementary
Figure 14-14 Upper panel shows early (E) and late (A) diastolic tricuspid methods for evaluation of RV diastolic function and prediction
inflow velocities. Lower panel shows the annular velocities during systolic of mean RA pressure. These include the evaluation of cardiac
ejection (Sa) and early (Ea) and late (Aa) diastole. The E/Ea ratio is 6.75,
predicting a mean right atrial pressure of 12 mmHg (catheter pressure structure and function; RV, RA, and IVC size; myocardial veloci-
11 mmHg). (From Nageh MF et al: Estimation of mean right atrial pressure ties; strain rate with tissue Doppler and speckle tracking technol-
using tissue Doppler imaging. Am J Cardiol 1999;84:1448–1451.) ogy; and hepatic venous flow patterns. These parameters allow a

35
y = 0.8 + 1.7x
r = 0.75
30 n = 62 20
(Doppler RAP – Catheter RAP)

15
25
10
20
RAP (mmHg)

5
15 0
–5
10
–10
5
–15
0 –20
0 2 4 6 8 10 12 14 16 0 5 10 15 20 25 30 35
E/Ea (Doppler RAP + Catheter RAP)/2
Figure 14-15 Upper panel: regression plot between mean right atrial pressure (RAP) and tricuspid E/Ea ratio in 62 patients with simultaneous invasive
and echocardiographic measurements. Lower panel: Bland-Altman plot of Doppler-derived RAP versus catheter RAP. Mean difference between Doppler
and catheter pressures was 0.3 ± 3.7 mmHg. Upper and lower lines represent mean + and mean −2 SDs, respectively. (From Nageh MF et al: Estimation of
mean right atrial pressure using tissue Doppler imaging. Am J Cardiol 1999;84:1448–1451.)
 Chapter 14 • Evaluation of Right Ventricular Diastolic Function 179

25 r = 0.79 20
n = 38
y = 1.76× – 3.7 15

(Doppler – Catheter RAP) (mmHg)

20
10

RAP (mmHg) 15
5

10 –5

–10
5
–15

0 –20
0 5 10 15 0 5 10 15 20 25
E/Ea (Doppler + Catheter RAP)/2
Figure 14-16 Left, relation between mean right atrial pressure (RAP) and tricuspid E/Ea ratio in patients who have undergone cardiac transplantation.
Right, Bland-Altman plot of Doppler-derived RAP versus catheter RAP. (From Sundereswaran L et al: Estimation of left and right ventricular filling pressures
after heart transplantation by tissue Doppler imaging. Am J Cardiol 1998;82:352–357.)

15 r = 0.83 15
n = 18 (Δ Doppler – Δ Catheter RAP) (mmHg)
y = x – 0.2
10 10
Δ Doppler RAP (mmHg)

5 5

0 0

–5 –5

–10 –10

–15 –15
–15 –10 –5 0 5 10 15 –15 –10 –5 0 5 10 15
Δ Catheter RAP (mmHg) (Δ Doppler + Δ Catheter RAP)/2
Figure 14-17 Left: relation between changes in mean right atrial pressure (RAP) and those predicted by Doppler in patients who have undergone cardiac
transplantation. Right: Bland-Altman plot of changes in RAP by Doppler and changes in mean RAP by right heart catheterization. (From Sundereswaran L
et al: Estimation of left and right ventricular filling pressures after heart transplantation by tissue Doppler imaging. Am J Cardiol 1998;82:352–357.)

comprehensive approach to the evaluation of RV diastolic func- several cardiovascular disorders that affect the right ventricle,
tion and its effect on filling pressures. The availability of three- including congenital heart disease and pulmonary hypertension.
dimensional technology will undoubtedly improve quantification
of RV volumes and systolic function. Whether three-dimensional
technology will further improve the evaluation of RV diastolic REFERENCES
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6. Darsinos, JT, Evagelou AM, Rassidakis AN: Rate of pressure fall in right 25. Sivaciyan V, Ranganathan N: Transcutaneous Doppler jugular venous flow
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7. Maeda, M, Yamakado T, Nakano T: Right ventricular diastolic function in 26. Ommen SR, Nishimura RA, Hurrell DG, Klarich KW: Assessment of right
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in canine models of pressure overload, volume overload, and ischemia. Am 27. Gonzalez-Vilchez F, Zarauza J, Vazquez de Prada JA, et al: Assessment of
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17. Cohen A, Guyon P, Chauvel C, et al: Relations between Doppler tracings 36. Cicala S, Galderisi M, Caso P, et al: Right ventricular diastolic dysfunction
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in patients with inferior wall acute myocardial infarction. Am J Cardiol function. Cardiology 2001;95:101–104.
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right ventricular diastolic function: A technical guide for obtaining optimal echocardiography in healthy subjects. Eur J Echocardiogr 2004;5:
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20. Zoghbi WA, Habib JB, Quiñones MA: Doppler assessment of right ven- 39. Nageh MF, Kopelen HA, Zoghbi WA, et al: Estimation of mean right atrial
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21. Berman G, Reicheck N, Brownson D, Douglas PS: Effects of sample volume 40. Boissiere J, Gautier M, Machet MC, et al: Doppler tissue imaging in assess-
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Doppler echocardiography in healthy adults. J Am Coll Cardiol 1987;10: pressure using Doppler tissue imaging. J Am Soc Echocardiogr 2004;17:
1032–1039. 1155–1160.
 MIGUEL A. QUINONES, MD
15
Evaluation of Intracardiac
Filling Pressures
INTRODUCTION Combination of Transmitral Velocity with
Newer Indices of Left Ventricular
PATHOPHYSIOLOGY
Relaxation
Definition of Left Ventricular Filling Pressure
Estimation of Filling Pressures
Two-Dimensional Echocardiography
Newer (Less Validated) Methods
Doppler Echocardiography—Transmitral and
A Recommended Algorithm for Estimation
Pulmonary Vein Velocities
of Filling Pressures
CLINICAL ASSESSMENT
FUTURE RESEARCH
Estimation of Filling Pressures
Limitations of Transmitral and Pulmonary
Vein Velocities

INTRODUCTION PATHOPHYSIOLOGY

Normal diastolic function allows a ventricle to fill to an adequate Definition of Left Ventricular Filling Pressure
volume while maintaining normal diastolic pressures at rest, Several pressure measurements are collectively referred to as filling
during exercise, and through a wide range of heart rates. This pressures. They include mean left atrial pressure (LAP), mean
occurs through the interaction of multiple intracardiac and extra- pulmonary capillary wedge pressure (PCWP) as a corollary of
cardiac factors (which have been discussed in detail in previous LAP, and LV end diastolic pressure (LVEDP). In addition, dia-
chapters). Failure of these factors to properly operate results in stolic LV pressure (LVP) prior to atrial contraction has been
the elevation of left ventricular (LV) diastolic (or filling) pressures shown to relate closely with mean LAP.1 It is important, however,
at rest or with exertion and consequently the occurrence of cardiac to understand the clinical difference between mean LAP (or
dyspnea, a common denominator in all forms of heart failure PCWP) and LVEDP. Although a high LVEDP is indicative of
regardless of the resting systolic function. However, there are as increased LV stiffness at end diastole, many of these patients have
many pulmonary causes of dyspnea as there are cardiac, and even normal diastolic LVP prior to atrial contraction, and consequently
in patients with known heart disease, the dyspnea may be of a a normal mean LAP. Therefore, when evaluating patients with
pulmonary origin. Likewise, elevations of right ventricular (RV) dyspnea, it is preferable to utilize indices that provide an estimate
filling pressures and right atrial pressures (RAPs) result in right- of mean LAP rather than LVEDP.
sided failure and edema as its common manifestation; as with
dyspnea, edema has also a common list of noncardiac etiologies.
Thus, over the past 20 years, there has been great interest in the
Two-Dimensional Echocardiography
development of noninvasive methods to estimate left- and right- Echocardiography plays a pivotal role in the evaluation of patients
sided filling pressures. In this chapter, we will discuss the estima- presenting with dyspnea of suspected cardiac origin. It provides
tion of left-sided filling pressures and propose an integrated an accurate assessment of LV size, regional wall motion, and ejec-
approach. Assessment of right-sided pressures is discussed in tion fraction (EF); allows recognition of patterns of LV hypertro-
detail in Chapter 14. phy and remodeling; and provides an accurate assessment of left
181
182 Chapter 15 • Evaluation of Intracardiac Filling Pressures

atrial (LA) enlargement, an extremely frequent finding in heart Methodist DeBakey Heart Center over the past year, 95% of
failure. The anteroposterior LA dimension has been used for 2500 patients with echo-Doppler evidence of elevated filling pres-
decades to determine LA size, primarily because it was the only sures had an enlarged LA volume (unpublished observation).
measurement available in the era of M-mode echocardiography.
However, enlargement of the left atrium does not occur symmet-
rically, and the anteroposterior dimension consistently underesti- Doppler Echocardiography—Transmitral and
mates the true LA volume (Fig. 15-1).2 A more accurate assessment Pulmonary Vein Velocities
is obtained with two-dimensional echocardiography by deriving
the volume of the left atrium from planimetry of the chamber in Determinants of Transmitral Velocity
the apical views, using either single or biplane methods.3,4 These With the advent of pulsed-wave (PW) Doppler echocardiogra-
volume estimates compare well with measurements obtained phy, recordings of transmitral velocity from the apical window at
with three-dimensional–cine computed tomography and mag- the tips of the mitral leaflets provided an easy-to-use noninvasive
netic resonance imaging.5,6 All subsequent reference in this chapter tool for the evaluation of diastolic filling. The peak early velocity
to the value of determining LA size for the estimation of filling (E) and its deceleration time (DT), the atrial (A) velocity, and the
pressures implies that volumes, rather than dimensions, are used. E/A ratio became popular indices of diastolic function (Fig.
Using echocardiography, the upper limit of normal LA volume, 15-2). E/A ratio is a normalized index that reflects early diastolic
indexed to body surface area, is 28 ml/m2.4 filling relative to atrial contraction. Isovolumic relaxation time
Echocardiography is currently the most widely used imaging (IVRT) is the interval between the end of ejection and the onset
technique to distinguish patients with systolic heart failure from of mitral inflow. IVRT is obtained by recording velocities from
those with diastolic heart failure; the former is characterized by an intermediate position between mitral inflow and LV outflow
LV dilatation, eccentric hypertrophy (dilated cavity with normal with either PW or continuous wave (CW) Doppler (Fig. 15-3)
ratio of radius to wall thickness), and depressed EF, and the latter (see Chapter 10).
by absence of LV dilatation, preservation of EF (≥50%), and often The determinants of transmitral velocity and its components
concentric hypertrophy or remodeling7 (see Chapters 2 and 6). have been described in detail elsewhere in this volume. Briefly,
Concentric LV hypertrophy is defined as increased mass with an transmitral velocity is driven by two major factors: flow and the
increased radius/thickness ratio (R/Th), and concentric remodel- instantaneous transvalvular pressure gradient (see Fig. 15-2).12,13
ing is defined as normal mass with increased R/Th. Another fre- During early diastole, active relaxation and LA pressure are the
quent finding in patients with diastolic heart failure is a reduction principal determinants of flow and transvalvular gradients. With
(<8 mm) in the extent of mitral annular descent, an index of the normal relaxation, LVP decay during isovolumic relaxation occurs
longitudinal vector of contraction and relaxation.8,9 rapidly (thus a shorter time constant of relaxation, or Tau), and
If the echocardiogram in the evaluation of dyspnea demon- early ventricular suction is enhanced. This results in a higher E
strates normal LV size without hypertrophy, normal EF and velocity and a shorter DT and IVRT; the opposite occurs with
regional wall motion, normal annular descent, and normal LA impaired relaxation (longer Tau): less suction, lower E velocity,
size, the cause of dyspnea is unlikely to be cardiac. The contrary and longer DT and IVRT. Likewise, with increasing LAP (and a
may not always be the case, since patients may present with abnor- higher LV-LA crossover pressure), IVRT shortens, the early LA-
malities of cardiac structure and function, including depressed EF, LV transmitral gradient and E velocity increase, and DT short-
and have dyspnea of a noncardiac etiology. Perhaps the most reli- ens; the opposite occurs with a fall in LA pressure.14,15
able finding is the LA size, since, in the absence of atrial fibrilla- The influence of relaxation and LA pressure on transmitral
tion or mitral regurgitation/stenosis, it represents a “poor man’s” velocity explains the different transmitral patterns described in
index of the diastolic load imposed by the left ventricle on the the literature (Fig. 15-4): the normal healthy pattern seen in
atrium10,11 (see Chapters 10 and 18). In our experience at the young hearts; the “impaired relaxation” pattern, also referred to as

Normal ↓ Relaxation ↓ Relaxation

ASSESSMENT OF LEFT ATRIAL SIZE elevated LVFP
IVRT

E E
LAd A A A
LA E

DT
Figure 15-2 Relation of transmitral velocity to the pressure gradient
between the left atrium and the left ventricle in three common hemody-
Figure 15-1 Example of a patient in whom the anteroposterior left atrial namic conditions: normal relaxation, impaired (↓) relaxation, and impaired
dimension (LAd) is mildly increased (4.0 cm), whereas in the apical view relaxation with elevated left atrial pressure. No pseudonormal noted. IVRT,
the left atrium is severely dilated with a volume derived from planimetry isovolumic relaxation time; E, peak early velocity; A, atrial velocity; DT,
of 160 ml (80 ml/m2). deceleration time; LVFP, left ventricular filling pressure.
 Chapter 15 • Evaluation of Intracardiac Filling Pressures 183

PW-DOPPLER CW-DOPPLER

IVRT

IVRT

A B
Figure 15-3 Recording of left ventricular outflow and transmitral velocity. A, PW Doppler; B, CW Doppler. Both recordings provide a measurement of iso-
volumic relaxation time (IVRT) as the interval from the end of ejection to the onset of mitral inflow.

↓ RELAXATION PSEUDO-NORMAL RESTRICTIVE

NORMAL STAGE I STAGE II STAGE III

Figure 15-4 Examples of normal trans-

mitral velocity with the three stages of
diastolic dysfunction patterns. Range of
values is listed under each pattern. IVRT,
isovolumic relaxation time; E, peak early
velocity; A, atrial velocity; DT, decelera- E/A >1 E/A <1 E/A 1–2 E/A >2
tion time; LVFP, left ventricular filling DT 150–240 DT >240 DT 150–240 DT <150
pressure. IVRT <90 msec IVRT >90 msec IVRT <90 msec IVRT <70 msec

stage I diastolic dysfunction13; and both the pseudonormal (stage E

Pulmonary Mitral inflow

II) and restrictive (stage III) patterns associated with high filling E
vein (cm/sec) (cm/sec)

100 A A
pressures. As discussed later, the relation of these patterns to LAP E
A
occurs best in patients with depressed EF.

Determinants of Pulmonary Vein Velocity 100

S
S D D
D
Recordings of pulmonary vein velocity (PVV) by PW Doppler S
are readily obtained in close to 80% of patients during routine
examinations. The determinants of the different components of
PVV are described in detail in Chapter 10. In brief, atrial relax- AR AR
AR
ation combined with the normal descent of the annulus during Normal Lap High Lap
Normal
ventricular systole contributes to a rapid decline in LAP (the relaxation Impaired LV relaxation
x-descent) that drives flow into the atrium. This is depicted in
Figure 15-5 Diagrammatic illustration of transmitral and pulmonary vein
the PVV recording as an antegrade flow velocity (S-wave) (Fig. velocities in normal relaxation, impaired left ventricular (LV) relaxation with
15-5). Following mitral valve opening, there is a second antegrade normal left atrial pressure (LAP), and impaired relaxation with high LAP.
velocity (D-wave) coincident with the transmitral E velocity. Values of deceleration time for pseudonormal should be 150–240; for
During atrial contraction, there is a small retrograde velocity restrictive, <150. E, peak early velocity; A, atrial velocity; S, systolic; D, dia-
stolic; Ar, retrograde A velocity.
(AR) into the pulmonary vein. When the x-descent is replaced by
an elevated v-wave (as seen frequently during decompensated
systolic heart failure), the S-wave becomes diminished and D
becomes accentuated in concert with the increase in E velocity
previously described. An S/D ratio of less than 1 (S/D derived
184 Chapter 15 • Evaluation of Intracardiac Filling Pressures

using the integral of the velocities) is an index of elevated mean In patients with depressed LVEF (<40%), the presence of a
PCWP that, like the E/A ratio and DT, performs more accu- stage I pattern is usually associated with normal (<15 mmHg)
rately in patients with depressed LVEF.16,17 resting mean LAPs and a PVV S/D ratio greater than 1.13,23 In
contrast, the pseudonormal (stage II) and restrictive (stage III)
patterns are associated with increasing elevation of filling pres-
CLINICAL ASSESSMENT sures. The stage III pattern is often associated with a diminished
A-wave due to the high afterload imposed on the atrium by the
Estimation of Filling Pressures elevated LVEDP. In these patients, an S/D ratio of less than 1 in
Given that impaired relaxation is present in the vast majority of the PVV also implies elevated mean LAP.13,16
patients with conditions leading to or associated with heart failure Although patients with stage I diastolic dysfunction are often
(Box 15-1),18–22 the influence of LAP on transmitral velocity asymptomatic at rest, they are more prone to develop exercise-
depends on how much LAP (and LV stiffness) overcomes the induced dyspnea and are at risk for developing heart failure over
opposite effect of impaired relaxation (Fig. 15-6). This opposite time, particularly the group with a dilated left atrium.24,25 These
interaction can be seen even in patients with normal hearts, in patients often have auscultatory evidence of a fourth heart sound
whom a very low LAP or preload results in a lowering of the E and may have a prominent A-wave in LVP tracing.
velocity and E/A ratio despite normal relaxation. A subtle differ- In patients with systolic dysfunction (EF <40%), the presence
ence between stage I diastolic dysfunction and normal relaxation of stage II and III diastolic dysfunction represents a progression
with low preload is that the reduction in early filling induced by of disease and implies a worsening of LV stiffness and higher
impaired relaxation results in a greater residual volume in the left LAP. Therefore, a gross estimate of mean LAP or PCWP can be
atrium at the time of atrial contraction and a compensatory inferred from these patterns: Stage I is associated with pressures
increase in A velocity that often brings the E/A ratio to less than less than 15 mmHg; stage II is usually associated with pressures
0.8. In addition, stage I diastolic dysfunction frequently has a DT between 15 and 25 mmHg; and stage III is associated with pres-
of greater than 240 msec. sures greater than 25 mmHg.
Several equations have been proposed in the literature to derive
mean PCWP.11,23,26–27 They all incorporate multiple measure-
Box 15-1 ments from transmitral velocity, and some of them add measure-
ments from the pulmonary veins, LA volume, or both. They all
Conditions Associated with Impaired Relaxation have better accuracy in patients with depressed EF and perform
poorly in those with normal systolic function. We have found that
Increased afterload
the equation
Aging
Systemic hypertension Mean PCWP = 17 + (5 × E/A) − (0.11 × IVRT)
Pathologic secondary left ventricular hypertrophy
Hypertrophic cardiomyopathy is simple to use and performs well in the estimation of mean
Ischemia PCWP in patients with depressed EF (Fig. 15-7).23
Myocardial diseases When estimating mean PCWP, we have not found additional
Infiltrative cardiomyopathies value from recordings of the PVV in patients with systolic heart
failure. In contrast, PVV is useful in estimating the LVEDP.
During atrial contraction with an elevated LVEDP, LVP may rise
over LA pressure, producing a reverse gradient that shortens the
↓ Relaxation ↑ LA pressure duration of the transmitral A velocity (AMV) relative to the pul-
monary vein retrograde A velocity (AR) (Fig. 15-8). The interval
↓ E-velocity ↑ E-velocity AR–AMV has been found to relate directly with LVEDP; when-
ever AR–AMV exceeds 20 msec, LVEDP is likely to be higher
than 20 mmHg.28 This finding is fairly reliable as long as the P-R
interval is within a normal range, that is, is neither too short nor
Measured E-velocity too long.
The progression from stage I diastolic dysfunction to stage II
and III is a “two-way street,” meaning that patients may decom-
pensate into the advanced stages and with proper treatment
regress back to stage I (i.e., lower filling pressures). The preceding
equation has been shown to track well changes in mean PCWP
in response to therapy. Application of the Valsalva maneuver can
be used to assess reversibility, since the increased intrathoracic
pressure during the maneuver causes a decrease in preload and a
shift in transmitral velocity from stage III to stage II or from II
to I.29 Stage IV diastolic dysfunction represents a restrictive
pattern that fails to reverse with either Valsalva or heart failure
therapy.13 In patients with systolic heart failure, this pattern
appears to be a marker of very high LV stiffness and fibrosis and
is associated with poor prognosis.30,31 In animal models of systolic
Figure 15-6 Influence of impaired (↓) left ventricular relaxation and ele- heart failure, DT has been shown to relate well with LV chamber
vated (↑) left atrial (LA) pressure on the transmitral E velocity. stiffness.15 Likewise, in patients with ischemic cardiomyopathy,
 Chapter 15 • Evaluation of Intracardiac Filling Pressures 185

40 20
n = 30
r = 0.88 15 r = 0.87
y = 4 + 0.7x
y = 0.2 + 1.2x
30 10

Doppler (mmHg)
Doppler (mmHg) 5

20 0

–5

10 –10

–15
= 5 points
0 –20
0 10 20 30 40 –20 –15 –10 –5 0 5 10 15 20
Catheter pressure (mmHg) Catheter pressure (mmHg)
Mean PCWP = 17 + (5 × E/A) – (0.11 × IVRT) Mean PCWP = 17 + (5 × E/A) – (0.11 × IVRT)
A B
Figure 15-7 A, Correlation of mean pulmonary capillary wedge pressure (PCWP) estimated by Doppler. B, Correlation of changes in mean PCWP with
therapy estimated by Doppler versus catheter measurement. E/A, ratio of peak early velocity to atrial velocity; IVRT, isovolumic relaxation time. (Modified
from Nagueh SF et al: Feasibility and accuracy of Doppler echocardiographic estimation of pulmonary artery occlusive pressure in the intensive care unit. Am J
Cardiol 1995;75:1256–1262.)

a depressed LVEF and dilated ventricles, the high atrial pressure

and prominent v-wave predominate, resulting in changes in trans-
mitral velocity and PVV, as previously discussed. By contrast,
patients with diastolic dysfunction but normal LV size and EF
often have elevated minimal LV diastolic pressure, greater pres-
ervation of the x-descent in the LAP, and increased filling pres-
sures without prominence of the v-wave. This can result in a stage
I pattern despite the presence of elevated filling pressures. In these
instances, the transmitral and the pulmonary vein velocities lose
sensitivity for detection of high filling pressures,20,33,34 with the
exception of the AR–AMV interval, which is less accurate but can
provide an estimate of LVEDP.33
Although infrequent, a pseudonormal or restrictive transmitral
velocity pattern may be seen in patients with diastolic heart failure
and mistakenly interpreted as normal diastolic function. Applica-
tion of the Valsalva maneuver can help by showing regression to
ARPV – AMV = 50 msec stage I diastolic dysfunction.29 These patients usually have other
Figure 15-8 Transmitral and pulmonary vein velocity recorded in a patient clues of diastolic heart failure, such as concentric LV remodeling,
with elevated left ventricular end diastolic pressure. Notice the prolonged LA enlargement, or both, and may also demonstrate a prolonged
duration of the pulmonary vein retrograde A-wave (ARPV ) relative to the AR–AMV.
mitral A-wave (AMV ).
Because of the complex interaction of LV relaxation and LAP,
transmitral velocity cannot detect elevated filling pressures in
normal hearts subjected to a high volume load, such as in acute
mitral regurgitation, and is also very limited in the absence of
we have demonstrated an inverse relation between DT and the sinus rhythm.
amount of LV scarring detected by thallium20 scintigraphy.32
Patients with a shorter DT (<150 msec) also had less evidence of
viability by dobutamine stress, less recovery of function, more
heart failure, and a shorter 12-month survival after coronary
revascularization. Combination of Transmitral Velocity with
Newer Indices of Left Ventricular Relaxation
As discussed at length elsewhere in this volume, there are cur-
Limitations of Transmitral and Pulmonary
rently two noninvasive indices of LV relaxation that have gained
Vein Velocities considerable clinical interest because they are less affected by
As mentioned, the effect of impaired relaxation is to reduce the changes in LAP or preload. They are the flow propagation veloc-
E velocity, while that of an elevated LAP is to increase the E ity, derived with color M-mode Doppler, and the early diastolic
velocity; thus, the absolute E velocity recorded is the net summa- mitral annular velocity, derived with tissue Doppler (see Chapters
tion of these two opposing forces (see Fig. 15-6). In patients with 11 and 12). We will discuss them in brief.
186 Chapter 15 • Evaluation of Intracardiac Filling Pressures

Flow Propagation Velocity aging, concordant with other indices of relaxation,42 and is
inversely affected by increasing afterload.40,43 In the normally con-
Following mitral valve opening and under the influence of relax- tracting and relaxing heart, Ea is directly altered by changes in
ation and ventricular suction, a sequence of intracavitary pressure preload.40 However, this relation virtually disappears in abnormal
gradients develop from base to apex that promote the propagation hearts with impaired relaxation.44 A reduced Ea (<8 cm/s) implies
of mitral inflow toward the LV cavity. The velocity of this flow impaired relaxation (whether caused by LV disease or advanced
propagation can be assessed with color Doppler by placing the age) and can be used to distinguish a pseudonormal mitral inflow
M-mode cursor within the center of the mitral inflow and obtain- pattern from a normal one.
ing a color M-mode recording, preferably at a sweep speed of
100 mm/s (Fig. 15-9) (see Chapter 11). The recording should
contain an edge of uniform color during early filling, the slope of Estimation of Filling Pressures
which represents the flow propagation velocity (Vp). Shifting the
Transmitral E velocity relates directly with LAP and inversely
color Doppler zero baseline to an aliasing velocity near 70% of
with Tau. This can be expressed mathematically as:
the E velocity has been proposed as a method to obtain a distinct
color border that improves reproducibility of this measurement.35 E α LAP/Tau
Vp has been shown to be fairly insensitive to changes in LAP36 or
and to relate inversely with Tau.37 A reduced Vp (<40 cm/s)
implies impaired relaxation and can be used to distinguish a LAP α E × Tau.
pseudonormal mitral inflow pattern from a normal one.38 Since Vp and Ea relate inversely with Tau, the above equation can
be expressed as:
Early Annular Diastolic Velocity LAP α E (1/Vp)

The left ventricle has two major vectors of contraction, circum- or

ferential and longitudinal. The longitudinal vectors result in LAP α E (1/Ea).
shortening of the LV long axis and descent of the mitral annulus From these derivations, one should expect E/Vp and E/Ea to
toward the apex. The velocity of this motion can be readily relate directly with LAP.
obtained with tissue Doppler by placing the sample volume at a In 1997, Garcia et al. reported a good relation between E/Vp
corner of the annulus; the recorded velocities reflect the longitu- and mean PCWP in patients in sinus rhythm.38 As noted in
dinal vector of contraction and relaxation of that particular wall Figure 15-11, an E/Vp greater than 1.8 is predictive of a mean
at its base (Fig. 15-10). Although one can obtain recordings from PCWP of at least 15 mmHg; however, the specificity is greater
the septal, lateral, anterior, and inferior corners of the annulus, in when the ratio is greater than 2.5. E/Vp has the added advantage
routine clinical practice the septal and lateral corners provide that it can be applied to patients in atrial fibrillation.45 Likewise,
most of the needed information.39 The early diastolic velocity in 1996, our laboratory reported a good correlation between E/Ea
(referred to in the literature as Ea, Em, or E′) has been shown in and mean PCWP (Fig. 15-12A).44 An estimate of mean PCWP
experimental animal work and in humans to relate well with can be obtained with the equation
invasive indices of relaxation such as Tau, (−)dP/dt, and the
lowest diastolic LVP.40–41 In addition, Ea declines gradually with Mean PCWP = 1.25E/Ea + 1.9.

FLOW PROPAGATION VELOCITY

A B

Figure 15-9 A, Color Doppler image

obtained in an apical four-chamber
view with the M-mode cursor posi-
tioned through the center of the mitral
inflow. B, Transmitral velocity with a
measurement of the E velocity. C, The
color M-mode tracing was obtained
with the aliasing velocity set at 70% of
E. Vp (flow propagation velocity) is mea-
C sured as the slope of the aliasing
velocity.
 Chapter 15 • Evaluation of Intracardiac Filling Pressures 187

ANNULAR VELOCITY WITH TISSUE DOPPLER

4.3 MHz 5 4.3 MHz 5 .21

10 10
15 15

15
Sa –.21
10
5
[cm]
–5
–10
Aa –15
Ea
–20
–1.5 –1.0 –0.5 0 –1.5 –1.0 –0.5 0.0
100mm/s 100mm/s

A Septal B Lateral
Figure 15-10 Recordings of annular velocity from the A, septal and B, lateral corners using tissue Doppler. Sa, peak systolic velocity; Ea, early diastolic
velocity (also referred to as Em and E′); Aa, atrial velocity.

Figure 15-11 At left is the transmitral

velocity and flow propagation velocity
(Vp) from a patient with clinical heart
failure and an ejection fraction of 35%;
E/Vp is 6.0. At right (top) is the correla-
tion between mean pulmonary capil-
lary wedge pressure (PW) and Vp
reported by Garcia, with (bottom) 95%
confidence limits. (Modified from Garcia
MJ et al: An index of early left ventricular
filling that combined with pulsed Doppler
peak E velocity may estimate capillary
wedge pressure. J Am Coll Cardiol 1997;
29:448–454.)

Our findings have been confirmed by other investigators.46 An found by Ommen et al. to be the most accurate in estimating
E/Ea ratio of no greater than 8 is over 90% predictive of a mean filling pressures.46
PCWP less than 15 mmHg, while a ratio of at least 15 is over
90% predictive of a mean PCWP of at least 15 mmHg. In the
range between 9 and 14, the presence of LA enlargement, a
pseudonormal transmitral velocity, or prolonged AR–AMV can be Limitations of E/Vp
very helpful in supporting a diagnosis of elevated filling pressures. E/Vp performs particularly well in dilated ventricles. However, it
Importantly, E/Ea can predict filling pressures fairly well in is limited in patients with concentric hypertrophy and small
patients with normal ejection fraction, including those with hyperdynamic ventricles with little space for flow propagation to
hypertrophic cardiomyopathy (see Fig. 12B).34,39 It can also be occur (see Chapter 11). Consequently, these patients can have
applied to patients with sinus tachycardia and atrial fibrilla- normal Vp and E/Vp despite having impaired relaxation and ele-
tion.47,48 When tested against several other indices, E/Ea was vated LAPs (Fig. 15-13). Recent studies have shown that in
188 Chapter 15 • Evaluation of Intracardiac Filling Pressures

45 35
r = 0.87 r = 0.76 Figure 15-12 A, Correlation of mean
40 n = 60 n = 35
30 pulmonary capillary wedge pressure

LV pre-A pressure (mmHg)

35 (PCWP) with E/Ea in a heterogeneous
Mean PCWP (mmHg)

25 population of patients with a wide range

30 of ejection fractions. B, Correlation of
20 left ventricular pressure before atrial
25
contraction (pre-A) with the ratio of the
20 15 mitral peak Doppler E-wave to peak
mitral annular velocity (E/Ea) in a group
15 of patients with hypertrophic cardiomy-
10
opathy. (Modified from Nagueh SF et al:
10
Doppler estimation of left ventricular
5 filling pressures in patients with hypertro-
5
phic cardiomyopathy. Circulation
0 0 1999;99:254–261; Nagueh SF et al: Doppler
0 5 10 15 20 25 30 5 10 15 20 tissue imaging: A noninvasive technique
for evaluation of left ventricular relaxation
E/Ea E/Ea and estimation of filling pressures. J Am
A B Coll Cardiol 1997;30:1527–1535.)

Figure 15-13 Example of a patient

with systemic hypertension, diastolic
heart failure, and a small end systolic
left ventricular (LV) volume with an
ejection fraction greater than 65%. Note
the normal flow propagation velocity
(Vp) of 60 cm/s. The mitral E velocity
(left upper panel) is 80 cm/s, resulting in
an E/Vp of 1.3, consistent with normal
mean pulmonary capillary wedge pres-
sure (PCWP). In contrast, peak mitral
annular velocity (Ea) from the lateral
wall (left lower panel) is much reduced
(5 cm/s), and the E/Ea ratio is 16, indica-
E/Vp = 1.3 E/Ea = 16 tive of an elevated mean PCWP.

patients with normal LV size and EFs, E/Ea estimates filling new technology is consistently lower than when derived with PW
pressures with more accuracy than does E/Vp (Fig. 15-14).39,46 Doppler; this results in a different set of normal values. Given
Vp is also limited by a lower reproducibility resulting from varia- that all of the literature relating E/Ea to filling pressures has been
tion in positioning of the M-mode cursor and in the actual mea- obtained using PW tissue Doppler, this technology should be the
surement of the slope. Quantitative computerized techniques one used for this purpose.
have been applied with excellent results, but they are not available Although Ea relates to global indices of LV relaxation, one
commercially.49 Vp cannot be applied in the presence of mechani- must realize that it is a regional index. Errors can, therefore, occur
cal inflow obstruction. when one extrapolates a single measurement to the entire ventri-
cle, particularly in patients with regional wall motion abnormali-
ties and in those with excessive cardiac translation (since the
Limitations of E/Ea velocities are measured relative to transducer position). For
Although measurements of Ea are easy to obtain with good instance, a patient with acute myocardial infarction can have a
reproducibility using PW tissue Doppler, it is essential that the depressed Ea in the affected wall and an augmented one in a
settings used provide a clear tracing with distinct edges. Some of distant site that is compensating with hyperdynamic motion.39
the older ultrasound systems produced a blurred recording that Because of the preload dependency of Ea in normal hearts, the
significantly limited the accuracy of the measurements. Some ratio E/Ea does not reflect filling pressures accurately in normal
newer systems allow derivation of a recording of annular or myo- young subjects or in patients with primary mitral regurgitation or
cardial velocities from a color tissue Doppler by placing a small pericardial constriction.50,51 However, the presence of functional
region of interest in the particular segment. However, Ea with this mitral regurgitation in a depressed ventricle does not affect the
 Chapter 15 • Evaluation of Intracardiac Filling Pressures 189

accuracy of this index.50 Preliminary observations in our labora- the same was true for patients with regional wall motion abnor-
tory using animal experiments suggest that even in depressed malities.39 However, in patients with normal wall motion and EF,
ventricles, Ea still has some preload dependency, particularly at the lateral wall was found to provide a better estimate of mean
the extremes of high LAPs.52 The clinical correlate of this is seen PCWP. Like E/Vp, E/Ea cannot be used in the presence of mitral
occasionally in young patients with dilated cardiomyopathy and inflow obstruction. The new European guidelines on diastolic
severe heart failure, who, despite having a restrictive mitral inflow heart failure suggest averaging the septal and lateral annuli.52a
pattern, continue to have a normal Ea at the lateral base. Ea in
the septum, however, is usually reduced.
These limitations lead to the question of where Ea should be Newer (Less Validated) Methods
measured: septum, lateral wall, or both? In a recent study from With a decline in myocardial relaxation, not only does Ea fall,
our laboratory, an average of the two sites provided a good esti- but its onset gets delayed relative to that of transmitral velocity
mate of mean PCWP in dilated ventricles with a depressed EF; (Fig. 15-15).53,54 The time interval between onset of mitral inflow
and onset of Ea (TEa-E) relates directly with Tau (r = 0.93) in
experimental animal studies and is not altered by changes in
LAP.54 TEa-E is derived by subtracting Q-Ea (the interval from the
IMPACT OF LVEF ON ESTIMATION OF FILLING PRESSURES
USING TISSUE DOPPLER AND FLOW PROPAGATION VELOCITY
Q-wave on electrocardiogram to the onset of Ea) from Q-E
(the interval from the Q-wave to the onset of mitral inflow) (see
r = 0.5 r = 0.7 Fig. 15-15).
p < 0.001 30 p < 0.001 Previous studies have shown that mean LAP can be derived
30
from the equation
PCWP (mmHg)

PCWP (mmHg)

LAP = LVes × e−IVRT/Tau,

20
20 where LVes = end systolic LVP.55 Our group has tested a non-
invasive version of this equation that substitutes TEa-E for Tau and
0.9 × systolic blood pressure for LVes. The results were accurate
10
across a wide range of LVEFs (Fig. 15-16).54 A simplified approach
10 consisting of the ratio of IVRT to TEa-E related inversely with
mean PCWP and allowed separation of patients with normal
0 0 versus elevated (≥15 mmHg) pressures with a sensitivity and
0 1 2 3 4 5 10 15 20 25
specificity of 91% and 89%, respectively (Fig. 15-17). Since this
E/Vp E/Ea-lateral new method does not require a measurement of the transmitral
LVEF > 50% E velocity, it is applicable in the presence of inflow obstruction
Figure 15-14 Correlation of mean pulmonary capillary wedge pressure and in patients with mitral regurgitation.56 However, as with all
(PCWP) with ratio of mitral peak Doppler E-wave and flow propagation new methods, it requires validation by other investigators. Its
velocity (E/Vp) and with ratio of E to peak mitral annular velocity (E/Ea) in main limitation is that TEa-E is a small time interval derived from
a population of patients with ejection fractions greater than 50%. Note the two different intervals measured at separate times, and this may
larger scatter and lower correlation coefficient for E/Vp. (Modified from
Rivas-Gotz C et al: Impact of left ventricular ejection fraction on estimation of limit its reproducibility. Future developments may allow simulta-
left ventricular filling pressures using tissue Doppler and flow propagation neous recording of annular motion and mitral inflow, facilitating
velocity. Am J Cardiol 2003;91:780–784.) the measurement of this interval.

TRANSMITRAL VELOCITY LATERAL ANNULAR VELOCITY

Figure 15-15 Transmitral velocity,

lateral annular velocity, and isovolumic
relaxation time (IVRT) in a 75-year-old TEa-E = 40 msec
hypertensive woman with concentric IVRT/TEa-E = 1.05
left ventricular hypertrophy, a normal
ejection fraction, and diastolic heart
failure. The transmitral velocity is ele-
vated (180 cm/sec) in part because of
annular calcification resulting in some
inflow stenosis. Note the delay in onset
of Ea relative to the onset of the trans-
mitral velocity; TEa-E was 40 msec and
IVRT/TEa-E was 1.05.
190 Chapter 15 • Evaluation of Intracardiac Filling Pressures

RELATION OF TEa–E TO FILLING PRESSURES

40 r = 0.84 20

Doppler PCWP – Catheter PCWP

n = 33
35 p < 0.01 15
Doppler PCWP (mmHg)

10
30
5
25
0 Figure 15-16 Relation of catheter-
20 measured mean pulmonary capillary wedge
–5
pressure (PCWP) to PCWP derived by
15
–10 Doppler using the equation LVes × e−IVRT/Ea–E
and substituting TEa-E for Tau. The 95% con-
10 –15 fidence limits obtained with the Bland-
Altman analysis are shown on the right.
5 –20 SBP, systolic blood pressure. (Modified from
0 5 10 15 20 25 30 35 15 5 10 15 20 25 30 35 40 Rivas-Gotz C et al: Time interval between
onset of mitral inflow and onset of early dia-
Catheter PCWP (mmHg) (Doppler PCWP + Catheter PCWP)/2 stolic velocity by tissue Doppler: A novel index
of left ventricular relaxation. Experimental
PCWP = LVes × e–IVRT/Tau = LVes × e–IVRT/TEa–E studies and clinical application. J Am Coll
where LVes = 0.9 × SBP Cardiol 2003;42:1463–1470.)

40 tively simple to use. The use of E/Vp or E/Ea may not be required
but can provide valuable confirmation of the findings derived from
Sens = 91% the transmitral velocity. However, there are instances where E/Ea
Spec = 89%
and E/Vp should be used. These include: (1) an E/A less than
30
1.0 with E greater than 80 cm/sec (E/Ea may be elevated if Ea is
<8 cm/sec); (2) E and A in close proximity due to a reduced diastolic
Mean PCWP (mmHg)

filling time; and (3) junctional or pacemaker rhythm in the presence

of atrial fibrillation (in these instances, a very short DT [<150 msec]
and/or IVRT [<60 msec] are specific for elevated LAP).
20

Patients with a Preserved Ejection Fraction

In the presence of near-normal (>40%) EF, E/Vp or E/Ea is rec-
10 ommended for the estimation of mean PCWP, with the latter
preferred in hypertrophic hearts with small LV cavities. An
enlarged left atrium is a sensitive marker of diastolic dysfunction
in these patients, particularly when confirmed by observing a
reduced Ea or Vp. Likewise, LAP is almost always less than
0 15 mmHg when LA size and systolic descent of the annulus are
0 5 10 15 20 normal (E/Ea is usually also normal). Although transmitral veloc-
IVRT/TEa − E ity is insensitive to an elevated LAP, we have found that when E/A
Figure 15–17 Correlation between catheter-measured mean pulmonary is less than 0.70 and E is no greater than 60 cm/sec, mean PCWP
capillary wedge pressure (PCWP) and isovolumic relaxation time (IVRT)/ is seldom, if ever, higher than 15 mmHg.57 The transmitral and
TEa-E. The vertical line demarcates a cutoff of 2 for IVRT/ TEa-E, and the the pulmonary vein velocities remain specific for elevated LAP
horizontal line demarcates a cutoff of 15 for PCWP. TEa-E, time interval when the E/A ratio is at least 2.0 or S/D is less than 1, as long as
between onset of mitral inflow and onset of early diastolic velocity;
Sens, sensitivity; Spec, specificity. (Modified from Rivas-Gotz C et al: Time the left atrium is enlarged and Vp or Ea confirm the presence of
interval between onset of mitral inflow and onset of early diastolic velocity by impaired relaxation. AR–AMV may be used to estimate LVEDP,
tissue Doppler: A novel index of left ventricular relaxation. Experimental although with less sensitivity than in the presence of a low EF.
studies and clinical application. J Am Coll Cardiol 2003;42:1463–1470.) In a prospective study of patients presenting with possible heart
failure, we found that a comprehensive approach that combined
A Recommended Algorithm for Estimation of echocardiographic and Doppler findings was superior to measure-
ments of B-type natriuretic peptide (BNP) in detecting heart
Filling Pressures failure in patients with a normal EF.58 Using the Framingham
The following comprehensive approach can provide an excellent criteria as the clinical standard, a BNP greater than 150 pg/ml
clinical tool for the estimation of filling pressures in patients pre- was 79% sensitive and 85% specific, whereas a comprehensive
senting with symptoms suggestive of heart failure. echo-Doppler evaluation was 85% sensitive and 96% specific.

Patients with a Depressed Ejection Fraction Evaluating Discrepant Results

In the presence of a depressed EF (<40%), the mitral E/A ratio, All of the currently available methods of estimating filling pres-
IVRT, and DT are excellent indicators of mean PCWP and are rela- sures are imperfect, and consequently there are times when these
 Chapter 15 • Evaluation of Intracardiac Filling Pressures 191

methods yield discrepant results, their findings are in a “gray area” 3. Lester SJ, Ryan EW, Schiller NB, et al: Best method in clinical practice and
(such as an E/Ea in the 10–15 range), or their estimates of filling in research studies to determine left atrial size. Am J Cardiol 1999;
84:829–832.
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it helps to look for other supporting data. quantification: A report from the American Society of Echocardiography’s
For instance, in a patient with dyspnea, if several echocardio- Guidelines and Standards Committee and the Chamber Quantification
graphic or clinical findings (see Box 15-1) indicate a very high Writing Group, developed in conjunction with the European Association of
Echocardiography, a branch of the European Society of Cardiology. J Am
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LAP is likely to be elevated even if E/Ea is between 10 and 15. biplane two-dimensional echocardiography: Validation by cine-computed
In day-to-day practice, we find the estimation of pulmonary tomography. Am Heart J 1991;121:864–871.
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by three- and two-dimensional echocardiography compared to MRI esti-
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10 and 14). As a general rule, it can be stated that an elevated ventricular systolic function determine left atrial reservoir function. Circula-
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36. Takatsuji H, Mikami T, Urasawa K, et al: A new approach for evaluation of 2005;111:3281–3289.
left ventricular diastolic function: Spatial and temporal analysis of left ven- 57. Dokainish H, Zoghbi WA, Lakkis NM, et al: Optimal noninvasive assess-
tricular filling flow propagation by color M-mode Doppler echocardiogra- ment of left ventricular filling pressures: A comparison of tissue Doppler
phy. J Am Coll Cardiol 1996;27:365–371. echocardiography and B-type natriuretic peptide in patients with pulmo-
37. Brun P, Tribouilly C, Duval AM, et al: Left ventricular flow propagation nary artery catheters. Circulation 2004;20:2432–2439.
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analysis. J Am Coll Cardiol 1992;20:420–432. B-type natriuretic peptide and tissue Doppler echocardiography in the
38. Garcia MJ, Ares MA, Asher C, et al: An index of early left ventricular filling diagnosis of congestive heart failure. Am J Cardiol 2004;93:1130–
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wedge pressure. J Am Coll Cardiol 1997;29:448–454. 59. Stoylen A, Slordahl S, Skjelvan GK, et al: Strain rate imaging in normal and
39. Rivas-Gotz C, Manolios M, Thohan V, et al: Impact of left ventricular ejec- reduced diastolic function: Comparison with pulsed Doppler tissue imaging
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tissue Doppler and flow propagation velocity. Am J Cardiol 2003;91: 60. Kukulski T, Jamal F, D’Hooge J, et al: Acute changes in systolic and diastolic
780–784. events during clinical coronary angioplasty: A comparison of regional veloc-
40. Nagueh SF, Sun H, Kopelen HA, et al: Hemodynamic determinants of the ity, strain rate, and strain measurement. J Am Soc Echocardiogr
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2001;37:278–285. 61. Takemoto Y, Pellikka PA, Wang J, et al: Analysis of the interaction between
41. Oki T, Tabata T, Yamada H, et al: Clinical application of pulsed Doppler segmental relaxation patterns and global diastolic function by strain echo-
tissue imaging for assessing abnormal left ventricular relaxation. Am J cardiography. J Am Soc Echocardiogr 2005;18:901–906.
Cardiol 199;79:921–928. 62. Kato TS, Noda A, Izawa H, et al: Discrimination of nonobstructive hyper-
42. Rodriguez L, Garcia M, Ares M, et al: Assessment of mitral annular dynam- trophic cardiomyopathy from hypertensive left ventricular hypertrophy on
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Doppler inflow in subjects without heart disease and in patients with left tion 2004;110:3808–3814.
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 CHUWA TEI, MD
YUTAKA OTSUJI, MD, PhD
16
Evaluation of Tei Index in
Heart Failure
INTRODUCTION Detection of Cardiac Dysfunction in Various
Concept of the Tei Index Diseases
Hemodynamic Assessment
PATHOPHYSIOLOGY
Evaluation of Right Ventricular Function
Measurement of the Tei Index
Effects of Interventions
CLINICAL RELEVANCE Evaluation of Patients with Tachycardia
Load Dependency of the Tei Index Limitations
The Tei Index and Prognosis
FUTURE RESEARCH

INTRODUCTION normal systolic function. Figure 16-2 shows a patient with typical
diastolic heart failure, with heart failure symptoms, a normal EF,
In clinical practice, we use many indices of cardiac function, such and LVH. Cardiac time interval analysis demonstrates abnor-
as left ventricular ejection fraction (LVEF), maximal positive mally prolonged ICT and isovolumic relaxation time (IRT),
or negative pressure/time change (dP/dt), Tau (τ), stiffness, indicating significant impairment of both systolic and diastolic
maximum elastance, and others. The number of indices of cardiac functions.5 Therefore, normal LVEF does not mean normal sys-
function indicates that the left ventricle performs multiple roles tolic function in patients with so-called diastolic heart failure,
during a single cardiac cycle, and each index of cardiac function which is one of the most common causes of chronic heart failure
expresses only a partial aspect of a heterogeneous process. This (HF).6 The 2005 guidelines of the American Heart Association/
can explain frequent discrepancies between patients’ status and American College of Cardiology prefers “HF and Normal
the value of functional indices. One such example is relatively LVEF” for this entity and does not use the phrase “diastolic heart
preserved LVEF in patients with end-stage chronic heart failure failure.”7 Even in patients with dilated cardiomyopathy,
due to cardiac amyloidosis (Fig. 16-1).1,2 Why is LVEF often frequently considered as pure systolic dysfunction,8 it is known
discrepant with patient status in cardiac amyloidosis? There can that LVEF only fairly correlates with exercise capacity, which is
be two reasons: (1) LVEF does not express left ventricular (LV) closely related to patient status and prognosis.9 Being the most
diastolic function, which is severely impaired in this pathology,3 representative index of cardiac function, LVEF expresses only
and (2) LVEF does not express true ventricular systolic function, systolic ejection among multiple aspects of systolic and diastolic
especially in the presence of increased LV wall thickness. functions.
Increased LV wall thickness, typically seen in patients with Therefore, we often encounter discrepancies between values of
cardiac amyloidosis, hypertrophic cardiomyopathy, or hyperten- cardiac functional indices and patient status. Physicians need to
sive heart disease, decreases wall tension, which allows for good evaluate patient status subjectively by combining multiple sources
wall motion and ejection even in the presence of significant myo- of information, including various indices of cardiac function. In
cardial systolic dysfunction.4 Therefore, relatively preserved LVEF this context, it is reasonable to create an index of cardiac function,
or wall motion in patients with cardiac amyloidosis does not mean which can be a global expression combining systole and diastole
that their systolic function is only mildly impaired. Severely or multiple aspects of heterogeneous LV function.
prolonged isovolumic contraction time (ICT) (see Fig. 16-1),
despite normal LVEF in patients with cardiac amyloidosis, highly
suggests that systolic function is severely impaired. Further,
Concept of the Tei Index
normal LVEF in the presence of LV hypertrophy (LVH), typi- Due to the big clinical need for an index expressing global cardiac
cally seen in patients with “diastolic heart failure,” may not mean function, the concept of the Tei index has been postulated.10
193
194 Chapter 16 • Evaluation of Tei Index in Heart Failure

LV-Tei index

Aortic pressure
LV pressure

LA pressure

Tei index
ICT ET IRT = (a – b)/b
= (ICT + IRT)/ET
a

Mitral
b
inflow
Figure 16-1 End-stage chronic heart failure despite relatively preserved Aorta outflow
left ventricular ejection fraction (73%) in a patient with cardiac amyloidosis.
IVCT (isovolumic contraction time) and IVRT (isovolumic relaxation time)
are severely prolonged. ET (ejection time) is severely shortened. Figure 16-3 Concept of the Tei index. Isovolumic contraction time (ICT)
and isovolumic relaxation time (IRT) express systolic and diastolic func-
tions. Ejection time (ET) expresses stroke volume. ICT/ET and IVRT/ET can
be sensitive and heart-rate-independent indices of systolic and diastolic
function, respectively. Therefore, the sum of ICT/ET and IRT/ET, which is the
Tei index, expresses combined systolic and diastolic, therefore global,
cardiac function. (From Tei C: New non-invasive index for combined systolic
and diastolic ventricular function. J Cardiol 1995;26:135–136.)

PATHOPHYSIOLOGY
Measurement of the Tei Index
The Tei index can be measured practically with conventional
Doppler echocardiography.10,11 Interval a between cessation and
re-onset of mitral filling flow includes ICT, ET, and IRT (Fig.
16-4). Interval b between onset and cessation of aortic ejection
flow equals ET. Therefore, the Tei index can be obtained by the
following formula:
Tei index = (a − b)/b = (ICT + IRT)/ET.
Figure 16-2 Abnormally prolonged ICT (isovolumic contraction time) and This measurement is simple, practical, and reproducible. Multiple
IRT (isovolumic relaxation time) despite normal left ventricular ejection investigators in multiple institutions have measured the Tei index
fraction (78%) in a patient with “diastolic heart failure” due to left ventricu-
lar hypertrophy.
with almost identical normal values with a narrow range both for
the LV and the right ventricular (RV) Tei index.14,15 The normal
LV and RV Tei indices in our institution are 0.38 ± 0.04 and
0.28 ± 0.04, respectively.
Although standard pulsed Doppler echocardiographic mea-
surement of the Tei index is practical and reproducible, multiple
ICT is inversely proportional to LV peak positive dP/dt investigators have applied alternative approaches. One such
and expresses systolic contraction (Fig. 16-3).12 LV ejection time approach is to utilize pulsed tissue Doppler annular velocity to
(ET) is proportional to stroke volume, which can be reduced measure the Tei index.16,17 This method has the merit of measur-
either by systolic or diastolic dysfunction.13 IRT is inversely ing intervals a and b simultaneously in a single cardiac cycle, while
proportional to LV peak negative dP/dt and expresses diastolic standard pulsed flow Doppler echocardiography requires mea-
relaxation.12 However, these cardiac time intervals are heart surement of intervals a and b in different cardiac cycles. Multiple
rate dependent. Systolic dysfunction can result in prolonged ICT investigators have reported that the Tei index by pulsed tissue
and shortened ET. Therefore, ICT/ET (which is ICT corrected Doppler echocardiography correlates well with that by pulsed
by ET) can be a sensitive index to express systolic dysfunction. flow Doppler echocardiography.16,18 However, discrepancy be-
ICT/ET is also expected to be heart rate independent, due to the tween the tissue Doppler Tei index and the flow Doppler Tei
cancellation of heart rate dependencies of ICT and ET. For the index has also been reported.19–21 It may be questionable whether
same reason, IRT/ET (which is IVT corrected by ET) can be a the Tei index from tissue Doppler annular velocity expresses
sensitive and heart-rate-independent index to express diastolic global cardiac function. Other approaches, including M-mode
function. The sum of ICT/ET and IRT/ET is the Tei index.10,11 color tissue Doppler echocardiogram of mitral leaflets and con-
Therefore, the Tei index has the potential to express combined ventional M-mode echocardiogram of mitral and aortic leaflets,
systolic and diastolic or global cardiac function. have been utilized to measure the Tei index, with good agreement
 Chapter 16 • Evaluation of Tei Index in Heart Failure 195

Figure 16-4 How to measure the Tei index. Interval a

between cessation and onset of mitral filling flow includes
isovolumic contraction time (ICT), ejection time (ET), and
isovolumic relaxation time (IRT). Interval b from onset to
cessation of aortic ejection flow is ET. Therefore, the Tei
index (0.35) can be simply calculated as (a − b)/b.

Figure 16-5 Measurement of the left ventricular Tei index

in a patient with dilated cardiomyopathy. Tei index was
clearly abnormal with a value of 0.99.

with the standard pulsed Doppler flow method.22,23 The LV area/ infarction.26 These preload alterations caused an increase in the
time curve by automated border detection was also utilized to Tei index, but only to a small degree (0.034 ± 0.05) in normal
measure the Tei index, with good agreement with the standard subjects, and did not cause significant changes in the Tei index in
pulsed flow Doppler method.24 patients with prior myocardial infarction. Therefore, the Tei index
is relatively preload independent in patients with cardiac disease.
In addition, the Tei index has no significant correlation with blood
CLINICAL RELEVANCE pressure in patients with LV dysfunction.11,27
Although these investigations indicate that the Tei index is
The Tei index was initially measured in normal subjects as well generally load independent, aortic stenosis causes it to signifi-
as in patients with clear RV or LV dysfunction.10,11 The value of cantly reduce. After surgery for valvular heart disease, patients
the Tei index has a narrow range in normal subjects. The RV Tei with aortic stenosis showed a significant 29% increase in the Tei
index is clearly increased (0.67 ± 0.20) in patients with RV dys- index, while those with aortic regurgitation, mitral stenosis, or
function, such as those with RV infarction, dysplasia, or cor pul- regurgitation showed only minor changes.28 Correction of the
monale. The LV Tei index is also clearly increased (0.92 ± 0.22) prolongation of ET by aortic stenosis was the main cause of
in patients with idiopathic or ischemic cardiomyopathies (Fig. increase in the Tei index after surgical valve replacement.
16-5). There is no overlap of values between normal subjects and
patients with clear RV or LV dysfunction. Therefore, the Tei
index is clearly abnormal in patients with a significant level of such The Tei Index and Prognosis
dysfunction. Because the Tei index is a global expression, it is related to multi-
ple pathophysiologic parameters of cardiac function. The prog-
nostic utility of the Tei index was initially evaluated in patients
Load Dependency of the Tei Index with cardiac amyloidosis.29 In this study, patients with a greater
Because load dependency needs to be evaluated for all indices of Tei index had significantly worse survival (Fig. 16-6). Of note is
cardiac function, the Tei index has also been evaluated regarding that the Tei index enabled better separation of patients with
its load dependency. Studies have shown no significant correlation poorer and better survival compared with LVEF. After this initial
between heart rate and the Tei index in normal subjects.10 Depen- study, many studies have demonstrated the utility of the Tei index
dency for heart rate has further been investigated by changing to evaluate prognosis in dilated cardiomyopathy, prior or acute
heart rate in patients with a pacemaker implantation.25 The Tei myocardial infarction, chronic HF, and others.30–37 A strong rela-
index significantly increased with elevation of heart rate in this tion between the Tei index and prognosis in patients with coro-
study. However, the increase was subtle, from a mean value of 0.40 nary artery disease suggests that the index may enable prediction
at 50 bpm to 0.51 at 100 bpm. Therefore, the Tei index is gener- of complications after acute myocardial infarction. An increased
ally heart rate independent in clinical practice. The Tei index has Tei index at admission to a coronary care unit predicted subse-
also been evaluated during preload modifications such as the Val- quent development of complications (Fig. 16-7).38–40 An increased
salva maneuver, leg lifting, or sublingual nitroglycerin administra- Tei index greater than 0.70 before mitral valvuloplasty is also a
tion in normal subjects as well as in patients with prior myocardial risk factor, doubling postoperative mortality.41 Recently, the utility
196 Chapter 16 • Evaluation of Tei Index in Heart Failure

of the Tei index to predict development of chronic HF or Detection of Cardiac Dysfunction in

cardiac death has been demonstrated in a population-based Various Diseases
cohort of elderly men.42,43 Therefore, an increased Tei index is a
risk factor for the development of chronic HF as well as cardiac Multiple studies have reported that rejection after cardiac trans-
death. plantation can cause myocardial damage and result in an increase
in the Tei index.44–47 The Tei index is also significantly correlated
with exercise capacity in several studies.48–52 Dobutamine stress
1.0 echocardiography often requires subjective evaluation in patients
with unclear response of LV wall motion. The Tei index showed
0.8 (11) (10) significant increase at peak stress only in patients with positive
response for ischemia, suggesting an incremental role of the Tei
0.6 (10) index in evaluation by dobutamine stress echocardiography.53
Reperfusion in patients with acute myocardial infarction results
0.4 (4) in an improvement in cardiac function. An increased Tei index of
greater than 0.50 suggests absence of adequate reperfusion with
0.2 thrombolysis in myocardial infarction (TIMI) grade 3 in patients
with acute anteroseptal myocardial infarction (Fig. 16-8).37,54
0.0 Because abnormalities in ICT, ET, and IRT by cardiac dys-
0.0 0.5 1.0 1.5 2.0 2.5 3.0 function can be augmented in ICT/ET and IRT/ET, the Tei
index has the potential to express subtle changes in cardiac func-
Years
tion. Many investigators have applied the Tei index to detect small
Tei index ≤ 0.77 changes in cardiac function by various conditions, including
Tei index > 0.77 hypothyroidism,56 diabetes mellitus,57 acromegaly,58 precondi-
tioning with preceding angina,59 sleep apnea syndrome,60 and
Figure 16-6 Relation between Tei index and survival in patients with
cardiac amyloidosis. Increased Tei index was a significant risk factor of later
others.
mortality. (From Tei C, et al: Doppler index combining systolic and diastolic
myocardial performance: Clinical value in cardiac amyloidosis. J Am Coll
Cardiol 1996;28:658–664.) Hemodynamic Assessment
As expected from its definition, the Tei index has close correlation
1.0 with both systolic and diastolic functions, such as maximal +
and − LV dP/dt, maximum mitral E-wave velocity, and τ.10,61
Although the Tei index does not include mid- to late-diastolic
Tei index

0.6 components, it has fair but significant correlation with LV stiff-

0.5 ness.62,63 The Tei index is also significantly correlated with LV
0.4
diastolic filling pressure. However, the correlation with pressure
Upper Normal Range is modest, potentially due to the fact that LV filling pressure
is determined by both ventricular function and loading.27,64,65
Ru a

Nevertheless, the Tei index enables practical evaluation of

re

ns
sm

h
k

ad , Vf
F

di
at
oc

CH

tu
,A

tio
ar
ry

de

VT

p
Sh

impaired hemodynamics in patients with acute myocardial infarc-

Af

ica
yc
eu

c
ia

pl
An

tion with potentially minimal modification of loading in the acute

rd

m
Br

co
Ca

phase before aggressive interventions to alter loading.32,67

No

A Tei index greater than 0.6 suggests impaired hemodynamics

Figure 16-7 Relation between initial Tei index at admission to coronary
care unit and subsequent complications in patients with acute anterosep-
with Forrester classifications II–IV in patients with acute antero-
tal myocardial infarction. (From Yuasa T, et al: Noninvasive prediction of com- septal myocardial infarction (Fig. 16-9). Further, the Tei index
plications with anteroseptal acute myocardial infarction by left ventricular Tei enables practical differentiation of normal from pseudonormal
index. J Am Soc Echocardiogr 2005;18:20–25.) mitral flow, defined by mitral E/A greater than 1.0 with elevated

0.7
LV-Tei index

0.5

0.3
Figure 16-8 Relation between Tei index at admis-
sion to the coronary care unit and coronary
reperfusion with thrombolysis in myocardial infarc-
0.1 tion, grade 3, immediately evaluated by angiogra-
phy in patients with acute anteroseptal myocardial
infarction. (From Kuwahara E, et al: Increased Tei
#6 #6 #7 #7 #8 #8 #9 index suggests absence of adequate coronary reper-
(–) (+) (–) (+) (–) (+) (–) fusion in patients with first anteroseptal acute myo-
Reperfusion Reperfusion Reperfusion cardial infarction. Circ J 2006;70:248–253.)
 Chapter 16 • Evaluation of Tei Index in Heart Failure 197

1.0 ❒ Category III: normal LV function and high filling

pressure
❒ Category IV: poor LV function and high filling pressure
0.8
Patients in category III are not common, and those in category
II seem to be the main reason for significant but only fair correla-
0.6
Tei index

tion between the Tei index and LV filling pressure. Normal LV

filling pressure despite LV dysfunction in category II suggests no
0.4 Upper normal significant increase in preload, and most patients with a discrep-
ant Tei index and filling pressure have mitral E/A of less than
1.0,68 being related to reduced preload.70 Therefore, the Tei index
0.2
has significant and good correlation with the LV filling pressure
in patients with mitral E/A greater than 1.0 and enables feasible
0 differentiation of normal from pseudonormal mitral flow.64,65,71 A
I II III IV significant correlation between the Tei index and brain natriuretic
Forrester class
peptide concentration also indicates significant relation between
the Tei index and degree of chronic HF.72,73
Figure 16-9 Relation between Tei index and Forrester’s hemodynamic
classification evaluated by catheterization in patients with acute antero-
septal myocardial infarction. (From Takasaki K, et al: Noninvasive estimation
of impaired hemodynamics in patients with acute myocardial infarction by Tei Evaluation of Right Ventricular Function
index. J Am Soc Echocardiogr 2004;17:615–621.)
Due to the complex geometry of the right ventricle, it is still dif-
ficult to evaluate RV function. Measurement of RVEF seems not
to be common practice in many institutions. However, the RV
Tei index can be measured independently from chamber geome-
try by cardiac time interval analysis with tricuspid filling and
Left ventricular filling pressure

pulmonary ejection flow.

High

Category III Category IV

(uncommon) (common) An increased RV Tei index predicts poor outcome in patients
with primary pulmonary hypertension.74 Of note is that prediction
of outcome is better with the Tei index compared with prediction
on the basis of systolic pulmonary artery pressure. This indicates
that RV dysfunction with increased pulmonary artery resistance
rather than increased pulmonary artery pressure per se is more
important to evaluate the severity of the disease. Clinical evalua-
Category I Category II
Low

(common) (not uncommon)

tion of the degree of RV dysfunction was proportional to the
increase in the RV Tei index in patients with Ebstein’s anomaly.75
RV involvement of cardiac amyloidosis has also been evaluated by
the Tei index.76 The RV Tei index is also significantly correlated
with EF, measured by radionuclide angiography or cine magnetic
Good Poor resonance imaging.77,78 Further, an increased RV Tei index in
patients with left-sided chronic HF is related to poor prognosis.79
Left ventricular function
Figure 16-10 Relation between cardiac function or Tei index and left ven-
tricular filling pressure. Categories II and III cause discrepancy between Effects of Interventions
cardiac function and the filling pressure. Patients in category III are uncom-
mon, and those in category II cause discrepancy between left ventricular Because the Tei index expresses global cardiac function with a
function and filling pressure. (From Zhang H, et al: Noninvasive estimation sensitive nature, it is reasonable to apply the index to evaluate
of left ventricular diastolic filling pressure from Doppler Tei index: Different
feasibilities in patients with higher and lower early to late diastolic mitral flow
interventions, especially with potentially minor influences. The
velocity ratio. J Echocardiogr 2003;1:15–22.) most common application of the Tei index to evaluate therapeutic
intervention is probably cardiac resynchronization. Multiple
investigators uniformly reported an improved Tei index with
LV filling pressure.64,65 It may seem strange that the Tei index
improvement in patient status.80–85 The Tei index has also been
practically separates patients with mitral E/A greater than 1.0
applied to guide pacemaker treatment to achieve maximal
with or without elevated LV filling pressure, while the index is
benefit.86–90 The Tei index is inversely proportional to quality of
only fairly correlated with filling pressure. The Tei index shows
life or cardiac output in these patients. Significant but relatively
significant and better correlation with LV filling pressure
small effects of various pharmacologic agents have been evaluated
in patients with mitral E/A greater than 1.0 compared with
by the Tei index.91–93 A decrease in the Tei index after administra-
those with mitral E/A no greater than 1.0 because LV function
tion of carvedilol is an early sign of improvement of chronic HF.94
and its filling pressure can be placed into four categories
Improvement in exercise capacity by exercise training in patients
(Fig. 16-10)68–69:
with recent myocardial infarction is not associated with changes
❒ Category I: normal LV function and normal filling in EF but may be detected by the Tei index.95 An improved Tei
pressure index with low-dose dobutamine is associated with myocardial
❒ Category II: poor LV function and normal filling viability.96 Improvement in RV function can also be evaluated by
pressure an RV Tei index in patients with pulmonary hypertension.97,98
198 Chapter 16 • Evaluation of Tei Index in Heart Failure

Worsening cardiac function following procedures can also be 40 r = 0.59

sensitively evaluated by the Tei index. An increase in the Tei index p < 0.0001
with low-dose dobutamine in patients with acute myocardial SEE = 6.0
infarction suggests poorer outcome with progressive remodeling 30

PCWP (mmHg)
and doubled events or mortality.99,100 Early detection of cardiac
toxicity by anthracycline can also be detected with the Tei index 20
before the development of abnormality in EF.101–103 Adverse
effects of RV pacing with augmented dyssynchrony can also be
evaluated by the Tei index.104,105 Therefore, many investigators or 10
clinical physicians utilize the Tei index to evaluate effects of
various interventions in multiple disease entities.
0
0.2 0.4 0.6 0.8 1
Evaluation of Patients with Tachycardia
Tei index
Measurement of LV volumes by two-dimensional echocardiogra- Figure 16-11 Relation between pulmonary capillary wedge pressure
phy can be a problem in the presence of high heart rate and rela- (PCWP) and Tei index in consecutive patients with acute anteroseptal myo-
tively low echocardiographic frame rate. However, pulsed Doppler cardial infarction. A marked increase in Tei index is usually associated with
echocardiography has excellent temporal resolution, suggesting significant increase in the filling pressure, and normal or only small increase
in the index is associated with normal or only finite increase in the filling
that the Tei index is suitable to evaluate cardiac function even in pressure. There is a wide scatter of left ventricular filling pressure in patients
the presence of advanced heart rate, such as in fetuses or small with mild to moderate increase in the Tei index. A significant increase in
animal models. The Tei index has been reported to be heart rate the filling pressure despite only mild increase in the index suggests that
independent in the fetus.106 Both the LV and RV Tei indices are the Tei index may be pseudonormalized in these patients.
abnormally increased in fetuses with intrauterine growth retarda-
tion.106,107 An increased LV Tei index suggests poor prognosis in
Not severe Severe
fetuses with severe tricuspid valve disease,108 and an increased RV Normal RV infarction RV infarction
Tei index is a marker of poor prognosis in fetuses with tetralogy
of Fallot and absent pulmonary valve.109 The Tei index is corre-
lated with both systolic and diastolic functions in small animal
models of chronic HF or myocardial infarction.110–112 Both the
LV and RV Tei indices are sensitive measures to detect cardiac
dysfunction in mice and rats.113,114

Limitations
Because the Tei index utilizes cardiac time intervals, it may ICT
not accurately express global cardiac function when ICT, ET, or ET IRT
IRT does not express cardiac function. One such example is Figure 16-12 Mechanism of pseudonormalized right ventricular Tei index
the case with a paradoxically shortened IRT caused by a marked in patients with severe right ventricular infarction. Severely elevated right
increase in left atrial pressure.115 A scattergram between LV filling ventricular end diastolic pressure results in advanced shortening of iso-
pressure and the Tei index in consecutive patients with acute volumic contraction time (ICT) despite clear right ventricular systolic dys-
function. ET, ejection time; IRT, isovolumic relaxation time. (From Yoshifuku
anteroseptal myocardial infarction demonstrated (1) an advanced S, et al: Pseudonormal Doppler Tei index in patients with right ventricular
increase in the Tei index with a significant increase in the acute myocardial infarction. Am J Cardiol 2003;91:527.)
filling pressure, (2) a normal or only small increase in the index
with a normal or only finite increase in the filling pressure, and and RV pressure, with extreme shortening of ICT despite severely
(3) a mild to moderate increase in the Tei index with a wide impaired RV systolic contraction (Fig. 16-12).118
scatter of the filling pressure (Fig. 16-11). A marked increase in
the filling pressure despite only a mild increase in the Tei index
suggests that the Tei index may be pseudonormalized in these FUTURE RESEARCH
patients.116,117 Most of these patients had shortened mitral E
deceleration time, which combined with the Tei index may enable We often see discrepancies between values of cardiac functional
better evaluation of hemodynamics in patients with HF. Of note indices and patient status. The reason is often due to the fact that
is that no patient showed a totally normal Tei index despite conventional indices express only one aspect of heterogeneous
advanced HF, although some showed a modest increase. The systolic or diastolic function. The Tei index enables evaluation of
Tei index is expected to be more resistant to pseudonormalization combined systolic and diastolic function, and therefore global
compared with IRT per se because the component of the cardiac function. The Tei index is related to patient prognosis.
Tei index or ratio of IRT to ET is more difficult to be pseudo- Because it sensitively expresses global cardiac function, evaluation
normalized, as ET usually shortens with elevation of the of interventions in cardiac function is feasible with this index and
filling pressure. In addition, the Tei index is a sum of ICT/ET should be an area of future research. The Tei index also enables
and IRT/ET, which seems to be further resistant to practical evaluation of RV function with geometric complexity
pseudonormalization.69 and clinical difficulty with other approaches. Other potential
In the right ventricle, elevation of RV end diastolic pressure clinical applications of the Tei index will require further
causes approximate equalization of diastolic pulmonary artery investigation.
 Chapter 16 • Evaluation of Tei Index in Heart Failure 199

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 DALANE W. KITZMAN, MD
JERRY M. JOHN, MD
17
Exercise Intolerance in
Diastolic Heart Failure
INTRODUCTION Angiotensin Receptor Blockers
Calcium Channel Blockers
PATHOPHYSIOLOGY OF EXERCISE
Aldosterone Inhibitors
INTOLERANCE
Glucose Cross-Link Breakers
Determinants of Oxygen Consumption
Pacemaker Therapy
Exercise Intolerance in Systolic Versus
Exercise Training
Diastolic Heart Failure
Hemodynamic Alterations During Exercise in FUTURE RESEARCH
Heart Failure Patients
ACKNOWLEDGMENT
CLINICAL RELEVANCE: INTERVENTIONS TO
IMPROVE EXERCISE TOLERANCE

INTRODUCTION tive methods, including timed walking tests (6-minute walk dis-
tance) and graded exercise treadmill or bicycle exercise tests.
Exercise intolerance is the primary symptom of chronic diastolic Cardiopulmonary exercise testing on a motorized treadmill or
heart failure (DHF). This chapter discusses the fundamental a bicycle ergometer provides the most accurate and reliable assess-
aspects of exercise physiology and the assessment, pathophysiol- ment of exercise tolerance and yields multiple important out-
ogy, and potential treatment of exercise intolerance associated comes, including exercise time, exercise workload, rate-pressure
with DHF. product, and metabolic equivalents (METs). Peak oxygen con-
Exercise intolerance is central to the very definition of heart sumption (VO2) and carbon dioxide generation (VCO2) can be
failure, as well as its pathophysiology, diagnosis, prognosis, and measured simultaneously by expired gas analysis using instru-
therapy. Heart failure is defined as a syndrome in which cardiac ments that are reliable and highly automated. The quality of the
output is insufficient to meet metabolic demands. Inherent in this exercise data, and in particular whether the patient gave a maximal
definition is that consequences of insufficient cardiac output will or near-maximal effort, can be assessed not only by perceived
be expressed symptomatically. Indeed, while the natural history exertion scales, such as the Borg scale, and percent age-predicted
of heart failure is punctuated by occasional episodes of acute maximal heart rate, but also by the respiratory exchange ratio,
decompensation with overt systemic volume overload and pulmo- which is unbiased by other variables. In addition to assessing peak
nary edema,1,2 the primary chronic symptoms in patients with exercise capacity with peak VO2, submaximal exercise capacity
chronic heart failure, whether associated with reduced or normal can be assessed by determining the ventilatory anaerobic thresh-
ejection fraction, are exertional fatigue and dyspnea.3 In addition, old. Submaximal exercise capacity is more applicable to everyday
these symptoms are the primary determinants of patients’ health- life and is relatively effort independent. We have shown that mea-
related quality of life. Furthermore, measures of exercise tolerance surements of both peak and ventilatory anaerobic threshold with
are powerful independent predictors of mortality.4,5 automatic instruments are valid and highly reproducible in elderly
The severity of exercise intolerance can be quantified by a patients with diastolic as well as systolic heart failure (Fig. 17-1).
variety of methods. These include semiquantitative assessments, In addition to these key variables, cardiopulmonary exercise
such as interviews (New York Heart Association [NYHA] clas- testing with expired gas analysis can assess the slope of expired
sification) and surveys (the Minnesota Living with Heart Failure ventilation (VE)/VCO2, which is a powerful predictor of sur-
and Kansas City Cardiomyopathy questionnaires), and quantita- vival, independent of VO2.6
203
204 Chapter 17 • Exercise Intolerance in Diastolic Heart Failure

PATHOPHYSIOLOGY OF EXERCISE INTOLERANCE Determinants of Oxygen Consumption

Assessment of peak VO2 gives insight into the pathophysiology
In a comparative study from our laboratory, maximal exercise of exercise intolerance, since, by the Fick equation, it is the product
testing with expired gas was performed in 119 older subjects of cardiac output and arteriovenous oxygen (A-V O2) difference.
divided among three groups: heart failure with severe LV systolic Thus, exercise intolerance will be closely related to one or both of
dysfunction (mean ejection fraction [EF], 30%); isolated DHF these factors and to the factors that comprise them. Measurement
(EF >50%; no significant coronary, valvular, pericardial, or pulmo- of peak exercise VO2 and at least one of these other two factors
nary disease; and no anemia); and age-matched controls.3 In com- (cardiac output or A-V O2) allows one to calculate the remaining
parison with the normal controls, peak VO2, an objective measure unknown factor and therefore to isolate specific factors that con-
of exercise capacity, was severely reduced in the patients with tribute to exercise intolerance within individual patients and
DHF, and to a similar degree as in those with systolic heart failure groups (Fig. 17-3).
(SHF) (Fig. 17-2).3 In addition, submaximal exercise capacity, as We performed a series of cardiopulmonary exercise studies in
measured by the ventilatory anaerobic threshold, was similarly order to examine the determinants of exercise performance in
reduced in patients with DHF versus those with SHF, and this normal humans and in patients with heart failure.7–13 The methods
was accompanied by reduced health-related quality of life.3 included symptom-limited upright bicycle exercise with indwell-
ing pulmonary artery and brachial artery catheters, and simulta-
2000
neous expired gas analysis and radionuclide ventriculography.7–15
Cardiac output was determined by the Fick principle for oxygen
Test 2 (VO2max, ml/min)

1800
and was indexed to body surface area. The left ventricular (LV)
1600 end diastolic volume index (EDVI) and end systolic volume index
1400 (ESVI) were calculated from the Fick stroke volume index (SVI)
1200 and the radionuclide LV ejection fraction (LVEF), according to
1000 the formulas: EDVI = SVI/LVEF, and ESVI = EDVI − SVI.
During upright bicycle exercise in healthy young and middle-
800 r = 0.92
p ≤ 0.0004
aged male volunteers, VO2 increased 7.7-fold from rest to peak
600 exercise.7 This was achieved by a 3.2-fold increase in cardiac
400 output and a 2.5-fold increase in A-V O2 difference. The increase
400 600 800 1000 1200 1400 1600 1800 2000 in cardiac output resulted from a 2.5-fold increase in heart rate
Test 1 (VO2max, ml/min) and a 1.4-fold increase in stroke volume. Stroke volume increased
during the initial low levels of exercise via the Frank-Starling
1500 mechanism, whereas end diastolic volume increased with small
Start of
VO2 (ml/min)

1000 exercise Heart rate:

Chronotropic incompetence
500 Test 1
Test 2 Stroke volume:
0 ↓ Contractility (systolic dysfunction: ESV)
↓ LV filling (diastolic dysfunction: EDV)
0 0.08 0.16 0.25 0.33 0.41 0.5 0.58
3 7 3 7 3
Time (min) Arteriovenous O2 difference:
↓ Peripheral vascular function
Figure 17-1 Excellent reproducibility of peak exercise VO2 in older patients ↓ Skeletal muscle bulk and function
with heart failure, including those with normal LV ejection fraction. ↓ Hemoglobin (anemia)
Group data shown in top panel; representative patient with 15-second
averaged data shown in bottom. (From Marburger et al: Reproducibility of Figure 17-3 Potential mechanisms of exercise intolerance from the factors
cardiopulmonary exercise testing in elderly heart failure patients. Am J Cardiol of the Fick equation. ESV, end systolic volume; LV, left ventricular; EDV, end
1998;82:905–909.) diastolic volume.

PEAK SUBMAXIMAL Figure 17-2 Exercise oxygen consumption (VO2) during

peak exhaustive exercise (left panel) and during sub-
16 maximal exercise at the ventilatory anaerobic threshold
(right panel) in age-matched normal subjects (NO), elderly
VO2 (ml/min/kg) at AT

14 patients with heart failure due to systolic dysfunction (SD),

25
Peak VO2 (ml/kg/min)

12 and elderly patients with heart failure with normal systolic

20 10 ‡ ‡ function and presumed diastolic dysfunction (DD). Exer-
cise capacity is severely reduced in patients with diastolic
‡ 8
15 ‡ heart failure compared with normals (p < 0.001) and to a
6 similar degree as in those with systolic heart failure. Overall,
10
4 peak exercise VO2 was 33% lower in the women compared
5 2 with the men (not shown). (Modified from Kitzman et al:
Pathophysiological characterization of isolated diastolic
0 0 heart failure in comparison to systolic heart failure. JAMA
NO SD DD NO SD DD 2002;288:2144–2150.)
 Chapter 17 • Exercise Intolerance in Diastolic Heart Failure 205

increases in pulmonary wedge pressure. During higher levels forming similar cardiopulmonary exercise testing in seven patients
of exercise, stroke volume increased predominantly because of with severe but stable chronic heart failure (NYHA functional
increased contractility with decreases in end systolic volume; end class III or IV). Six of the patients had had at least one episode of
diastolic volume may even decline slightly because of tachycardia clinically and radiographically documented pulmonary edema.10
and limited filling time. A similar hemodynamic exercise response No patient was included who had significant coronary artery
occurs in healthy women.14 disease by coronary angiography, abnormal LVEF (<50%), wall
Aging is known to be accompanied by reduced peak exercise motion abnormalities by radionuclide ventriculography, or clinical
VO2. This is due to age-related declines in peak exercise cardiac or echocardiographic evidence of valvular or pericardial disease.
output, heart rate, stroke volume, LVEF, and end diastolic volume, Most of the patients had a history of chronic systemic hyperten-
while pulmonary wedge pressure is relatively unaffected.8,9 Thus, sion; there was also increased LV wall thickness and mass by echo-
stroke volume and end diastolic volume response are important cardiography compared with normal controls (107 ± 27 vs. 79 ±
contributors to the increase in VO2 and cardiac output during 14 g/m2; p < 0.01). Ten age-matched and gender-matched healthy
upright exercise in normal subjects and are altered by normal volunteers underwent similar testing to serve as normal controls.
aging but not by gender. The patients with DHF exhibited marked exercise intolerance,
indicated by a reduction in peak workload compared with the
normal subjects. This corresponded to a 48% reduction in peak
Exercise Intolerance in Systolic Versus
VO2 (11.6 ± 4.0 vs. 22.7 ± 6.1 ml/kg/min; p < 0.001). In all
Diastolic Heart Failure patients and normal subjects, exercise was limited primarily by leg
In order to examine the cardiovascular response to exercise in fatigue, although dyspnea was also frequently reported at peak
classic SHF, 30 patients with heart failure associated with severe exercise.10 The peak respiratory exchange ratio was similar in
LV systolic dysfunction (mean LVEF = 24 ± 8%) were compared patients and normal subjects (1.24 ± 0.15 vs. 1.33 ± 0.16; p =
with 12 healthy volunteers of similar gender and age group.11 0.24), suggesting a near-maximal exercise effort in both groups.
Exercise tolerance was severely reduced in the patients, whose Arterial lactate concentration increased from 0.5 ± 0.3 mmol/
mean peak workload was 50% of that achieved by the healthy liter at rest to 3.7 ± 2.8 mmol/liter at peak exercise in the patients
subjects. Maximal VO2 was reduced by 53%, and this was associ- and from 0.5 ± 0.4 mmol/liter to 7.2 ± 2.0 mmol/liter in the
ated with a 53% reduction in cardiac output; maximal A-V O2 normal subjects. During submaximal exercise at 50 watts, where
difference was lower but not significantly different from normals. VO2 was similar in patients and normals, lactate concentration
Maximal stroke volume was severely reduced in the patients. In tended to be higher in the patients compared with the normal
addition, maximal heart rate was mildly reduced, a finding that subjects (2.2 ± 1.1 vs. 1.4 ± 0.7 mmol/liter; p < 0.07).
has been reported by others as well. When the patients were At rest, there were no differences in cardiac output, central A-V
grouped according to whether their exercise was limited by fatigue O2 difference, SVI, or heart rate between the two groups. However,
or by dyspnea, the peak pulmonary capillary wedge pressure during exercise in the patients compared with normal subjects,
(PCWP) was similar in both groups. Furthermore, in a signifi- cardiac output was significantly reduced at comparable submaxi-
cant fraction of patients, pulmonary wedge pressure was normal mal workloads and was markedly reduced by 41% at peak exercise
during rest and exercise, even though all had marked exercise (p < 0.001), in proportion to the reduction in peak VO2 (Fig.
intolerance and early lactate formation at submaximal workloads. 17-4A). Central A-V O2 difference was increased by approxi-
These data suggest that in patients with chronic heart failure and mately 10% in the patients during the submaximal exercise work-
severe systolic LV dysfunction, exercise intolerance is closely loads, partially compensating for the reduced cardiac output (Fig.
related to reduced exercise cardiac output, which is caused by 17-4B). However, at peak exercise, this mechanism was out-
severely reduced stroke volume and mildly reduced heart rate stripped, and A-V O2 difference was reduced by 13% compared
responses during exercise. with the normal subjects (p = 0.08). In the patients, the change
A subsequent report in 40 patients with severe LV systolic dys- in cardiac output from rest to peak exercise correlated closely with
function confirmed that stroke volume was reduced during rest the increase in VO2 during exercise (r = 0.81, p < 0.03), but the
and exercise compared with normal subjects.8 However, the rela- change in A-V O2 difference did not (r = 0.34, p = 0.43).
tive increase in stroke volume from rest to peak exercise was
similar and was 48% in patients and 42% in normal subjects.8
While some of the increase in stroke volume during exercise was Hemodynamic Alterations During Exercise in
attributable to increased contractility, stroke volume increased in Heart Failure Patients
patients in whom there was no change in LVEF. Furthermore,
there was a significantly greater increase in EDVI during exercise Stroke Volume
in the patients compared with the normal subjects, and the increase The indexed stroke volume is reduced by 26% in heart failure
in LV end diastolic volume per increase in PCWP was nearly patients compared with the normal subjects during submaximal
threefold greater in patients compared with normal subjects. Shen exercise (p < 0.01) (Fig. 17-4C). In contrast to the increase in SVI
et al.16 reported similar findings, although some patients do not during low levels of exercise followed by a plateau observed in the
increase end diastolic volume during exercise, due either to dia- normal subjects, a flat stroke volume response was observed in
stolic LV dysfunction or to pericardial constraint.8 Thus, in most these patients.10 Heart rate increased slightly in patients com-
patients with heart failure caused by systolic LV dysfunction, the pared with controls during submaximal exercise, but was reduced
Frank-Starling mechanism not only contributes significantly to by 18% compared with controls at peak exercise (p < 0.01) (Fig.
the increase in stroke volume during exercise but also partially 17-4D). The change in SVI from rest to peak exercise correlated
compensates for reduced inotropic and chronotropic reserves. closely with the increase in cardiac output during exercise (r =
With these background data in SHF, we sought to examine the 0.86, p < 0.01) in heart failure patients, but the change in heart
cardiovascular response to exercise in patients with DHF by per- rate did not (r = 0.60, p = 0.14). Thus, in patients with DHF at
206 Chapter 17 • Exercise Intolerance in Diastolic Heart Failure

Arteriovenous O2 difference (ml/dl)

Cardiac index (l/min/m2)

10.0 12

8.0 10

6.0 8

4.0 6

2.0 * * † 4

0 2
Rest 150 300 450 600 750 Rest 150 300 450 600 750
A B
Stroke volume index (ml/m2)

60 200
Heart rate (min –1) Figure 17-4 Cardiovascular function as-
† sessed by invasive cardiopulmonary exer-
50 160
cise testing in patients with heart failure
* and normal systolic function (blue boxes)
40 120
and age-matched normals (red boxes).
A, B, The primary components of the Fick
30 80 equation for oxygen consumption: cardiac
† † output and arteriovenous oxygen differ-
20 * 40 ence. C, D, The components of cardiac
output: stroke volume and heart rate. The
10 0 x-axis is exercise workload in kpm/min;
Rest 150 300 450 600 750 Rest 150 300 450 600 750 150 kpm/min is equivalent to 25 watts.
(From Kitzman et al: Exercise intolerance in
PT max NL max PT max NL max patients with heart failure and preserved left
ventricular systolic function: Failure of the
Workload (kpm/min) Workload (kpm/min)
Frank-Starling mechanism. J Am Coll Cardiol
C D 1991;17:1065–1067.)

peak exercise, reduced SVI was the primary factor responsible for (0.12 ± 0.11 vs. 0.03 ± 0.03 mmHg/ml; p = 0.07) at rest, during
reduced cardiac output, and reduced peak cardiac output was the exercise this ratio became markedly elevated in the patients com-
primary factor responsible for the 48% reduction in peak VO2 pared with the normal subjects (peak, 0.28 ± 0.15 vs. 0.06 ±
observed in our study.10 0.05 mmHg/ml; p < 0.0001).
Factors that could contribute to the abnormal stroke volume The abnormal LV end diastolic pressure-volume relationship
response in patients with DHF are displayed in Figure 17-5. The demonstrated by patients with DHF is further illustrated in
LVEF and ESVI during rest and exercise and the change from Figure 17-6. At rest, the patients demonstrated a shift upward
rest to peak exercise were not different from those in the normal and to the left. In contrast to the normal subjects, who demon-
subjects (see Fig. 17-5A and B). In contrast, EDVI was reduced strated approximately linear increases in end diastolic volume and
markedly during submaximal and at peak exercise in patients pulmonary wedge pressure during exercise, the patients’ exagger-
compared with normal subjects. This results in an abnormal, flat- ated and progressive increases in pulmonary wedge pressure were
tened curve that is similar to the abnormal stroke volume response not accompanied by increases in end diastolic volume.10 Thus,
(see Fig. 17-5C). In patients with DHF, the change in EDVI from these patients with normal rest and exercise LVEF demonstrated
rest to peak exercise correlated strongly with the change in SVI an abnormal pressure-volume relationship during exercise and
(r = 0.97, p < 0.0001) and in cardiac output (r = 0.80, p < 0.03) an inability to augment stroke volume by means of the Frank-
during exercise.10 Starling mechanism, suggesting that their exercise intolerance was
due primarily to diastolic LV dysfunction. This is in contrast to
patients with heart failure and reduced systolic function, who
Left Ventricular Filling Pressures
have an operating pressure-volume relationship that is shifted
Pulmonary wedge pressure was mildly increased in patients with upward and to the right during exercise.17
DHF compared with normal subjects at rest and became mark-
edly elevated during exercise (see Fig. 17-5D). However, the
change in pulmonary wedge pressure from rest to peak exercise
Noninvasive Measures of Left Ventricular
did not correlate significantly with the change in SVI or the Filling Pressures
increase in VO2 during exercise. The pattern of invasively assessed LV filling pressures offers key
insights into exercise intolerance; however, their invasive nature
limits their overall utility. Noninvasive Doppler mitral filling
Left Ventricular Compliance
indices have given substantial insight into LV diastolic function
Although the LV end diastolic pressure-volume ratio tended to but are confounded by many variables. The more recently devel-
be elevated in patients with DHF compared with normal subjects oped tissue Doppler indices are relatively free of confounding
 Chapter 17 • Exercise Intolerance in Diastolic Heart Failure 207

100

End systolic volume index

L.V. ejection fraction
80 40

60 30

(%)

(ml/m2)
40 20

20 10

0 0

A B
Figure 17-5 A–D, The components of the

Pulmonary wedge pressure

40
LV stroke volume response during exer-

End diastolic volume index

† †
cise, LV ejection fraction, end systolic 90 32
volume, end diastolic volume, and LV
filling pressure. Not shown are systolic †

(mmHg)
75 24
and mean arterial pressure, which were
(ml/m2)
not different between groups. The x-axis 60 16 *
is exercise workload in kpm/min;
150 kpm/min is equivalent to 25 watts.
45 8
(From Kitzman et al: Exercise intolerance in
patients with heart failure and preserved *
30 0
left ventricular systolic function: Failure of
the Frank-Starling mechanism. J Am Coll
Cardiol 1991;17:1065–1067.) C D

35 Moreover, an increase in E/E′ during exercise correlates

with exercise intolerance.22 M-mode color Doppler has been
30 used to noninvasively estimate the intraventricular pressure
Pulmonary capillary wedge pressure

Peak gradient (IVPG) from the left atrium to the left ventricle, a cor-
25
exercise relate of τ and an analogue of ventricular “suction.” Changes in the
IVPG from rest to peak exercise are powerful independent
predictors of maximal exercise tolerance in patients with heart
20 failure and systolic dysfunction.23 These eloquent noninvasively
(mmHg)

obtained data confirm findings from invasive studies and show

15 that individuals with heart failure as a group have increased LV
filling pressures at rest and during exercise associated with
10 Peak impaired diastolic function and that impaired myocardial relax-
exercise ation is associated with reduced diastolic suction during
Rest
exercise.
5
It is instructive to compare and contrast the exercise cardiovas-
cular responses in the two different groups of heart failure patients
0 described: those with normal EFs10 and those with reduced
60 80 100 120 140 160 EFs.8,10,11 Both heart failure patient groups have severe exertional
Left ventricular end diastolic symptoms and objective evidence of exercise intolerance, as well
volume (ml) as markedly reduced peak cardiac output and stroke volume,
Figure 17-6 LV diastolic function assessed by invasive cardiopulmonary mildly reduced peak heart rate, and slightly reduced peak A-V O2
exercise testing. The pressure-volume relation was shifted upward and difference (Fig. 17-7). In addition, both groups had mildly
leftward at rest. In the patients with exercise, LV diastolic volume did not
increase despite marked increase in diastolic (pulmonary wedge) pressure.
elevated resting and markedly elevated exercise mean PCWPs.
Due to diastolic dysfunction, failure of the Frank-Starling mechanism However, the mechanisms by which LV stroke volume was
resulted in severe exercise intolerance. The x-axis is exercise workload in reduced differed markedly between the two groups. In one
kpm/min; 150 kpm/min is equivalent to 25 watts. (From Kitzman et al: Exer- group,8,11 patients had profound systolic contractile dysfunction
cise intolerance in patients with heart failure and preserved left ventricular and were able to utilize markedly increased LV filling pressure to
systolic function: Failure of the Frank-Starling mechanism. J Am Coll Cardiol
1991;17:1065–1067.) produce greater than normal use of the Frank-Starling mecha-
nism to partially compensate and maintain some increase in exer-
influence. Further, the time constant of isovolumic pressure cise stroke volume. In the other group, despite normal systolic
decline (τ) can be estimated noninvasively by measuring the early contractile function,10 patients were unable to use the Frank-
diastolic velocity of the mitral annulus (E′).18 In addition, the Starling mechanism to increase stroke volume during exercise and
ratio of early LV diastolic filling velocity (E) to E′ correlates well had markedly increased LV filling pressure. These data highlight
with invasively measured LV end diastolic pressures.19 Notably, the pivotal influence of the end diastolic pressure-volume response
an increased E/E′ ratio at rest has been correlated with maximal during exercise in healthy subjects and in patients with heart
and submaximal exercise intolerance.20,21 failure (see Fig. 17-7).24
208 Chapter 17 • Exercise Intolerance in Diastolic Heart Failure

CENTRAL HEMODYNAMIC RESPONSE TO UPRIGHT BICYCLE EXERCISE

IN SHF vs. DHF COMPARED WITH NORMALS

SHF (EF 30%) DHF (EF 56%)

Sullivan 1989, Higginbotham 1987 Kitzman 1991

• RER 1.18 • RER 1.24

• Peak VO2 ↓ 50% • Peak VO2 ↓ 48%
• CO ↓ 40% • CO ↓ 41%
• A-V O2 diff ↓ 12% • A-V O2 diff ↓ 13%
• SV ↓ 30% • SV ↓ 26%
• Heart rate ↓ 13% • HR ↓ 18%
• Upright resting PCWP ↑ at 9 • Upright resting PCWP ↑ at 9
mmHg (normal = 3) mmHg (normal = 3)
Figure 17-7 Comparison of characteristic central and periph-
• Peak PCWP ↑ 27 mmHg (nl = 12) • Peak PCWP ↑ at 25 mmHg (nl = 12)
eral cardiovascular response to exercise in patients with heart
• Unable to decrease ESV • Unable to increase EDV
failure associated with severe LV systolic dysfunction versus
(↑ contractility) during exercise (↑ diastolic filling) during exercise
normal LV ejection fraction. RER, respiratory exchange ratio.

Group Young Old Elderly

Normal Normal Diastolic HF
VO2 Max
28.6 22.6 12.7
(ml/kg/min)

Aortic
distensibility 9.1 4.7 0.2
(10–3 mmHg)–1
Figure 17-8 MRI data and images from representative sub-
jects from healthy young, healthy elderly, and elderly
patients with diastolic heart failure (HF). Maximal exercise
oxygen consumption (VO2 max), aortic distensibility at rest,
and left ventricular mass/volume ratio. Patients with dia-
stolic heart failure have severely reduced exercise tolerance
(VO2 max) and aortic distensibility and increased aortic wall
thickness. (Modified from Hundley et al: Cardiac cycle depen-
Ascending dent changes in aortic area and aortic distensibility are
aortic wall reduced in older patients with isolated diastolic heart failure
thickness 2.1 2.2 3.3
and correlate with exercise intolerance. J Am Coll Cardiol
(mm) 2001;38:796–802.)

Arterial Compliance ously defined (in the section “Pathophysiology of Exercise Intoler-
ance”). Young healthy subjects and age-matched healthy subjects
Abnormal afterload and abnormal ventricular-vascular coupling were studied as healthy normal controls. The patients with DHF
are prime candidates to be responsible for the abnormal Frank- had severe exercise intolerance that was associated with increased
Starling response seen in patients with DHF. Nearly all (88%) of pulse pressure and concentric hypertrophic LV remodeling.
such patients have a history of chronic systemic hypertension.25–27 Thoracic aortic wall thickness was increased 50%, and there was
In animal models, diastolic dysfunction develops early in systemic markedly decreased aortic distensibility (Fig. 17-8). In univariate
hypertension, and LV diastolic relaxation is very sensitive to analysis, decreased aortic distensibility correlated closely with
increased afterload.28–33 Increased afterload may impair relax- patients’ severely decreased peak exercise VO2 (Fig. 17-9).36 In
ation, leading to increased LV filling pressures, decreased stroke multivariate analysis, decreased aortic distensibility was the stron-
volume, and subsequently in patients, symptoms of dyspnea and gest independent predictor of reduced exercise capacity. These
congestion.1,2,31 data support a potentially important role of increased aortic
From studies in animal models and humans it is known that stiffness, due to underlying aging and amplified by chronic
chronic systolic hypertension accelerates and magnifies the age- hypertension, in the pathophysiology of chronic heart failure
related increase in fibrotic thickening of the aortic wall and the symptoms.37
resultant increase in aortic stiffness, which in turn is a major
determinant of LV afterload and ventricular-vascular coupling.34,35
In order to test the hypothesis that abnormally decreased aortic
distensibility contributes to the severe exercise intolerance in
Chronotropic Response
heart failure with normal EF, we performed magnetic resonance In addition to reduced stroke volume, decreased heart rate
imaging and maximal exercise testing with expired gas analysis in response can also contribute to reduced peak exercise cardiac
a group of elderly patients with so-called isolated DHF, as previ- output and thence reduced peak exercise VO2. Indeed, chrono-
 Chapter 17 • Exercise Intolerance in Diastolic Heart Failure 209

RELATIONSHIP OF AORTIC DISTENSIBILITY

WITH EXERCISE CAPACITY

10
y = 0.0002x − 0.0021, r = 0.665
9.5
9
8.5
8

Aortic distensibility (10 –3 mmHG–1)

7.5
7
6.5
6
5.5
5
4.5
4
3.5
3
2.5
Figure 17-9 There is a close relationship between peak exer- 2
cise VO2 (horizontal axis) and proximal aortic distensibility 1.5
(vertical axis) in a group of 30 subjects (10 healthy young, 10 1
healthy old, and 10 elderly DHF patients). Each symbol repre-
sents the data from one participant. (From Hundley et al: 0.5
Cardiac cycle dependent changes in aortic area and aortic dis- 0
tensibility are reduced in older patients with isolated diastolic 0 10 20 30 40
heart failure and correlate with exercise intolerance. J Am Coll
Cardiol 2001;38:796–802.) Peak VO2 (ml/kg/min)

tropic incompetence has been a frequent finding during cardio- HEART RATE ACCELERATION
pulmonary exercise studies in SHF. However, few if any data had
been available in older patients and particularly those with normal 110
EFs. Accordingly, we examined heart rate and expired gas analysis p = 0.02
responses in elderly patients with DHF in comparison with a 100
group of age- and gender-matched patients with SHF and healthy Con
normal controls. Using the most standard definition of chrono-
Beats per minute

tropic incompetence, we found that it was present in 20% to 25% 90

of older heart failure patients, that the prevalence was similar in HFpEF
DHF compared with SHF, that the presence of chronotropic
incompetence was a significant contributor to the degree of exer- 80
cise intolerance, measured as maximal VO2, and that this was
independent of medications, including beta-adrenergic antago-
70
nists.38 The important contribution of chronotropic incompe-
tence to exercise intolerance in patients with DHF was confirmed
by Borlaug et al., who studied a cohort of primarily elderly, African 60
American women with hypertension and heart failure with a 0 30 60 90
preserved EF. The researchers reported significant reductions in
Seconds
heart rate increase during exercise, which was a primary contribu-
Figure 17-10 Chronotropic incompetence during exercise. Blunted
tor to reduced peak cardiac output and maximal exercise VO2 increase in heart rate during exercise in 7 patients with heart failure and
(Fig. 17-10).39 preserved ejection fraction >50% (HFpEF) compared with 14 matched
Despite the many physiological exercise studies that have been control subjects. (From Borlaug BA et al: Impaired chronotropic and vasodila-
performed with heart failure patients, there has remained uncer- tor reserves limit exercise capacity in patients with heart failure and a pre-
tainty regarding the final stimulus that causes heart failure patients served ejection fraction. Circulation 2006;114:2138–2147.)
to stop exercising at lower workloads than healthy subjects.40,41 It
has been thought that increased exercise pulmonary wedge during exercise in patients with heart failure and that excess
pressure and stimulation of pulmonary J-receptors cause reflex ventilation is related to pulmonary hypoperfusion and reduced
hyperventilation and hypoxia, leading to the sensation of severe cardiac output rather than elevated LV filling pressures. The
dyspnea, causing the patient to stop exercise prematurely. decreased exercise cardiac output likely causes skeletal muscle
However, about 50% of patients with heart failure, whether sys- hypoperfusion, a potent stimulus for early anaerobic metabolism,
tolic or diastolic, discontinue exercise, due primarily to general and subsequent generation of muscle lactate and other metabo-
fatigue or leg fatigue rather than dyspnea. In addition, investiga- lites, which could produce the sensation of peripheral and central
tors15,42 have demonstrated that arterial hypoxia does not occur fatigue.43,44
210 Chapter 17 • Exercise Intolerance in Diastolic Heart Failure

CLINICAL RELEVANCE: INTERVENTIONS TO In a randomized, crossover, blinded trial, Little et al. compared
IMPROVE EXERCISE TOLERANCE the calcium channel antagonist verapamil with the angiotensin
receptor antagonist candesartan with the outcomes of peak exer-
Angiotensin Receptor Blockers cise blood pressure, exercise time, and quality of life.62 While both
Pulse pressure can provide a crude estimate of the stiffness of the agents blunted the peak systolic blood pressure response to exer-
central large arteries, and its major determinant is systolic blood cise, only candesartan, and not verapamil, improved exercise time
pressure.45 During exercise in normal subjects, systolic and pulse and quality of life (Fig. 17-12).62
pressures increase substantially, and this response is magnified In a subsequent trial with similar randomized, crossover,
by increased arterial stiffness. Data from animal models suggest blinded design, the diuretic hydrochlorothiazide was compared
that the exercise-related increase in systolic blood pressure is with the angiotensin receptor antagonist losartan on the out-
mediated in part by exercise-induced increases in circulating comes of peak exercise blood pressure, exercise time, and quality
angiotensin II. Indeed, in a randomized, double-blind, placebo- of life.63 While both agents blunted the peak systolic blood pres-
controlled crossover trial, angiotensin receptor blockade reduced sure response to exercise, only losartan, not hydrochlorothiazide,
the exaggerated exercise increase in systolic and pulse pressures, improved exercise time and quality of life.63
resulting in significantly improved exercise treadmill time and
quality of life (Fig. 17-11).46 Aldosterone Inhibitors
Aronow et al. showed in a group of patients with NYHA class
III heart failure and presumed diastolic dysfunction (EF >50%) The addition of low-dose spironolactone (12.5–50.0 mg daily) to
that the angiotensin converting enzyme (ACE) inhibitor enalapril standard therapy has been shown to improve exercise tolerance in
significantly improved functional class, exercise duration, EF, dia- patients with severe SHF. Aldosterone antagonism has numerous
stolic filling, and LV mass.47 potential benefits in patients with DHF, including LV remodel-
ing, reversal of myocardial fibrosis, and improved LV diastolic and
vascular function.64–66 However, few data are presently available
regarding aldosterone antagonism in DHF. In one small study,
Calcium Channel Blockers low-dose spironolactone was well tolerated and appeared to
In hypertrophic cardiomyopathy, a disorder in which diastolic improve exercise capacity and quality of life in older women with
dysfunction is common, verapamil appears to improve symptoms isolated DHF.67 In another, spironolactone improved measures of
and objectively measured exercise capacity.48–51 This agent also myocardial function in hypertensive patients with DHF.68
improves ventricular-vascular coupling and exercise performance
in aged individuals with hypertension.52 In laboratory animal
models, calcium antagonists, particularly dihydropyridines, Glucose Cross-Link Breakers
prevent ischemia-induced increases in LV diastolic stiffness53 Glucose cross-links increase with aging and presence of
and improve diastolic performance in pacing-induced heart diabetes, and they cause increased vascular and myocardial stiff-
failure.54–56 However, negative inotropic calcium antagonists ness. Alagebrium, a novel cross-link breaker, improved vascular
significantly impair early relaxation56–60 and have in general shown and LV stiffness in dogs. In a small, open-label, 4-month trial of
a tendency toward adverse outcome in patients with SHF.56 this agent in elderly patients, LV mass, quality of life, and tissue
Setaro et al. examined 22 men (mean age 65) with clinical heart Doppler diastolic function indices improved, but there were no
failure despite an EF greater than 45% in a randomized, double- significant improvements in exercise capacity or aortic distensibil-
blind, placebo-controlled crossover trial of verapamil.61 There was ity, the primary outcomes of the trial.69 A variety of other agents
a 33% improvement in exercise time and significant improve- and strategies are currently being evaluated or are under consid-
ments in clinico-radiographic heart failure scoring and peak filling eration for this syndrome, including a selective endothelin
rate. antagonist.

PEAK SYSTOLIC BP DURING EXERCISE EXERCISE TIME

300
18
275
16
Peak systolic BP (mmHg)

250
Exercise time (min)

14
225
12
200 Figure 17-11 Plots of peak systolic blood
10 pressure and exercise duration during base-
line, during placebo, and during losartan
175 8 therapy in a randomized, controlled, cross-
over trial. Treatment with the angiotensin II
150 6 antagonist losartan increased exercise time.
p = ns p<0.05 p = ns p<0.05 (From Warner et al: Losartan improves exercise
p<0.05 p<0.05 tolerance in patients with diastolic dysfunction
125 4 and a hypertensive response to exercise. J Am
Baseline Placebo Losartan Baseline Placebo Losartan Coll Cardiol 1999;33:1567–1572.)
 Chapter 17 • Exercise Intolerance in Diastolic Heart Failure 211

400 40
30

Change in quality of life score

Change in exercise time (sec)
300
20

(# of symptoms)
200 10
0
100 –10

0 –20
–30
–100 –40
p<0.05
p<0.05
p = ns –50 p = ns
–200
A Control Candesartan Verapamil B Control Candesartan Verapamil
Figure 17-12 Effect of candesartan angiotensin receptor antagonist compared with verapamil calcium channel blocker on A, exercise time and B, quality
of life in patients with diastolic dysfunction. From survival of patients admitted with congestive heart failure by ejection fraction. (From Little WC et al: Effect
of candesartan and veramapil on exercise tolerance in diastolic dysfunction. J Cardiovasc Pharmacol 2004;43:288–293.)

Pacemaker Therapy large, multicenter, randomized, controlled trial (HF-ACTION)

sponsored by the U.S. National Institutes of Health. Presently,
The substantial chronotropic incompetence seen in DHF and its there is no trial examining this issue in patients with heart failure
correlation with reduced exercise capacity we have described and normal EF.
provide a rationale for electronic pacing interventions to improve
exercise capacity. Indeed, one modest-sized single-center study
used such a strategy in selected patients with hypertensive LV FUTURE RESEARCH
hypertrophy with supranormal systolic ejection and distal cavity
obliteration who had debilitating exertional fatigue and dyspnea Patients with heart failure and normal EF have severe, chronic
and demonstrated substantially improved exercise performance.70 exercise intolerance. The pathophysiology of exercise intolerance
These data merit confirmation in larger, multicenter, randomized, in this syndrome is incompletely understood, but as in SHF, it is
controlled trials. likely multifactorial. Current data suggest that important con-
Thus, a variety of pharmacological and other interventions tributors include decreased LV diastolic compliance, decreased
in small studies have shown improvements in exercise tolerance aortic distensibility, exaggerated exercise systolic blood pressure,
with verapamil,61 enalapril,47 angiotensin receptor antagonism,46,62 relative chronotropic incompetence, and possibly anemia and
and aldosterone antagonism.67 It should be remembered that in skeletal muscle remodeling. Exercise intolerance is an attractive
patients with SHF, some types of pharmacological interventions therapeutic target because it is a primary determinant of quality
that improve exercise tolerance have had paradoxical effects on of life, can be quantified objectively, is reproducible, and is modifi-
long-term survival.71,72 Because of this, the VE/VCO2 slope able. Based on lengthy experience seeking to understand exercise
during exercise, which is a powerful predictor of survival indepen- intolerance in patients with SHF, it is likely that several factors in
dent of VO2, should be included in future intervention trials of addition to those discussed in this chapter may contribute to
exercise tolerance.6 exercise intolerance in patients with DHF, including chronotropic
incompetence, abnormal peripheral arterial vasodilation, anemia,
Exercise Training and skeletal muscle bulk, fiber type, and function.11,80–88 This will
likely be a fruitful area for future research. A number of pharma-
Aerobic exercise training has the potential to improve a variety cological and other interventions appear to improve exercise intol-
of key abnormalities in patients with heart failure and normal erance in DHF. Although it is unknown whether these will be
EF, including LV diastolic compliance, aortic distensibility, accompanied by improved survival, the concomitant findings of
blood pressure, and skeletal muscle function.73–75 Indeed, improved quality of life confirm the clinical relevance of exercise
in SHF, aerobic exercise training has been shown to improve performance outcomes.
exercise tolerance, likely via favorable effects on multiple
factors.12,76,77 A recent report indicates that LV diastolic com-
pliance is preserved in older master athletes compared with ACKNOWLEDGMENTS
their age-matched and young counterparts, suggesting that
exercise training may be beneficial in DHF as well.78 A prelimi- This work was supported in part by NIH R37 AG18915.
nary report indicates that exercise training improves exercise tol-
erance and quality of life in older patients with heart failure and
normal EF.79 REFERENCES
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 ANNITTA J. MOREHEAD, BA, RDCS
18
Sonographer’s Perspective
of Evaluating
Diastolic Function
INTRODUCTION Superior Vena Cava
Sonographic Approach to Imaging Strain,
TECHNIQUE OF PERFORMING A DIASTOLIC
Strain Rate, and Torsion
ECHOCARDIOGRAPHIC DOPPLER
EXAMINATION TOOLS USED TO ASSIST THE SONOGRAPHER
Atrial Chamber Size IN GAINING ADDITIONAL INFORMATION
Left Ventricular Inflow Respirometer
Isovolumic Relaxation Time Doppler Enhanced Contrast
Pulmonary Venous Flow Echocardiography
Color M-Mode Evaluation of Left Ventricular Maneuvers
Inflow
SUMMARY AND FUTURE DIRECTIONS
Tissue Doppler Imaging
Right Ventricular Inflow ABBREVIATIONS
Hepatic Veins
Inferior Vena Cava

INTRODUCTION routinely perform a diastolic examination on all patients to

perfect their imaging skills and establish a consistent examination
Heart failure, a common ailment in older adults, is a major protocol. A comprehensive and systematic approach to perform-
public health epidemic in the United States1–3 that affected 5.2 ing a diastolic examination is outlined in this chapter and involves
million people in 2006.4 Diagnosis of systolic heart failure with a the use of echocardiographic tools, such as M-mode, two-
reduced ejection fraction is well documented, while diastolic heart dimensional echo, conventional Doppler, and tissue Doppler. A
failure in the presence of a normal ejection fraction is less under- skilled sonographer must be proficient in these techniques and
stood.5–8 The cardiac sonographer plays a crucial role in the evalu- be able to recognize common pitfalls. When armed with this
ation process of patients with both systolic and diastolic heart knowledge, the sonographer plays an important role in the
disease. noninvasive assessment of diastolic function.
There is truly an art to collecting accurate and reproducible A diastolic echocardiographic evaluation begins with a careful
imaging data in the evaluation of these patients. One must possess review of the patient’s medical chart. Diastolic dysfunction is
high technical competence, sufficient knowledge of left ventricular associated with a wide array of common clinical presentations and
(LV) filling mechanics, and a thorough understanding of Doppler related diseases. Common clinical presentations and related dis-
principles in order to obtain high-quality flow velocity data that orders should alert the sonographer that a diastolic echocardio-
are required for obtaining an accurate and reproducible diastolic graphic examination is indicated. The sonographer should pay
function examination. Echocardiographic diastolic function in- close attention to obvious and subtle two-dimensional clues
formation, when collected correctly, can yield meaningful results indicating potential diastolic heart disease, such as increased LV
that will help guide patient management.9–15 Sonographers should wall thickness, left atrial (LA) enlargement, a “ground glass” or
215
216 Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function

speckled myocardium, a thickened pericardium, and reduced lateral mitral annulus. Commence tracing the chamber until
atrioventricular (AV) motion (Table 18-1). reaching the opposite mitral annulus, subsequently closing the
area automatically from one annulus to the other. Avoid inclusion
of the LA appendage, pulmonary veins, and the mitral tenting
TECHNIQUE OF PERFORMING A DIASTOLIC area to prevent overestimation of the LA volume measurement
ECHOCARDIOGRAPHIC DOPPLER EXAMINATION
(Fig. 18-1).16,18
In combination with a standard echocardiographic examination,
a diastolic evaluation includes two-dimensional, M-mode, pulsed- Left Ventricular Inflow
wave (PW) Doppler, and color Doppler modalities (see Chapter The LV inflow Doppler is probably the most commonly used
10).16,17 An attribute of color Doppler is that it can help reduce measurement in the diastolic echo examination because the
the length of time needed to perform the examination by aiding
the sonographer in locating the center of ventricular inflow, the
pulmonary veins, the hepatic vein, and the superior vena cava
(SVC). Additionally, color Doppler M-mode (CMM) is a useful
tool in displaying a preview of the LV filling pattern.
The examination should also include evaluation of chamber
size, especially the left atrium and right atrium, LV wall thickness,
myocardial tissue characterization (i.e., ground glass appearance),
movement of the AV groove from the apical four-chamber view,
increased pericardial thickness, and abnormal septal bounce.

Atrial Chamber Size

Increased atrial size in a patient without valvular disease or atrial
fibrillation may be an indicator of increased LA pressures associ-
ated with diastolic dysfunction. A diastolic evaluation should
always include an assessment of LA and RA volumes. The sono- Figure 18-1 Biplane left atrial (LA) area and volume are measured at end
grapher should assess LA size by panning and using slight ventricular systole (maximum atrial area) from the apical four- and two-
rotational manipulation of the transducer with biplane images chamber views. Depicted by arrows, trace from the lateral annulus outlin-
from the apical four-chamber and two-chamber views to “fully ing the atrium to the medial annulus using the automatic tracing feature
to “close” the tracing at the annular level. Avoid including the area between
open” the LA area. LA volume measurement should be obtained the mitral annulus and the closed mitral leaflets as this will falsely increase
at end systole, when the chamber is at its fullest. The LA volume the atrial measurement. RV, right ventricle; LV, left ventricle; LA, left atrum;
is planimetered by placing the cursor at either the medial or the RA, right atrium.

TABLE 18-1
STAGES OF DIASTOLIC DYSFUNCTION
STAGE I
DELAYED,
IMPAIRED, OR STAGE II STAGE III
NORMAL NORMAL ABNORMAL PSEUDONORMAL RESTRICTIVE STAGE IV
YOUNG ADULT RELAXATION FILLING FILLING IRREVERSIBLE RESTRICTIVE

E/A ratio 1–2 1–2 <1.0 1–1.5 (reverses >1.5 1.5–2.0 (Doppler values similar
with Valsalva to stage III except no change
maneuver) with preload reduction
maneuvers)
DT (msec) <240 150–240 ≥240 150–200 <150 <150
IVRT (msec) 70–90 70–90 >90 <90 <70 <70
PV S/D ratio <1 ≥1 ≥1 <1 <1 <1
MVa / PVa ≥1 ≥1 ≥1 or <1 <1 <1 <1
duration
PVs2 / PVd ≥1 or <1 ≥1 >>1 <1 <<1 <<1
ratio
AR (cm/sec) <35 <35 <35 ≥35 ≥35 ≥35
CMM (cm/sec) >55 >55 >45 <45 <45 <45
TDI (cm/sec) >10 >8 <8 <8 <8 <8
Anatomic None None Normal or mildly Mild to moderate Severe LA enlargement, Severe LA enlargement, LV
abnormalities enlarged LA LA enlargement, LV systolic dysfunction, systolic dysfunction, MV or
LVH, normal or MV or TV regurgitation TV regurgitation with
abnormal EF possible MV systolic
regurgitation

From Bursi F, Weston SA, Redfield MM: Systolic and diastolic heart failure in the community. JAMA 2006:296;2209–2216. Yamada H, et al: Prevalence of left ventricular diastolic
dysfunction by Doppler echocardiography: Clinical application of the Canadian consensus guidelines. J Am Soc Echocardiogr 2002;15:1238–1244. Garcia MJ, et al: New Doppler
echocardiographic applications for the study of diastolic function. J Am Coll Cardiol 1998;32:865–875.
 Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function 217

SV too far away SV too close to Perfect!

from MV tips MV annulus

LV LV
LV

Figure 18-2 A, Pulsed Doppler sample

volume (SV) placed too far away from
the mitral valve (MV) leaflet tips (49 cm/
sec) into the left ventricle demonstrat- LA LA LA
ing blunted “E” wave velocities with a
thick course spectral envelope. B, Pulsed
Doppler sample volume placed too E 70 cm/sec
close to the mitral annulus (60 cm/sec), E 60 cm/sec
resulting in blunted “E” wave velocities E 49 cm/sec A
A
with a thick course spectral envelope as A
well. C, Pulsed wave Doppler sample
volume correctly placed at the mitral
valve leaflet tips of left ventricular inflow
with a Doppler spectral display of
70 cm/sec. Strive for the highest obtain-
able velocity signals. Note the clean
spectral envelope of panel C as com- A B C
pared with panels A and B.

various patterns represent increasing degrees of LV diastolic

impairment. LV filling patterns are easily recognized. The sonog-
Decel
rapher is able to record transmitral velocity using PW Doppler. E
The routine measurements performed are the early diastolic (E)
and atrial contraction (A) peak velocities, as well as early filling
deceleration time.17 The sonographer should obtain these by A
using color Doppler as a guide to align the pulsed Doppler cursor
parallel with the center of the LV inflow. Attention must be given
to appropriate sizing and placement of the Doppler sample
volume box between the tips of the mitral valve in the middle of
the color Doppler velocity map. Placing the sample volume box
too far into the left ventricle or too close to the mitral annulus
will result in underestimated LV inflow Doppler velocities (Fig.
18-2). Using a sample volume box that is too large is likely to
produce a coarse velocity profile due to spectral broadening from Figure 18-3 Example of measurement of peak velocities E (early filling)
and A (atrial contribution) and E-wave deceleration time from the slope of
wall motion artifact, thus yielding an incorrect velocity recording. peak “E” to baseline. Note that deceleration time is measured from peak E
A low filter setting is required as well to allow the operator to wave following the descent to the zero baseline. Be careful not to include
obtain timing information at the zero-velocity baseline. The signal noise. BPM, beats per minute.
sonographer should adjust sample volume at 1–2 mm, velocity
filter at 200 Hz, sweep speed at 50–100 mm/sec, and optimize
the Doppler gain. The sonographer should then measure the peak Doppler, the sample volume is adjusted to 3–4 mm and placed
E- and A-wave velocities, as well as the E-wave deceleration time midway between the mitral valve leaflet tips and the LV outflow
(Fig. 18-3). To measure mitral A-wave duration, place the sample tract until both the aortic valve closure and the mitral valve
volume box approximately 5 mm closer to the mitral annulus and opening spikes are visualized above and below the zero-Doppler
collect additional pulsed Doppler waveforms. The same Doppler baseline. Alternatively, continuous wave (CW) Doppler may be
settings previously described are recommended. The A-wave used if the operator is unable to obtain clear aortic valve closure
duration is a measure of time that must be taken from the begin- and mitral valve opening spikes. The velocity filter setting should
ning to the end of the A wave using the leading-edge-to-leading- be adjusted at 200–400 Hz, the chart speed at 100 mm/sec, and
edge approach (Fig. 18-4). Doppler gain optimized. An IVRT interval that is prolonged is
representative of impaired relaxation, while an IVRT that is short
may be indicative of increased LA pressure.
Isovolumic Relaxation Time
Isovolumic relaxation time (IVRT) is a measure of time (in
milliseconds) from the onset of the aortic valve closure spike Pulmonary Venous Flow
artifact to the onset of the mitral valve opening spike artifact Pulmonary venous (PV) flow occurs during both systole and
(Figs. 18-5 and 18-6).17 The IVRT is obtained from the apical diastole, as well as with atrial contraction (see Chapter 10). Sys-
five-chamber view by aligning the Doppler beam midway between tolic PV flow occurs while the mitral valve is closed. Diastolic PV
the LV inflow and the LV outflow (see Fig. 18-5). Using PW flow occurs while the mitral valve is open. While in the apical
218 Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function

A
E

RV
LV

RA
LA

A Dur

Figure 18-4 Example of measurement of atrial duration (A Dur). Move Figure 18-5 Place the Doppler cursor between the mitral and aortic valves
sample volume approximately 5 mm nearer to the mitral annulus from the panning between apical four- and five-chamber views to obtain isovolu-
peak left ventricular inflow velocities measurements. This technique results mic relaxation time. Adjust Doppler filter and gain settings to optimize the
in a smaller E wave and a slightly better defined A wave, making clearer aortic valve closure and mitral valve opening spike artifacts.
visualization of the onset of the A wave and mitral valve closure. Measure
the A-wave duration time from these two points.

four-chamber view, one can assess PV flow using PW Doppler.

The right upper PV is most frequently visualized and accessible
from the transthoracic echo examination.17 Color Doppler should
be used as a guide to find the strongest PV flow signal, which has
been described as appearing like a candle flame. The sample
volume box should be placed approximately 1–2 cm into the pul-
monary vein to obtain the purest forward-flow Doppler signal
(Fig. 18-7). The sonographer must take care to ensure that the IVRT
sample volume box is indeed in the pulmonary vein and not in
60
the left atrium or at the junction of the left atrium and the pul- MV
monary vein, or the resulting signal will be contaminated by other Flow
40
blood flow velocities. The Doppler sample volume box should be
adjusted to 3–4 mm in size, and the Doppler filter should be set
to 200 Hz to allow full visualization of the spectral Doppler 20
signal to the zero baseline. Sweep speed is then adjusted to
50–100 mm/sec. cm/s
There are several components of the PV Doppler waveform.
AoV -20
These components are PVs1, PVs2, PVd, and PVa. PVs1 occurs Flow
during early systolic filling and is representative of LA relaxation.
PVs2 occurs during late systolic filling and is representative of -40
LA compliance and pressure. PVd occurs during diastolic filling
and is representative of LV filling properties. Finally, PVa repre- -60
sents atrial reversal and is representative of flow reversal due to
75
atrial contraction. PVs1 and PVs2 are commonly merged. PVs1 BPM
is more likely to be observed with a slower heart rate. The sonog-
rapher measures peak PVs1, PVs2, and PVa velocities as well as Figure 18-6 Measure isovolumic relaxation time (IVRT) from the end of
PVar duration (Fig. 18-8). aortic valve (AoV) closure to the beginning of mitral valve (MV) opening.
 Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function 219

Color M-Mode Evaluation of

Left Ventricular Inflow
As described earlier in this chapter, CMM is a useful tool in that
it provides an instant display of the LV filling pattern. CMM can
be used to measure the rate of propagation of LV peak filling
velocity during early diastole, with representative “E” and “A”
CMM propagation signals or waves that represent distance/time
(velocity). CMM propagation velocity (Vp) is reduced with
impaired LV relaxation and may be used to differentiate restric-
LV tion from constriction, as well as normal from pseudonormal
diastolic function.12,17–19
RV To obtain a quality CMM examination of LV filling, begin
with an apical four-chamber view and avoid foreshortening the
apex. Then reduce the two-dimensional depth to approximately
RA 16 cm or at least to a depth that includes the entire left ventricle
LA
and a portion of the left atrium. Finally, adjust the color sector to
fit over the entire LV chamber, including the mitral valve annulus.
Reducing the color sector maximizes the color frame rate
and provides a better-quality CMM. Place the CMM cursor
through the center of the LV flow, aligned as parallel as
possible to the direction of the inflow jet (Fig. 18-9). One of the
most common errors in obtaining a CMM is incorrect placement
of the cursor. The sonographer should align it with the aliasing
color of mitral inflow, being conscientious not to cut off the tips
of the E and A waves. Attention to detail will make the difference
between accurate and inaccurate waveforms and subsequent
measurements.
Figure 18-7 Pulmonary venous (PV) flow may be visualized using
two-dimensional color Doppler guided imaging to depict the “flame”
appearance of forward PV flow. The Doppler sample volume is placed
approximately 1–2 cm into the right upper pulmonary vein (RUPV).

0.8
LV
S2
S1
D 0.6

AR dur 0.4

RV
0.2

[m/s]

-0.2

AR
-0.4

49
0 HR

Figure 18-8 Pulsed wave Doppler spectral display of pulmonary vein flow
with correct sample volume placement. Clear distinction of pulmonary Figure 18-9 Use two-dimensional color Doppler to guide placement for
vein flow systolic (S1, S2), diastolic (D), and atrial reversal (AR) is demon- the highest-velocity signals. Place the M-mode cursor in left ventricular
strated. Measure the peak S, D, and AR velocities as well as the AR (LV) flow propagation, demonstrating appropriate alignment of M-mode
duration. cursor.
220 Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function

Keep in mind that the left ventricle fills from the base in a lateral color two-dimensional—and can be collected from either the lon-
direction as blood flow propagates toward the apex. It is important gitudinal apical images (to collect annular velocities from the
to avoid crossing the myocardial boundary regions. The sonogra- apical four- and two-chamber views with spectral Doppler data)
pher needs to set the color gain just at subsaturation and proceed or short-axis images (to collect myocardial Doppler velocities
to CMM display. He or she should adjust the color velocity scale from 2D color) (Fig. 18-12). Color myocardial TDI data can be
for color aliasing by shifting the baseline up so that it is in the collected from the apical views as well.
30–40 cm/sec range, or approximately 70% of the aliasing A diastolic echocardiographic assessment includes TDI data.
velocity from the zero baseline (Fig. 18-10).19 The CMM sweep The sonographer begins with an apical four-chamber view, initi-
should be recorded at a speed of 100 mm/sec. The goal is to obtain ates TDI mode, and places a 5 mm sample volume on the lateral
the longest column of color from the base of the mitral annulus to mitral annulus. This can be repeated at the medial mitral annulus.
the LV apex with an edge of uniform color during early filling. The right ventricular free wall annulus also can be interrogated
Measure the Vp slope starting from the aliasing velocity during using TDI.21 Attention should be given to ensure proper place-
early filling from the mitral valve plane to 4 cm into the LV cavity ment of the Doppler sample volume on the annulus, avoiding the
as illustrated in Figure 18-11. Ideally five or six high-quality con- basal segments of the ventricular myocardium (Figs. 18-13 and
secutive cardiac cycles should be averaged. Normal CMM has a 18-14).
vertical slope with distinct “E” and “A” waves that resemble con-
ventional PW Doppler E and A waves of ventricular filling.

Tissue Doppler Imaging

Tissue Doppler imaging (TDI) is a modality that measures myo-
cardial velocity, in contrast to traditional Doppler, which mea-
sures blood flow velocity. While in the TDI mode, the ultrasound
system is programmed to amplify and display low-velocity signals
generated by the myocardium and to filter out higher-velocity
signals generated by blood flow. This is the opposite of the tradi-
tional use of Doppler imaging to measure blood flow, where
lower-velocity signals generated by the myocardium are sup-
pressed and only the high-velocity signals from moving blood are
displayed. TDI is a sensitive tool in the assessment of diastolic
function in that it can differentiate normal from pseudonormal
diastolic dysfunction. TDI spectral waveforms mimic diastolic
and systolic patterns of conventional ventricular filling and ven- Figure 18-11 Example of color M-mode of left ventricular (LV) inflow
tricular outflow pulsed Doppler flow signals in that it includes propagation velocity (Vp). Measure Vp from the intersection of the anterior
two diastolic (E′ and A′) peaks and one systolic (S′) peak.17,20,21 mitral valve leaflet M-mode extending along the first edge of uniform color
TDI can be displayed in the same three formats as conven- or aliasing velocity approximately 4 cm into the left ventricle. Schematic
tional Doppler—(1) pulsed (spectral display), (2) CMM, and (3) diagram in upper left corner represents color M-mode measurement of LV
inflow propagation. E, early LV filling; A, late filling or atrial contribution.

+58 +42

–58 –68 cm
cm/sec cm/sec
Figure 18-12 Example of tissue Doppler image displayed from the
Figure 18-10 Diagram depicting color Doppler baseline before and after short-axis view used to collect myocardial Doppler velocities from two-
adjustment for color M-mode. dimensional color images.
 Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function 221

Right Ventricular Inflow display that includes an E and A wave during the diastolic phase
should be obtained. The peak E- and A-wave velocities are mea-
PW Doppler assessment of right ventricular (RV) inflow is per- sured, as well as RV inflow deceleration time (Fig. 18-17). The
formed while in the apical four-chamber view to obtain informa- sonographer should avoid sampling the RV inflow by crossing the
tion on RV diastolic function. This is obtained by using color LV apex. This will result in unreliable Doppler data (Fig. 18-18).
Doppler to find the highest RV inflow velocity (Fig. 18-15). Next,
a PW Doppler cursor is aligned parallel with the center of the RV
color Doppler inflow. The sonographer may need to move Hepatic Veins
the transducer slightly more medial to obtain correct alignment. Pulsed Doppler assessment of the hepatic venous (HV) flow is
The two-dimensional image in this slightly off axis view may not obtained from the short-axis subcostal view. Color Doppler is
be aesthetically pleasing; however, the Doppler signal will be more used to guide the transducer and cursor placement to locate the
accurate. The Doppler cursor must not cross the LV apex, as this highest flow velocity (Fig. 18-18A). The sonographer should
will result in a blunted Doppler signal (Fig. 18-16). The sample place the sample volume in the center of the highest flow velocity
volume box should be adjusted at 1–2 mm and placed between the so that it is parallel with flow and approximately 2–3 cm into the
tips of the tricuspid valve. The velocity filter is set to approximately hepatic vein beyond the junction of the inferior vena cava (IVC).
200 Hz, and the Doppler gain optimized to display a clean spec-
tral envelope. Some respiratory variation (up to 15%) is normal
and commonly observed in the RV outflow pattern.17 The chart
speed is set at 50–100 mm/sec. A biphasic Doppler spectral

Correct SV placement

RV LV
LV RV

RV
LV

a′

RA LA

e′

A B
A B
Figure 18-15 A, Correct pulsed wave Doppler cursor and sample volume
Figure 18-13 Example of tissue Doppler with a 5 mm sample volume (SV) placement. B, Use of color Doppler guided cursor placement. Note that the
correctly placed at the lateral mitral annulus. Note that early left ventricular cursor crosses the right apex and is parallel with right ventricular inflow
(LV) filling is represented by e′ wave and late LV filling or atrial contribution and that the sample volume is appropriately placed at the tricuspid valve
is represented by a′ wave. Measure the peak e′ and a′. leaflet tips.

Incorrect SV placement

LV

Figure 18-14 Example of incorrectly

placed tissue Doppler sample volume a′
(SV) near the lateral mitral annulus. RA LA e′
Note that the SV was placed in the left
ventricular (LV) basal lateral wall
segment rather than at the lateral
mitral annulus. This results in a tissue
Doppler velocity signal that is blunted,
yielding an inaccurate estimation of A B
tissue velocity.
222 Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function

0 SV Angle 0º The sonographer should adjust the sample volume at 1–3 mm,
+67.3 Dep 9.6 cm optimize the Doppler gain, and adjust the sweep speed to 50–
5 Size 1.0 mm
Freq 2.0 MHz
100 cm/sec. The systolic (S) and diastolic (D) filling components,
10 WF Low as well as venous reversal (VR) and atrial reversal (AR), are dis-
15 -67.3 Dop 68% Map 3 played and measured (see Fig. 18-18B). It is common to observe
cm/s Prf 2500 Hz
70
mild respiratory variation in the HV Doppler profile in normal
RV
60 patients.17
E
50
LV
40
A
30
Inferior Vena Cava
Decel
20 A diastolic echocardiographic examination includes an M-mode
10 interrogation of the IVC to determine its diameter and to rule
cm/s
-10
out plethora. The IVC is generally best visualized while in the
-20 short-axis subcostal view. The two-dimensional depth is reduced
A B
51 to improve visualization. The M-mode cursor is placed so that it
BPM crosses and is perpendicular to the IVC. Once in M-mode, the
Figure 18-16 Example of correct pulsed wave spectral Doppler cursor gain is optimized and the sweep speed is recorded at 25–50 cm/
alignment and correct sample volume placement at the tips of the tricus- sec. Several regular respiratory cycles should be included during
pid valve leaflets, resulting in the clean “E” and “A” Doppler waveforms. M-mode interrogation. The patient is instructed, “Take
several quick, short sniffs, as if you have a stuffy nose,” while the
sonographer records the IVC diameter via M-mode sweep
(Fig. 18-19A). This maneuver allows the sonographer to observe
and evaluate the IVC for collapse during quick forceful inspira-
1.0.65 tions. A lack of 50% collapse of the IVC during the “sniff ” test is
considered IVC plethora (see Fig. 18-19B).
A
E 0.5
RV LV
[m/s]

-0.5

-1.0
0.0 78
-0.5 HR

A B
Figure 18-17 Incorrect pulsed wave Doppler cursor placement of right
ventricular inflow with the Doppler cursor crossing the left ventricular
apex, resulting in blunted peak E and A waves.

Col 84% Map 1

WF High
PRF 4000 Hz
HV Flow Opt: FR

30 AR
IVC 20 VR
10
cm/s
-10
-20
-30 D B
-40 Figure 18-19 A, Normal response to the “sniff ” test with M-mode repre-
-50 S sentation of inferior vena cava (IVC) diameter during “sniffing” maneuver.
The double arrow illustrates the IVC diameter at end expiration as com-
A B pared with the change in diameter during the sniff test. The IVC is consid-
ered plethoric if during the sniff test it collapses only minimally or does not
Figure 18-18 A, Example of color Doppler guided cursor placement of collapse at all, indicating increased right atrial pressures. B, Abnormal
hepatic vein flow. B, Pulsed wave spectral Doppler of hepatic vein flow response to the sniff test with M-mode representation of IVC diameter
demonstrating measurement of peak S (systolic) and D (diastolic) waves, during “sniffing” maneuver. Note minimal or no IVC collapse during the
VR (venous reversal), and AR (atrial reversal.) test.
 Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function 223

Superior Vena Cava understand the energy expended during the cardiac cycle, in both
systolic and diastolic phases. The definition of torsion is to twist
The SVC flow is obtained by positioning the patient flat on his or turn. Torsion imaging, also known as torsional deformation, is
or her back without a pillow for head support. The patient is then used to measure the energy expended throughout systole and
asked to extend his or her chin slightly up and to the left. diastole.24–26 As the ventricles contract and relax, the myocardium
This position helps to better expose the SVC for transducer thickens and thins in the radial, circumferential, and longitudinal
placement and subsequent Doppler assessment. The transducer directions. At the same time, the ventricles move in a twisting or
is placed in the right supraclavicular fossa (Fig. 18-20A). coiling (torsion) motion. The respiratory cycle further contributes
Using color Doppler as a guide, the sonographer should to cardiac motion by translating the heart in the chest cavity
search for a vertical blue column of color flow, indicating blood without affecting strain.
flow toward the right atrium via the SVC (see Figs. 18-20B Strain imaging requires additional skill and understanding of
and 18-20C). The PW Doppler cursor is placed in the center of Doppler principles pertinent to optimization of strain Doppler
the blue, parallel to the highest flow velocity. The sample volume data (Table 18-3). Keep in mind that the heart is moving in
size is adjusted to 4–5 mm and the sample volume placed at multiple directions during the course of the cardiac cycle. Special
approximately 5–8 cm in depth (close to the junction of the SVC attention to detail will help avoid collection of inaccurate data.
and the right atrium, although well into the SVC). The Doppler The sonographer can avoid common pitfalls by incorporating
filter is set at 200 Hz and the Doppler gain optimized. The technical tips in the strain image examination to improve Doppler
sonographer should use a sweep speed of 50–100 cm/sec to data quality.23 One must bear in mind that strain measurement is
collect and measure peak S and D waves, as well as AR (see Fig. angle dependent. The sonographer must acquire the data by align-
18-20D). As with other right-heart Doppler evaluations, it is ing the LV walls as much as possible along the insonation angle
common to observe respiratory variation in the SVC Doppler (Fig. 18-21). Sometimes, it is necessary to separately image two
profile. opposing LV walls. Finally, one has to take care to maximize the
acquisition frame rate: with TDI, one should strive to acquire the
Sonographic Approach to Imaging Strain, data at 60–100 fps. Strain may also be displayed by speckle track-
Strain Rate, and Torsion ing (see Fig. 18-22), where multiple natural acoustic speckles are
automatically tracked in the two-dimensional image.27 Speckle
When a stress is imposed on myocardial muscle, it will deform, or tracking images are not derived from TDI, so images are often
change shape and often change volume. Deformation is defined as easier to acquire because they are not angle dependent. Speckle
a change in shape due to an applied force. This can be the result tracking can be obtained from the basal, mid-, and apical short-
of pulling, pushing, or twisting. The change in shape as a result axis levels of the left ventricle, where the resulting 18 segments
of imposing a stress is referred to as strain.22,23 Strain in echo can be displayed as a bull’s-eye diagram (Fig. 18-23). Table 18-2
Doppler is defined as the change in length of the myocardial fiber. provides a summary that may be used as a pocket guide for quick
Strain imaging is derived from TDI (one-dimensional strain) or reference.
from speckle tracking (two-dimensional strain). Strain occurs in
radial and longitudinal directions. The myocardial muscle short-
ens and thickens during ventricular contraction. Negative strain
is demonstrated by myocardial muscle shortening in the circum- TOOLS USED TO ASSIST THE SONOGRAPHER IN
ferential and longitudinal dimensions, and positive strain is dem- GAINING ADDITIONAL INFORMATION
onstrated by thickening or lengthening in the radial direction.
Strain imaging is particularly useful to assess geometric changes
Respirometer
of LV function. A respirometer is a useful tool in the evaluation of diastolic func-
Strain rate is the measure of deformation of myocardial muscle tion. While not necessary, it is recommended and can enhance the
over time.22,23 LV torsion is a measure of energy and is used to interpretation of a diastolic examination by providing respiratory

20 VR
AR
2 10

SVC cm/s
4 Color -10
Doppler
-20 D
-30
-40

SVC -50
-60 S
-70
A B C D
Figure 18-20 A, Transducer placement at the right supraclavicular fossa for interrogation of superior vena cava (SVC) flow. B, 2D image of SVC. C, 2D
color flow Doppler guided cursor placement in the SVC. The sonographer should obtain solid blue color demonstrating flow away from the transducer.
D, Typical SVC pulsed wave Doppler spectral display demonstrating measured peak S, D, and AR velocities.
224 Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function

TABLE 18-2
DIASTOLIC EXAM: COLLECTING AND MEASURING LEFT- AND RIGHT-HEART PARAMETERS
SAMPLE VOLUME
PLACEMENT
OR CURSOR SAMPLE
PLACEMENT VOLUME VELOCITY SWEEP SPEED
OBSERVATION VIEW MODALITY OR FRAMES/SEC SIZE (mm) FILTER (Hz) (mm/sec)

Left Heart
AV groove PLAX 2D
LA size (volume/ A4Ch and A2Ch 2D
area)
LV inflow A4Ch PWD SV between mitral valve 1–2 200 50 or 100
leaflet tips
A-wave duration A4Ch PWD SV 5 mm nearer to mitral 1–2 200 50 or 100
annulus than where
sampled for LV inflow
PV flow A4Ch PWD SV 1–2 cm into pulmonary 3–4 200 50 or 100
vein
LV inflow CMM A4Ch CMM Activate color Doppler 100
in LV. Cursor placement
in highest velocity color
signal. Activate M-mode
IVRT Between A4Ch and PWD or CWD Cursor placement 200–400 50 or 100
A5Ch intermediate between
LV inflow and LV outflow
MV lateral annulus A4Ch TDI SV lateral mitral annulus 5 100 50 or 100
MV medial annulus A4Ch TDI SV medial mitral annulus 5 100 50 or 100
Right Heart
RV inflow A4Ch PWD Between tricuspid valve 1–2 200 50 or 100
leaflet tips
HV Subcostal SAX PWD 2–3 cm into hepatic vein 3–4 200 50 or 100
beyond junction of IVC
TV free wall A4Ch TDI SV free wall annulus 5 100 50 or 100
annulus
IVC Subcostal SAX 2D guided M-mode Place M-mode cursor 25 or 50
perpendicular to IVC
SVC Right supraclavicular PWD SV 5–8 cm depth and 3–4 200 50 or 100
fossa close to the junction of
the right atrium
Strain Imaging
Strain Apical Views TDI or 2D speckle 60–100 frames/sec
tracking
Strain rate Apical Views TDI or 2D speckle 60–100 frames/sec
tracking
Torsion SAX and Apical TDI or 2D speckle 60–100 frames/sec
Views tracking

cycle timing information in relation to other dynamics influencing Doppler Enhanced Contrast Echocardiography
intracardiac pressure, as described in detail in Chapter 15. To
collect accurate respiratory timing information, the nasal ther- Myocardial contrast echocardiography (MCE) is an excellent
mistor must be place appropriately in the patient’s nostril tool for optimizing LV endocardial borders in technically
(Fig. 18-24). Once the thermistor is comfortably placed, the difficult cases; however, it can also be used to enhance a diastolic
sonographer should perform a practice maneuver by instructing Doppler evaluation. It is particularly helpful in improving
the patient to inhale and exhale through the nose. The sono- PV Doppler signals if the sonographer is struggling with an
grapher must observe the respiratory signal on the screen dis- examination. Because contrast is used for LV opacification (LVO),
play and adjust the gain enough to ensure that inhalation it is important to allow the contrast effect to visually dissipate in
and exhalation are recognized. He or she should then identify order to avoid Doppler signal blooming or overcompensation in
positive and negative deflections of the respiratory waveform to the Doppler spectral signal. After contrast administration, the
ensure correct interpretation. Upon completion of use, the nasal sonographer should continue with the image examination until
thermistor should be cleaned with alcohol prep pads and allowed 2D visualization of contrast effect subsides (which can take up to
to air dry. Alternatively, electrodes placed on the chest wall can 5 minutes), then proceed with the PV Doppler evaluation (Fig.
detect respiratory variation by motion of the chest wall with 18-25). In most cases, the two-dimensional contrast effect
breathing. will appear to have disappeared; however, there will still be an
 Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function 225

Base

A Apex

Figure 18-21 A, Correctly aligned versus B, incorrectly

aligned left ventricular wall segments. C, Upper panel is
an example of the color M-mode display of strain rate
values in the left ventricular (LV) septum. Lower panel rep-
resents strain rate obtained in the middle of the LV septum
(represented by the green line). Note that the S, E, and A S E A
waves appear like mirrored images of the septal tissue
velocities. If the transducer is not aligned correctly with
the LV septum, peak values of strain rate waves will be B C
decreased (represented by the yellow line).

-2 9

-9 3

-10
-5

Figure 18-22 Example of two-dimensional speckle

tracking longitudinal strain.

Figure 18-23 Example of two-dimensional speckle tracking representing all

18 segments in a bull’s-eye diagram.
226 Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function

TABLE 18-3
TO OPTIMIZE STRAIN IMAGE DATA, THE THE
FOLLOWING TECHNIQUES SHOULD BE EMPLOYED
S D
To optimize Doppler velocity Include harmonic image mode
signal, avoid reverberation Use an appropriate pulse
artifacts, and minimize signal repetition frequency to avoid
noise aliasing
Use a narrow sector to improve
spatial resolution
Ensure that the sample volume AR
tracks within the myocardium A
throughout the entire cardiac
cycle and avoid tracking the
left ventricular blood pool
To avoid underestimation Select a high frame rate (greater S
than 100 frames per second) D
To avoid angle dependence Align the axis of cardiac motion
with the scan lines
To avoid respiratory drift and Acquire strain data at end
angle changes expiration

From Marwick TH: Measurement of strain and strain rate by echocardiography: Ready
for prime time? J Am Coll Cardiol 2006;47:1313–1327. AR
B
Figure 18-25 A, A technically difficult pulmonary venous (PV) Doppler
signal. B, The improved contrast enhanced PV Doppler signals.

(Fig. 18-26). Clinically these techniques can enhance or suppress

cardiac sounds and murmurs.
LV filling patterns are known to have preload dependence and
alterations in preload indices and can be useful in detecting
increased filling pressures. Attention must be paid to the
mitral A wave, as it will increase during maneuvers due to
increased filling pressures (Fig. 18-27). Close attention should
also be given to the relationship between the Doppler and the
respiratory variation when evaluating patients with constrictive
pericarditis versus restrictive cardiomyopathy (see Chapter 24).
Reducing preload with an upright positioning maneuver should
be done if needed. If mitral E-wave respiratory variation greater
than 25% is not present in a patient with suspected constriction,
this may be secondary to a marked increase in LA pressure.
Reduction of preload, as with upright sitting positioning, may
bring out this respiratory variation.

Valsalva Maneuver
Figure 18-24 Demonstration of appropriate placement of the nasal The mitral E/A ratio alone does not differentiate normal from
thermistor, resulting in an accurate respiratory signal display that can be pseudonormal filling patterns. This is where the Valsalva maneu-
superimposed on the spectral Doppler display.
ver is indicated. It is probably the most useful maneuver and is
achieved by straining against a closed glottis for 10–15 seconds
adequate amount of contrast to enhance the Doppler signal to after deep inspiration. Intrathoracic pressure should be elevated
yield reproducible high-quality Doppler waveforms. The risks to about 40 mmHg. The Valsalva maneuver can also be particu-
and benefits of administering echo contrast must always be con- larly helpful when determining reversible from irreversible restric-
sidered and the decision to give echo contrast must be made by a tive filling patterns.
physician on a case-by-case basis.28 The Valsalva maneuver can be performed by either having the
patient blow into a tube connected to a dial sphygmomanometer
(Fig. 18-28) or by bearing down. Performed incorrectly, the
Maneuvers maneuver will result in equivocal data. It is the sonographer’s
Techniques of manipulation may be performed to aid in the responsibility to thoroughly explain the Valsalva maneuver to the
assessment of filling pressures and subsequently of diastolic func- patient and then to conduct a practice session to coach the patient
tion during an echocardiographic examination.8,13 Valsalva, pos- on how to fully participate in the maneuver with expectations of
tural changes, isometric exercise, and respiration are maneuvers full compliance. The sonographer should explain to the patient
that can be used to temporarily alter cardiac hemodynamics that prior to actually recording it he or she will first practice the
 Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function 227

Figure 18-26 Demonstration of the Valsalva effect on

heart rate, blood pressure, and left ventricular filling pres-
sures. In this example, the A wave increases in velocity
during Valsalva and returns to baseline upon release of
Valsalva. Heart rate and blood pressure return to baseline
as well.

Figure 18-27 A, Note the increasing A-wave response to the Valsalva

Figure 18-28 Example of a patient “blowing” into the sphygmomanome-
maneuver while pulsing left ventricular inflow. B, Note the relationship of
ter tube to achieve a Valsalva effect.
the E and A waves as they return to baseline peak velocities once Valsalva
effect subsides.

maneuver once or twice while the sonographer checks the “Bear down as if you were going to have a bowel movement.”
placement of the cursor and the sample volume. If using the “Push as if you were pushing a lawn mower up a big hill.”
sphygmomanometer, the patient should be instructed to exert “Simulate the act of blowing up a large balloon.”
enough forward airflow to increase the gauge to approximately
40 mmHg. The sonographer should use the following analogies The patient’s abdomen should be observed for verification of
to help the patient understand what a Valsalva maneuver should active contraction of abdominal muscles. The sonographer’s hand
feel like: should be placed on the abdomen to ensure adequacy of strain.
228 Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function

The jugular veins are examined to confirm distention of strain

phase. An adequate amount of expiratory effort is needed to cause
physiologic changes. The sonographer should strive for about a
40 mmHg change from baseline. Though not mandatory, a
manometer is most commonly used during research protocols to
document the exact measurement and change in expiratory effort
from baseline. Contraindications to performing Valsalva are
unstable angina or recent myocardial infarction, severe valvular
disease, recent transient ischemic attack or stroke, and uncon-
trolled hypertension.

Isometric Hand Exercise

Isometric exercise such as a sustained handgrip is used to increase
afterload. The patient should be instructed to squeeze rolled
towels or tennis balls simultaneously in a squeeze/release, squeeze/
release pattern and continue performing it until the maneuver
yields an adequate response. The patient should not hold his Figure 18-29 Demonstration of image evaluation during upright sitting
breath or perform Valsalva while doing isometric exercise. position maneuver.
Physiologically, the hemodynamic effects of an isometric hand-
grip are related to decreased vagal tone and increased sympathetic
tone. In a patient with normal diastolic function, performing an Postural Maneuvers
isometric handgrip causes increased heart rate, blood pressure, Postural changes, such as sitting or standing from a supine posi-
cardiac output, and venous reversal. Individual response depends tion, decrease venous reversal (Fig. 18-29). Physiologically, gravity
on the amount of exercise, baseline LV function, and baseline causes pooling in the venous beds of the legs, decreasing venous
hemodynamic state. In patients with baseline LV dysfunction, reversal. RV and LV stroke volumes also fall, causing hypoten-
isometric exercise will increase LV filling pressures. sion. This in turn causes reflex tachycardia and an increase in
vascular resistance.
Respiratory Maneuvers
Respiratory changes are divided into two categories: those that Leg Raising Maneuver
increase with inspiration due to increased venous reversal and
those that increase with expiration due to decreased lung volume. Passive leg raising is the opposite of those maneuvers described
Physiologically, during deep inspiration, intrathoracic pressure earlier in this chapter, causing increased intra-abdominal pres-
decreases, causing increased venous reversal while augmenting sure, venous reversal, stroke volume, cardiac output, and central
right-heart preload, which increases RV stroke volume. During aortic pressure (Fig. 18-30). This will cause reflex bradycardia, as
deep expiration, lung volume decreases as air leaves the lungs, and in phase IV of the Valsalva maneuver.
the heart moves closer to the thoracic wall. PV flow enters the left
atrium secondary to increased intrathoracic pressures. Vascular
resistance is not solely a result of respiration but depends on the
position of the patient. A supine position increases venous rever-
sal; a standing position decreases venous reversal; sitting or stand-
ing accentuates respiratory induced changes. Right-sided velocities
increase with inspiration, and left-sided velocities decrease with
inspiration. Ischemic heart disease and arrhythmias are contrain-
dicated for respiratory maneuvers.
As mentioned, a respirometer is a useful tool in the assessment
of timing Doppler data during the respiratory cycle to determine
respiratory induced changes. Doppler data should be recorded
during inspiration and expiration to better define the respiratory
effect on intracardiac chamber filling pressures. A respirometer is Figure 18-30 Demonstration of image evaluation during leg elevation
particularly useful in evaluating respiratory variation to help dif- maneuver.
ferentiate between constriction and restriction, for assessing peri-
cardial effusion, and for ruling out IVC plethora.
A nasal thermistor is appropriately placed, and the cable is SUMMARY AND FUTURE DIRECTIONS
connected to the respirometer port of the ultrasound system.
Some ultrasound systems incorporate a respiratory sensing device Echocardiography is the workhorse of cardiac imaging and
in the echocardiographic leads. The respirometer signal is dis- requires skillful sonographers. Echocardiography provides a diag-
played as a cine wave superimposed on the echo Doppler images. nostic examination that is noninvasive, portable, and able to be
When using a nasal thermistor, the patient is asked to breath repeated multiple times without risk to the patient while yielding
through the nose. The sonographer should always test the respi- unique functional and hemodynamic information. The cardiac
rometer by first practicing to demonstrate the inspiration and sonographer plays an extremely important role in the diagnosis
expiration signal on the screen. of diastolic heart disease. In-depth knowledge regarding cardiac
 Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function 229

hemodynamics and Doppler principles and high-quality imaging 2. Gutierrez C, Blanchard DG: Diastolic heart failure: Challenges of diagnosis
skills are required to yield useful clinical data. The growing heart and treatment. Am Fam Physician 2004;69:2609–2616.
3. Appleton CP, Jensen JL, Hatle LK, et al: Doppler evaluation of left and right
failure epidemic necessitates the demand for competent sonogra- ventricular diastolic function: A technical guide for obtaining optimal flow
phers who are a critical part of the diagnostic team. velocity recordings. J Am Soc Echocardiogr 1997:10:271–292.
Newer technology is being developed that will enhance the 4. Rosamond W, Flegal K, Friday G, et al: Heart disease and stroke statis-
information yielded from a diastolic exam, allowing for earlier tics—2007 update: A report from the American Heart Association Statis-
tics Committee and Stroke Statistics Subcommittee. Circulation 2007;115:
recognition of impaired diastolic dysfunction. Advances in imaging e69–e171.
strain, strain rate, torsion, and tissue or speckle tracking will 5. Bursi F, Weston SA, Redfield MM, et al: Systolic and diastolic heart failure
provide the sonographer with more sensitive and accurate tools; in the community. JAMA 2006;296:2209–2216.
however, this necessitates advanced levels of training and education 6. Hawkins NM, Wang D, McMurray JJ, et al: Prevalence and prognostic
and should always be consistently practiced. Formal education implications of electrocardiographic left ventricular hypertrophy in heart
failure: Evidence from the CHARM programme. Heart 2007;93:59–64.
through medical diagnostic training curricula as well as continuing 7. Galderisi M: Diastolic dysfunction and diabetic cardiomyopathy: Evalua-
education programs must include core training in diastolic heart tion by Doppler echocardiography. J Am Coll Cardiol 2006;48:
failure assessment by echocardiography. 1548–1551.
8. Oh JK, Appleton CP, Hatle LK, et al: The noninvasive assessment of left
ventricular diastolic function with two-dimensional and Doppler echocar-
ABBREVIATIONS diography. J Am Soc Echocardiogr 1997;10:246–270.
9. Appleton CP, Jensen JL, Hatle LK, et al: Doppler evaluation of left and right
ventricular diastolic function: A technical guide for obtaining optimal flow
2D two-dimensional velocity recordings. J Am Soc Echocardiogr 1997:10:271–292.
A2Ch apical 2-chamber 10. Vasan RS, Benjamin EJ: Diastolic heart failure—no time to relax. N Engl J
A4Ch apical 4-chamber Med 2001;344:56–59.
A5Ch apical 5-chamber 11. Maurer MS, Spevack D, Burkhoff D, et al: Diastolic dysfunction: Can it be
ALAX apical long axis diagnosed by Doppler echocardiography? J Am Coll Cardiol 2004;44:
1543–1549.
AoV aortic valve 12. Quiñones MA: Assessment of diastolic function. Prog Cardiovasc Dis
AR atrial reversal 2005;47:340–355.
CO cardiac output 13. Mottram PM, Marwick TH: Assessment of diastolic function: What the
CMM color M-mode general cardiologist needs to know. Heart 2005;91:681–695.
14. Garcia MJ: Comprehensive echocardiographic assessment of diastolic func-
CWD continuous wave Doppler tion. Heart Failure Clin 2006;2:163–178.
E/A LV inflow E and LV inflow A ratio 15. Oh JK, Hatle L, Tajik AJ, et al: Diastolic heart failure can be diagnosed by
EF ejection fraction comprehensive two-dimensional and Doppler echocardiography. J Am Coll
DT deceleration time Cardiol 2006;47:500–506.
HV hepatic vein 16. Lang RM, Bierig M, Devereux RB, et al: Recommendations for chamber
quantification: A report from the American Society of Echocardiography’s
HR heart rate Guidelines and Standards Committee and the Chamber Quantification
ITP intrathoracic pressure Writing Group, developed in conjunction with the European Association of
IVC inferior vena cava Echocardiography, a branch of the European Society of Cardiology. J Am
IVRT isovolumetric relaxation time Soc Echocardiogr 2005;18:1440–1463.
17. Quiñones MA, Otto CM, Stoddard M, et al: Recommendations for quan-
LA left atrial tification of Doppler echocardiography: A report from the Doppler Quan-
LV left ventricular tification Task Force of the Nomenclature and Standards Committee of the
LVH left ventricular hypertrophy American Society of Echocardiography. J Am Soc Echocardiogr 2002;15:
MV mitral valve 167–168.
MVa / PVa mitral valve A wave and pulmonary vein A wave 18. Gilman G, Nelson TA, Hansen WH, et al: Diastolic function: A sonogra-
pher’s approach to the essential echocardiographic measurements of left
ratio ventricular diastolic function. J Am Soc Echocardiogr 2007;20:199–209.
PLAX parasternal long axis 19. Garcia MJ, Thomas JD, Klein AL: New Doppler echocardiographic
PP pulse pressure applications for the study of diastolic function. J Am Coll Cardiol
PSAX parasternal short axis 1998;32:865–875.
20. Ho CY, Solomon SD: A clinician’s guide to tissue Doppler imaging. Circula-
PV pulmonary venous tion 2006;113:e396–e398.
PV S/D pulmonary vein systolic / diastolic ratio 21. Dokainish H, Sengupta R, Patel R, et al: Usefulness of right ventricular
PVs2 / PVd pulmonary vein systolic peak 2 and pulmonary tissue Doppler imaging to predict outcome in left ventricular heart failure
vein diastolic independent of left ventricular diastolic function. Am J Cardiol
PWD pulsed wave Doppler 2007;99:961–965.
22. Abraham TP, Nishimura RA: Myocardial strain: Can we finally measure
RA right atrial contractility? J Am Coll Cardiol 2001;37:731–734.
RV right ventricular 23. Marwick TH: Measurement of strain and strain rate by echocardiography:
SV sample volume Ready for prime time? J Am Coll Cardiol 2006;47:1313–1327.
SVC superior vena cava 24. Galderisi M. Can technical limitations of strain rate imaging be overtaken
by particular arrangements? J Am Coll Cardiol 2006;48:1729.
TDI tissue Doppler imaging 25. Notomi Y, Setser RM, Shiota T, et al: Assessment of left ventricular tor-
TV tricuspid valve sional deformation by Doppler tissue imaging: Validation study with tagged
VR venous reversal magnetic resonance imaging. Circulation 2005;111:1141–1147.
26. Notomi Y, Lysyansky P, Setser RM, et al: Measurement of ventricular
torsion by two-dimensional ultrasound speckle tracking imaging. J Am Coll
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1. Barker HB, Mullooly JP, Getchell W: Changing incidence and survival for imaging by echocardiography—from technical considerations to clinical
heart failure in a well-defined older population, 1970–1974 and 1990– applications. J Am Soc Echocardiogr 2007;20:234–243.
1994. Circulation 2006;113:799–804. 28. FDA online: Available at http://www.fda.gov/
 DOUGLAS S. LEE, MD, PhD
RAMACHANDRAN S. VASAN, MD, DM
19
Hypertension and Valvular
Heart Disease

INTRODUCTION PATHOPHYSIOLOGY AND CLINICAL

RELEVANCE OF DIASTOLIC DYSFUNCTION IN
PATHOPHYSIOLOGY AND CLINICAL
VALVULAR DISEASE
RELEVANCE OF DIASTOLIC DYSFUNCTION IN
Acute Aortic Insufficiency
HYPERTENSION
Chronic Aortic Insufficiency
Mechanical Considerations
Aortic Stenosis
Cellular and Molecular Bases of Left
Acute Mitral Regurgitation
Ventricular Diastolic Dysfunction in
Chronic Mitral Regurgitation
Hypertension
Mitral Stenosis
Clinical Basis of Hypertensive Heart
Disease FUTURE RESEARCH

INTRODUCTION malities, the term diastolic heart failure (DHF) has been used.1,2
In cases of heart failure on the basis of hypertension, blood pres-
Hypertension and valve disease are key risk factors for heart sure control may lead to amelioration or resolution of abnormal
failure. Uncontrolled hypertension results in left ventricular (LV) LV diastolic function, and therefore may change the natural pro-
remodeling, often with an increase in LV mass. Valve disease is gression to hypertension-associated DHF.3–6 In the case of valve
associated with pressure or volume overload of the left ventricle, disease, medical management and/or surgical correction of the
depending on its etiology. Significant valve disease is associated condition is associated with resolution of heart failure and LV
with LV remodeling, usually with LV hypertrophy (LVH). The diastolic dysfunction.
pattern of LV remodeling and its severity vary depending on the In this chapter, we discuss pathophysiologic and clinical con-
nature, severity, and chronicity of valve disease. LV remodeling is siderations in DHF due to hypertension or valvular heart disease.
a fundamental substrate for overt heart failure. Thus, an overlap Although valvular heart disease constitutes an exclusion in some
exists between the pathophysiology of LV remodeling in hyper- definitions of DHF,7 we employ a broader view by examining
tensive heart disease and severe valve disease. The hypertrophic these conditions in the context of the syndrome of heart failure
response in patients with valve disease results from the activation with preserved LV systolic function.
of biological pathways that also play a key role in the evolution of
hypertensive heart disease. LV diastolic impairment occurs in
patients with hypertension or valve disease, even in those without PATHOPHYSIOLOGY AND CLINICAL RELEVANCE
evidence of LVH or systolic dysfunction. Cases of heart failure OF DIASTOLIC DYSFUNCTION IN HYPERTENSION
due to hypertension and valve disease both frequently manifest
with a preserved LV ejection fraction.
Mechanical Considerations
When heart failure occurs in association with a normal LV Hypertension increases the load on the left ventricle, with a resul-
ejection fraction but with concomitant LV diastolic filling abnor- tant increase in LV mass (referred to as hypertrophy). The LV
233
234 Chapter 19 • Hypertension and Valvular Heart Disease

response to increased load is to normalize wall tension. According 160

to Laplace’s law, wall stress is defined by its relationship with
pressure (p), chamber radius (r), and wall thickness (h), thus:
120

LV pressure (mmHg)
Laplace’s law: Wall stress = p × r/2 × h.
To normalize wall stress in the presence of pressure overload,
LV wall thickness increases, and this concept is applicable to both 80
hypertension and valvular disease. Initially, this response to
increased wall tension occurs with thickening of the LV walls
within the “normal” range. However, progression toward an 40
abnormal increase in LV wall thickness occurs with prolonged
exposure.
The development of LVH is not only load dependent but mul- 0
tifactorial and may be influenced by endocrine, autocrine, para- 0 25 50 75 100 125 150
crine, and genetic factors. It is of interest that both blood pressure
and LV mass exhibit familial aggregation and are heritable quan- LV volume (ml)
titative traits.8–11 Additionally, familial aggregation of LV diastolic A
measures12,13 and left atrial (LA) size14 (a marker of diastolic 160
dysfunction) has also been reported, suggesting that LV diastolic
dysfunction in response to stressors such as pressure overload
may be modulated in part by genetic influences and shared envi- 120

LV pressure (mmHg)
ronmental factors.

Hypertension and Left Ventricular Mass 80

Systolic blood pressure is an important determinant of LV mass

in hypertension.15 LV mass (LVM), in grams, is calculated by 40
echocardiography using the following equation16:
LVM (g) = 1.04 × [(IVS + LVEDD + PWT)3
− LVEDD3] − 13.6, 0
0 25 50 75 100 125 150
where IVS = thickness of interventricular septum, LVEDD = LV
end diastolic dimension, and PWT = posterior wall thickness. LV volume (ml)
Indexed for body surface area, an LV mass index greater than B
131 g/m2 for men and greater than 100 g/m2 for women repre- 160
sents LVH.15 Other cutpoints for LVH have also been suggested,
indexing for height raised to a power.17–19 LVH is one of the most
common causes of isolated diastolic dysfunction and is an impor- 120
LV pressure (mmHg)

tant independent risk factor for heart failure.20–22 The patterns of

diastolic filling and its relation to LV pressure in chronic hyper-
tension are shown in Figure 19-1. Early diastolic filling abnor- 80
malities in hypertension correlate with increased LV mass.23–26
In hypertensive individuals, observed LV mass may be signifi-
cantly greater than that which is predicted based on demographic, 40
clinical, and hemodynamic factors (e.g., systolic blood pressure,
stroke volume, sex, height). For instance, de Simone et al. calcu-
lated predicted LV mass as27: 0
LVM = 39.95 + 14.61 × height (m2.7) + 0.65 × SW 0 25 50 75 100 125 150
(grams-meters/beat) − 17.17 × sex, LV volume (ml)
where male sex is assigned a value of 1 and female sex is C
assigned a value of 2. An inappropriately increased LV mass was Figure 19-1 Ventricular systolic and diastolic pressure-volume loops asso-
defined as an observed to predicted ratio of LV mass greater than ciated with heart failure (HF) with normal ejection fraction (normal condi-
tions shown in black). A, Diastolic HF that is not due to hypertensive
approximately 1.3. Such individuals, who have inappropriately etiology, with normal end systolic pressure-volume relationship (ESPVR),
increased LV mass that exceeds the compensatory needs for a an upward and left-shifted end diastolic pressure-volume relationship
given workload, have been found to exhibit further abnormalities (EDPVR), and normal or low blood pressure (red loop). B, Pressure-volume
of systolic and diastolic function. These abnormalities include loops of HF with normal ejection fraction and chronic hypertension (note
delayed LV relaxation with prolonged isovolumic relaxation time elevated blood pressure). ESPVR is elevated and EDPVR is shifted upward
and to the left (blue loop). C, Same as B, except that ESPVR is normal or
(IVRT), increased myocardial stiffness, and mild systolic near-normal and EDPVR is normal or shifted to the right (green loop). (From
dysfunction of the midwall and LV chamber (see the section Maurer J et al: Left heart failure with a normal ejection fraction: Identification
“Echocardiographic Features of Hypertensive Left Ventricular of different pathophysiologic mechanisms. J Card Failure 2005;11:177.)
Hypertrophy”).27
 Chapter 19 • Hypertension and Valvular Heart Disease 235

Regression of increased LV mass is correlated with reduction “Clinical Epidemiology of Hypertensive Heart Disease”) although
particularly in systolic blood pressure and parallels similar changes they do not always accompany hypertension.39,40 An indication
in the electrocardiogram (ECG).28 In patients with regression of that diastolic dysfunction may be present in the context of the
LVH on ECG with treatment, there is regression of LV mass.29 pressure-overloaded ventricle is the identification of LVH or an
abnormal increase in LV mass. Although diastolic filling abnor-
malities often occur when LV mass is increased, ventricular
Hypertension and Left Ventricular Geometry hypertrophy is not a requisite for LV diastolic dysfunction, which
may also occur at an earlier stage in hypertensive patients without
The effect of hypertension on LV diastolic dysfunction is also
overt LVH. Early diastolic filling abnormalities in hypertension
partly dependent on LV geometry (see the section “Echocardio-
correlate with increased LV mass.23–26 As noted previously, LVH
graphic Features of Hypertensive Left Ventricular Hypertrophy”),
is one of the most common causes of isolated LV diastolic dys-
a phenotype defined on the basis of presence versus absence of
function and is an important independent risk factor for heart
LVH, and the relative wall thickness (RWT). The RWT has
failure.20–22
been calculated as:
Myocardial fibrosis with increased interstitial collagen deposi-
RWT = 2 × PWT/LVEDD. tion is another mechanism underlying LV diastolic dysfunction
in hypertensive subjects. There is a strong relation between LV
The RWT is considered to be increased if greater than 0.42.30,31
stiffness and myocardial collagen content41,42 and plasma levels of
Alternatively, RWT has also been calculated as:
fibrosis markers43 in hypertensive persons. Improvement of LV
RWT = (IVS + PWT)/LVEDD diastolic function during antihypertensive treatment is related to
regression in myocardial collagen content.41,42 This may indicate
and is considered increased if greater than 0.45.32
that LV mass is determined mainly by loading conditions, whereas
In those without LVH, normal LV geometry is represented by
myocardial fibrosis and LV diastolic dysfunction may be the con-
normal LV mass and normal RWT, whereas concentric LV remod-
sequence of the detrimental effects of neurohormonal activation.
eling is defined by normal LV mass and increased relative wall
The hypothesis that LVH and myocardial fibrosis are regulated
thickness. Concentric remodeling represents the early adaptive
independently of each other, and to some extent of blood pres-
changes to decrease LV wall tension in response to an increase in
sure, is supported by limited experimental evidence.44–46
pressure overload. In the presence of LVH, LV geometry may be
concentric or eccentric. Concentric hypertrophy occurs when RWT
is increased and LVH is present, often in the presence of reduced
ventricular internal dimensions. Eccentric hypertrophy is charac- Left Atrial Function in Hypertension
terized by ventricular enlargement and an increase in LV mass,
Compensatory changes in the left atrium reflect functional
where wall tension is increased by virtue of an increase in radius
so that RWT is normal. changes due to LVH that occur as a result of hypertensive load.
Because the impairment in LV relaxation decreases early LV
filling, the contribution of the left atrium to ventricular filling in
later diastole increases. These changes may operate under the
Hypertensive Overload and Left Ventricular
Frank-Starling principle, to prevent marked changes in mean LA
Diastolic Dysfunction pressure that can occur with elevated LV diastolic pressure or
In hypertension, ventricular hypertrophy occurs to compensate with an increase in LA preload.47,48 Increases in LA size and sys-
for elevated wall stress and increased ventricular stiffness, and tolic force have been associated with aging, and both have been
impaired LV relaxation may ensue.33 Impairment in LV relaxation suggested as a compensatory response to age-related reduction of
decreases early LV filling, and the atrial contribution to ventricu- ventricular relaxation.49,50 LA systolic force (LASF), can be calcu-
lar filling increases. In hypertensive states, due to increased after- lated echocardiographically as:
load from vascular or valvular etiologies, increased LV chamber
LASF = 0.53 × MOA × (peak A velocity)2,
stiffness may result from an increase in myocyte hypertrophy
and/or alterations in the cardiac interstitium. An increase in LV where MOA = mitral orifice area. The degree of change in LA
stiffness or reduction in ventricular compliance results in increased size and systolic force in the pressure- or volume-overloaded
LV diastolic pressure for any degree of ventricular preload, and left ventricle is highly dependent on the degree of LV diastolic
subsequent pulmonary venous congestion with symptoms of dysfunction, reflected by an impairment of active ventricular
dyspnea. relaxation.51
In adult patients with diastolic,24 isolated systolic,25 borderline A change in LA size over time is not a feature of “normal
isolated systolic,34 and combined systolic and diastolic hyperten- aging.”52 The left atrium enlarges in response to changes in LV
sion,35 as well as in children with hypertension,36 an abnormal filling patterns that characterize abnormal LV relaxation, with a
diastolic filling pattern characterized by impaired early diastolic reduction in the emptying volume from the left atrium to the left
ventricular filling with an enhancement in late diastolic ventricle and a reduced flow from the pulmonary veins into the
filling (due to atrial systole) has been reported, indicating sub- left ventricle in early diastole.52,53 The left atrium may compensate
normal LV relaxation with normal ventricular compliance.37 A by an increase in its size, an augmentation of active contraction,
prolonged IVRT has also been demonstrated in hypertensive and an increase in late diastolic emptying.52–54 Therefore, LA size
persons.38 or volume is an indicator of LV diastolic dysfunction in patients
Possible contributing factors for the LV diastolic dysfunction without valve disease or atrial fibrillation. In one study, patients
observed in hypertensive patients include myocardial fibrosis and with an LA volume index of less than 27 ml/m2 had a similar
increased LV mass (see the sections “Cellular and Molecular Basis future risk of atrial fibrillation or heart failure as those with
of Left Ventricular Diastolic Dysfunction in Hypertension” and normal LV diastolic filling.55
236 Chapter 19 • Hypertension and Valvular Heart Disease

Impaired LA contractility arising from a loss of LA systolic alterations in the vasculature, and atherosclerotic disease.77
force or atrial arrhythmia will result in a further reduction in LV However, hypertension may increase aortic stiffness even in the
preload, a decrease in cardiac output, and increased LA pressure. absence of coronary artery disease.78 LV diastolic function in
Hypertension is associated with LA enlargement, depression of hypertension is associated with indices of aortic stiffness and may
LA contractile function, and an increased risk for atrial fibrilla- be even further increased by the coexistence of other conditions,
tion,56,57 all of which can precipitate overt heart failure in patients such as diabetes.78 Given the associations demonstrated in early
with underlying LV diastolic dysfunction.58 studies, evaluation of aortic stiffness may take on greater impor-
tance in future studies of DHF.
Evaluation of aortic stiffness includes assessment of aortic
Effect of Associated Metabolic Risk Factors on Left
strain and distensibility, which are aortic elasticity parameters and
Ventricular Diastolic Function in Hypertension can be calculated as:
The concomitant presence of other cardiovascular disease risk
Aortic strain (%) = (AoSD − AoDD) × 100/AoDD
factors can worsen the impairment of LV diastolic function in
hypertension.59 Metabolic factors such as dyslipidemia and dys- Distensibility (cm2/dyne) = 2 × aortic strain/(SBP − DBP),
glycemia may be important in this regard. Indices of LV mass and
where AoSD = aortic systolic diameter, AoDD = aortic diastolic
diastolic function have been correlated with lipid profile.60 Addi-
diameter, dyne = dynamic measurement, SBP = systolic
tionally, elevated glucose levels, insulin resistance, and hyperinsu-
blood pressure, and DBP = diastolic blood pressure.78,79 Aortic
linemia have been associated with LV diastolic dysfunction in
strain and distensibility were related positively with E/A
hypertensive patients.61–64 The development of LV diastolic dys-
ratio and inversely with deceleration time and IVRT in one
function with elevated glucose levels in persons with and without
study.78 Although other factors, such as age, sex, blood pressure,
diabetes has been reported in hypertensive patients, and even
and LVH, may also influence arterial compliance, analyses
slight elevations in fasting glucose levels have been reported to
adjusted for these variables suggest a significant independent
affect LV diastolic function.65
relationship between arterial compliance and LV diastolic
Experimental treatment interventions with thiazolidinediones
dysfunction.80
and insulin-sensitizing agents have been found to inhibit cardiac
Pulse wave velocity (PWV) is a measure of large artery stiff-
hypertrophy and improve LV diastolic function. These effects are
ness, based on the principle that PWV is inversely related to the
thought to be mediated in part by activation of the peroxisome
elasticity of the vascular wall and directly related to arterial stiff-
proliferator-activated receptor-γ (PPAR-γ).66–68 Additionally,
ness. PWV is calculated by dividing the pulse transmission time,
these treatments may decrease cardiac fibrosis by inhibiting col-
in milliseconds, typically from carotid to femoral arteries by the
lagen synthesis, mediated by a decrease in the ratio of matrix
distance traveled by the pulse wave using body surface measure-
metalloproteinases (MMPs) and tissue inhibitors of metallopro-
ments.81 The augmentation index (AI) is a manifestation of the
teinases (TIMPs).69,70
early return of the reflected wave from the periphery to the heart
during systole, when the heart is ejecting blood. Both increased
Effect of Obesity on Left Ventricular Diastolic PWV and AI increase with greater arterial stiffness and increase
Function in Hypertension cardiac afterload.
Prior studies have reported that LV concentric remodeling
Obesity may also modulate the development of LV diastolic
and hypertrophy are associated with vascular stiffness in hyper-
filling abnormalities in hypertensive patients. In a study of lean
tensive patients.82,83 Even in those with recently diagnosed
(body mass index [BMI] <25 kg/m2), overweight (BMI 26–
hypertension without evidence of LVH, there is demonstrable
29 kg/m2), and obese (BMI >30 kg/m2) persons with hyperten-
increased aortic stiffness that occurs concurrently with the pres-
sion, LV mass itself and LV mass indexed to height increased
ence of LV diastolic dysfunction.84 Aortic stiffness is associated
progressively with higher BMI.71,72 The LA diameter, which
not only with indices of LV diastolic dysfunction, but with the
reflects LA diastolic filling abnormalities, is also significantly
occurrence of heart failure with normal LV ejection fraction.85
increased in obese individuals.72 An increasing trend of E-wave
Despite what we have discussed, it is not known whether these
deceleration time and IVRT with increasing BMI has been
findings indicate a causal mechanistic link between DHF and
observed, and the E/A ratio was significantly lower in overweight
vascular stiffness or simply the coexistence of systemic changes in
and obese versus lean hypertensive individuals.71 When those
hypertension.
with normal and abnormal LV diastolic function were compared,
A number of potential mechanisms link aortic stiffness in
the major differences were older age and higher LV mass in the
hypertensive patients with diastolic dysfunction (Fig. 19-2)80:
latter group.71
1. It is possible that increased aortic stiffness may increase
afterload, resulting in LV changes, including ventricular
Aortic Stiffness and Left Ventricular Diastolic
hypertrophy and delayed LV relaxation.86
Dysfunction in Hypertension 2. Increased vascular stiffness is associated with a higher
Among hypertensive patients, aortic stiffness has been identified velocity of transmission of the pulse wave ejected by the
as a predictor of cardiovascular mortality and all-cause death.73 left ventricle, and early return of reflected waves may
Aortic stiffness has been closely linked with DHF in hyperten- augment the amplitude of the central aortic pressure wave.
sion and may contribute to the pathophysiology and progression This would further increase LV afterload and central pulse
of diastolic dysfunction: Patients with DHF have stiff, large arter- pressure.87
ies and increased blood pressure lability.74–76 Mechanisms of 3. The reduction in central aortic diastolic pressure may also
increased aortic stiffness in hypertension include hemodynamic reduce coronary perfusion, which, coupled with ventricu-
stress caused by high pressure in the arterial walls, structural lar hypertrophy, may increase subendocardial ischemia.
 Chapter 19 • Hypertension and Valvular Heart Disease 237

Aortic stiffening hormonal factors also contribute to LV diastolic dysfunction.

Angiotensin II acts via the angiotensin II type 1 (AT1) receptor
to stimulate myocardial atrial natriuretic peptide (ANP) gene
expression, endothelin (ET-1) production, and collagen accumu-
lation. Angiotensin converting enzyme (ACE) inhibitors and
↑ Central aortic SBP ↓ Central aortic DBP
angiotensin receptor blockers reduce DHF, presumably partly via
the inhibition of this mechanism.103 Blockade of the AT1 receptor
may improve LV diastolic function by a decrease in myocardial
↑ LV afterload ↓ Coronary perfusion
stiffness, an increase in SERCA expression, promotion of phos-
phorylation of phospholamban, and attenuation of the prolonga-
tion of Tau (τ, the time constant of LV relaxation).104,105
Myocyte hypertrophy Subendocardial ischemia
A number of other prohypertrophic factors may contribute to
the development of LV diastolic dysfunction. Pathways that may
alter LV hypertrophic remodeling include guanosine 3′,5′-cyclic
Impaired relaxation Myocardial fibrosis
monophosphate (cGMP) and phosphodiesterase-5A (PDE5A)
signaling.106,107 Sildenafil, an inhibitor of cGMP catabolism and
a PDE5A inhibitor, prevented the development of myocyte
Diastolic dysfunction
and cardiac hypertrophy and reversed preexisting hypertrophy
Figure 19-2 Pathophysiological pathways through which aortic stiffness in an animal model.108 The ET-1 pathway may also contribute
may contribute to the development of diastolic dysfunction. DBP, diastolic to the pathogenesis of LV diastolic dysfunction and DHF. The
blood pressure; SBP, systolic blood pressure. (From Mottram et al: Relation ETA receptor mediated an increase in myocardial stiffness in
of arterial stiffness to diastolic dysfunction in hypertensive heart disease. Heart
2005;91:1551.) hypertensive animal models,109 and upregulation of myocardial
ET-1 is present in hypertrophied ventricles that transition
to progressive LV diastolic dysfunction.110 Signaling pathways
The association of arterial stiffness and LV diastolic dysfunc- activated in hypertension include members of the mitogen-
tion may also be modulated by sex, since there may be differential activated protein kinase (MAPK) superfamily (the p38 MAPK,
degrees of concentric remodeling with increased afterload in the extracellular regulated kinases [ERK] and c-Jun kinases), the
women versus men and a higher prevalence of DHF in women.88,89 gp130 family (the JAK/STAT pathway), and the calcineurin
In a large community-based study, age and female sex were associ- pathway.111
ated with the vascular elastance index (Ea) normalized to body The transition from compensated LVH to heart failure occurs
surface area,90 calculated as: by remodeling processes, which may involve myocardial fibrosis,
Ea = Pes/SV, myocyte degeneration, autophagic cell death, oncosis, an increase
in length, and reduction in cross-sectional area.112,113 Abnormal
where Pes = end systolic pressure and SV = stroke volume.91 collagen deposition and accumulation may contribute to increased
Similar associations were observed for age, female sex, and LV LV stiffness in DHF. These interstitial changes are mediated by
diastolic elastance (Ed),90 calculated as: excessive collagen synthesis and an increase in the ratio of type I
Ed = E/E′, to type III collagen subtypes.104,114 In patients with hypertension,
greater turnover of type III collagen was associated with increased
where, E = early mitral inflow diastolic filling velocity and E′ = LV mass and impairment of diastolic function.115 DHF is associ-
mitral annular early diastolic velocity measured by tissue ated with reduced TIMP gene expression and increased MMP-2
Doppler.92–94 It was speculated that the ventricular-vascular stiff- and MMP-9 activity.116 In patients with hypertension, circulating
ening profiles may contribute to DHF.90 TIMP-1 levels correlated with indices of LV diastolic filling,
Genetic and environmental factors may also influence the including E′, which is an indicator of load-independent early
development of aortic stiffness. Arterial stiffness is increased in diastolic relaxation and ventricular wall movement in early
those with a parental history of essential hypertension95 and also diastole.117
varies according to race.96 Polymorphism of the GNB3 gene,
which encodes the G protein β3 subunit, has been associated
with increased PWV and AI.97 Although regular resistance and Clinical Basis of Hypertensive Heart Disease
aerobic exercise programs do not affect PWV,98 a regimen of
intensive, long-term blood pressure control may decrease arterial Epidemiology
stiffness.99 Hypertension is a prevalent condition with significant implica-
tions for the development of heart failure. Data from the Fram-
Cellular and Molecular Bases of Left Ventricular ingham Heart Study found that hypertension often preceded the
onset of heart failure in those in the third to sixth decades of
Diastolic Dysfunction in Hypertension life.118 Since the incidence of hypertension and heart failure both
A number of cellular processes regulate or affect LV diastolic increase with age, the coexistence of these conditions in later years
function. In myocytes, relaxation of the ventricle is dependent on may be of even greater importance.119 In a study of the transition
calcium (Ca2+) traffic that is influenced by the activity of sarco- from hypertension to congestive heart failure, hypertension was
plasmic/endoplasmic reticulum Ca2+-ATPase (SERCA2) and its present in 91% of new heart failure cases.120 The risk of heart
regulator, phospholamban.100,101 Dephosphorylation of phosphol- failure was increased twofold in men and threefold in women, and
amban reduces SERCA2 activity, resulting in impaired relaxation, the population attributable risk associated with hypertension was
and in contrast, phosphorylation has a lusitropic effect.102 Neuro- 39% in men and 59% in women.120 Survival after the onset of
238 Chapter 19 • Hypertension and Valvular Heart Disease

hypertensive heart failure was poor, with only 24% of men and in E-wave deceleration time, an increase in IVRT, and an increase
31% of women surviving 5 years.120 in the ratio of the magnitude of motion due to atrial systole rela-
A common precursor of DHF is a condition referred to as tive to total diastolic atrioventricular plane displacement (AV-
hypertensive hypertrophic cardiomyopathy of the elderly.121 This term LA/AV-mean) (Fig. 19-3A).135
refers to elderly patients who frequently are female, have systolic Measures of LV wall thickness (including interventricular wall
hypertension, and present with marked ventricular hypertrophy, thickness and posterior wall thickness), relative wall thickness,
a supernormal LV ejection fraction, and a propensity for develop- and blood pressure are inversely associated with LV diastolic
ing pulmonary edema. function, independent of blood pressure. Thus, the E/A ratio and
the IVRT exhibit a linear pattern of correlation with blood pres-
sure, interventricular septum thickness, relative wall thickness,
Clinical Presentation
and LV mass index (see Fig. 19-3B).135 Stepwise regression analy-
Diastolic dysfunction due to hypertension may be asymptomatic, sis of the determinants of LV diastolic function suggests that age,
may manifest as exercise intolerance, or may present acutely with systolic blood pressure, heart rate, and relative wall thickness are
the clinical syndrome of decompensated heart failure with pre- significant predictors of both the E/A ratio and the E-wave decel-
served LV ejection fraction. Thus, LV diastolic dysfunction that eration time, with model R2 of 0.43 and 0.23, respectively. Among
occurs in concert with hypertension and associated LVH may these factors, age and systolic blood pressure explain most of the
have an insidious course. Some hypertensive persons with LVH variation in E/A ratio and E-wave deceleration time. Predictors
are asymptomatic under resting conditions but may experience of IVRT are relative wall thickness, systolic blood pressure, and
exertional dyspnea due to a relative inability to augment their LV age, in decreasing order of importance (model R2 0.22).135
end diastolic volume upon exercise.122 The decreased cardiac In addition to the effects of LV mass, LV geometry also has
output arising from LV diastolic filling abnormalities may result an effect on ventricular diastolic function, as noted previously.
in symptoms of “fatigue.” There may be a slow progression of Hypertensive patients with concentric LVH manifest echocardio-
exercise intolerance, and finally rest symptoms may develop.123 At graphically with a lower transmitral peak E velocity, prolonged E
the other end of the spectrum, some patients present with severe deceleration, increased IVRT, and an increase in LA size and
uncontrolled hypertension and acute pulmonary edema, which systolic force, in comparison with those with a normal LV geom-
can be reversed by lowering blood pressure.124,125 Clinically, it is etry.136–138 In contrast, those with eccentric LV geometry have
difficult to reliably distinguish acute decompensated heart failure different diastolic properties—in particular, an attenuation of the
on the basis of LV diastolic dysfunction from primarily systolic delay in LV relaxation.49 In eccentric LV geometry, the association
heart failure.126,127 The pathophysiologic bases for these abnor- with abnormal LA structure and function is also attenuated,
malities are (1) the increased left-sided filling pressures arising as further suggesting that LA changes are a reflection of impaired
a result of impaired LV relaxation and (2) subsequent pulmonary LV filling in myocardial hypertrophic states.
interstitial edema. LV diastolic filling abnormalities (e.g., prolonged IVRT and
Patients may also present with evidence of myocardial ischemic E deceleration time, lower E/A ratio) are also associated with
symptoms, which may or may not be associated with significant greater propensity to a reduction in midwall fractional shortening,
epicardial coronary stenosis. In patients with hypertension and a subtle abnormality of ventricular contractile function.139,140
LVH, an increase in wall tension decreases subendocardial perfu-
sion. Therefore, patients with hypertensive heart failure may Limitations of Mitral Inflow Parameters
develop ischemic symptoms in the presence of normal epicardial Although the most common method for evaluation of diastolic
coronary arteries on angiography.128 It is highly likely that patients function in hypertension is derived from transmitral flow veloci-
with hypertensive LV diastolic dysfunction may also develop ties using pulsed-wave (PW) Doppler echocardiography, there
ischemic symptoms from epicardial coronary artery disease, are a number of potential limitations to this approach. The E/A
particularly in the setting of an adverse coronary risk profile, since ratio, which is widely adopted as an index of diastolic function, is
hypertension is an important component of atherosclerotic subject to “pseudonormalization” with increasing age.141 Addition-
disease risk. ally, mitral inflow parameters are dependent on changes in preload,
afterload, and contractility. Interpretation of transmitral flow may
be aided by information obtained from pulmonary venous flow
Echocardiographic Features of Hypertensive
velocities. The normal pulmonary venous flow consists of forward
Left Ventricular Hypertrophy flow during systole (S wave) and diastole (D wave) and retrograde
Mitral Inflow Parameters flow during atrial systole (AR). The S/D pulmonary venous flow
The diastolic properties of the left ventricle are often estimated velocity ratio is increased in isolated relaxation abnormality con-
in clinical practice by Doppler indices of early and late peak flow ditions and is decreased, together with increased retrograde flow,
velocities, the latter representing atrial contraction. In hyperten- during atrial contraction (AR) as LV diastolic compliance abnor-
sive LVH, the ratio of early to late peak flow velocities (E/A ratio) malities advance.142 PW tissue Doppler imaging (TDI) measured
is reduced as the LV relaxation phase is prolonged.129,130 The E/A in the myocardium and at the mitral annulus in systole and dias-
ratio in the hypertensive condition is a reflection of LV active tole may be a better method to identify load-independent changes
relaxation, myocardial passive stiffness, and LA work needed for in LV relaxation. These TDI measures correlate with τ, the time
diastolic LV filling.131–134 constant of isovolumic relaxation; and early studies suggest that
Hypertensive patients have their diastolic function significantly the early (Em) and late (Am) tissue Doppler waves at the mitral
influenced by the presence of LVH compared with such patients annulus may change directionally in response to antihypertensive
without increased LV mass and compared with normotensive treatment.143 The Em/Am ratio, a global TDI index of diastolic
patients. In hypertensive patients with LVH in particular, there dysfunction, tracked with the reduction in LV mass that
is a decrease in E/A ratio of mitral inflow velocities, an increase occurred with ACE inhibitor therapy in hypertensive patients.143,144
 Chapter 19 • Hypertension and Valvular Heart Disease 239
***
1.8 **
***
1.8 *
1.4

E/A ratio
1.4

E/A ratio
1.0

1.0
0.6
*
* 0.6
300
**

E-dec (msec)
300
250

E-dec (msec)
Figure 19-3 A, Evaluation of left ventric- 250
ular (LV) diastolic function in normoten- 200
sives (NT, n = 38), hypertensive patients 200
without LV hypertrophy (HT without LVH, 150
n = 38), and hypertensive patients with LV
hypertrophy (HT with LVH, n = 114). E/A 150
150 ***
ratio, ratio of peak early (E) and peak of ***
IVRT (msec)

late (A) mitral inflow velocities; E-dec, E- 150 *

wave deceleration time; IVRT, isovolumic 130

IVRT (msec)
relaxation time; AV-LA/AV-mean, ratio of 130
the magnitude of motion due to atrial 110
systole to the total diastolic atrioventricu-
lar plane displacement. Mean and stan- 110
90
dard deviations are shown. *p < 0.05,
**p < 0.01, ***p < 0.001. B, Evaluation
AV-LA/AV-mean (%)

0.65 90
*
of LV diastolic function in those with ***
normal geometry (normal, n = 63), LV 0.55
0.65 *
remodeling (LV remod, n = 13), eccentric

AV-LA/AV-
mean (%)
LV hypertrophy (Ecc LVH, n = 47), and con- 0.55
0.45
centric LV hypertrophy (Conc LVH, n = 64).
(From Muller-Brunotte R et al: Blood pres- 0.45
sure and left ventricular geometric pattern 0.35
determine diastolic function in hypertensive 0.35
myocardial hypertrophy. J Hum Hypertens NT HT without HT with
2003;17:841–849.) A LVH LVH B Normal LV remod Ecc LVH Conc LVH

Color M-mode Doppler echocardiography, which evaluates all pressure correlate with the beneficial effects of hypertension
velocities along a scan line aligned with mitral inflow, may also be treatment.151
used to supplement information from transmitral filling pat-
terns.145 The velocity of flow propagation (Vp) into the left ven- Reduction of Cardiac Fibrosis
tricle can be determined by the slope of the color wave front. A Cardiac fibrosis in hypertensive patients has been identified as
left ventricle with normal relaxation demonstrates rapid flow a potential contributor to LV stiffness. ACE inhibitors and AT
propagation, whereas a slowly relaxing ventricle is associated with II receptor antagonists may regress myocardial fibrosis and
blunted flow propagation. decrease LV stiffness in hypertension.152,153 Aldosterone antago-
nism also has a prominent effect on inhibiting cardiac fibrosis,
which improves diastolic function and decreases LV stiffness.154
Effects of Treatment Aldosterone antagonism also may improve subtle abnormalities
Hypertension Treatment in systolic function that may be present in hypertensive patients
Hypertension is a key risk factor for the development of car- with preserved ejection fractions (>50%) and diastolic dysfunc-
diovascular disease. Studies have found that systolic blood pres- tion, including increases in strain rate, peak systolic strain, and
sure and pulse pressure, which are both highly correlated, are cyclic variation of integrated backscatter.154
major predictors of heart failure.146–149 By comparison, diastolic
blood pressure was not found to be a risk factor for future
heart failure. In the Systolic Hypertension in the Elderly PATHOPHYSIOLOGY AND CLINICAL
Program (SHEP), which was designed to reduce blood pressure RELEVANCE OF DIASTOLIC DYSFUNCTION IN
in those with systolic hypertension, one of the major cardiovas- VALVULAR DISEASE
cular endpoints was the reduction of heart failure events.150 Treat-
ment of hypertension has been shown in multiple randomized Valvular heart disease may contribute to the syndrome of heart
trials to reduce cardiovascular events irrespective of age at treat- failure with preserved systolic function. However, it is important
ment initiation.151 Reduction in systolic blood pressure has been to delineate with patient history, physical examination, and cardiac
proposed as the primary mechanism by which these benefits imaging studies whether the syndrome is attributable to severe or
occur, since neither the change nor the achieved diastolic blood to symptomatic valvular disease, since the management principles
240 Chapter 19 • Hypertension and Valvular Heart Disease

differ. One of the primary differences is the potential for surgical Infective endocarditis or a structurally compromised native or
correction of valve disease, which can alleviate the underlying prosthetic aortic valve is a common underlying etiology for acute
structural cause of heart failure. The natural history of severe aortic insufficiency. Medical therapy targeted at the underlying
aortic or mitral valve lesions has been well described, and a wide condition, such as treatment with antibiotics, may be required.
array of surgical options is available. Other medical therapies are generally temporizing measures, and
It is recognized that DHF has been defined by an absence of emergency surgery is often required. Vasodilators may unload the
significant valvular heart disease.7 It is also relatively uncommon left ventricle to increase forward flow but may compromise dia-
as an underlying etiology for the syndrome of heart failure with stolic coronary perfusion. Pressor agents that increase blood pres-
preserved LV function. In elderly patients, aged 65 years and sure by increasing peripheral vasoconstriction may worsen the
older, who were hospitalized for heart failure and met the degree of aortic regurgitation. Avoidance of bradycardia may also
Framingham diagnostic criteria for congestive heart failure, less decrease aortic runoff time and ameliorate acute aortic insuffi-
than 10% with preserved systolic function had severe aortic or ciency. The intra-aortic balloon pump is contraindicated because
mitral valvular disease.155 However, the left-sided valvular lesions it may exacerbate the degree of aortic insufficiency.
largely share features of LV diastolic dysfunction and/or hyper-
trophy with hypertensive DHF and therefore merit discussion in
this chapter alongside the topic of hypertension. Chronic Aortic Insufficiency
We will here describe the features of left-sided valvular disease Chronic aortic insufficiency is often observed clinically in the
as they pertain to heart failure syndromes with potential for dia- context of LV enlargement and eccentric hypertrophy. Chronic
stolic dysfunction. We have limited the scope of this section to a volume overload results in increases in myocyte length and LV
discussion of the more commonly occurring conditions of acute volume, thereby accommodating the increased regurgitant volume.
or chronic regurgitation or stenosis of the mitral and aortic Despite larger end diastolic volumes, LV compliance remains
valves. normal, so that LV end diastolic pressure is not elevated. The
increased stroke volume accompanied by an increase in systolic
force, via the Frank-Starling mechanism, results in an elevation of
Acute Aortic Insufficiency systolic blood pressure and a widened pulse pressure. The filling
Acute aortic insufficiency may be the underlying cause in some pressures in chronic aortic insufficiency are decreased, and there-
cases of heart failure with preserved systolic function. Unlike fore pulmonary congestive symptoms may be minimal to none.
chronic aortic insufficiency, where the ventricle may undergo As LV dilation progresses, the ventricle operates on a higher
enlargement and eccentric hypertrophy, the left ventricle does segment of the pressure-volume curve, with minimal symptom-
not have the opportunity to accommodate a sudden increase atic burden.
in preload from the regurgitant volume. Therefore, the widened In chronic aortic insufficiency, there may be elevated afterload;
pulse pressure and the myriad of signs and symptoms of and in response to increased wall tension, there may be initial con-
chronic aortic insufficiency are not present in the acute setting. centric followed by eccentric hypertrophy.156,157 The concentric
Instead, there is an increase in LV end diastolic pressure and a hypertrophy that develops may have an adverse effect on LV dia-
decrease in forward cardiac output and stroke volume; conse- stolic function, which could result in development of congestive
quently, a drop in blood pressure may be observed. In acute aortic symptoms.158 The adverse effect of increased afterload in chronic
insufficiency, the left ventricle operates at the high end of the severe aortic regurgitation is illustrated by the association of
pressure-volume relationship (Fig. 19-4C). In the setting of acute systolic hypertension (defined as a systolic blood pressure
aortic insufficiency, overt pulmonary edema may be partly attenu- >140 mmHg) with increased risk of cardiovascular events, includ-
ated by preclosure of the mitral valve, which occurs due to the ing heart failure onset.159,160 The adverse effects of systolic hyper-
regurgitant jet and increase in LV pressures during the diastolic tension in aortic regurgitation remained even after accounting for
filling phase. other risk factors, including age, gender, diastolic blood pressure,

SYSTOLIC DYSFUNCTION NORMAL DIASTOLIC DYSFUNCTION

Pressure

Pressure

Pressure

Figure 19-4 Left ventricular pressure-volume loops in sys-

tolic and diastolic dysfunction. A, In systolic dysfunction, LV
contractility is depressed, the end systolic pressure-volume
relationship (ESPVR) is displaced downward and to the right
(black arrow), and the end diastolic pressure is normal (open
arrow). B, Normal left ventricular pressure-volume loop. C, In
diastolic dysfunction, the diastolic pressure-volume relation-
ship is shifted upward and to the left (black arrow), there
Left ventricular Left ventricular Left ventricular
is diminished capacity to fill at low left atrial pressures,
volume volume volume
and the end diastolic pressure is elevated (open arrow). (From
A B C Aurigemma G: Diastolic heart failure. NEJM 2004;351:1097.)
 Chapter 19 • Hypertension and Valvular Heart Disease 241

LV diastolic dimension, and LV ejection fraction at rest.160 Changes small and the effective orifice area large. Although significant
in the extracellular matrix may engender an increase in LV stiffness regression of LV mass may be realized with such surgical proce-
that is observable in chronic aortic insufficiency as well.161 dures, incomplete reversal of LVH may occur, particularly in
Treatment for chronic aortic insufficiency may require surgery. patients with elevated blood pressure, smokers, and those with
The primary management issue is the timing of surgical interven- high presurgical LV mass index at baseline.174
tion, which is influenced by the natural history of the condition, The abnormalities of LV diastolic dysfunction that were present
prevention of often irreversible myocardial damage, and technical in aortic stenosis may also be reversed after surgical relief of val-
considerations at surgery. In relatively asymptomatic individuals vular obstruction, but this may occur over a period of years after
with preserved LV ejection fraction, nifedipine delayed time to the procedure. Reduction in LV diastolic stiffness and normaliza-
surgery, which was indicated on the basis of symptoms or LV tion of relaxation are accompanied by reduction of interstitial
systolic dysfunction.162 However, there are relatively few trials of fibrosis.175
medical therapy in this condition. Once symptoms develop, surgi-
cal therapy is generally indicated, because prognosis worsens dra-
matically after symptom onset.163 Undue delay of surgery once Acute Mitral Regurgitation
symptoms have developed may lead to worsened LV function and Acute mitral regurgitation may also present as heart failure with
poor surgical outcome. preserved systolic function. In acute mitral regurgitation, there is
acute volume overload of the left atrium and left ventricle, which
have not accommodated to the regurgitant volume by chamber
Aortic Stenosis enlargement. As a result of mitral regurgitation, forward cardiac
Hemodynamically significant aortic valve obstruction increases output is also reduced, resulting in the potential for lowered sys-
LV pressure and increases the LV work to eject blood out of the temic blood pressure and an increase in peripheral resistance,
narrowed valve. By Laplace’s law, an increase in ventricular pres- which may further increase regurgitation. There is an acute rise
sure leads to an increase in LV wall thickness to maintain wall in LA and LV diastolic pressures, leading to pulmonary conges-
stress. However, ventricular hypertrophy leads to LV diastolic tion. The ejection fraction may be supranormal because of the
filling abnormalities and increased chamber stiffness, resulting in increased stretch of ventricular myocytes arising from an increase
the need for increased filling pressure to attain any given ventricu- in LV volume.
lar volume when compared with the nonhypertrophied state. In acute mitral regurgitation, medical therapy with arterial
Ventricular hypertrophy in chronic aortic stenosis may also be vasodilators may decrease afterload and also diminish regurgitant
accompanied by subendocardial ischemia. Chronically, ongoing volume.176 However, hypotension may be present, limiting the use
aortic valve obstruction leads to a decline in LV systolic and dia- of vasodilators, and in some cases, an intra-aortic balloon pump
stolic function and potentially a reduction in the transaortic valve may be required as a bridge to surgical repair of the structurally
gradient, due to reduced LV ejection fraction. Patients with aortic abnormal mitral valve. The intra-aortic balloon pump may
valvular stenosis frequently present with heart failure symptoms decrease afterload while maintaining mean arterial blood pressure
with a normal LV ejection fraction, suggesting an important role in such cases. In acute, severe mitral regurgitation due to a flail
of diastolic dysfunction in the pathogenesis of the symptoms.164 leaflet, mortality rate was high with medical therapy and markedly
In the pressure-overloaded heart of aortic stenosis, myocardial increased in those who even transiently had New York Heart
fibrosis occurs, and there are increased levels of enzymes that Association class III or IV symptoms. Surgical correction was
reflect greater collagen deposition.165,166 In aortic stenosis, there is associated with a significant reduction in mortality rate.177 In
an increase in collagen synthesis relative to collagen degradation, asymptomatic individuals with perhaps less severe degrees of
procollagen endopeptidase, and lysine and proline hydroxylases, mitral regurgitation, the best management strategy is not eluci-
compared with controls without valve disease.167 Expression of dated. Uncorrected mitral regurgitation may lead to eccentric
TIMPs and MMPs are increased in patients with aortic stenosis hypertrophy with progressive chamber enlargement and a decrease
compared with controls, and increased TIMP/MMP ratios have in LV ejection fraction, which may render later surgical correction
been noted in humans.167 Increased TIMPs can stimulate fibro- untenable. There may also be an increased risk of sudden death
blast growth and may have a direct stimulatory effect on collagen in such individuals.178,179
production by cardiac fibroblasts.168,169
As noted previously, the diastolic dysfunction in hypertensive
LVH and chronic aortic stenosis are parallel in many aspects. Chronic Mitral Regurgitation
However, one very important difference is the impact of surgical In chronic, severe mitral regurgitation, there is an increase in
intervention on LV systolic and diastolic function. Aortic valve ventricular preload that over time may lead to the development
surgery relieves LV pressure overload and decreases afterload. In of eccentric hypertrophy. Enlargement of the LV chamber and
patients with systolic dysfunction due to severe aortic stenosis increased wall thickness are accompanied by LA enlargement.
without concomitant cardiomyopathy, LV ejection fraction may Initially, chronic mitral regurgitation is compensated by chamber
return to normal. enlargement, and the patient may be asymptomatic. LV diastolic
In patients with dominant aortic stenosis, replacement of the function is altered in chronic mitral regurgitation: Early diastolic
aortic valve has been demonstrated to decrease LV mass.170,171 In filling is enhanced, τ remains unchanged, but chamber stiffness
dominant aortic insufficiency, aortic valve surgery decreases both decreases.180–182 The enhanced diastolic function returns to
LV dimension and mass.172 The beneficial effects of surgery may normal after mitral valve replacement.182 The major clinical issue
be measurable as early as one week after the procedure.173 The is deciding whether surgical intervention is required, while sys-
degree of reverse LV remodeling after aortic valve replacement is tolic function is still relatively preserved and ventricular dilation
partly dependent on the type of valve employed. In the case of the is minimized. A regurgitant fraction of 40%–50% may be an
pulmonary autograft or Ross procedure, the relative stenosis is indication that surgery will ultimately be required, since mitral
242 Chapter 19 • Hypertension and Valvular Heart Disease

valve repair that can reduce this fraction to less than 35% reversed LV diastolic dysfunction or progresses to systolic heart failure
myocardial dysfunction in an animal model.183 have not been described adequately.
Once symptoms develop, even if mild, the prognosis of mitral The primary treatment strategy for diastolic dysfunction in
regurgitation worsens.177 Additionally, if LV ejection fraction hypertensive patients is blood pressure control. However, the sig-
decreases below 60% or if the LV end diastolic dimension is nificant degree of cardiac fibrosis in DHF may present a thera-
greater than 45 mm, there is worsened prognosis,184,185 and peutic target to improve LV diastolic dysfunction. Whether LV
surgery is warranted. Valve repair or replacement should be per- diastolic dysfunction and stiffness can be reversed significantly,
formed, and ideally the former is the preferred procedure because and whether this translates into a clinical effect (such as reduced
preservation of the subvalvular apparatus improves LV ejection symptom burden or improved outcome), may provide valuable
fraction and decreases the likelihood of development of symp- insights. Valvular heart diseases with a significant component of
tomatic heart failure postoperatively.186–189 cardiac fibrosis may also represent a potential therapeutic target
of antifibrotic regimens. Ultimately, the clinical effectiveness of
such novel therapies targeted toward decreasing ventricular stiff-
Mitral Stenosis ness will need to be tested in controlled clinical trials.
More study is required in the longitudinal follow-up of pre-
Mitral stenosis causes pulmonary congestion by inhibiting filling
clinical hypertrophic states with evidence of LV diastolic dysfunc-
of the left ventricle across the stenosed orifice. LA and pulmonary
tion but without overt heart failure. It is known that once the
venous pressures become elevated, and cardiac filling and output
initial onset of heart failure has occurred, the prognostic outlook
are decreased. Subsequently, pulmonary hypertension may
is grim. Greater efforts are needed to study these patients and
develop. Factors affecting LV filling in mitral stenosis are an
possibly prevent DHF. One area of investigation may be in the
increased pulmonary driving pressure and elevated LA pressure.
setting of LVH and LV diastolic dysfunction, whether
Intrinsic LV diastolic dysfunction, therefore, does not contribute
“how” blood pressure is reduced is more important than the “mag-
to this syndrome of heart failure with preserved LV function.
nitude” of blood pressure reduction. For example, would drugs
Medical management consists primarily of diuretics and slowing
that target putative myoproliferative pathways (e.g., ACE inhibi-
of heart rate, to maximize the period available for diastolic LV
tors, angiotensin receptor blockers) be better preventatively than
filling. Surgical intervention with mitral balloon valvulotomy or
antihypertensive agents that are not pathophysiologically specific?
valve replacement may be required if symptoms are uncontrolled
Additionally, it is unknown whether different degrees of diastolic
by medical management.
dysfunction at baseline should be treated differently. Specifically,
it is unknown whether more severe degrees of diastolic dysfunc-
tion in hypertensive patients should be treated more aggressively
FUTURE RESEARCH using multimodality drug therapy. It is also unknown how such
patients should be followed longitudinally. To this end, echocar-
Investigations into the role of hypertension in DHF should diography and other imaging studies can identify the presence
include studies of pathophysiology, longitudinal analyses, and of LV diastolic dysfunction, but whether these modalities can
treatment. The relative importance of risk factors and prognostic be used serially to assess progress over time has not been
factors for systolic and diastolic heart failure is also not elucidated. determined.
It is unknown, for example, whether hypertension is more (or
equally) important for the development of diastolic versus systolic
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on myocardial dysfunction in hypertensive patients with diastolic heart 173. Djavidani B, Schmid FX, Keyser A, et al: Early regression of left ventricular
failure. Circulation 2004;110:558–565. hypertrophy after aortic valve replacement by the Ross procedure detected
155. Pedersen F, Raymond I, Mehlsen J, et al: Prevalence of diastolic dysfunction by cine MRI. J Cardiovasc Magn Reson 2004;6:1–8.
as a possible cause of dyspnea in the elderly. Am J Med 2005;118:25–31. 174. Duebener LF, Stierle U, Erasmi A, et al: Ross procedure and left ventricular
156. Wisenbaugh T, Spann JF, Carabello BA: Differences in myocardial perfor- mass regression. Circulation 2005;112:I415–I422.
mance and load between patients with similar amounts of chronic aortic 175. Villari B, Vassalli G, Monrad ES, et al: Normalization of diastolic dysfunc-
versus chronic mitral regurgitation. J Am Coll Cardiol 1984;3:916–923. tion in aortic stenosis late after valve replacement. Circulation 1995;91:
157. Taniguchi K, Nakano S, Kawashima Y, et al: Left ventricular ejection per- 2353–2358.
formance, wall stress, and contractile state in aortic regurgitation before and 176. Yoran C, Yellin EL, Becker RM, et al: Mechanism of reduction of
after aortic valve replacement. Circulation 1990;82:798–807. mitral regurgitation with vasodilator therapy. Am J Cardiol 1979;43:
158. Feiring AJ, Rumberger JA: Ultrafast computed tomography analysis of 773–777.
regional radius-to-wall thickness ratios in normal and volume-overloaded 177. Ling LH, Enriquez-Sarano M, Seward JB, et al: Clinical outcome of mitral
human left ventricle. Circulation 1992;85:1423–1432. regurgitation due to flail leaflet. N Engl J Med 1996;335:1417–1423.
159. Spagnuolo M, Kloth H, Taranta A, et al: Natural history of rheumatic aortic 178. Grigioni F, Enriquez-Sarano M, Ling LH, et al: Sudden death in
regurgitation. Criteria predictive of death, congestive heart failure, and mitral regurgitation due to flail leaflet. J Am Coll Cardiol 1999;34:2078–
angina in young patients. Circulation 1971;44:368–380. 2085.
160. Supino PG, Borer JS, Herrold EM, et al: Prognostic impact of systolic 179. Carabello BA: Sudden death in mitral regurgitation: Why was I so sur-
hypertension on asymptomatic patients with chronic severe aortic regurgita- prised? J Am Coll Cardiol 1999;34:2086–2087.
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2005;96:964–970. properties in chronic mitral regurgitation. Circulation 1991;83:797–
161. Borer JS, Truter SL, Herrold EM, et al: The cellular and molecular basis of 807.
heart failure in regurgitant valvular diseases: The myocardial extracellular 181. Zile MR, Tomita M, Nakano K, et al: Effects of left ventricular volume
matrix as a building block for future therapy. Adv Cardiol 2002;39:7–14. overload produced by mitral regurgitation on diastolic function. Am J
162. Scognamiglio R, Rahimtoola SH, Fasoli G, et al: Nifedipine in asymptom- Physiol 1991;261:H1471–H1480.
atic patients with severe aortic regurgitation and normal left ventricular 182. Zile MR, Tomita M, Ishihara K, et al: Changes in diastolic function during
function. N Engl J Med 1994;331:689–694. development and correction of chronic LV volume overload produced by
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tion in women. Contrasting indications and outcomes compared with men. 183. Nagatsu M, Ishihara K, Zile MR, et al: The effects of complete versus
Circulation 1996;94:2472–2478. incomplete mitral valve repair in experimental mitral regurgitation. J Thorac
164. Dineen E, Brent BN: Aortic valve stenosis: Comparison of patients with to those Cardiovasc Surg 1994;107:416–423.
without chronic congestive heart failure. Am J Cardiol 1986;57:419–422. 184. Enriquez-Sarano M, Tajik AJ, Schaff HV, et al: Echocardiographic predic-
165. Krayenbuehl HP, Hess OM, Monrad ES, et al: Left ventricular myocardial tion of survival after surgical correction of organic mitral regurgitation.
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valve replacement. Circulation 1989;79:744–755. 185. Wisenbaugh T, Skudicky D, Sareli P: Prediction of outcome after valve
166. Villari B, Campbell SE, Hess OM, et al: Influence of collagen network on replacement for rheumatic mitral regurgitation in the era of chordal preser-
left ventricular systolic and diastolic function in aortic valve disease. J Am vation. Circulation 1994;89:191–197.
Coll Cardiol 1993;22:1477–1484. 186. Enriquez-Sarano M, Schaff HV, Orszulak TA, et al: Valve repair improves
167. Heymans S, Schroen B, Vermeersch P, et al: Increased cardiac expression of the outcome of surgery for mitral regurgitation. A multivariate analysis.
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168. Visse R, Nagase H: Matrix metalloproteinases and tissue inhibitors of tion. Mechanisms for differences in postoperative ejection performance.
metalloproteinases: Structure, function, and biochemistry. Circ Res 2003; Circulation 1992;86:1718–1726.
92:827–839. 188. David TE, Uden DE, Strauss HD: The importance of the mitral apparatus
169. Lovelock JD, Baker AH, Gao F, et al: Heterogeneous effects of tissue inhibi- in left ventricular function after correction of mitral regurgitation. Circula-
tors of matrix metalloproteinases on cardiac fibroblasts. Am J Physiol Heart tion 1983;68:II76–II82.
Circ Physiol 2005;288:H461–H468. 189. Sarris GE, Cahill PD, Hansen DE, et al: Restoration of left ventricular sys-
170. Monrad ES, Hess OM, Murakami T, et al: Time course of regression of tolic performance after reattachment of the mitral chordae tendineae. The
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1988;77:1345–1355. 1988;95:969–979.
 HSUAN-HUNG CHUANG, MBBS
FILIPPOS TRIPOSKIADIS, MD
RANDALL C. STARLING, MD, MPH
20
Dilated Cardiomyopathy
and Cardiac
Transplantation

INTRODUCTION Diastolic Dysfunction in Dilated

Cardiomyopathy
PATHOPHYSIOLOGY
Prognostic Significance of Right Ventricular
Diastolic Dysfunction in Dilated
Diastolic Dysfunction in Dilated
Cardiomyopathy
Cardiomyopathy
Diastolic Dysfunction in the Transplanted
Impact on Treatment Strategies in Dilated
Heart
Cardiomyopathy
CLINICAL RELEVANCE
FUTURE RESEARCH
Prognostic Significance of Left Ventricular

INTRODUCTION Blacks and males have a 2.5-fold increase in risk compared with
Caucasians and females. The natural history of DCM is often
Dilated cardiomyopathy (DCM) is a heterogeneous disease of progressive, and the clinical picture at the time of diagnosis can
the myocardium that is characterized by left ventricular (LV) or vary widely, with the most common initial manifestation being
biventricular dilatation and systolic dysfunction. In the classifica- HF in 75% to 85% of patients.6–8 Echocardiography plays an
tion of the World Health Organization/International Society essential role in the diagnosis and the follow-up of DCM. A
and Federation of Cardiology Task Force, DCM in its primary portion of patients fortunately experience recovery of function
(e.g., idiopathic, familial) and secondary forms (most commonly and “reverse remodeling,” which can be documented with serial
ischemic, hypertensive, valvular, alcohol-related, or viral or auto- echocardiographic examinations.
immune in origin) is the most common cause of the clinical syn-
drome of heart failure (HF).1 Familial DCM accounts for
approximately 20% to 35% of DCM cases and has been linked to PATHOPHYSIOLOGY
a diverse group of loci and genes.2
The reported annual incidence of the primary form of DCM
Diastolic Dysfunction in Dilated Cardiomyopathy
varies between five and eight cases per 100,000 population3,4; true In patients with DCM, there are abnormalities in the LV systolic
incidence is likely underestimated, since many asymptomatic pressure-volume (P-V) relationship, which are almost always
cases remain unrecognized. Primary DCM can occur at any age associated with changes in the diastolic portion of that relation-
but is first seen mostly between the ages of 20 and 50 years.5,6 ship. Indeed, nearly all patients with systolic dysfunction have
247
248 Chapter 20 • Dilated Cardiomyopathy and Cardiac Transplantation

impaired relaxation and variable decreases in ventricular compli- below approximately 30%.15 To maintain cardiac output, relax-
ances.9 LV diastolic dysfunction may lead to an increase in LV ation begins to prolong, becomes more afterload dependent, and
diastolic pressure and greatly influence the symptomatic status eventually leads to elevation in LV end diastolic pressure
and outcome of patients.10 Despite improved treatment, the mor- (LVEDP).16 Thus, while the diastolic P-V relationship may reflect
tality rate in DCM remains high, accounting for 10,000 deaths a more compliant chamber, the other abnormal diastolic indices
annually in the United States.3 support the conclusion that all patients with systolic HF and ele-
Diastolic function has traditionally been evaluated by cardiac vated diastolic pressures in fact have combined systolic and dia-
catheterization with direct measurement of filling pressures and stolic HF (Fig. 20-1).10 Alternatively, some patients may have only
relaxation. This invasive approach, describing LV filling pressures, a modest decrease in LV EF and a modest increase in end diastolic
compliance, and relaxation as major determinants of LV diastolic volume, but a marked increase in LVEDP and a diastolic P-V
function, is neither feasible nor suitable for routine evaluation. relationship, reflecting decreased chamber compliance. Conversely,
The development and validation of several noninvasive Doppler improvement in systolic function following treatment often leads
echocardiographic techniques that are relatively load independent to concomitant improvement in relaxation, especially if these
have made echocardiography the clinical standard for the assess- changes are mediated through the β-adrenergic pathways.
ment of LV diastolic function.
Echocardiographic Indices of Left Ventricular
Pathomorphology and Pathogenesis of Diastolic Dysfunction
Dilated Cardiomyopathy
Abnormal ventricular contractility and dilatation are the hall-
DCM is heterogeneous in its morphology. Common to the whole marks of DCM. Although DCM is usually a diffuse process, LV
group is a poorly contracting dilated LV with a normal or reduced dysfunction can exist independently of concomitant right ven-
LV wall thickness. The lack of an increase in LV wall thickness tricular (RV) involvement in some patients. The early opening of
often masks a significant increase in LV mass. The histological mitral valve leaflets on M-mode echocardiography (the so-called
changes are variable and nonspecific, including (a) increased C-hump) may reflect a high LVEDP. A large body of literature
myocyte diameter and nuclear size, (b) myofibrillary loss, (c) focal has accrued describing the various Doppler echocardiographic
myocyte apoptosis and death, (d) increase in interstitial T- techniques in assessment of diastolic function. These techniques
lymphocytes/macrophages, and (e) interstitial fibrosis.11 can be used alone or in combination, but most of them are depen-
The pathogenesis of DCM remains uncertain despite intense dent on heart rate, preload, and afterload. The LV filling or trans-
research. Four basic mechanisms have been hypothesized, includ- mitral flow pattern remains the starting point. The pulmonary
ing familial and genetic factors, chronic viral infection of the myo- venous flow signal should always be sought as an adjunct to the
cardium and other cytotoxic insults, immune abnormalities mitral inflow pattern. These have been described in great detail
leading to cellular and humorally mediated myocyte damage, and in Chapters 2, 10, and 18. Briefly, most patients can be categorized
metabolic, energetic, and contractile abnormalities.12,13 With the into one of the three patterns based on the following Doppler
onset of failure of the heart’s intrinsic mechanisms for sustaining indices and timing (Fig. 20-2):
a reasonable ejection fraction (EF) (e.g., contractile protein and
❒ Impaired relaxation (IR) pattern. Intracardiac pressures are
excitation-contraction coupling mechanisms, cellular remodeling,
bioenergetics), the cardiac remodeling process gradually becomes unaffected, but less effective suction from LV relaxation
maladaptive. This is compounded by the effects of endogenous results in a delayed and diminished left atrial (LA)-to-LV
bioactive chemicals (e.g., hormones, neurotransmitters, cytokines) early diastolic pressure gradient. This is characterized by
and cell loss via myocyte apoptosis or necrosis compounds, which long isovolumic relaxation time (IVRT), prolonged decel-
alter the expression of genes regulating contractility, contributing eration time (DT) of the early diastolic E wave, a high late
to the progressive myocardial dysfunction in DCM. diastolic A-wave velocity, and a decreased E/A ratio.
❒ Pseudonormal (PN) pattern. Increased LA pressure offsets
the reduced flow related to impaired relaxation. Trans-
Diastolic Dysfunction and mitral flow pattern appears normal in terms of E/A ratio
the Pressure-Volume Relationship and DT.
❒ Restrictive filling (RF) pattern. LV distensibility is reduced
In patients with DCM and systolic HF, the abnormalities in the
P-V relationship occur during systole, including decreased LV EF, because of increased intrinsic stiffness or decreased operat-
stroke volume, and stroke work. As diastolic function is critically ing compliance, and LA pressure is increased. The elevated
important to systolic function and is linked to it symbiotically, LA pressure results in an increased E velocity. The decrease
virtually all patients with symptomatic HF have abnormalities in in mid-to-late diastolic distensibility produces a more rapid
diastolic function. Conversely, as diastolic function worsens and transmitral pressure equilibration, creating a “dip-and-
filling pressures increase, systolic function is affected by the Frank- plateau” effect. This is characterized by short IVRT, high
Starling mechanism. This is often called the “yin and yang” of E velocity and short DT, and reduced A velocity. This
cardiac function. Ventricular diastole involves the complex inter- pattern can be further stratified into “reversible” and “irre-
play of numerous components, including LV relaxation, diastolic versible” subgroups with loading manipulations, resulting
suction, stiffness or compliance of the myocardium, pericardial in incremental prognostic value.17,18
restraint, ventricular interaction, and atrial contribution.14 LV Because the majority of patients with DCM are studied while
relaxation is related to the time constant of intracavitary pressure on medications, drug effects must also be considered. A study
decay during isovolumic relaxation, whereas LV compliance and by Makhoul et al.19 demonstrated a direct relationship between
stiffness are related more to the local slope of the diastolic P-V changes in pulmonary capillary wedge pressure (PCWP) induced
curve. LV relaxation remains relatively intact until LV EF falls by intravenous isosorbide dinitrate and the transmitral E/A ratio.
 Chapter 20 • Dilated Cardiomyopathy and Cardiac Transplantation 249

LV PRESSURE-VOLUME LOOP
LV PRESSURE-VOLUME LOOP

LV pressure (mmHg)
LV pressure (mmHg)

LV pressure (ml/m2) LV volume (ml/m2)

Normal
Combined systolic and
Normal diastolic HF NYHA class III–IV
Systolic HF NYHA class III–IV Combined systolic and
Systolic HF following treatment diastolic HF after treatment
A B
Figure 20-1 Pressure-volume (P-V) loops in A, systolic heart failure (HF) and B, combined systolic and diastolic HF. A normal left ventricular (LV) P-V loop
is shown on the left side of the curve (red loop). Systolic HF manifests as an increase in LV end diastolic volume and a reduction in stroke volume. LV end
diastolic pressure (LVEDP) is increased. As a result, the diastolic portion of the curve simply shifts to the right, along the same P-V relationship (green loop).
This returns to an intermediate state following treatment (blue loop). In panel B, illustrating combined diastolic and systolic HF, the LVEDP is elevated.
Owing to a decrease in LV distensibility, whereby a higher diastolic pressure is necessary to achieve the same diastolic volume, there is a significant upward
shift of the diastolic P-V relationship. This is in contrast to pure diastolic HF, where there is only an upward shift in P-V relationship, but no change in LV
end diastolic volume. (Modified from Zile MR et al: New concepts in diastolic dysfunction and diastolic heart failure: Part I. Diagnosis, prognosis, and measure-
ments of diastolic function. Circ 2002;105:1387–1393.)

Diastolic Normal Mild DD Moderate DD Severe DD

Function Normal Impaired relaxation Pseudonormal Reversible restrictive Fixed restrictive
E
A
Mitral inflow

E
Mitral inflow A
after Valsalva

Sa
DTI mitral
annulus
Aa
Ea

Pulmonary S E
venous flow

LV relaxation Normal Impaired Impaired Impaired Impaired

LV compliance Normal Normal to ↓ ↓↓ ↓↓↓ ↓↓↓↓
Atrial pressure Normal Normal ↑↑ ↑↑↑ ↑↑↑↑
Tau ↑ ↑ ↑↑ ↑↑↑

Figure 20-2 Doppler parameters in progressive diastolic dysfunction. DD, diastolic dysfunction; TDI, tissue Doppler imaging; LV, left ventricle; E, early
diastolic velocity (cm/sec); A, late diastolic velocity (cm/sec); Sa, myocardial systolic velocity (cm/sec); Ea, myocardial early diastolic velocity (cm/sec);
Aa, myocardial late diastolic velocity. (Modified from Redfield MM et al: Burden of systolic and diastolic ventricular dysfunction in the community: Appreciating
the scope of the heart failure epidemic. JAMA 2003;289:194–202.)
250 Chapter 20 • Dilated Cardiomyopathy and Cardiac Transplantation

The initial high E/A ratio, typical of the RF pattern, was reduced Reported positive and negative predictive values for E/Vp
by more than 50% after administration of nitrates in nearly all greater than 1.5 to predict PCWP greater than 12 mmHg were
patients with New York Heart Association class IV HF. In addi- 93% and 70%, respectively. Correlation between E/Vp and
tion to analysis of filling pattern, the mean LA pressure (MLAP) PCWP outperformed correlations with maximal E and E/A,
may be accurately predicted from the DT of the pulmonary independent of LV EF (see Chapter 11).
venous diastolic (DTD) flow slope, using the following regression
equation20:
Tissue Doppler Imaging
MLAP = 53.236 − [0.302 DTD] + [0.000484 (DTD2)].
Early diastolic LV longitudinal expansion, as represented by mitral
Other echocardiographic indices of diastolic function pertain- annular velocity (Ea), and late diastolic mitral annular velocity (Aa)
ing to DCM include rate of LV pressure decline, the Tei index, correspond fairly to the E and A waves on mitral inflow. Although
color kinesis, and flow propagation velocity (Vp). Ea has been suggested as being less load sensitive than mitral inflow
variables, this remains debatable.36,37 Ea is often reduced to less than
Rate of LV Pressure Decline 8 cm/sec in the RF pattern. Blunting of the magnitude of Ea cor-
This can be obtained by tracing the deceleration phase of the relates closely with diastolic dysfunction established invasively.36
mitral regurgitation Doppler spectral signal and applying the Tissue Doppler imaging (TDI) may even be of value in the pres-
Bernoulli equation to obtain the instantaneous pressure gradient ence of atrial fibrillation, where there is no A wave.
between the left ventricle and the left atrium. This derivative of The ratio of transmitral peak inflow E velocity to Ea has also
Tau (τ) from the velocity curve, validated in human studies as a been shown to correlate significantly with invasively derived mean
standard for assessment of active relaxation, is not applicable to PCWP using a regression equation,
those cases of DCM without a complete mitral regurgitant
envelope. Mean PCWP = 1.24 (E/Ea) + 1.9 (mmHg),
The Tei Index and shows better correlation with LVEDP (r = 0.87) than do
This is a combined myocardial performance index (isovolumic other Doppler variables38,39 (see Chapter 12). As a general clinical
contraction time plus IVRT divided by ejection time) that may guideline, an E/Ea ratio greater than 10 is predictive of a mean
be more effective for analysis of global cardiac dysfunction than PCWP above 15 mmHg with a sensitivity and specificity of 92%
for systolic and diastolic measures alone. Although it may be a and 80%, respectively. The interval between the onset of mitral E
sensitive indicator of overall cardiac dysfunction in patients with and annular Ea by TDI (TE–Ea) has also been used to estimate
mild to moderate HF,21 it has variable prognostic significance in LV filling pressure and correlate with τ.40 It has been proposed
both adults and children with DCM22–24 (see Chapter 16). that PCWP is closely related to IVRT/TE–Ea. In fact, IVRT/
TE–Ea less than 2 was found to have a sensitivity of 91% and a
Color Kinesis specificity of 89% for detecting PCWP greater than 15 mmHg
Color kinesis is an echocardiographic technique based on acous- in other disease states.41 However, the cutoff limit for this index
tic quantification that allows color encoding of endocardial motion in DCM requires further evaluation.
in real time.25–27 The regional LV filling properties can be derived Finally, it is noteworthy that TDI may reveal subtle abnormali-
from segmental analysis of diastolic color kinesis images. Increased ties of systolic and diastolic function in asymptomatic relatives of
diastolic asynchrony has been found in patients with DCM and patients with familial DCM with LV enlargement and preserved
severe mitral regurgitation, which are known to adversely affect LV EF and therefore may help predict those who will go on to
global diastolic function.28–30 However, this technique is dependent develop clinical DCM.41
on the quality of two-dimensional images and may be affected by
significant cardiac translation and/or rotation.
Diastolic Dysfunction in the Transplanted Heart
Flow Propagation Velocity
With advances in surgical techniques and immunosuppression,
This method offers a glance at different intrinsic LV properties
the survival rate following orthotropic heart transplantation
that determine LV filling, such as geometry and LV synchrony.
(OHT) significantly exceeds that of medical therapy for advanced
The color M-mode velocity propagation of early diastolic flow
HF. However, the transplanted heart does not provide the recipi-
correlates with intraventricular pressure gradients and has been
ent with normal cardiac function, as posttransplant cardiac physi-
proposed as a load-independent indicator of LV diastolic func-
ology and hemodynamics differ significantly from those in healthy
tion. Brun et al. were the first to show that Vp is related to
subjects. Despite anticipated 1- and 5-year survival rates of 90%
LV relaxation.31 The progressive decrease of Vp runs in parallel
and 70%, respectively, acute and chronic allograft rejections have
with the increase of τ, irrespective of rising filling pressure.32 It is
remained major determinants of patient outcome. Other impor-
therefore free of pseudonormalization, unlike transmitral flow.
tant perioperative issues are persistently elevated pulmonary
Compared with the brisk Vp in normal patients, there is often
hypertension and RV dysfunction. As acute rejection is initially
significantly delayed propagation and prolongation of the dura-
asymptomatic, regular rejection surveillance is obligatory. For
tion of inflow in patients with DCM.33 In fact, continuous apical
detecting allograft rejection and monitoring immunosuppressive
flow can be visualized in 25% of DCM. The ratio of E/Vp is
treatment, clinical and laboratory examinations, along with endo-
a widely used index in the estimation of filling pressure. Coelho
myocardial biopsies (EMBs), are conducted following a predeter-
et al. found that in patients with severe LV dysfunction, Vp cor-
mined time schedule.
related closely with E/A ratio, IVRT, DT, and the Tei index.34 In
Despite the inherent limitations and complications associated
a heterogeneous group comprising normal, ischemic, and dilated
with biopsy, current noninvasive surveillance methods, though
hearts,35 PCWP was calculated as:
preferable, have yet to match EMBs in terms of sensitivity and
PCWP = [5.27 × E/Vp] + 4.6 (mmHg). specificity. These limitations have fueled the continuing challenge
 Chapter 20 • Dilated Cardiomyopathy and Cardiac Transplantation 251

to develop noninvasive methods to detect acute rejection and to integral part of long-term follow-up. Changes in myocardial
monitor response to therapy. Serial echocardiography, with each structure caused by rejection-induced edema, lymphocyte infiltra-
individual patient serving as his or her own control, appears to be tion, increased mass, and myocardial necrosis have been shown to
most promising. compromise myocyte function, resulting in increased myocardial
stiffness and abnormal relaxation.66–68 With mild or even early
rejection, two-dimensional echocardiographic changes are subtle
Surgical Techniques and Physiology of
and are not accurate or reproducible enough. Pathophysiologi-
the Transplanted Heart cally, rejection-induced myocardial edema manifested by an echo-
It is important to recognize the expected anatomical and physio- cardiographically discernible increase in wall thickness is a rather
logical changes of a transplanted heart. For more than 30 years, late event. During episodes of rejection, restrictive physiology of
OHT has been performed mostly with biatrial anastomoses, a the allograft becomes more prominent.
technique first described by Lower and Shumway.42,43 Using this Commonly cited Doppler changes in acute rejection include (1)
technique, systemic and pulmonary venous communications decreased pressure half-time of the early diastolic E wave, (2)
between the donor and recipient hearts are simplified with biatrial decreased IVRT, and (3) increased E velocity. Using the patient as
anastomoses. The downside of this technique includes enlarge- his or her own baseline, a significant change—defined as greater
ment of the atria with abnormal geometry; asynchronous contrac- than 20% for E velocity and greater than 15% for pressure half-time
tion of the donor and recipient atria with alteration in ventricular or IVRT—is fairly consistent with rejection.67,69 Valantine et al.
filling; tendency for thrombus formation, arrhythmias, and con- evaluated 64 patients undergoing hemodynamic and Doppler echo-
duction disturbances in 10%–30% of patients; and residual atrio- cardiographic studies as part of the routine follow-up 1–13 years
ventricular valve regurgitation.44–47 More recently, bicaval and after OHT.70 Ten patients were found to have strikingly abnormal
total techniques to improve cardiac anatomy, physiology, and (restrictive) transmitral flow patterns. This group had a higher inci-
postoperative outcome have gained popularity.48 The bicaval tech- dence of rejection as the only identifiable clinical difference. RF
nique consists of complete excision of the recipient atria and pattern was associated with impaired systolic performance, and
direct anastomoses of the left and right pulmonary veins and the there was correlation between transtricuspid (RV IVRT) and
inferior and superior vena cavae.49 This technique reconstitutes transmitral (LV IVRT) flow patterns and degree of rejection.
atrial geometry with the theoretical advantage of preserving atrial Barba et al. studied 56 OHT recipients 6 weeks postopera-
contractility and reduction in valvular regurgitation.50 There is tively and found that during acute rejection, LV wall thickness
also less sinus node dysfunction and reduced need for chronic significantly increased compared with negative biopsies, while
pacemaker post-OHT. IVRT and pressure half-time significantly decreased.71 However,
Immediately after OHT, the heart is relatively noncompliant, the increase in mitral E velocity was significantly associated with
with significantly elevated filling pressures and abnormal LV iso- only severe rejection. The progressive shortening of IVRT as a
volumic relaxation.51,52 The early postoperative noncompliance is marker of graft rejection showed a high sensitivity (85%) and low
attributed to factors such as ischemic myocardial injury, high specificity (57%). In another prospective study, Berwing et al.
peripheral vascular resistance, denervation, donor-recipient size reported that parameters of systolic function such as percent frac-
mismatch, interaction between donor and recipient atria, allo- tional shortening and systolic wall thickness of the posterior wall
graft rejection, preexistent recipient pulmonary hypertension, remained without significant changes at moderate (grade 2) and
and volume overload.53–57 Long-term studies of OHT recipients severe (grade 3) rejections.72 The same is valid for relaxation
suggest that these hemodynamics remain mildly abnormal parameters such as maximum velocity of posterior wall reduction
months after the procedure,58,59 while others with an initial RF (in terms of peak thinning rate [PTR]), the time interval of end
pattern may become nonrestrictive in the first 6 weeks after OHT.60 systole to maximum velocity of posterior wall reduction (tES-
Young et al. showed that abnormal PCWP and right atrial (RA) PTR), and IVRT. Although LV filling parameters such as mitral
and pulmonary artery pressures improved markedly during the E velocity increased significantly from 73.3 + 15.2 cm/sec in the
fourth to eighth weeks.61 The average PCWP was 19 mmHg rejection-free interval (grade 0) to 103.9 + 15.0 cm/sec at grade
immediately after OHT and improved to 12 mmHg at 4–8 weeks. 2 rejection and 101.1 + 9.2 cm/sec at grade 3 rejection, these
In contrast, Greenberg et al. demonstrated that LV filling pressures parameters are too insensitive to diagnose or exclude a moderate
improved but never completely normalized.58 At 1 year after OHT, or severe acute rejection in the individual case. Analyses of trans-
PCWP and RA and pulmonary artery pressures were elevated in mitral Doppler and pulmonary venous flow velocity have not lived
comparison with age-matched controls. Likewise, Valantine et al. up to their promise to detect rejection-related diastolic dysfunc-
found that up to 15% of patients exhibited restrictive physiology at tion for two main reasons. Firstly, transmitral Doppler indices are
6 years post-OHT.62 The functional significance is that although influenced by variables other than ventricular diastolic function,
the exercise capacity of OHT recipients usually improves in com- such as age, heart rate, and, most importantly, ventricular loading
parison with their pretransplant status, this is only about 60%– conditions.73 Pulmonary venous flow velocities are particularly
70% of that found in healthy subjects.63,64 The LVEDP during variable, even in individuals without heart disease. Secondly,
exercise is often normal or elevated in comparison with control denervation of the transplanted heart, with its lack of autonomic
subjects, suggestive of a leftward shift of the P-V curve, which is regulation and the usual sinus tachycardia, leads to a form of RF
consistent with diastolic dysfunction.65 filling pattern that amounts to diastolic dysfunction in the absence
of acute rejection.74
TDI and Vp measurements appear promising in allowing earlier
Alterations in Diastolic Function During
and more accurate detection of LV dysfunction in the transplanted
Allograft Rejection heart. Derumeaux et al. found values for sensitivity and specificity
The noninvasive evaluation of the transplanted heart, particularly of 92% using mitral annular Ea velocity during mild or moderate
echocardiographic measures of diastolic function, has become an and severe rejection.75 With increasing rejection grade, Ea decreased
252 Chapter 20 • Dilated Cardiomyopathy and Cardiac Transplantation

significantly. Puleo et al. tested 121 OHT recipients who under- ficient to predict symptoms, exercise tolerance, or outcome or to
went TDI at the time of EMB surveillance.68 These investigators identify those who may benefit the most from OHT, particularly
found a significant decrease in mitral annular Ea at the inferior wall when the LV EF falls under 25%.81–85 Combination of available
during moderate allograft rejection but no change in peak systolic clinical, laboratory, hemodynamic, electrophysiological, and func-
velocity in comparison with nonrejecting allograft recipients, with tional parameters for each individual may more accurately predict
a sensitivity of 76% and a specificity of 88%. survival.86–88 Doppler-derived diastolic abnormalities have shown
In 78 OHT recipients (among whom 75 histological analyses additional prognostic values.89–93
revealed no significant rejection), Mankad et al. found a reduction An RF filling pattern is common in patients (37%–58%) with
in posterior wall peak systolic and diastolic velocity gradients with DCM and is associated with elevated LVEDP and PCWP, more
rejection, as well as a reduction in mitral annular systolic Sa and atrioventricular valvular regurgitation and symptoms, and mark-
diastolic Ea velocities, with a sensitivity of 93% and a specificity edly depressed biventricular systolic function.86,89–91,94–96 Studies
of 71%.76 Dandel et al. also reported that in all patients with acute by Xie et al. and Werner et al. have shown the RF pattern to
rejection, a significant reduction in Ea velocity was obtained from predict a higher mortality rate in patients with systolic dysfunc-
the basal LV posterior wall in the short axis. They suggested that tion.89,92 Both series found that patients with a DT less than
absence of such a change could practically exclude acute trans- 140 msec and an E/A ratio greater than 2.0 had a 2-year survival
plant rejection. In 91.7% of cases, the pulsed Doppler findings rate of approximately 50%, compared with those without this
reverted completely during antirejection therapy within 65 pattern, who had a survival rate of greater than 90%. This was
hours.77 Stengel et al. found that late diastolic mitral annular Aa independent of the degree of mitral regurgitation, often found in
velocity and mitral annular systolic Sa velocity were higher in these DCM patients. Whalley et al. attempted to further distin-
patients with rejection grade less than 3A compared with those guish the prognostic implication of the PN filling pattern in 115
of 3A or greater (Aa, 8.8 cm/sec vs. 7.7 cm/sec; Sa, 19.3 cm/sec HF patients with mixed etiologies.97 The one-year follow-up
vs. 9.3 cm/sec). Sensitivity and specificity of Aa less than 8.7 cm/ results showed that (1) all-cause mortality in RF, PN, and IR
sec in predicting significant allograft rejection were 82% and 53%, patterns was 37.5%, 23.4%, and 17.4%, respectively; (2) hospital
respectively.78 Unlike findings in other studies, neither early dia- readmission for HF in the three patterns was 40.7%, 30.9%,
stolic mitral annular Ea velocity nor Vp was associated with the and 15.2%, respectively; and (3) death/HF hospital readmission
histological degree of allograft rejection, though there was a trend was 62.9%, 47.6%, and 26.1%, respectively. These data are
toward lower Ea values during episodes of rejection. Although an consistent with the notion that the PN pattern reflects a less
Aa velocity can reliably exclude severe rejection, the fact that the advanced disease state compared with the RF pattern in the con-
best threshold of an Aa velocity less than 9 cm/sec falsely detected tinuum of diastolic dysfunction. Dini et al. reported that the dif-
rejection in almost 50% of cases indicates that it is not specific ference in duration of pulmonary venous flow and mitral flow at
enough and that the pathophysiological problem of restriction to atrial contraction (ARd-Ad) provided an incremental prognostic
allograft LV filling impairs the reliability of any tool assessing value to predict outcome in HF patients.98 The index of ARd-Ad
diastolic function during the early rejection process. has been shown to directly reflect LVEDP.99 They found that
In our own series at the Cleveland Clinic, Sun et al. noted that patients with a nonrestrictive pattern and ARd-Ad greater than
in pericardial effusion, with IVRT less than 90 msec and mitral 30 msec had an intermediate prognosis between patients with a
inflow E/A ratio greater than 1.7, the diameter of the inferior restrictive pattern (worse) and those with a nonrestrictive pattern
vena cava and the duration of pulmonary venous reversal were and ARd-Ad less than 30 msec (better) in terms of survival and
independently associated with rejection by multivariate analysis. event rates.
However, no single predictor or combination of predictors was Exercise tolerance is often reduced in DCM, and resting
powerful enough to eliminate surveillance EMB.79 PCWP as well as resting LA volume and systolic function cor-
Palka et al. analyzed TDI-derived early diastolic indices of LV relate with and influence peak oxygen consumption (VO2)
and RV function.80 They found that significant differences in the and exercise capacity.39,100–102 Abnormal ventilatory response has
late isovolumic relaxation myocardial velocity gradient, as well as been shown to correlate with M-mode IVRT. Studies by
differences in timing between onsets of mitral E and mitral Vanoverschelde et al. and Xie et al. have demonstrated a clear
annular Ea waves and between mitral and tricuspid annular Ea, relationship between LV filling pattern and functional class.91,103
might help identification of those with acute rejection, with a Patients with increased transmitral E wave or shortened DT, or
sensitivity and specificity greater than 0.80. They attributed these both, had poorer treadmill performance compared with those
differences to altered early diastolic untwisting of the oblique LV who had an IR pattern. This is consistent with the notion that
fibers and the delay in early diastolic RV relaxation. More refined the RF pattern represents increased preload and abnormal LV
approaches to ultrasonic tissue characterization appear promis- compliance. Hansen et al. evaluated the incremental value of
ing, since they may detect interstitial edema early in the course transmitral flow patterns to peak VO2, as obtained by cardiopul-
of rejection. Preferential adherence of intercellular adhesion monary exercise testing, in determining the prognosis of patients
molecule-1–targeted microbubbles may also offer a noninvasive with systolic dysfunction (LV EF <40%).104 In this study of 311
imaging technique for detection of acute rejection that may be consecutive patients (of which 223 had DCM) evaluated for
characterized by endothelial dysfunction. OHT, independent predictors of mortality were transmitral flow
pattern, peak VO2, and LV end diastolic diameters. In patients
with an RF pattern, peak VO2 was lower (13.2 ± 4.2 ml/min/kg)
CLINICAL RELEVANCE than in those without an RF pattern (16.6 ± 5.8 ml/min/kg,
Prognostic Significance of Left Ventricular p < 0.0001). In patients with peak VO2 less than 14 ml/min/kg
body weight, the outcome was markedly poorer in the presence
Diastolic Dysfunction in Dilated Cardiomyopathy of the RF pattern compared with its absence (2-year survival rate,
Although the overall prognosis of DCM patients is most clearly 52% vs. 80%). Similarly, despite peak VO2 greater than 14 ml/
related to the severity of LV systolic dysfunction, it alone is insuf- min/kg, the outcome was less favorable in the presence of the RF
 Chapter 20 • Dilated Cardiomyopathy and Cardiac Transplantation 253

pattern (2-year survival rate, 80% vs. 94%) (Fig. 20-3). The sever- E-wave velocity.105 In contrast, mitral annular Aa velocity corre-
ity of diastolic dysfunction is thus closely related to survival. lated significantly with peak VO2, whereas transmitral A velocity
However, one must keep in mind that even though the RF did not reflect exercise capacity. Aa velocity might be a better
pattern has prognostic value, there is substantial overlap of filling marker of LA function, reflecting the adaptive capacity of the left
indices between survivors and nonsurvivors. Although Doppler- atrium to compensate for increased diastolic volume and LV
derived diastolic function may have important prognostic infor- filling pressures.
mation for the patient groups as a whole, it may not be applicable
to an individual patient. Others have attempted to use TDI data
to predict exercise capacity, though results have been conflicting, Prognostic Significance of Right Ventricular
possibly related to different patient subsets and treatment strate- Diastolic Dysfunction in Dilated Cardiomyopathy
gies. Some have found that mitral annular Ea velocity was not
The presence of RV dilatation and systolic dysfunction is known
better at predicting exercise capacity than was conventional
to significantly worsen the prognosis of patients with DCM,
and several echocardiographic RV systolic parameters, such as
tricuspid annular plane systolic excursion (TAPSE) less than
100 14 and peak systolic tricuspid annular velocity (Sa) less than
10.8 cm/sec, have been shown to possess independent prognostic
80 Non-RFP power106–109 (see Chapter 14). RV diastolic dysfunction is also
common, but less is known about its prognostic impact.110,111 The
Total peak early diastolic velocity (EaTri) and peak late velocity (AaTri)
Survival (%)

60 of the tricuspid annulus, as well as their ratio EaTri /AaTri, may be

RFP used. Significant decrease in EaTri and EaTri /AaTri were found in
disease states including DCM.111 These velocities are also depen-
40 dent on age112 and RV systolic function,113 with an inverse rela-
tionship to RV filling pressures. The RV EaTri /AaTri ratio was
significantly correlated to the LV Ea/Aa ratio, and there is no
20
pseudonormalization of EaTri during progressive increase in RV
filling pressure, indicating that these parameters are not load
p = 0.005 dependent.113 Yu et al. examined RV Doppler filling parameters
0
0 1 2 3
and defined RV diastolic dysfunction by a shortening of DT of
the transtricuspid early diastolic E wave to less than 143 msec,
t (years) and by a reversal in EaTri /AaTri.114 They showed that the presence
Total n = 140 84 34 6 of RV diastolic dysfunction significantly predicted cardiac mor-
Non-RFP n = 61 45 20 4 bidity, including nonfatal hospitalization for HF or angina, but
RFP n = 79 41 14 3 no mortality.
A Meluzin et al. evaluated the prognostic impact of combination
100 Non-RFP of RV systolic and diastolic function in 177 consecutive patients
with symptomatic HF due to ischemic or idiopathic DCM and
Total mean LV EF of 23%.115 Over a mean follow-up of 16 months,
80 RV systolic and diastolic functions were found to be independent
RFP
predictors of event-free survival on multivariate analysis. The sur-
vival pattern was, however, determined mainly by the EaTri value,
Survival (%)

60
with EaTri of less than 8.9 cm/sec predicting a high risk of cardiac-
related death irrespective of RV systolic function.
40

Impact on Treatment Strategies in

20 Dilated Cardiomyopathy
p = 0.03 Therapies targeting the interruption of persistent neurohormonal
0 activation have formed the cornerstone in the management of
0 1 2 3 DCM and HF over the last decade. These therapies, directly or
t (years) indirectly, play an influential role in the improvement of diastolic
Total n = 125 86 41 7 function. There is growing evidence that beta blockers, angioten-
Non-RFP n = 82 62 31 4 sin converting enzyme (ACE) inhibitors, and angiotensin recep-
RFP n = 43 25 10 4 tor blockers, as well as nitric oxide donors, can be beneficial.
B Patients with DCM and HF have elevated circulating and tissue
Figure 20-3 Mitral inflow patterns provide prognostic information incre- concentrations of angiotensin II, which may promote hyper-
mental to that of peak VO2 in patients with ischemic or dilated cardiomy- trophy, apoptosis, interstitial fibrosis, ventricular and vascular
opathy. The outcome is significantly poorer in the presence of a restrictive remodeling, and secretion of aldosterone. Aldosterone itself pro-
filling pattern (RFP) than in its absence, both in A, patients with peak VO2 motes fibroblast proliferation and collagen deposition, leading to
≤14 ml/min/kg and in B, patients with peak >14 ml/min/kg. (Modified from
Hansen A et al: Prognostic value of Doppler echocardiographic mitral inflow an increase in passive stiffness of the ventricles and the arterial
patterns: Implications for risk stratification in patients with chronic congestive bed, and thus ventricular filling and arterial compliance.116 Thus
heart failure. J Am Coll Cardiol. 2001;37:1049–1055.) various inhibitors of the renin-angiotensin-aldosterone system
254 Chapter 20 • Dilated Cardiomyopathy and Cardiac Transplantation

have all been found to have salutary effects on improving diastolic clinical applications of TDI in the assessment of LV diastolic
function. function, loading conditions, and synchronization have moved
Beta blocker therapy is now recommended for all but the most from the experimental lab to clinical practice. Further advances,
advanced cases of symptomatic systolic HF. In addition to the particularly in strain and strain rate imaging, will establish the use
improvement of systolic function, beta blockers have been shown of this technique to quantify LV systolic and diastolic function.
to lengthen diastole and affect neurohormonal activation, thereby In the field of advanced HF therapeutics, biventricular pacing
improving outcome.117 Capomolla et al. reported improvement in has been shown to alleviate symptoms effectively, improve cardiac
diastolic filling following therapy with carvedilol, with concomi- function, and reverse LV remodeling (see Chapter 29). Studies
tant significant reduction in effective regurgitant orifice area have shown that systolic asynchrony, but not QRS complex
and mitral regurgitation.118 Similar findings were reported by duration, is a better predictor of acute hemodynamic, echocardio-
Andersson et al. among the patients enrolled in the Metoprolol graphic, or clinical response. Similar to systolic asynchrony, dia-
in Dilated Cardiomyopathy (MDC) study.119 The authors stolic asynchrony also occurred in more than 40% of DCM
reported a good correlation between decrease in heart rate and patients with narrow QRS complexes and in about 70% of those
prolongation of DT at 3 months in the metoprolol group. with wide QRS complexes. Another observed predictor of dia-
Although short-term studies did not reveal any change in chamber stolic asynchrony is the degree of diastolic dysfunction, as illus-
stiffness, Kim et al. found a reduction in chamber stiffness after trated by the negative correlation with mitral annular Ea velocity.
a longer follow-up period of 6 months.120 This is not unexpected, Since cardiac output is dependent on both systolic emptying and
as, unlike the improvement in relaxation and contractility that can diastolic filling, systolic and diastolic asynchrony may cause addi-
occur over a shorter duration,121 a longer treatment period with tive hemodynamic compromise in the failing heart. This relation-
beta blockers would be necessary before any significant change in ship between diastolic asynchrony and cardiac resynchronization
geometry and chamber stiffness, as the regression of hypertrophy therapy needs further evaluation.
and interstitial remodeling is a slower process.121,122 In those with The mean survival rate for DCM was approximately 50% at 5
mild to moderate LV dysfunction, beta blockers seem to improve years, but this has improved with the advent of neurohormonal
exercise capacity through improvement in LV compliance and blockade. When all other treatment options prove unsuccessful
diastolic function. Likewise, the benefits have recently been dem- and the patient is deemed to have end-stage HF, OHT may be
onstrated in those with moderate to severe LV dysfunction. considered. Because the supply of donor organs is limited and
Therapy can be tailored to the individual patient with the use many of those on the waiting list die before finding a donor, risk
of noninvasive hemodynamic information obtained. For example, stratification in individual patients is important; Doppler-derived
there is diastolic ventricular interaction in DCM patients with information on diastolic function may thus aid in better prognos-
the RF pattern,123 and volume unloading in this setting allows for tication and selection of patients likely to benefit the most from
increased LV filling. Such patients generally receive significant OHT.
symptomatic benefit from diuretics and venodilator therapy. On Lastly, mild hemodynamic abnormalities characterize the
the other hand, patients with normal or only mildly elevated transplanted heart. Early recognition of acute rejection episodes
filling may have further deterioration of cardiac output with the in cardiac allograft recipients remains a major challenge during
use of diuretics and preload reduction. In such patients, manage- follow-up after OHT. Echocardiography cannot supplant inva-
ment should be directed at optimizing cardiac output with after- sive methods for monitoring acute rejection but is a useful adjunct
load reduction using ACE inhibitors and/or other vasodilators. for surveillance and monitoring of allograft function after
Studies are ongoing to ascertain the value of this noninvasive OHT. Protocols now combine routine biopsies with supplemen-
hemodynamically based or echo-guided management of HF. tal biopsy in the event of echocardiographic evidence of
acute restrictive physiology.124 Recently gene expression profiling
(GEP) has been utilized in heart transplant recipients to deter-
FUTURE RESEARCH mine a state of quiescence and to exclude significant cardiac
allograft rejection.125 New algorithms are currently being evalu-
Although much is known about the mechanisms underlying dia- ated in clinical trials to determine whether GEP combined with
stolic dysfunction in HF, many basic issues remain to be resolved. echocardiography can reduce the need for invasive monitoring
Clinically relevant diastolic dysfunction integrates abnormalities with EMB.
emanating from sarcomere, extracellular matrix, vasculature, and
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 Chapter 20 • Dilated Cardiomyopathy and Cardiac Transplantation 257
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 CRAIG R. ASHER, MD
ALLAN L. KLEIN, MD
21
Primary Restrictive,
Infiltrative, and Storage
Cardiomyopathies
INTRODUCTION cardiomyopathy” no longer exists, and most infiltrative and storage
disorders are considered specific secondary cardiomyopathies
PATHOPHYSIOLOGY
(i.e., amyloid cardiomyopathy).
CLINICAL RELEVANCE From the point of view of the clinician, however they are com-
Primary Restrictive Cardiomyopathies piled, these are disorders in which diastolic dysfunction is at least
Infiltrative Cardiomyopathies initially the predominant pathophysiological derangement. They
Storage Cardiomyopathies are rare diseases, generally with a poor prognosis and often pre-
senting with advanced right- or left-sided heart failure. Much of
FUTURE RESEARCH
the data regarding these diseases are based on observational retro-
spective studies from tertiary centers with little prospective and
randomized information. Although a cardiologist will often initi-
ate testing, a multidisciplinary team of geneticists, pathologists,
radiologists, hematologists, and oncologists is often required to
“A classification serves to bridge the gap between ignorance and refine the diagnosis and determine management strategies. Since
knowledge.” infiltrative and storage cardiomyopathies occur as part of a multi-
J. F. Goodwin1 system disorder, treatments with chemotherapeutic agents, stem
cells, and enzyme replacement are increasingly becoming options.
This chapter will review primary restrictive cardiomyopathy
INTRODUCTION and the most prevalent forms of infiltrative and storage disorders
encountered among patients surviving into adulthood. A practical
Historically, restrictive cardiomyopathies were among the three approach to diagnosis, differentiation, and exclusion of other,
primary forms of idiopathic heart muscle disease characterized by more common disorders with similar pathophysiology and struc-
the World Health Organization as “restrictive filling and reduced tural appearance will be presented along with current treatment
diastolic volume of either or both ventricles with normal or near- options.
normal systolic function.”2,3 This early grouping of cardiomyopa-
thies highlighted the readily evident morphological and functional
features of these disorders, which were largely of unknown cause. PATHOPHYSIOLOGY
With advances in diagnostic testing (biochemistry, genetics,
immunology, and pathology) and cardiac imaging techniques Most primary restrictive cardiomyopathies are characterized by
(echocardiography, computed tomography [CT], magnetic reso- at most mild degrees of increased wall thickness on gross inspec-
nance imaging [MRI]), the etiology of many cardiomyopathies tion.5–7 Cardiac biopsy will distinguish whether at the cellular
can now be identified. The most recent classification proposal of level there is myocyte hypertrophy (increased myocte diameter
the American Heart Association (AHA) defines primary (involv- and nuclear area), endocardial and interstitial fibrosis (increased
ing predominantly the heart) and secondary (related to systemic collagen to muscle ratio), or both (Fig. 21-1).8,9 Exclusion of fiber
disorders) cardiomyopathies.4 Using this new classification, except disarray, inflammation, eosinophilia, lymphocytes, amyloid or
for primary restrictive cardiomyopathy, the entity of “restrictive iron deposits, and pericardial disease via light and electron micros-
259
260 Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies

with exertion. No other past medical history (PMH) is present.

Family history is significant for an aunt with hypertrophic cardio-
myopathy (HCM). On examination, she is found to be tachy-
cardic. The cardiac exam is notable for an elevated jugular venous
pressure of 10 cm H2O, an S3 gallop, and 1+ lower extremity
pitting edema. An electrocardiogram (ECG) shows first-degree
atrioventricular (AV) block with a P-R interval of 240 msec. A
chest x-ray (CXR) shows mild pulmonary congestion. Brain
natriuretic peptide (BNP) level is 750 pg/ml, and the creatine
phosphokinase (CPK) level is 280 units/L. An echocardiogram
shows normal LV and RV size and function, with moderately
dilated atria, stage 3 diastolic dysfunction (restrictive filling
pattern), E/E′ of 15, and a delayed color M-mode slope of 35 cm/
sec. Cardiac MRI shows normal pericardial thickness and reduced
tissue signal intensity. Subsequent cardiac catheterization is
Figure 21-1 Idiopathic restrictive cardiomyopathy in a 63-year-old notable for pressures (mmHg) as follows: right atrial, 15; right
woman. Left panel: Gross specimen, shown in four-chamber format, dem- ventricular end diastolic, 17; left ventricular end diastolic, 24;
onstrating prominent biatrial enlargement with normal-sized ventricles. pulmonary artery systolic pressure, 55; pulmonary capillary wedge
Right panel: Light microscopy showing marked interstitial fibrosis (light pressure, 25; and cardiac index, 2.3 L/min/m2. Cardiac biopsy
pink areas) (hematoxylin and eosin; magnification ×120). (From Ammash
NM et al: Clinical profile and outcome of idiopathic restrictive cardiomyopathy. confirms idiopathic restrictive cardiomyopathy and excludes spe-
Circulation 2000;101:2490–2496.) cific infiltrative and storage diseases.

Diagnosis
copy is required to distinguish primary restrictive diseases. Primary (or idiopathic) restrictive cardiomyopathy is a rare
Absence of an endocardial fibrotic shell with extension into the disorder of advanced diastolic impairment, often leading to biven-
myocardium excludes endomyocardial disease. tricular diastolic heart failure and sudden cardiac death. It was
Structural characteristics of primary restrictive cardiomyopa- first described by Benotti et al. in nine patients with heart failure,
thies include (a) biatrial enlargement, (b) nondilated or reduced elevated RV and LV filling pressures, normal systolic function,
left ventricular (LV) cavity size, and (c) normal or mild wall thick- and dip-and-plateau hemodynamic tracing.16 In children, the
ness.10 The pathogenesis of diastolic impairment may be second- disease is more common in females, and the prognosis is worse
ary to myocyte abnormalities, including abnormal calcium compared with adults.17,18 Familial autosomal dominant trans-
handling, accumulation of desmin (a cytoskeletal component), mission and the association with skeletal myopathies (predomi-
myocyte hypertrophy, and extracellular matrix interstitial fibrosis nantly distal) and heart block have been reported in several gen-
with proliferation of collagen fibers and elastic elements.11–13 A erations of families.8,19,20 Other associations include family
marked increase in stiffness of the myocardium or endocardium members with HCM and Noonan’s syndrome.21 Genetic linkage
causes the ventricular pressure to rise dramatically with only small analysis studies have shown mutations in cardiac troponin-I
changes in volume, causing an upward shift of the LV pressure- (TNNI3) and defects in genes coding for myocyte desmin accu-
volume relationship and a “dip and plateau” or “square root” hemo- mulation in patients with restrictive cardiomyopathy.22
dynamic pattern.14 Both ventricles are affected by the process, but The clinical signs and symptoms of primary restrictive cardiac
usually the pressures are higher on the left than the right, which disease relate closely to the degree of left atrial (LA) hypertension
may reflect the relatively decreased compliance of the left ventricle required to compensate for reduced ventricular filling.5,23 Initially,
compared with the right ventricle. there is exercise intolerance and fatigue, progressing to dyspnea
Secondary infiltrative and storage cardiomyopathies result with minimal effort. Exertional chest pain is usually absent. Atrial
from the presence of myocardial cellular or extracellular sub- fibrillation is common due to the atrial enlargement. Ventricular
stances that impair diastolic function. In infiltrative diseases, there arrhythmias or heart block are commonly present in advanced
is localization to the interstitium (between myocardial cells), as cases and are often the causes of death. Symptoms of proximal or
with cardiac amyloidosis; whereas in storage disorders, the depos- distal myopathy may be present. Cardiac examination may reveal
its are within cells, as with hemochromatosis and Fabry’s disease.15 pulmonary congestion, jugular venous distention with a promi-
The infiltrative and storage cardiomyopathies may have heteroge- nent X and Y descent, an S3 depending on the filling characteris-
neous morphological and hemodynamic findings, depending on tics, hepatomegaly, ascites, peripheral edema, and anasarca in
the specific underlying process and the stage of disease, which advanced cases.5,10 Kussmaul’s sign can be detected, while apical
often involves LV dysfunction, increased wall thickness, and non- retraction (as in constrictive pericarditis) is not seen.
restrictive diastolic filling patterns. Laboratory testing may provide supportive information.
BNP levels are elevated proportional to the level of filling pres-
sures and stage of diastolic dysfunction. Elevated BNP levels
CLINICAL RELEVANCE also may aid in excluding constrictive physiology.24 CPK levels
may be elevated with concomitant myopathy. No data are avail-
Primary Restrictive Cardiomyopathies able on troponin levels in patients with idiopathic restrictive
cardiomyopathy.
Case 1 Echocardiography is often the first-line test and may be virtu-
A 23-year-old woman presents to her family physician complain- ally diagnostic.25,26 Atrial enlargement with nondilated ventricles
ing of fatigue, exercise intolerance, muscle aches, and dyspnea with near normal systolic function is uniformly present on echo-
 Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies 261

cardiography. Mild LV dysfunction may develop among patients Texas Children’s Hospital found that predictors of sudden death
with advanced disease requiring transplantation. Generally, if included female sex, chest pain, syncope, and ischemia on Holter
hypertrophy is present, it is mild. The pathophysiological findings monitor. The annual mortality rate was 7%, with sudden death
of advanced diastolic dysfunction are evident with a comprehen- occurring in 28% of patients.34 Predictors of poor outcome in the
sive echocardiographic Doppler study (elevated filling pressures pediatric population include age, female sex, ischemic manifesta-
± restrictive physiology). Restrictive physiology may not be tions, decreased cardiac index, pulmonary venous congestion, and
present, depending on the stage of disease and loading conditions, elevated pulmonary vascular resistance.8,18,35,36
but abnormal diastolic function should be evident by evaluation Beta blockers are the primary therapy to reduce the risk of
of mitral and tricuspid inflow patterns, pulmonary and hepatic sudden death. Additional medical therapy includes diuretics for
venous flows, and isovolumic relaxation time (IVRT).27,28 Tissue symptomatic relief and consideration of antiplatelet agents or
Doppler echocardiography (TDE) E and A annular velocities are anticoagulation, due to the high risk of atrial fibrillation and
low, with mitral E/E annular ratios elevated consistent with high embolism reported in some series.33 Vasodilators should be used
filling pressures.29 Concomitantly, the color M-mode propagation cautiously unless LV dysfunction is present, since they may cause
slope is slow.29 TDE and color M-mode, along with pulsed hypotension. Pacemakers are often required for heart block.
Doppler flow patterns with a respirometer, can help distinguish Implantable cardioverter-defrillators are recommended for any
restrictive from constrictive physiology. patients with ischemic manifestations, along with listing for trans-
MRI and CT may be useful to exclude increased pericardial plantation.34 Transplantation can substantially improve survival
thickness, septal bounce, or conical compression.30,31 Cine MRI and is usually required within 4 years of diagnosis, optimally
may show abnormal filling patterns in early and advanced stages before pulmonary vascular resistance is irreversibly high.37 Heart-
of restrictive cardiomyopathy similar to echocardiography. MRI lung transplantation is an option for some children.37 When
is capable of distinguishing tissue characteristics and shows a concomitant skeletal myopathy is present, the benefits of trans-
diffuse reduction in signal intensity due to fibrosis in idiopathic plantation may be partial.
restrictive cardiomyopathy, with more specific patterns in other Idiopathic restrictive cardiomyopathy may also be diagnosed in
infiltrative processes like amyloidosis or hemochromatosis.31 adults after exclusion of secondary causes of restrictive physiology
Cardiac catheterization is often used as a confirmatory test. (Fig. 21-2). A large series of 94 patients (mean age, 64 years)
Using strict criteria, either right- or left-sided filling pressures are was identified from 1979 to 1996 at the Mayo Clinic, with
elevated, with a typical dip-and-plateau RV and LV filling pattern typical structural and hemodynamic features of restrictive cardio-
and an “M”- or “W”-shaped venous filling pattern with prominent myopathy.38 At follow-up of 68 months, 50% of patients had
X and Y descents.6 LV diastolic pressures are greater than died, primarily from cardiac causes, and 4 required heart trans-
5 mmHg more than RV filling pressures. Cardiac index is reduced, plantation. Using multivariate analysis, predictors of death
and pulmonary artery pressure is greater than 50 mmHg in most included male sex, LA dimension greater than 60 mm, age older
patients with a ratio of RV systolic to diastolic pressure greater than 70 years, and advanced New York Heart Association class
than 1/3. Often RV endomyocardial biopsy is done at the same (Fig. 21-3).
time as hemodynamic assessment and importantly excludes other
specific etiologies.7,32
Infiltrative Cardiomyopathies
Management Using the most recent AHA classification, cardiac amyloidosis is
The prognosis of idiopathic restrictive cardiomyopathy depends the most important infiltrative cardiomyopathy in adults. Sar-
most on the age of the patient and presenting hemodynamic coidosis has been recategorized as a secondary inflammatory dis-
factors. Although variable, the course is usually progressive and order.4 The exceedingly rare infiltrative disorders—Gaucher’s,
generally poor among the pediatric population, with survival rates Hurler’s, and Hunter’s diseases—are familial defects in metabo-
of less than 50% over 2 years.17,33 A serial study of 18 children (9 lism that involve multiple systems, including the heart, and will
male; mean age, 4.3 years) evaluated over a course of 31 years at not be discussed in this chapter.

Diastolic dysfunction
Restrictive physiology

Primary restrictive Secondary “Restrictive-like diastolic filling”

(Predominant cardiac restrictive (catheterization/echocardiogram)
involvement)

Figure 21-2 Algorithm with differential End stage End stage • Severe TR (right side)
diagnosis of restrictive physiology deter- other primary other secondary • RV dysfunction (right side)
mined either by cardiac catheterization or cardiomyopathy cardiomyopathy • Severe MR
echocardiogram. TR, tricuspid regurgita- (Predominant cardiac (Systemic involvement) • Constriction
tion; RV, right ventricular; MR, mitral involvement) • Atrial fibrillation
regurgitation.
262 Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies

100 100 p = 0.007

79%
80 80
45%
I
Survival

Survival
60 44% Women 60
40 40 II
20 27% 20
p = 0.033 III
Men IV
0 0
0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10
A Years B Years

100 100
78%
80 80 69%
47%
Survival

Survival
60 51% No 60
42%
40 40 33% No
20 29% 20
p = 0.026 Yes p = 0.027 11%
0 0 Yes

0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10
C Years D Years
Figure 21-3 Kaplan-Meier survival curves in relation to A, sex; B, New York Heart Association functional class (I or II); C, pulmonary venous congestion;
and D, left atrial dimension >60 mm. (From Ammash NM et al: Clinical profile and outcome of idiopathic restrictive cardiomyopathy. Circulation
2000;101:2490–2496.)

Cardiac Amyloidosis linear, nonbranching, aggregated protein fibrils with a cross-β

pleated configuration are deposited in various organs of the
Case 2 body, including the heart.42 Within the heart, the amyloid parti-
A 44-year-old man presents to a cardiologist for a second opinion cles can infiltrate the myocardium (atria and ventricles), valves,
regarding amyloid cardiomyopathy. He complains of dyspnea pericardium, conduction system, and coronary arteries.41 The
with exertion, orthopnea, orthostasis, abdominal distention, and fibrils deposit between cells (interstitial), with a replacement
lower extremity swelling and numbness. No other PMH is of the normal tissue structures. When stained with Congo
present. The man is African American. Family history is signifi- red, this material shows apple-green birefringence under a
cant for his father and brother, who died in their forties with polarizing microscope. Alcian blue can also be used to diagnose
cardiomyopathy. On examination, he appears cachectic and has a amyloid.39,43
supine blood pressure of 96/64 and upright 80/68 mmHg. The Amyloidosis can be classified by the type of protein deposited.
cardiac exam is notable for jugular venous distention to the jaw. The primary type is the most common form, occurring in 85% of
There is S3 gallop, reduced intensity heart sounds and a moderate patients with fibrils composed of kappa or lambda immunoglobu-
apical regurgitant murmur. There is ascites and 3+ lower extrem- lin light chains (AL type for amyloid light chain), often associated
ity pitting edema. An ECG shows low voltage in the limb leads with a plasma cell dyscrasia such as multiple myeloma.39,43 There
and an intraventricular conduction delay. CXR shows a globular may be extracellular deposition of amyloid protein in the kidney,
heart silhouette and mild pulmonary congestion. BNP level is heart, liver, nerves, skin, and tongue, resulting in tissue damage
4000 pg/ml. An echocardiogram shows severe biventricular and organ malfunction.42 The most common manifestations
increased wall thickness with moderately impaired systolic func- include nephrotic syndrome or renal failure, congestive heart
tion. The atria are dilated and the pulmonary artery pressure is failure, sensorimotor peripheral neuropathy, and orthostatic
60 mmHg. There is moderate mitral regurgitation. There is stage hypotension. Nearly half of patients have cardiac involvement,
2 diastolic dysfunction (pseudonormal filling pattern), E/E′ of 18, including congestive heart failure; however, the heart is involved
with a delayed color M-mode slope of 40 cm/sec. There is a in most all patients by pathological examination.43 Death from
moderate-sized pericardial effusion. Serum and urine electro- cardiac involvement secondary to congestive heart failure or
phoresis with immunofixation and bone marrow biopsy shows arrhythmia occurs in greater than 50% of patients with systemic
no evidence of abnormal immunoglobulin. A laboratory analysis amyloidosis.44,45
shows a mutation in transthyretin (TTR) protein, confirming the Familial amyloidosis results from the production of a mutant
diagnosis of familial TTR amyloidosis. pre-albumin protein (i.e., TTR), and there are different types,
which present with cardiomyopathy, neuropathy, or nephropa-
Etiology and Classification thy.46 TTR is made up of 125 pairs of amino acids, and more than
Cardiac amyloidosis is the prototype of infiltrative cardiomy- 100 mutations have been recognized.47 This type of amyloidosis
opathies and the most frequently encountered in clinical prac- is important to recognize because liver transplantation may be
tice.39–41 There are several types of cardiac amyloidoses, each with lifesaving, though optimally it should be performed before cardiac
its own clinical presentations, treatment strategies, and prognosis involvement has occurred. Laboratory testing should be per-
(Table 21-1).39 Amyloidosis is a multisystem disease in which formed to test for TTR if a family history is present or there is
 Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies 263

TABLE 21-1
MAJOR FORMS OF AMYLOIDOSIS
CARDIAC OTHER ORGAN ASSOCIATED
TYPE PROTEIN INVOLVEMENT INVOLVEMENT DISORDERS TREATMENT

AL (primary) Immunoglobulin light Common Liver, kidney, nervous Plasma cell dyscrasias Chemotherapy; cardiac
chain (λ, κ) system, (e.g., multiple transplant if isolated
gastrointestinal tract, myelomas) cardiac
skin
AA (secondary) Nonimmunoglobulin, serum Rare Kidney Inflammatory diseases Underlying disease
protein A (e.g., rheumatoid
arthritis, familial
Mediterranean fever,
tuberculosis)
ATTR (familial) Nonimmunoglobulin, Common Nervous system None Liver transplant if no
transthyretin cardiac involvement
SSA (senile) Nonimmunoglobulin, Common None Congestive heart Supportive treatment for
transthyretin failure congestive heart
failure
AANP (atrial) Nonimmunoglobulin, atrial Common None Atrial fibrillation Supportive treatment for
natriuretic peptide atrial fibrillation

Modified from Falk RH: Diagnosis and management of the cardiac amyloidoses. Circulation 2005;112:2047–2060.

no evidence of AL type amyloid on biopsy. In familial amyloidosis, natriuretic peptide.58 It is more common in females and seems to
cardiac involvement occurs in 28% of patients at the time of be associated with the presence of atrial fibrillation.59,60
diagnosis; however, it usually presents later in the course of the
disease and is less ominous prognostically compared with AL Clinical Presentation
(primary) amyloidosis.46 Peripheral neuropathy may be the pre- Cardiac amyloidosis may present with a spectrum of disease
senting feature, but cardiac manifestations may subsequently pre- severity. In the nonfamilial forms, it generally affects males over
dominate.48 The disease was reported over 30 years ago in a age 30.44,61 In early cardiac amyloidosis, patients may be asymp-
Danish family but has also been described in several other fami- tomatic, while those with advanced disease will have the typical
lies of different ethnic origin and has an autosomal dominant evidence of restrictive cardiomyopathy with severe right-heart
expression.49,50 Cardiac failure or cardiac arrhythmia is responsi- failure, ascites, and peripheral edema.62,63 Left-heart failure is a
ble for the deaths in over 50% of patients.46 Familial amyloidosis less common manifestation. Additional symptoms include chest
has been reported in African Americans as a cause of heart failure pain, presyncope/syncope, and sudden cardiac death. Chest pain
secondary to a mutation in TTR isoleucine-122 (substitution for resembling angina pectoris may be present despite normal epicar-
valine).51 This mutation has been found in nearly 4% of African dial coronary arteries due to partial obliteration of the distal coro-
Americans in the United States and in approximately one-quarter nary arteries by amyloid infiltration or intramyocardial vessels.64,65
of elderly patients with cardiac amyloidosis. Orthostatic hypotension occurs in 10%–15% of patients second-
Senile systemic amyloidosis (SSA) occurs in elderly men from ary to amyloid infiltration of the autonomic nervous system, with
the production of a wild-type TTR and has been associated with symptoms of syncope, diarrhea, lack of sweating, and impo-
congestive heart failure without significant noncardiac involve- tence.42,66 Renal involvement with nephrotic syndrome and
ment.52,53 Survival is reasonably good relative to AL amyloid or adrenal disease may aggravate postural hypotension. Syncope
other etiologies of congestive heart failure.52,54 There may be may be due to postural hypotension or supraventricular or ven-
extensive deposits in the heart producing congestive heart failure, tricular arrhythmias. Other symptoms may be attributable
or there may be minor deposits in the atria with no symptoms. to peripheral neuropathy, macroglossia, or carpal tunnel
The prevalence of senile amyloid at autopsy appears to be highest syndrome.39,67
in African Americans. It is important to differentiate senile cardiac Physical examination may reveal signs of cardiac cachexia in
amyloidosis from immunoglobulin-derived amyloidosis (AL advanced disease. Low cardiac output may cause decreased blood
type) and familial amyloidosis because the treatment regimens pressure, and orthostatic hypotension may still occur. Macroglos-
differ. The favorable prognosis of SSA relative to AL is concor- sia, periorbital edema, petechia, and bruising may be evident on
dant with the accumulating evidence that light chains are respon- general examination.39 The cardiac exam may reveal an S4 (very
sible for toxicity and poor outcome in AL amyloidosis.55 early disease) or S3 (advanced disease) on auscultation from either
Secondary amyloidosis (AA type) is rare, with the fibrils con- the right or the left heart.68 Mitral and tricuspid valvular regurgi-
sisting of protein A, a nonimmunoglobulin acute phase reactant tation may also be present, though usually not severe. There is
resulting from a multitude of chronic inflammatory conditions often evidence of biventricular heart failure with predominant
(e.g., tuberculosis, familial Mediterranean fever, rheumatoid right-heart failure.63 The jugular venous pulse will be elevated
arthritis, inflammatory bowel disease).56 Cardiac involvement is with a prominent X and Y descent, and hepatomegaly, ascites, and
unusual in secondary amyloidosis, with renal manifestations peripheral edema will be present, especially in the advanced
being predominant.57 Isolated atrial amyloidosis is often found disease.39 Neurological examination may reveal findings consis-
limited to the atria at autopsy in the elderly and derives from atrial tent with peripheral neuropathy.
264 Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies

The cardiac silhouette on CXR is usually enlarged in patients dium at the site of the sparkling echoes. However, the specificity
with advanced disease with evidence of pulmonary congestion or of this finding is reduced with improved echocardiographic
pericardial effusion.69 The electrocardiogram typically has low imaging techniques, including harmonic imaging. Global LV sys-
voltage in the limb leads and shows a pseudoinfarction pattern tolic function is usually preserved in early disease, whereas systolic
with Q waves simulating a myocardial infarction in the precordial function is usually impaired in advanced disease. The interatrial
leads (∼50% of patients).70,71 More specifically, patients with septum and valve leaflets are thickened. Both atria are enlarged,
cardiac amyloidosis have a low ratio of electrocardiographic and small to moderate pericardial effusions are usually
voltage to LV wall thickness.72 However, the usefulness of this present.80,82
ratio is limited by the presence of coexisting diseases that may
result in reduced voltage. Arrhythmias, especially atrial fibrilla-
tion, are common, and sick-sinus syndrome may be present.39 AV
conduction defects may be present, especially in familial amyloi-
dosis associated with myopathy, though right and left bundle
branch block is uncommon.73 Ventricular arrhythmias are not as
common as expected and are not often the cause of sudden cardiac
death in nonfamilial forms.74

Echocardiography
Two-dimensional and Doppler echocardiography are the
procedures of choice for diagnosis, serial follow-up, and prog-
nostic determination of patients with cardiac amyloidosis,75–82
which gives a distinctive appearance on two-dimensional echocar-
diography and is associated with abnormal LV and RV diastolic
function. The findings of a normal or small LV cavity size with
markedly thickened myocardium associated with a highly abnor-
mal texture often described as “granular sparkling” in appearance
is the classical presentation (Fig. 21-4). Other disorders
that cause increased LV wall thickness must be considered
(Fig. 21-5). The sparkling appearance is thought to be due to the
acoustic mismatch between the highly reflective amyloid deposits Figure 21-4 Apical four-chamber view of patient with cardiac amyloidosis
demonstrating severe increased wall thickness of the left and right ventri-
in the endocardium, myocardium, and pericardium and the cles, dilated atria, and a pericardial effusion. The myocardium has a “granu-
normal tissue.83,84 Moreover, autopsy and clinical biopsy series lar sparkling” appearance caused by hyperrefractile amyloid particles
have demonstrated the presence of amyloid fibrils in the myocar- intermixed with normal myocardium.

↑ LV wall thickness

Hypertrophy Cardiomyopathy

Primary Secondary Myocardial Endomyocardial

• Hypertrophic CM Physiological Pathological Primary Secondary • EMF/Loffler’s

• LV noncompaction • Carcinoid
• Radiation

Athlete’s Idiopathic
heart • HTN Valvular restrictive Storage Inflammatory Infiltrative
• ESRD

• AS • Fabry’s Sarcoidosis Amyloidosis

• AR • Hemochromatosis
• Glycogen storage

Figure 21-5 Algorithm with differential diagnosis of increased left ventricular (LV) wall thickness. CM, cardiomyopathy; HTN, hypertension; ESRD, end-stage
renal disease; AS, aortic stenosis; AR, aortic regurgitation; EMF, endomyocardial fibrosis.
 Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies 265

Cardiac amyloidosis has traditionally been considered to require Noncardiac sites of biopsy can include the bone marrow, fat
a restrictive pattern of ventricular filling. However, a spectrum of pad, rectum, gingiva, kidney, and liver, though fat aspirate may
LV filling abnormalities using pulsed-wave Doppler echocardiog- detect amyloidosis in most patients (>70%).44,92,93 If the echocar-
raphy is detected in patients with cardiac amyloidosis.68,77,85 In a diogram is not diagnostic or the fat pad aspirate is negative and
study of 53 patients with the classic echocardiographic features of cardiac amyloidosis is still suspected, an endomyocardial biopsy
cardiac amyloidosis, those with advanced disease demonstrated a can be performed to make the diagnosis. A confirmatory cardiac
mean LV wall thickness greater than 15 mm and a “restrictive” biopsy may be particularly important if there are other confound-
physiology pattern of LV filling.68 Furthermore, in serial studies of ing causes of increased LV mass, such as LV hypertrophy (LVH)
individual patients, the “impaired relaxation” pattern gradually or HCM. The presence of low electrocardiographic voltage
evolved into a “restrictive” pattern through a “pseudonormal,” or favors a diagnosis of amyloidosis rather than hypertensive or
intermediate, phase in the progression of the disease.77 The mech-
anism for this serial change in LV filling pattern is thought to be
the gradual decrease in the compliance of the left ventricle with
progressive deposition of amyloid fibrils in the myocardium,
leading to loss of myocardial cells from pressure necrosis.86 When
the duration of the pulmonary venous atrial reversal wave is longer
than the mitral A-wave duration, filling pressures are elevated and
the disease is advanced with restrictive physiology.87 Eventually
the pulmonary atrial reversal wave may be lost due to atrial involve-
ment of amyloid infiltration.
RV diastolic impairment also may occur in patients with
cardiac amyloidosis.76 The RV filling pattern is often similar to
that of the left ventricle or may be less advanced. In early cases,
there is an RV free wall thickness of less than 7 mm and abnormal
relaxation. In advanced cases, the RV wall is greater than 7 mm
in thickness, with restrictive physiology present. The systolic
forward flows by Doppler echocardiography in the superior vena
cava and hepatic vein are also decreased with advanced disease,
and the diastolic flow is increased compatible with restrictive
physiology.
Newer diagnostic techniques, including TDE, strain and strain
rate, and two-dimensional strain imaging, have been utilized to
characterize early systolic dysfunction in patients with cardiac
amyloidosis before the onset of congestive symptoms or reduced
LV ejection fraction.88,89 Using these methods, it has been shown
that there are differences between the longitudinal basal peak
systolic strain rate and strain among amyloid patients with no
cardiac involvement, cardiac involvement and no symptoms, and
cardiac involvement with symptoms (Figs. 21-6 and 21-7).89 This
finding allows for detection of patients with early amyloid heart
disease to be targeted for therapy.

Other Diagnostic Tools

Cardiac amyloidosis can be diagnosed noninvasively antemor-
tem in most cases from the typical features obtained from the
history, examination, ECG, and echocardiogram. However, con-
firmatory testing is needed before treatment is initiated, and Figure 21-6 Color-coded map of myocardial long-axis strain recorded
further classification of the subtype of amyloid is necessary. Serum from the ventricular septum. Top left image is from the apical four-chamber
and urine protein immunofixation and electrophoresis are view, with a bar representing a key to the color-coding. The numbers on
recommended to assess for the secretion of a monoclonal protein the ventricular septum correspond to the numbers on the map; the apical
septal strain is represented on the top part of the map, and the base is
associated with a plasma cell dyscrasia.39,43,44,66,90 Although some represented on the bottom. A, Recording from a normal subject. Immedi-
patients with AL amyloid will have multiple myeloma, a greater ately after the onset of systole (arrow indicates R wave), there is a brief light
proportion may have unassociated monoclonal gammopathies of blue vertical line, representing isovolumic systole, followed by a broad,
uncertain significance. In 10% of cases, there is no monoclonal uniform orange/red-coded band, representing ventricular contraction. This
is followed by early relaxation in blue, diastasis in green, and a late diastolic
protein secreted (nonsecretory primary amyloidosis). Laboratory relaxation in a second blue area. B, Strain map from a patient with cardiac
testing of antisera against TTR, the kappa and lambda light amyloid, heart failure, and a mildly reduced ejection fraction. The arrow
chains, and protein A in biopsy or blood samples can be per- again represents the onset of the QRS complex. There is almost no longi-
formed. A serum free–light chain assay is available to assess the tudinal motion in any portion of the septum, with the large area of green
ratio of kappa-to-lambda free light chains and may be more sensi- representing absent motion and the brief patches of color representing
slight elongation in late diastole (light blue). Systolic longitudinal motion
tive than immunofixation.43,91 A positive serum immunofixation at the base and a brief, reduced contraction in midsystole near the apical
plus an abnormal kappa/lambda ratio are highly sensitive to diag- septum are yellowish orange. (From Falk RH: Diagnosis and management of
nose AL amyloidosis.90 the cardiac amyloidoses. Circulation 2005;112:2047–2060.)
266 Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies

hypertrophic cardiomyopathy; however, endomyocardial biopsy pneumonic of hypertrophic cardiomyopathy, it has also been rec-
may be necessary in some cases to give a definitive diagnosis ognized in a series of patients with cardiac amyloidosis.95
because of the grim prognostic implications of a diagnosis of MRI can be used to identify the increased myocardial thickness
cardiac amyloidosis.94 Although systolic anterior motion (SAM) and small LV cavity in cardiac amyloidosis. It can be used to
of the mitral valve on echocardiogram is thought to be patho- demonstrate the lack of increased pericardial thickening with the
ancillary findings of biatrial enlargement and inferior vena cava
dilatation, similar to echocardiography. Myocardial wall thicken-
ing due to hypertrophy or amyloid infiltration may be distinguish-
able.96–98 A pattern of global and subendocardial late gadolinium
enhancement and specific features of T-1 blood pool kinetics are
seen in patients with suspected amyloidosis.99 Subendocardial late
enhancement involves the right and left ventricles, including the
septum, causing the so-called zebra appearance of the septum
(Fig. 21-8). This subendocardial late enhancement matches the
deposition of amyloid seen histologically. The sensitivity of this
finding in a series of 30 patients with echocardiographic features
of amyloid was 69%.
Nuclear medicine techniques have been used to diagnose
cardiac amyloidosis, including technetium-99m pyrophosphate
scintigraphy and imaging of indium-labeled antimyosin anti-
bodies, though the reported sensitivities of these techniques are
low.100–102 However, a recent small study with technetium-99m
dicarboxypropane diphosphonate (DPD) was 100% specific for
Figure 21-7 Speckle tracking image of a patient with advanced cardiac
differentiating TTR amyloid from AL type.103 Figure 21-9 shows
amyloidosis showing decreased longitudinal systolic strain. Top left image the diagnostic evaluation of suspected amyloidosis.
is from the apical four-chamber view with a bar representing a key to the
color-coding varying from −20% to 20%. Each apical segment is color
Prognosis
coded. The global strain is −4.3%. Lower right image shows the actual peak The prognosis of cardiac amyloidosis is generally poor, but it
systolic strain values for each segment. For example, the basal septum has depends on the type of disease, with AL (primary) amyloidosis
a peak strain of −1% (n = −20%). The apical segments have greater peak having the worst prognosis.43,44,46,57,61,104 In a serial study of over
systolic strain values. Top right image (graph) and lower right image (ana- 800 patients with primary amyloidosis over a 10-year period, the
tomic M-mode) show decreased peak systolic strain over the cardiac cycle.
All the segments in different colors show decreased systolic strain. Basal median survival was 2.1 years and less than 6 months once con-
and midventricular segments have the worst systolic strain, while the gestive heart failure had occurred.104 Several prognostic indicators
apical segment has the best systolic strain. have been determined (Table 21-2). Mean LV wall thickness and

Figure 21-8 Cardiovascular magnetic resonance (CMR) image of a patient with systemic AL amyloidosis. Top row shows diastolic frames from cines (vertical
long axis, horizontal long axis, and short axis, respectively), showing a thickened left ventricle (LV) and pleural effusion (Pl eff ) and pericardial effusion
(Pc eff ) (arrows) associated with heart failure. Bottom row shows late gadolinium enhancement images in the same planes. The CMR sequence forces the
myocardium remote from the pathology to be nulled (black) such that the abnormal region is enhanced. In cardiac amyloidosis, however, the region of
greatest abnormality is enhanced, as the entire myocardium is affected with amyloid infiltration, and the result is diffuse global subendocardial enhance-
ment (straight arrows). The endocardium of the right ventricle (RV) is also heavily loaded with amyloid, and therefore the septum in the horizontal long-axis
view shows biventricular subendocardial enhancement with a dark midwall (zebra appearance; dotted arrows). The right ventricular free wall is also
enhanced (curved arrow). Note that the blood pool is dark, which does not occur in other reported conditions, including abnormal gadolinium handling
in these patients. LA, left atrium; RA, right atrium. (From Maceira AM et al: Cardiovascular magnetic resonance in cardiac amyloidosis. Circulation
2005;111:186–193.)
 Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies 267

Suspected cardiac amyloidosis

(e.g. heart failure with typical echocardiogram)

Careful physical exam seeking other potential organ involvement

(e.g. proteinuria, periorbital purpura)

Biopsy of selected cardiac or non-cardiac tissue

Biopsy positive:
amyloidosis confirmed

Where feasible, special Special stains unavailable

stains such as immunogold

Serum and urine IFE, FLC assay,

bone marrow biopsy

One or (usually)
All negative
more positive

Genetic testing for

mutant TTR or ApoA1

Amyloid type confirmed

Positive Negative

TTR AL amyloidosis Familial Probably SSA

Therapy as below

Genetic testing Quantify light chains

for mutant TTR (as baseline for follow-up)
and exclude concomitant
myeloma

Positive Negative

Familial amyloidosis SSA AL amyloidosis

Supportive therapy. Supportive therapy. Chemotherapy and
Assess for liver transplant supportive therapy.
and need for cardiac
transplant.

Figure 21-9 Flow diagram outlining the evaluation of a patient with suspected cardiac amyloidosis. Clinical evaluation may reveal clues that strengthen
the likelihood of amyloidosis, but a tissue diagnosis is mandatory. Although special staining of the biopsy may confirm the type of amyloid, further workup
of AL amyloid is required to exclude myeloma and to quantify free light chains. If the biopsy stains positive for transthyretin (TTR), further testing is needed
to determine whether this is a wild type or mutant. ApoA1, apolipoprotein A1; IFE, immunofixation electrophoresis; FLC, free–light chain assay; SSA, senile
systemic amyloidosis. (From Falk RH: Diagnosis and management of the cardiac amyloidoses. Circulation 2005;112:2047–2060.)
268 Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies

TABLE 21-2 a high morbidity and mortality in patients with advanced cardiac
disease. Autologous stem cell transplantation has shown favorable
ECHOCARDIOGRAPHIC/LABORATORY PROGNOSTIC results, mostly in patients without cardiac disease or early cardiac
DETERMINANTS IN AMYLOIDOSIS involvement, and is the treatment of choice for AL amyloido-
sis.110,111 The toxicity of blood cell transplantation, however, limits
Left ventricular wall thickness ≥15 mm
Right ventricular wall thickness >7 mm its use to a minority of patients.
Mitral inflow deceleration time ≤150 msec Diuretics are the main drugs used to treat the cardiac symp-
Left ventricular dysfunction toms. Avoidance of digoxin has been suggested because of concern
Right ventricular enlargement for digoxin binding to amyloid fibrils and the risk of arrhythmias,
Abnormal Tei index >0.77 although the data to support this recommendation are mostly
↑ Troponin level
↑ Brain natriuretic peptide level experimental or anecdotal.112 With careful monitoring, digoxin
has been used for heart rate control in patients with atrial fibril-
lation.61 Patients with cardiac amyloidosis may also be very sensi-
tive to the negative inotropic effects of calcium-channel blockers,
either because of their abnormal binding to amyloid fibrils or
LV impairment have been suggested as useful variables in assess- because of their vasodilator effects.113 Vasodilator agents such as
ing the degree of cardiac involvement and prognosis. In a study angiotensin converting enzyme (ACE) inhibitors or angiotensin
of 132 patients with biopsy-proven amyloidosis, those with a II inhibitors are poorly tolerated, with a risk of significant hypo-
mean wall thickness of 15 mm had a median survival of 0.4 year tension.39 Pacemakers may be useful to treat symptomatic high
compared with 2.4 years for those with a mean wall thickness of AV block. Anticoagulation should be considered because of the
12 mm.80 Doppler echocardiography has also been shown to be risk of thrombus formation with atrial amyloid involvement and
useful in prognostic stratification of patients with cardiac amyloi- atrial standstill, even among patients in sinus rhythm.114,115
dosis. Patients with a deceleration time of the mitral early filling Cardiac transplantation is generally not performed in patients
wave at a baseline study of no greater than 150 msec had signifi- with AL type amyloid, since systemic involvement of other organs
cantly reduced survival compared with those whose deceleration is usually present and may progress.116–120 It has been considered
time was greater than 150 msec (1-year probability of survival, in select patients without extracardiac disease (<5% of cases),
49% vs. 92%; p < 0.001).78 Bivariate analysis showed that since the transplanted heart is usually not clinically affected.119,120
the combination of a shortened deceleration time of no greater In this situation, heart transplantation is coupled to chemother-
than 150 msec and an increased mitral E/A ratio were stronger apy and stem cell transplantation. Liver transplantation has been
predictors of cardiac death than were two-dimensional variables performed for the familial type (TTR variant), since the circulat-
of mean LV wall thickness and fractional shortening. A Doppler ing TTR is produced in the liver.121–123 Thus, the new liver will
echocardiographic derived parameter, the Tei index, combining replace the variant TTR with a normal TTR. Ideally, this is per-
systolic and diastolic performance, has been determined to have formed before cardiac involvement occurs. Nonsteroidal anti-
significant prognostic importance in cardiac amyloidosis (see inflammatory drugs, such as Diflunisal, that can stabilize TTR
Chapter 16 in this volume).105 RV enlargement and LV dysfunc- and prevent the formation of amyloid are being evaluated.124
tion have also been identified as independent predictors of poor There is no specific treatment for the senile type of amyloid,
outcome among patients with primary amyloidosis.45,79 Both ele- though usually patients can be managed medically.
vated troponin and BNP levels have been associated with a poorer
prognosis.106
Storage Cardiomyopathies
Treatment There has been a growing recognition that cardiac storage dis-
The mainstay of treatment is relief of symptoms, though efforts orders often go unrecognized and may be frequent mimics of
are being undertaken to suppress the principal disease process. HCM.4,125,126 Intracellular accumulation of various substances
The definitive treatment for cardiac amyloidosis (AL type) within myocytes generally results from defects in genes coding for
involves antiplasma cell therapy that stops production of light metabolic pathways. It is likely that the list of these disorders
chains and includes alkylating agents, such as melphalan and continues to expand rapidly. Currently, primary cardiomyopathies
prednisone.39,104 Few randomized trials of chemotherapy have due to PRKAG2 and LAMP2 proteins have been described,
shown benefit in AL amyloidosis.107,108 A trial of 100 patients and secondary cardiomyopathies include Fabry’s, Pompe’s, and
with primary amyloidosis using melphalan, prednisone, and col- Nieman-Pick diseases and hemochromatosis.4 Fabry’s disease and
chicine showed improvement of systemic disease when the major the primary cardiomyopathies will be discussed, since they are
features were not cardiac or renal.108 A subsequent trial random- most prevalent in adults. Hemochromatosis, though more likely
ized 220 patients to colchicine, melphalan, prednisone, or com- to manifest as a dilated cardiomyopathy, will also be reviewed.
bined therapy. A median duration of survival of 17–18 months
occurred in the regimens including melphalan, with only 15% of
patients surviving for at least 5 years. Fabry’s Disease
Colchicine has also been used to prevent amyloidosis associ-
ated with familial Mediterranean fever; however, there is no evi- Case 3
dence that it halts the progression of amyloid deposition in A 48-year-old man presents with dyspnea on exertion. He has
primary amyloidosis.104 Various dosing regimens of melphalan been diagnosed with nonobstructive HCM. There is a family
have been used with modest success, including among patients history of Fabry’s disease. On cardiac examination, there is a
with cardiac disease without significant LV dysfunction or moderate intensity ejection murmur that is unchanged with Val-
advanced heart failure.109 Chemotherapy has been associated with salva. ECG shows a short P-R interval and LVH. Echocardio-
 Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies 269

gram shows severe symmetric hypertrophy (interventricular females (mean age, 51.5 years) with late-onset hypertrophy were
septum, 1.9 cm; posterior wall, 1.8 cm). There is no SAM of the demonstrated to have Fabry’s disease by endomyocardial biopsy,
mitral valve or the LV outflow tract gradient at rest or with exer- despite electrocardiographic and echocardiographic appearances
cise echocardiogram. A laboratory test for alpha-galactosidase of HCM (Fig. 21-10).132 Among female patients with Fabry’s
shows levels less than 10% of normals. Genetic testing confirms disease screened for LVH in one study, 63% had evidence of
Fabry’s disease with a mutation in the gene coding for alpha- concentric or eccentric hypertrophy, suggesting cardiac involve-
galactosidase. An endomyocardial biopsy shows inclusion bodies ment.133 In the same study, among females older than 45 years of
in the sarcoplasmic reticulum. The patient is referred for enzyme age with Fabry’s, hypertrophy was evident in all patients.
replacement therapy. The diagnosis of Fabry’s disease in adults is first suspected by
findings on the ECG and echocardiogram. The ECG may show
Etiology and Presentations AV block and a short P-R interval with evidence of LVH.137
Fabry’s disease is a rare X-linked recessive disorder of metabo- Cardiac manifestations described by echocardiography include
lism due to gene mutations coding for alpha-galactosidase. This increased aortic dimension, mitral regurgitation with mitral valve
defect results in a deficiency in the enzyme alpha-galactosidase A prolapse, and increased LV wall thickness.138–143 Although most
that leads to accumulation of glycosphingolipids, the most common often the pattern of increased LV wall thickness is concentric
of which is globotriaosylceramide, Gb(3), in lysosomes.127 hypertrophy or remodeling, asymmetric hypertrophy has been
Although described decades ago, isolated cardiac manifestations described.132 The systolic function is usually preserved. SAM of
have not been widely recognized until the past decade, and enzyme the mitral valve has been described.142 Diastolic function, though
replacement therapy has only recently become available.128,129 typically abnormal, is usually not restrictive.144
Fabry’s disease most severely affects homozygous males, with gen- The diagnosis of Fabry’s disease can be confirmed in hemizy-
erally milder symptoms occurring in females.130–133 Abnormal gous males by detection of reduced levels of leukocyte alpha-
deposition of glycolipid occurs in the cardiovascular system (myo- galactosidase levels.136 Heterozygous females may have normal or
cardium, valves, conduction system, blood vessels), nerves, skin, mildly decreased levels, and therefore tissue biopsy or gene testing
and kidney.134 Lysosomal inclusions are seen by electron micro- of affected tissue for diagnosis may be required.132 Efforts have
scopy with vacuolization of myocytes, endothelial and smooth been made to use different imaging modalities to screen patients
muscle cells with a concentric lamellar configuration.133 with LVH for Fabry’s disease, including echocardiography and
The noncardiac manifestations of Fabry’s disease include angio- MRI, since treatment to reduce the accumulation of cardiac infil-
keratoma, acroparesthesias, hypohidrosis, and corneal opacities.132 tration with glycolipid has become available.144–146
Among children in the European Fabry Outcome Survey (FOS), Echocardiographic screening of mutation-positive patients for
the most frequent symptoms were acroparesthesias, altered tem- Fabry’s disease, though negative for LVH, has shown reduced
perative sensitivity, gastrointestinal effects, vertigo, tinnitus, and tissue Doppler systolic, E-annular, and A-annular velocities com-
fatigue.135Adults may present with renal failure and stroke, though pared with controls.144 MRI has also shown abnormalities in
cardiac-related symptoms alone may occur, including dyspnea, patients with Fabry’s plus LVH with reduced radial and longitu-
chest pain, syncope, and congestive heart failure.136 Recent studies dinal strain and strain rate relative to controls and improvement
have shown that Fabry’s disease may be the cause of LVH in in strain and strain rate with concomitant reduction in wall thick-
4%–6% of men with late-onset HCM.130,131 Furthermore, 12% of ness with treatment.147 MRI studies show a mildly increased

Figure 21-10 Fabry’s cardiomyopathy. A, 12-lead electrocardiogram showing signs of left ventricular (LV) hypertrophy and ST-segment depression with
giant negative T waves in precordial leads, suggesting apical hypertrophic cardiomyopathy. B, End diastolic (left) and end systolic (right) echocardiographic
apical four-chamber view showing severe wall hypertrophy and cavity obliteration of ventricular apex. C, LV angiography in right anterior oblique (30˚)
view showing massive apical hypertrophy of LV. D, LV endomyocardial biopsy showing normal cells (arrows) intermingled with cells containing glycolipid
inclusion vacuoles (arrowheads) (hematoxylin and eosin; ×200). (From Chimenti C et al: Prevalence of Fabry disease in female patients with late-onset hyper-
trophic cardiomyopathy. Circulation 2004;110:1047–1053.)
270 Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies

signal intensity of the myocardium but no specific pattern except liver function tests.125,126 The clinical course progresses rapidly,
a tendency toward posterior-basal late enhancement with gado- with premature death. PRKAG2 has a less ominous prognosis.
linium.147,148 Reduction in radial and longitudinal strain deter- There is a dominant inheritance pattern and lack of noncardiac
mined echocardiographically in patients with Fabry’s disease involvement, with patients surviving to adulthood, though often
shows a correlation between hypertrophy and late enhancement with arrhythmias and conduction disease.125
by MRI.149 A study of 50 unselected patients (mean age, 6 years) with the
Thus far, the most accurate and promising finding to distin- diagnosis of HCM who underwent gene analysis for LAMP2
guish LVH due to hypertension and HCM from Fabry’s cardio- found 2 (4%) with mutations. Both of these patients had Wolff-
myopathy is the presence of a binary appearance of the LV Parkinson White syndrome and skeletal myopathy.126 A similar
endocardium border.145 In one study, the sensitivity and specificity study of 75 unselected patients with HCM found 3 (4%) with
of this finding was 94% and 100%, respectively. The finding is LAMP2 or PRKAG2 mutations.125 The same investigators per-
demonstrated histologically by compartmentalization of glyco- formed a subgroup analysis of 24 patients with LVH and preex-
sphingolipids to the endocardium (Fig. 21-11). citation and found 11 with mutations in LAMP2 or PRKAG2
Once cardiac involvement with Fabry’s disease has been con- with associated findings of LAMP2, including male sex, severe
firmed, treatment with enzyme replacement (recombinant human hypertrophy, early onset of HCM, preexcitation, and elevated
alpha-galactosidase A) can be initiated. Several studies have dem- liver and muscle enzymes. An algorithm for the diagnosis of
onstrated a reduction in LVH and improvement in cardiac func- patients with suspected LAMP2 or PRKAG 2 mutations is pro-
tion with galactose infusion therapy.147,150,151 posed in Figure 21-12.

Glycogen Storage Disorders Hemochromatosis

Two gene mutations (PRKAG2 and LAMP2) causing glycogen Case 4
storage disease have recently been recognized as primary cardio-
A 50-year-old man is undergoing consideration for liver trans-
myopathies mimicking HCM.125,126 PRKAG2 codes for a regula-
plantation due to primary hemochromatosis. He has no known
tory gene for cyclic adenosine monophosphate (cAMP)–activated
cardiac disease and no cardiac risk factors. On examination, his
protein kinase, and LAMP2 (also called Danon’s disease) codes
skin is bronze. The cardiac examination is notable for a positive
for a lysosome membrane protein.4 Neither of these diseases is
S4 gallop. ECG shows low voltage in the limb leads. An echocar-
associated with myocyte disarray or interstitial fibrosis, but rather
diogram shows normal LV size and function with abnormal dia-
glycogen-rich vacuoles. Additional gene mutations affecting non-
stolic function (stage 2 filling pattern) and reduced tissue Doppler
sarcomeric proteins involved in metabolism are likely to be
systolic annular (6 cm/sec) and E-annular velocities (4 cm/sec).
discovered.
A cardiac MRI is done and shows abnormalities consistent with
Danon’s disease occurs as an X-linked gene affecting male chil-
hemochromatosis. A cardiac biopsy confirms iron overload in the
dren younger than 20 years of age, though females are usually
myocardium.
detected as adults. Noncardiac manifestations include skeletal
myopathy, mental retardation, behavioral changes, and ocular Etiology and Presentations
abnormalities.125,126 Cardiac manifestations include early onset of Hemochromatosis is an iron storage disease that affects the
HCM, preexcitation, and elevated creatine kinase, troponins, and heart, pancreas, liver, gonads, joints, and skin.152 Primary idio-

Figure 21-11 Two-dimensional echocardiography in four-chamber apical view and left ventricular (LV) endomyocardial biopsy from two patients with
Fabry’s disease cardiomyopathy (A, D and B, E, respectively) and a patient with hypertrophic cardiomyopathy (C, F). Comparison of the three echocardio-
graphic frames reveals the presence of a binary appearance of the LV endocardial border in the two Fabry patients (A, B). This echocardiographic finding
reflects glycosphingolipid compartmentalization involving a thickened endocardium (End) with enlarged and engulfed smooth muscle cells (SMC), a
subendocardial empty space (SES), and a prominent involvement of subendocardial myocardial layer (SL), while the middle layer (ML) appears partially
spared (D, E). The echocardiographic pattern is absent in hypertrophic cardiomyopathy (C), despite a similar thickening of the endocardium (F). (From
Pieroni M et al: Fabry’s disease cardiomyopathy: Echocardiographic detection of endomyocardial glycosphingolipid compartmentalization. J Am Coll Cardiol
2006;47:1663–1671. )
 Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies 271

Unexplained left ventricular

hypertrophy: is ventricular
preexcitation present?

No Yes

Analyze sarcomere-protein Young, male patient

genes; is mutation present? prominent left ventricular
voltage; massive hypertrophy?

Yes No No Yes

Hypertrophic Measure alanine

Analyze PRKAG2; No
cardiomyopathy aminotransferase and creatine
is mutation present?
phosphokinase; elevated?
Yes
Yes No

Glycogen-associated Analyze LAMP2;

cardiomyopathy is mutation present?

Yes No

Cardiac Danon’s Consider other glycogen

disease storage disease

Figure 21-12 Algorithm for the diagnostic evaluation of patients with unexplained hypertrophy, where hypertrophic cardiomyopathy may not be the
etiology. A family history of the dominant inheritance of left ventricular (LV) hypertrophy, unaccompanied by systemic manifestations or electrocardio-
graphic findings of ventricular preexcitation, suggests hypertrophic cardiomyopathy; the identification of a sarcomeric mutation confirms the diagnosis.
In young patients with echocardiographic findings of unexplained LV hypertrophy and electrocardiograms with prominent LV voltage and short P-R
intervals, delta waves, or both, glycogen storage disease should be suspected. Dominant inheritance and an absence of systemic disease suggest the
presence of glycogen-associated cardiomyopathy due to PRKAG2 mutations. Male sex and abnormalities in liver, musculoskeletal, or neurologic function
suggest a diagnosis of Danon’s disease, although systemic manifestations can be modest or absent in the cardiac form of this disease. When the cause is
not established by genetic analyses, a tissue biopsy and a biochemical study may be helpful. (From Arad M et al: Glycogen storage diseases presenting as
hypertrophic cardiomyopathy. N Engl J Med 2005;352:362–372.)

pathic hemochromatosis is an autosomal recessive disorder related level to total iron binding capacity, urinary iron, liver iron, and
to the human leukocyte antigen on chromosome 6 that results in saturation of transferrin.160 Cardiomegaly may be seen on CXR.
excessive iron absorption.152,153 It is the most common autosomal Electrocardiographic findings have included arrhythmias, con-
recessive disease in Caucasians.154 Both men and women are duction disorders, and low voltage. Echocardiography is a useful
affected in middle age (fifties/sixties), with women usually pre- noninvasive technique in the assessment of cardiac involvement
senting after menstruation has ceased.155 Secondary hemochro- in primary hemochromatosis, detecting clinically occult heart
matosis results from hemoglobin synthesis abnormalities leading involvement, following patients serially, and assessing LV function
to ineffective erythropoiesis, chronic liver disease, excessive intake after phlebotomy.156,161–163
of iron, or multiple blood transfusions.153 A retrospective review from the Mayo Clinic described 19
Histologically, iron is deposited in the sarcoplasmic reticulum, patients with primary hemochromatosis and demonstrated that
mostly within the subepicardium and to a lesser extent the sub- 7 (37%) had chamber dilatation and systolic dysfunction second-
endocardium of the myocardium.155 Interstitial iron is not seen, ary to hemochromatosis, while 12 patients did not.157 Increased
characterizing hemochromatosis as a storage, not an infiltrative, ventricular wall thickness was not evident in this cohort of
disorder.4 The ventricles and conduction system are most often patients. Patterns consistent with dilated or restrictive cardiomy-
affected.155 The degree of myocardial iron correlates with the opathy or mixed patterns have been described in patients with
severity of cardiac dysfunction.156–159 primary hemochromatosis, though the earliest finding is
Manifestations of cardiac involvement occur when there is a usually a restrictive pattern.155,159 Ventricular dysfunction and
large amount of iron deposited over a long period of time. One- increased ventricular mass may normalize after successful phle-
third of patients manifest cardiac symptoms with evidence of botomy.163–165 The presence of systolic dysfunction usually signi-
congestive heart failure, supraventricular or ventricular arrhyth- fies a poor prognosis.156 Manifestations of secondary hemochro-
mias, and conduction defects.152 Cardiac involvement is usually matosis in the heart include increased LV wall thickness and
recognized after a noncardiac diagnosis is already known. Less mass, increased cavity dimension, and LA enlargement.166 Spe-
often, patients will present with a cardiomyopathy of unknown cific Doppler filling indexes and TDE are useful to differentiate
etiology without known hemochromatosis. Laboratory tests will patients with hereditary hemochromatosis from normal subjects
show an elevated serum ferritin and increased ratio of plasma iron and therefore may be useful for screening.167 Exercise radionu-
272 Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies
.69 Figure 21-13 Middle-aged man with
hemochromatosis developed congestive
heart failure and a dilated cardiomyopa-
.69 thy. He was treated with deferoxamine
PW:2MHz and phlebotomy. A, Systolic frame illus-
1.0 trating systolic dysfunction. B, Mitral
inflow pattern illustrating Stage 2 dia-
stolic dysfunction. Thirteen months later,
m/s systolic frame illustrated normal systolic
function (C), and mitral inflow pattern
illustrated reversion to Stage 1 diastolic
1.0 dysfunction (D).
A B

1.6MHZ

1.2
0.8
0.4
0.0 +
m
0.4 /
s
0.8 –
1.2
1.6
C D

clide cine angiography demonstrating exercise-related LV dys- tive diseases. Furthermore, over the past few decades, it is not
function in patients with normal baseline function has also been readily evident to most physicians that progress has occurred.
shown to be sensitive to detect preclinical disease.168 Advances in studying uncommon problems rely on reminding
Other noninvasive tests, including CT and MRI, may be useful clinicians that treatment investigations are ongoing. Patients and
in demonstrating subclinical involvement of hemochromatosis their doctors should be encouraged to pursue evaluations at spe-
(Fig. 21-13).169,170 The MRI may show a low myocardial signal on cialty referral centers, allowing them to receive the latest therapies
the cine gradient echo, consistent with myocardial iron deposi- and to be participants in prospective registries or clinical trials.
tion.169 Endomyocardial biopsy may be useful to exclude the diag- Many of these centers, such as Amyloid or Fabry’s Cardiomyopa-
nosis, especially when echocardiographic or clinical features are thy Clinics, exist both nationally and internationally and are
not evident.171 essential for promoting excellence in care and future research.
Treatment by repeat phlebotomies in primary hemochromato- At the present time, there is reason for modest optimism.
sis or the use of chelating agents (desferoxamine) in secondary Patients with idiopathic restrictive or amyloid cardiomyopathy
hemochromatosis may result in improvement of cardiac involve- without significant noncardiac disease can be considered for
ment, making early diagnosis important.163–165 Thus, cardiac cardiac or liver transplantation. Storage cardiomyopathies such as
hemochromatosis is a potentially reversible form of cardiomyopa- Fabry’s disease and hemochromatosis may be largely reversible
thy. Heart transplantation may be considered when the heart with known accepted therapies. Amyloid cardiomyopathy still
involvement is life threatening, or combined heart and liver trans- presents a difficult challenge; however, a better recognition of
plantation may be useful in patients with heart and liver non-AL forms of amyloid has allowed more patients to be eligible
failure.155,172–174 for treatment.
Although at one time the diseases encompassed by the entity
of “restrictive cardiomyopathy” were considered the topic of case
FUTURE RESEARCH presentations and few therapeutic options, in the future we antici-
pate earlier diagnosis, enhanced understanding of pathophysio-
The AHA 2006 reclassification of cardiomyopathies has shifted logical mechanisms, and increasing options for treatment and
the focus toward understanding the genetic and cellular causes of clinical research, with the ultimate goal of improved outcomes.
specific heart muscle diseases.4 Ultimately, the most effective
approach to early diagnosis and targeted treatment will be guided
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1995;76:739–741. thy by tissue Doppler imaging. Circulation 2003;107:1978–1984.
118. Kpodonu J, Massad MG, Caines A, Geha AS: Outcome of heart transplan- 145. Pieroni M, Chimenti C, De Cobelli F, et al. Fabry’s disease cardiomyopathy:
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2005;24:1763–1765. mentalization. J Am Coll Cardiol 2006;47:1663–1671.
119. Dubrey SW, Burke MM, Hawkines PN, et al: Cardiac transplantation for 146. Matsui S, Murakami E, Takekoshi N, et al: Myocardial tissue characteriza-
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120. Pelosi F Jr, Capehart J, Roberts WC: Effectiveness of cardiac transplantation 147. Weidemann F, Breunig F, Beer M, et al: Improvement of cardiac
for primary (AL) cardiac amyloidosis. Am J Cardiol 1997;79:532–535. function during enzyme replacement therapy in patients with Fabry disease:
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Fabry’s disease. A high incidence of mitral valve prolapse in hemizygotes and ated with hemochromatosis. N Engl J Med 1972;287:866–867.
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276 Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies
167. Palka P, Macdonald G, Lange A, Burstow DJ: The role of Doppler left ven- 171. Przybojewski JZ: Endomyocardial biopsy: A review of the literature. Cath
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Echocardiogr 2002;15:884–890. matotic cardiomyopathy despite reversal of iron deposition after liver trans-
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tion in patients with severe beta-thalassemia and chronic iron overload. 173. Caines AE, Kpodonu J, Massad MG, et al: Cardiac transplantation in
N Engl J Med 1979;21:1143–1148. patients with iron overload cardiomyopathy. J Heart Lung Transplant
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Assist Tomo 1994;18:136–138. patients undergoing biopsy of both organs, with implications for heart or
170. Niwano S, Yokoyama J, Niwano H, Aizawa Y: Images in cardiovascular liver transplantation. Mayo Clin Proc 2004;79:492–501.
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 ARUMUGAM NARAYANAN, MD
GERARD P. AURIGEMMA, MD
22
Coronary Artery Disease

INTRODUCTION The prevalence of coronary disease in patients who develop

PATHOPHYSIOLOGY diastolic heart failure is high. This conclusion is based on
Acute Ischemia data compiled from several types of studies: cross-sectional
Postinfarction Left Ventricular Remodeling studies; randomized, placebo-controlled, clinical trials; and
community-based studies. Gottdiener et al. studied over 5000
CLINICAL RELEVANCE community-based individuals, age 65 or greater, enrolled in the
Diagnosis by Doppler Echocardiography multicenter Cardiovascular Health Study (CHS). These investi-
FUTURE RESEARCH gators tabulated incidence rates of heart failure over a 5-year
period. Prevalent CAD was associated with more than a threefold
higher rate of incident CHF (15.3% vs. 41%). Other predictors
of CHF include other indicators of prevalent atherosclerotic
disease, such as reduced ankle-brachial index, history of stroke,
and increased levels of C-reactive protein. The population-
attributable risk of prevalent CAD in this study was roughly
INTRODUCTION equivalent to that of arterial hypertension, which itself is epide-
miologically important.5–9 In a subsequent analysis of CHF by EF
While the importance of hypertension in the pathogenesis of in the CHS database,11 prevalent coronary heart disease was
diastolic dysfunction and diastolic heart failure is well known,1–6 present in 58% of patients with CHF and normal EF and in 78%
relatively less attention has been paid to the interaction between of patients with CHF and reduced EF.
coronary artery disease (CAD) and diastolic dysfunction. Accord- Framingham Study investigators confirmed the importance of
ingly, this chapter will be devoted to reviewing aspects of diastolic CAD in patients with diastolic heart failure, using the concept of
dysfunction in patients with coronary disease, with an emphasis population-attributable risk. When adjusting for age and heart
on the role of Doppler echocardiography in elucidating aspects of failure risk factors in proportional hazards regression models,
the pathogenesis of heart failure. hypertension accounted for 39% of cases in men and 59% of cases
Diastolic heart failure is a condition characterized by signs and in women.5 Among hypertensive subjects, CAD (in this instance,
symptoms of heart failure, where “the dominant abnormality a history of myocardial infarction) was associated with increased
resides in diastole.”2 Cross-sectional and population-based studies risk for CHF in both sexes.5
indicate that at least one-third of all patients with congestive heart Similarly high rates of CAD have been reported in a survey
failure (CHF) have a normal or near-normal ejection fraction of clinical characteristics of patients hospitalized in New York
(EF) and that most have diastolic heart failure.1–3 The prevalence City with diastolic heart failure reported by Klapholz et al.,6 as
is highest in patients over age 75.1,2,7 Historically it has been well as those enrolled in the “Candesartan in Heart Failure:
assumed that the mortality rate of diastolic heart failure is less Assessment of Reduction in Mortality and Morbidity”
than that of systolic heart failure, ranging from 5% to 8% annually, (CHARM)–Preserved study, the only published randomized
compared with 10% to 15% in patients with systolic heart failure.2 clinical trial to date of treatment for diastolic heart failure.12 In
However, recent data8–10 have challenged this notion. As is the the study by Klapholz et al., roughly one half of patients hospital-
case with systolic heart failure, the mortality rate of diastolic heart ized in New York City for CHF who had a normal EF had a
failure is directly related to age and the presence of coronary history of CAD. In the CHARM study, roughly one fifth had
disease.2 The reported prevalence of diastolic heart failure depends a prior coronary artery bypass graft; one half, myocardial infarc-
not only on age, but on the diagnostic criteria used to define dia- tion; and one quarter, angina.12 These data demonstrate the
stolic dysfunction, the etiology of the disease, and the methods importance of coronary heart disease in the pathogenesis of dia-
and design of the particular study in question.2,7 stolic heart failure.
277
278 Chapter 22 • Coronary Artery Disease

PATHOPHYSIOLOGY the rate of LV pressure decline.16–17 This subject is reviewed in

detail elsewhere.18
As is reviewed in Chapter 2 of this volume, diastolic function is
determined by the passive elastic properties of the left ventricle Postinfarction Left Ventricular Remodeling
and the process of active relaxation.1,2 Active relaxation is an
energy-dependent process that is affected by ischemia. By con- The subject of postinfarction LV remodeling is complicated, and
trast, abnormal passive elastic properties are generally caused by excellent reviews of this topic have been published.19–21 To sum-
a combination of increased myocardial mass and alterations in the marize briefly, myocardial infarction produces global and regional
extramyocardial collagen network.2 The effects of impaired active changes in ventricular function in both infarcted and noninfarcted
myocardial relaxation, caused by acute ischemia, can lead to regions, resulting in alterations in LV shape and geometry. The
further stiffness. The interplay between this impaired relaxation immediate changes following infarction involve mainly the
and passive stiffness determines left ventricular (LV) filling infarcted region. Subsequently, over weeks to months, further
pressure.2 changes occur, and these involve the noninfarcted region. This
constellation of changes is known as ventricular remodeling. In the
consensus paper by Cohn et al., LV remodeling is defined as
Acute Ischemia “changes in size, shape, and function of the heart after cardiac
It has been demonstrated that acute myocardial ischemia effects injury. [The process] . . . is influenced by hemodynamic load,
changes in both global and regional LV diastolic properties.13 The neurohumoral activation, and other processes.”20
results of these alterations include a slower LV pressure decay A review of the processes involved in LV remodeling make it
with a consequent slowing of diastolic filling. Acute changes in clear that what may begin as an adaptive process can have malefic
the passive properties of the left ventricle result in an upward consequences for LV diastolic function. During acute ischemia,
shift in the diastolic pressure-volume relationship (Fig. 22-1). injury, and the attendant reduction in systolic function, the region
As a result, the LV diastolic pressure-volume relationship undergoing infarction may develop systolic expansion and perform
changes: Chamber compliance is reduced, the time course is a reduced amount of effective work.18,20 Following a large myocar-
altered, and diastolic pressure is elevated. Under these circum- dial infarction, LV end diastolic pressures remain elevated, and
stances, a relatively small increase in central blood volume or an the volume of viable myocardium increases approximately 30%
increase in venous tone or arterial stiffness can produce a substan- because of increases in both myocyte cell length and diameter.18
tial increase in filling pressures and may result in acute pulmonary In some instances, the ventricle may undergo progressive infarct
edema.14 expansion, usually within the first 24–72 hours.18–21 In part, this
The slowed relaxation following acute ischemia or infarction expansion and volume increase help to compensate for the reduc-
may persist for days.15 However, a slower rate of LV pressure fall tion in effective work via the Frank-Starling mechanism.18–21
is not the only result of direct effects of ischemia on myocardial Even in the absence of acute LV expansion, LV dilation
relaxation. Ischemia may also affect contractility, loading condi- may develop, usually over several months after myocardial infarc-
tions, and may worsen nonuniformity, which may also act to slow tion18–21 involving both the infarcted and the noninfarcted
regions.
Given the curvilinear diastolic pressure-volume relationship,
lengthening/dilation of noninfarcted regions is associated with an
increase in LV end diastolic pressure.18–21 High wall stresses and
30 Angina ventricular remodeling may provide the stimuli for deleterious
changes and further remodeling.21 The signal for progressive
Diastolic pressure (mmHg)

remodeling in the postinfarction ventricle may be diastolic wall

stress, with parallels between this process and what is observed
20 in chronic volume overload due to valvular regurgitation.21
Myocyte hypertrophy and changes in the extracellular matrix also
are part of the remodeling process.18–21

10
CLINICAL RELEVANCE
Control Diagnosis by Doppler Echocardiography
Doppler echocardiography plays a critical diagnostic role in all
patients with heart failure for a variety of reasons. First, diagnosti-
20 40 60 80 100 cally, it should be emphasized that the physical examination,
Diastolic volume (cc/m2) electrocardiogram, and chest roentgenogram do not reliably dis-
Figure 22-1 The acute effect of ischemia on the pressure-volume relation-
tinguish diastolic from systolic heart failure. Second, an accurate
ship. These data are taken from the study of a 60-year-old individual under- EF determination is essential for the diagnosis of diastolic
going catheterization. The control diastolic pressure-volume relationship heart failure. Echocardiography can also rapidly exclude diagno-
is shown. During the procedure, the patient developed angina; volume ses such as acute mitral or aortic regurgitation or constrictive
assessment and hemodynamic measures were repeated. As can be seen, pericarditis, conditions also associated with signs and symptoms
the pressure-volume relationship shifted dramatically upward, so that at
any given diastolic volume, the pressure during the angina episode is of heart failure and a normal EF. Finally, Doppler echocardiogra-
higher; note that the ejection fraction has not changed dramatically. phy can be used in many instances to reliably estimate filling
(Figure courtesy of Dr. William H. Gaasch.) pressures.
 Chapter 22 • Coronary Artery Disease 279

General Principles generally provided by pulmonary vein velocities26,27 and tissue

Doppler analysis.25 Tissue Doppler techniques appear to be
As is reviewed in Chapter 5 of this volume, Doppler echocardiog- somewhat less sensitive to loading conditions than standard
raphy measures the velocity of intracardiac blood flow. Doppler Doppler velocities (Fig. 22-2). It is important to bear in mind, in
transmitral flow analysis has become the mainstay of the clinical this connection, that the height of the transmitral E wave merely
assessment of diastolic function. In normal sinus rhythm, dia- reflects the early diastolic LA-LV gradient. As is shown in Figure
stolic flow from the left atrium to the left ventricle across the 22-3, it is possible that the E-wave height and E/A ratio may be
mitral valve occurs in two phases, denoted by two distinct waves: low, not necessarily because of low LA pressure, but because of a
the E wave, which reflects early diastolic filling, and the A wave, protracted decline in LV diastolic pressure.28 As we will see, such
in late diastole, which reflects atrial contraction. Because the a protracted decline in diastolic pressure may be caused by acute
velocity of blood flow across the mitral valve depends on the ischemia.
transmitral pressure gradient, the E-wave velocity is influenced by
both the rate of early diastolic relaxation and left atrial (LA) pres-
sure. Alterations in the pattern of these velocities give insight into
LV diastolic function and prognosis.22–25 As has been pointed
Acute Effects of Ischemia on Doppler
out previously (see Chapter 10), standard mitral inflow patterns Inflow Patterns
are extremely sensitive to loading conditions, particularly LA There have been a number of studies of mitral inflow patterns in
pressure. patients with acute myocardial ischemia (Table 22-1). Labovitz
Stated another way, early diastolic filling rates might be et al. studied functional changes by Doppler echocardiography in
increased by elevated LA pressure. Therefore, just as a “normal” 32 patients during transient myocardial ischemia induced by
(E > A) filling pattern does not necessarily indicate normal dia- percutaneous transluminal coronary angioplasty (PTCA).29
stolic function, a reduced E-wave velocity and E/A ratio might be Ventricular filling during coronary occlusion showed significant
found in the presence of elevated filling pressures. As we have change, evident within 15 seconds of balloon occlusion; there was
come to realize over the past decade, other data are necessary to an acute decrease in peak E velocity as well as E/A ratio (Fig.
give a complete picture of diastolic function. Such other data are 22-4A and B), with a return to baseline values within 15 seconds

50 Diastolic dysfunction

Normal
40
LV pressure (mmHg)

Remodeling
30

20

10
Figure 22-2 A, End diastolic pressure-
volume relationship (EDPVR) curves in
0
normal, diastolic dysfunction, and
remodeling groups. Inserted in the 0 50 100 150 200 250
figure are the mitral inflow and tissue
Doppler recordings for the three groups. A LV volume (ml)
The EDPVR is shifted left-upward for dia-
stolic dysfunction compared with a
right-downward shift for a heart that has
remodeled. B, While mitral inflow veloc-
ity appears similar in all three groups,
mitral annulus tissue Doppler early dia-
stolic velocities are reduced in patients
with diastolic dysfunction or remodel-
ing. Two-dimensional echo shows com-
pletely normal cardiac structures for the
normal subject at the center and
increased wall thickness and LA enlarge-
ment but normal left ventricular size in
the left panel, consistent with diastolic
heart failure. On the right is displayed
left ventricular (LV) enlargement typical
of the remodeling heart. (A, Modified
from Maurer MS, Spevack D, Burkhoff D,
et al: Diastolic dysfunction: Can it be
diagnosed by Doppler echocardiography?
J Am Coll Cardiol 2004;44:1543–1549.
B, From Oh JK et al: Diastolic heart failure
can be diagnosed by comprehensive two-
dimensional and Doppler echocardiogra-
phy. J Am Coll Cardiol 2006;47:500–506.)
280 Chapter 22 • Coronary Artery Disease

TABLE 22-1
TRANSMITRAL INFLOW (E AND A WAVES) IN ACUTE ISCHEMIA
NUMBER OF
AUTHOR PATIENTS (n) PATIENT POPULATION E A E/A AFF DT IVRT

Labovitz et al.29 32 Patients undergoing PTCA NA NA ↓ NA NA NA

Snow et al.30 22 Patients in the unstable angina group who underwent elective NA NA ↔ ↔ ↓ ↓
PTCA*
Iliceto et al.31 9 Patients with significant CAD who developed ischemic ECG changes ↓ ↑ ↓ ↑ NA NA
with transesophageal atrial pacing

*Doppler echocardiography performed 43 ± 27 hours after PTCA.

E, early diastolic filling; A, atrial contraction in late diastole; E/A, ratio of E wave to A wave; AFF, atrial filling fraction; DT, deceleration time; IVRT, isovolumic relaxation time;
PTCA, percutaneous transluminal coronary angioplasty; CAD, coronary artery disease; ECG, electrocardiogram.

LVP

Figure 22-3 Schematic representation of simulta-

neous recordings of left ventricular pressure (LVP),
left atrial pressure (LAP), and Doppler mitral flow
LAP
velocity (MVF) in (1) a normal subject, (2) a patient
with impaired relaxation without clinical heart
failure, and (3) a patient with acute heart failure
and a delayed relaxation. This figure illustrates that
MVF under certain conditions, such as acute ischemia,
a low E/A ratio can be associated with elevated
filling pressures. (From Bogaty P et al: New insights
into diastolic dysfunction as the cause of acute left-
sided heart failure associated with systemic hyper-
Normal Impaired relaxation “Hyperabnormal relaxation” tension and/or coronary artery disease. Am J Cardiol
(1) (2) (3) 2002;89:341–345.)

1.8

1.7

1.6
Baseline Inflation Recovery
1.5

1.4
E A
1 m/sec– 1.3

1.2
E/A

1.1

1.0

.9

V2 .8
V2 V2
.7

.6

.5 p < .001

0
A B Baseline 15 seconds
Figure 22-4 A, Simultaneous recording of pulsed Doppler left ventricular inflow velocities with accompanying electrocardiographic lead V2 during left
anterior descending coronary occlusion/balloon inflation during percutaneous transluminal coronary angioplasty. There is a marked diminution in early
(E) and the E/A ratio, which coincides with ST segment elevation induced by coronary occlusion. The flow profile returned to the baseline state in recovery.
B, There was a significant decrease in the ratio of peak early to peak atrial diastolic velocities (E/A) by 15 seconds after coronary occlusion, with the E/A
ratio falling in the vast majority of patients. (From Labovitz AJ et al: Evaluation of left ventricular systolic and diastolic dysfunction during transient myocardial
ischemia produced by angioplasty. J Am Coll Cardiol 1987;10:748–755.)
 Chapter 22 • Coronary Artery Disease 281

following balloon deflation. The diastolic changes occurred prior early diastole. It is conceivable that an acute ischemia–related
to systolic and other clinical changes.29 reduction in peak E is more related to a slow decline in LV dia-
Snow et al. prospectively evaluated 42 patients undergoing stolic pressure than to reduced LA pressure.
elective PTCA for severe ischemia (22 patients with unstable Iliceto et al.31 evaluated the effect of atrial pacing-induced isch-
angina pectoris and 20 patients with post–acute myocardial emia on Doppler-derived LV filling parameters in 17 patients
infarction [AMI] ischemia).30 Doppler echocardiographic studies with significant CAD (Fig. 22-5A). The patients were divided
were performed before (8 ± 5 hours) and after (43 ± 27 hours) into two groups on the basis of ischemic changes on electrocardi-
PTCA. Patients with severe ischemia (both the unstable angina ography (ECG) (ST depression ≥1.5 mm) immediately after ces-
and the postinfarction ischemia groups) showed abnormal dia- sation of atrial pacing. Group 1 (without ischemic changes)
stolic filling patterns before PTCA, characterized by prolonged showed no significant changes in LV filling variables, while group
isovolumic relaxation time (IVRT) and mitral deceleration time 2 (with ischemic changes) showed a significant decrease in early
(DT), decreased E/A peak velocity ratio, and increased atrial peak flow velocity from rest to postpacing, along with a compen-
filling fraction (AFF). Following PTCA, IVRT and DT decreased satory increase in the atrial component of the mitral inflow veloci-
in both groups; the decrease in IVRT was significant. The E/A ties. As was observed in the studies headed by Labovitz and Snow,
ratio increased, and AFF decreased in the post-AMI ischemia the E/A ratio decreased and the atrial fraction of the time-
group at the same time.30 velocity integral increased in the group with manifest ischemia.
It is noteworthy that both studies demonstrated a reduced E/A The filling alterations gradually returned to baseline levels one
ratio following acute ischemia, induced by either PTCA or the minute after cessation of atrial pacing. The changes in LV filling
acute ischemia. The improvement in diastolic function and trans- occurring only in group 2 possibly reflect significant ischemia
mitral flow velocities post-PTCA likely reflects early recovery of noted by ECG changes and indicate that a threshold for these
diastolic determinants, active ventricular relaxation, and compli- changes may exist (see Fig. 22-5B).
ance. These data may be interpreted in light of the hypothesis of In a more recent investigation using tissue Doppler imaging
Bogaty28: The reduced peak E is probably the result of reduced techniques, Donal and coworkers studied 28 consecutive patients
“driving pressure” between the left atrium and the left ventricle in with AMI involving either the left anterior descending or the right

POST-AP POST-AP POST-AP

PRE-AP 17 th
3rd 1st Min

E A

Figure 22-5 A, Sequential recording of

the transmitral flow velocities before
atrial pacing, at the 3rd beat, the 17th
beat, and 1 minute postatrial pacing
(PAP), demonstrating changes with isch- A
emia and recovery in a patient in group
2 (which developed ischemic electrocar- GROUP 1 GROUP 2
diographic changes on pacing). The first 1.5 1.5
panel at left shows normal left ventricu-
lar (LV) filling characteristics at rest before
atrial pacing (PRE-AP). The next record-
ing (second panel), at the 3rd postatrial
pacing beat, shows a significant decrease
in the early peak flow velocity, along with
an increase in atrial peak flow velocity. At
the 17th postatrial pacing beat (third
panel), a gradual tendency toward recov- 1.0 1.0
ery of the LV filling values is observed. At
1 minute after pacing (fourth panel),
E/A ratio

E/A ratio

transmitral flow velocities are very similar

to those of the 17th beat. B, Illustration
comparing early/atrial (E/A) peak flow
velocity ratio changes with atrial pacing
in group 1 (no pacing-induced ischemia)
and group 2 (pacing-induced ischemia).
Early/atrial peak flow velocity ratio dem- .5 .5
onstrated a significant decrease in
group 2 patients, without any significant
change in group 1 patients, paralleling P: NS P: <.001
electrocardiographic ischemic changes.
(From Iliceto S et al: Doppler echocardio-
graphic evaluation of the effect of
atrial pacing-induced ischemia on left ven-
tricular filling in patients with coronary
artery disease. J Am Coll Cardiol
1988;11:953–961.) B Rest Pacing Rest Pacing
282 Chapter 22 • Coronary Artery Disease

coronary artery territory treated by primary PTCA.32 Echocar- DT was a strong prognostic marker both for LV remodeling and
diographic studies were performed within 24 hours of angio- for survival following AMI (Fig. 22-6). A subset of 571 patients
plasty. A control group comprised 17 individuals with normal with confirmed AMI and serial Doppler echo performed at 24 to
coronary angiography and transesophageal echocardiography. 48 hours (baseline) from symptom onset, at hospital discharge,
The authors recorded systolic (S), early diastolic (E), late diastolic and at 6 months enrolled in the GISSI-3 (Gruppo Italiano per lo
(A), isovolumic contraction (IVC), and isovolumic relaxation Studio della Sopravvivenza nell’infarto) substudy formed the
(IVR) peak velocities by tissue Doppler. Not surprisingly, esti- basis of the sample. Patients were assigned to two groups based
mated LV filling pressures were significantly higher in the two on mitral DT, either restrictive (DT <130 msec) or nonrestrictive
AMI groups compared with controls.32 The IVR peak velocities (DT >130 msec). During follow-up, the end diastolic volume
were significantly lower in each of the two AMI populations index (EDVi) and the end systolic volume index (ESVi) increased,
compared with controls.32 The combination of IVC greater than and percent of wall motion abnormality decreased in both groups.
0 and IVR less than 1 separated ischemic from non-ischemic The magnitude of these changes was more pronounced in patients
segments with 82% sensitivity and 85% specificity. Notably, with a short DT compared with those with DT greater than
among the two AMI groups, even non-ischemic segments or walls 130 msec. A progressive impairment in EF was limited to patients
showed significantly decreased velocities and displacements.32 with restrictive filling. LV dilation was twofold in the baseline
restrictive filling group compared with the nonrestrictive filling
Doppler Filling Profiles in Acute group.33 By multivariate analysis, baseline EDVi and percent wall
motion abnormality, along with predischarge persistent short DT,
Myocardial Infarction demonstrated a higher likelihood of severe late LV dilation (an
Doppler echocardiography has been used to estimate prognosis increase in EDVi of more than 20%).33 These Doppler parameters
in acute infarction (Table 22-2). Temporelli et al.33 showed that also had prognostic importance. Follow-up at 4 years showed that

1.05

1.00

0.95
Survival (%)

p < 0.06
0.90

0.85

0.80 Baseline DT ≤130 msec (restrictive group)

Baseline DT >130 msec (nonrestrictive group)

0.75
0 200 400 600 800 1000 1200 1400 1600
Time (days)

1.05

1.00

0.95
Survival (%)

0.90
p < 0.0003
0.85

Figure 22-6 Cumulative survival rates for all-cause mortal-

0.80 Pre-discharge persistent short (≤130 msec) DT ity according to baseline and predischarge deceleration time
Pre-discharge prolonged (>130 msec) DT (DT). The predischarge persistent short DT predicted a higher
mortality. (From Temporelli PL et al: Doppler-derived mitral
0.75 deceleration time as a strong prognostic marker of left ventricu-
0 200 400 600 800 1000 1200 1400 1600 lar remodeling and survival after acute myocardial infarction:
Results of the GISSI-3 echo substudy. J Am Coll Cardiol 2004;
Time (days) 43:1646–1653.)
 Chapter 22 • Coronary Artery Disease 283

TABLE 22-2
PREDICTIVE VALUE OF DOPPLER ECHOCARDIOGRAPHIC PARAMETERS IN ACUTE MYOCARDIAL INFARCTION
NUMBER OF PATIENT FOLLOW-UP
AUTHOR PATIENTS (n) POPULATION PARAMETERS PERIOD ENDPOINTS RESULTS

Temporelli et al.33 571 AMI DT ≤130 msec 6 months Severe LV dilation Severe dilation (>20%)
predischarge and death from was increased 1.6-
persistent any cause fold (patients with
predischarge
persistent restrictive
filling vs. reversible
restrictive filling;
p < 0.04).
4 years All-cause mortality rate
was 2.9-fold higher
(patients with
predischarge
persistent restrictive
filling vs. reversible
restrictive filling;
p < 0.0003).
Poulsen et al.34 58 First AMI (ST DT ≤140 msec 12 months In-hospital CHF or CHF was 1.4 times
elevation) cardiac death more common and
NYHA class was
higher; p < .01
(patients with
restrictive LV filling
vs. impaired
relaxation).
All 6 deaths were
observed in patients
with restrictive LV
filling pattern.
Naqvi et al.35 59 First AMI (ST DT <170 msec 6 months In-hospital events: DT <170 msec was 2.4-
elevation) who E/e′ ratio >10 of non- cardiac death, fold more often
underwent infarct–related CHF, sustained observed in patients
primary PCI mitral annulus VT, or urgent with events than in
within 12 hours surgical patients without
revascularization events; p < 0.001.
E/e′ >10 was observed
13.2-fold more often
in patients with
events than in those
without events; p <
0.0001.
Hillis et al.37 250 AMI E/e′ ratio >15 13 months All-cause mortality Two thirds of the
deaths occurred in
patients with E/e′
>15.
Patients with E/e′ >15
were 2.2 times more
likely to present
with CHF; p < 0.001.
Hillis et al.36 47 First AMI with E/e′ ratio >15 8 weeks Remodeling (>15% Patients with E/e′ >15
TIMI grade III increase in had a 5.5-fold
flow in infarct- indexed LV end increase in indexed
related diastolic LV diastolic volume;
coronary artery volume) p < .01.
by angiography
and akinesia of
the arterial
territory

AMI, acute myocardial infarction; DT, deceleration time; LV, left ventricular; CHF, congestive heart failure; NYHA, New York Heart Association; PCI, percutaneous coronary intervention;
VT, ventricular tachycardia; TIMI, thrombolysis in myocardial infarction.
284 Chapter 22 • Coronary Artery Disease

predischarge persistent restrictive filling (DT ≤130 msec) was the 1.0
best predictor of mortality, compared with other clinical and
Doppler echocardiographic variables.33
Poulsen et al. studied longitudinal changes and prognostic .9 E/e′ ≤ 15
implications of LV diastolic function in patients with first AMI
and found similar results.34 They evaluated 58 consecutive patients
.8
admitted with first AMI prospectively by two-dimensional and

Survival
Doppler echocardiography, along with clinical evaluation on day 1
and day 5 and at 3 months and 12 months. The patients were clas- .7
sified into three groups based on the LV diastolic filling pattern at
admission: normal, impaired relaxation, and pseudonormal/
restrictive patterns. CHF during hospitalization was noted more .6
often in patients with the restrictive pattern than in patients with E/e′ > 15
impaired relaxation at baseline (71% vs. 50%). Those with a restric-
tive pattern had more severe CHF by New York Heart Associa- .5
tion class compared with normal and impaired relaxation filling 0 6 12 18 24
Number
patterns. Mitral E-wave DT less than 140 msec and age were at risk 250 195 113 49 16
determined as independent predictors of development of in-hos-
pital CHF and cardiac death by multivariate regression analysis. Duration of follow-up (months)
Naqvi et al. evaluated 85 consecutive patients with a first ST- Figure 22-7 Kaplan-Meier plot demonstrating decreased survival in
elevation AMI, who underwent primary percutaneous coronary patients with E/e′ ratio >15 compared with those with E/e′ ratio <15. (From
Hillis GS et al: Noninvasive estimation of left ventricular filling pressure by E/e′
intervention (PCI) within 12 hours of hospital admission by is a powerful predictor of survival after acute myocardial infarction. J Am Coll
echocardiography within 24 hours of primary PCI. The subjects Cardiol 2004;43:360–367.)
were divided into two groups based on development (group A) or
no development (group B) of in-hospital events, including cardiac
death, CHF, sustained ventricular tachycardia (VT), and urgent complements the prognostic value of a combination of other clini-
surgical revascularization after primary PCI. Group A had restric- cal and echocardiographic parameters.36
tive mitral inflow and lower diastolic mitral annular Doppler tissue The same researchers, in a more recent study, investigated the
imaging (DTI) velocities, resulting in a high E/e′ (mitral inflow relationship between echocardiographic indices of acute and
peak early velocity/mitral annular peak early velocity of the non- chronic LV filling pressures and dilation in 47 patients after their
infarct annulus) ratio. Using peak early diastolic velocity of the first AMI.37 All patients demonstrated a patent infarct-related
lateral mitral annulus instead of the averaged peak early diastolic artery with a thrombolysis in myocardial infarction grade III flow
velocity of the non-infarcted annulus resulted in a higher E/e′ in on coronary angiography and akinesia within this arterial terri-
group A versus B.35 The E/e′ ratio and mitral inflow tory on baseline echo. Patients were prospectively designated as
E-wave DT were shown to be independent predictors of an remodeling (>15%) and nonremodeling (≤15%) groups based on
in-hospital event on multivariate stepwise logistic regression the increase in indexed LV end diastolic volume at follow-up
analysis. E/e′ ratio less than 10 and a DT less than 170 msec were echocardiography at approximately 8 weeks. In this study, E/e′
highly specific (98%) for absence of an in-hospital event. At the 6- was higher among the remodeling group, with a moderate correla-
month follow-up echocardiographic assessment, baseline mitral tion between basal E/e′ and changes in indexed LV diastolic
inflow DT was the most important determinant of later LV EF. volume (Fig. 22-8). Interestingly, LA volume index (LAVi) did
The E/e′ ratio (estimate of myocardial wall relaxation) and mitral not predict LV dilation. Both receiver operating characteristic
inflow E-wave DT (estimate of global LV filling and relaxation) (ROC) curve analysis and multivariate regression analysis con-
were superior to other echocardiographic parameters in determin- firmed that E/e′ ratio greater than 15 was a strong predictor of
ing in-hospital events and follow-up LV EF at 6 months.35 remodeling, as defined above.
Hillis et al.36 examined the prognostic value of E/e′. The study Finally, Sakata et al. investigated the prognostic value of
group consisted of all 250 patients who had both Doppler Doppler transmitral flow velocity patterns in AMI. Two hundred
transmitral flow velocities and DTI performed among patients and six patients with first AMI recruited to the study underwent
admitted for AMI at the Mayo Clinic with a clinically indicated two-dimensional and Doppler echocardiography on admission,
echo during the index admission. Patients with E/e′ greater than and hemodynamic measurements (pulmonary capillary wedge
15 were older, more likely female, more likely to present with pressure [PCWP] and cardiac index) were obtained by using a
CHF, and more often had diabetes and a history of MI. These thermodilution catheter.38 The A-wave velocity was significantly
investigators found that patients with an E/e′ ratio greater than lower in nonsurvivors than in survivors. The E-wave velocity and
15 had lower EF and a shorter DT. Twenty-nine patients died the E/A ratio were significantly higher, while DT was signifi-
during a median follow-up period of 13 months, two thirds of cantly shorter in survivors with heart failure and nonsurvivors
whom had an E/e′ ratio greater than 15. After stratifying patients than in survivors without heart failure. Comparing patients with
based on LV EF, E/e′ ratio of at least 15 predicted decreased low A and those without a low A, the low A group had a signifi-
survival in patients with an EF of 40% or greater. When DT was cantly higher frequency of mitral regurgitation, incidence of
used to further delineate the groups, E/e′ ratio greater than 15 three-vessel coronary disease, PCWP, cardiogenic shock, and a
was a powerful predictor of mortality only in patients with DT higher mortality after angioplasty or thrombolytic therapy.
greater than 140. The E/e′ ratio was the most powerful indepen- Cardiac index and LV EF, on the other hand, were significantly
dent prognostic indicator of survival after AMI on stepwise mul- lower in the low A group. The low A was strongly associated with
tivariate analysis (Fig. 22-7). The E/e′ ratio more importantly heart failure in the acute phase as well as in-hospital mortality. As
 Chapter 22 • Coronary Artery Disease 285

120 diography and tissue Doppler imaging, including deceleration

time, E/E′ ratio, and E- and A-wave velocity, are associated with
E/E′ ≤ 15 LV remodeling and predict acute in-hospital complications and
100 cardiac mortality.
Newer imaging modalities including speckle-strain imaging
and three-dimensional echocardiography in association with bio-
LVEDV (ml/m2)

80 markers (BNP, MMP, TIMP) may provide additional informa-

tion and improve understanding of diastolic function in coronary
artery disease.
60

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worsened LV compliance or increased LV diastolic volume. An 14. Gandhi SK, Powers JC, Nomeir AM, et al: The pathogenesis of acute pulmo-
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volume curve upward and leftward. Such a shift in the diastolic 15. Hess OM, Osakada G, Lavelle JF, et al: Diastolic myocardial wall stiffness
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applications for the study of diastolic function. J Am Coll Cardiol 33. Temporelli PL, Giannuzzi P, Nicolosi GL, et al: Doppler-derived mitral
1998;32:865–875. deceleration time as a strong prognostic marker of left ventricular remodel-
25. Nagueh SF, Middleton KJ, Kopelen HA, et al: Doppler tissue imaging: ing and survival after acute myocardial infarction: Results of the GISSI–3
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estimation of filling pressures. J Am Coll Cardiol 1997;30:1527–1533. 34. Poulsen SH, Jensen SE, Egstrup K: Longitudinal changes and prognostic
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27. Tabata T, Thomas JD, Klein AL: Pulmonary venous flow by Doppler echo- left ventricular diastolic versus systolic function as a predictor of
cardiography: Revisited 12 years later. J Am Coll Cardiol 2003;41:1243– outcome following primary percutaneous coronary angioplasty for
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the cause of acute left-sided heart failure associated with systemic hyperten- 36. Hillis GS, Ujino K, Mulvagh SL, et al: Echocardiographic indices of
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29. Labovitz AJ, Lewen MK, Kern M, et al: Evaluation of left ventricular systolic infarction. J Am Soc Echocardiogr 2006;19:450–456.
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 SHEMY CARASSO, MD
HARRY RAKOWSKI, MD
23
Hypertrophic
Cardiomyopathy
INTRODUCTION Prognosis
Diagnosis
PATHOPHYSIOLOGY
Differential Diagnosis
Molecular Level: Mutations and Calcium
Identification of Subclinical Disease
Economy
Clinical and Prognostic Correlates
Tissue Level: Hypertrophy, Fibrosis, and
Disarray TREATMENT
Medical
CLINICAL PRESENTATION AND PROGNOSIS
Interventional Procedures
Phenotypic Heterogeneity of Hypertrophic
Cardiomyopathy FUTURE RESEARCH
Genotype/Phenotype Relations
Origin of Symptoms

INTRODUCTION and relaxation characteristics. These include changes in the affin-

ity between the various contractile proteins and in the sensitivity
Hypertrophic cardiomyopathy (HCM) is a primary autosomal- to Ca2+, as well as in the efficiency of energy utilization (from
dominant disorder of the myocardium caused by mutations in ATP) and its expenditure.
several genes encoding cardiac contractile proteins (Fig. 23-1).
Histopathologically it is associated with myocardial hypertrophy,
fiber disarray, increased loose connective tissue, and fibrosis, Changes in Diastolic Calcium Levels
which are all thought to interfere with the generation of force and Myosin Heavy Chain Mutations
relaxation of the cardiac muscle (Fig. 23-2).1–5 Although HCM Mysosin heavy chain (MHC) mutations represent approxi-
has been traditionally described as a hyperdynamic systolic dis- mately 35% of HCM patients, and more than 50 different point
order causing obstruction of the left ventricular outflow tract mutations have been described in families or probands with
(LVOT), a large fraction of patients with HCM experience heart HCM. These are clustered in four particular locations in the S1
failure symptoms with a normal-appearing systolic function and (head/rod junction) of the protein.6,7 The Arg403Gln has been
without obstruction. This emphasizes the importance of myocar- extensively studied and is an example of a high-risk mutation. It
dial relaxation and left ventricular (LV) filling in symptom gen- lies close to the actin-binding interface7 and is a common severe
eration in this disorder. The origin of diastolic dysfunction in mutation (100% penetrance and high incidence of sudden death).
HCM is multifactorial, with changes at the molecular, myocardial Its primary result is in reduction of filament sliding velocity and
tissue, and global LV levels. diminished rate of actin-activated myosin-ATPase activity, leading
to a hypocontractile state.8–10 Diastolic function in patients with
the Arg403Gln mutation is often impaired, with an end diastolic
PATHOPHYSIOLOGY pressure (EDP) greater than 15 mmHg in most patients.11
Studies in mice12 showed two forms of diastolic dysfunction
Molecular Level: Mutations and Calcium Economy during inotropic stimulation: an increase in EDP and a slower
The mutations related to HCM result in the production of abnor- maximal rate of relaxation (−dP/dt). The most direct explana-
mal myocardial sarcomeric proteins that have altered contraction tion for impaired relaxation in αMHC403/+ hearts is that the
287
288 Chapter 23 • Hypertrophic Cardiomyopathy

Figure 23-1 Mutations in HCM. Cardiac

contraction occurs when calcium binds
the troponin complex (subunits C, I, and
T) and α-tropomyosin, making possible
the myosin-actin interaction. Actin stimu-
lates ATPase activity in the globular
myosin head and results in the produc-
tion of force along actin filaments. Cardiac
myosin binding protein C, arrayed trans-
versely along the sarcomere, binds myosin
and, when phosphorylated, modulates
contraction. In hypertrophic cardiomyop-
athy, mutations may impair these and
other protein interactions, result in inef-
fectual contraction of the sarcomere, and
produce hypertrophy and disarray of
myocytes. Percentages represent the esti-
mated frequency with which a mutation
on the corresponding gene causes
hypertrophic cardiomyopathy. (From
Spirito P, et al: The management of
hypertrophic cardiomyopathy. N Engl J Med
1997;336:775–785.)

Figure 23-2 Pathology of hypertrophic

cardiomyopathy. A, Gross pathology
demonstrating asymmetric septal
hypertrophy. B, Histopathology dem-
onstrating fibrosis (thin arrows) and
myocardial fiber disarray (thick arrows).
Magnified figure shows normal myocar-
dial architecture.

arginine-to-glutamine amino acid switch has slowed the kinetics young and adult homozygous cardiac-MyBPC knockout mice,
of actin-myosin dissociation and led to prolonged activation of isovolumic relaxation time (IVRT) was shown to be increased,
the thin filament.8 These observations indicate that the relaxation indicating that relaxation was significantly impaired.14 Skinned
dysfunction is due to altered myosin binding kinetics. At high fibers from LV papillary muscle from MyBPC mutant transgenic
work loads, αMHC403/+ hearts reach an energetic state where mice showed increased calcium sensitivity of force development
sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) is and decreased maximum power compared with control fibers.15
unable to maintain the cytoplasm–sarcoplasmic reticulum Ca2+
gradient, causing diastolic Ca2+ overload12 due to a fall in the free Cardiac Troponin T
energy stored in the high-energy phosphate bonds of ATP. Taken At least 10 mutations have been recognized in cardiac troponin
together, these observations indicate that the relaxation dysfunc- T (cTnT), including missense, truncation, and deletion muta-
tion is a primary consequence of altered myosin binding tions. Their effects include several aspects of increased function
kinetics. (higher sliding or shortening speed, higher Ca2+ affinity) and
decreased force (altered Ca2+ sensitivity, impairment of folding/
thin filament binding/sarcomere structure).16 Ca2+ sensitivity of
Changes in Sensitivity to Calcium force development increased moderately in some mutations and
Myosin Binding Protein C more dramatically in others. In one mutation, TnT(In16), both
As with MHC, there are a large number of HCM-causing the activation and the inhibition of force were significantly
mutations (both missense and truncation mutations) affecting decreased, and the mutation substantially decreased the activation
variable regions of the protein.6 Myosin binding protein C and inhibition of actin-Tm-activated myosin-ATPase activity.
(MyBPC) has modules responsible for binding to myosin fila- ATPase activation was also impaired by other TnT mutations.
ments and to titin. MyBPC does not have a solely structural role These observed changes in the Ca2+ regulation of force develop-
but is also able to participate in regulatory signals, potentially in ment would likely cause altered contractility and contribute to the
several pathways, linked through protein kinase cascades.13 In development of HCM.17 The relaxation in these fibers was also
 Chapter 23 • Hypertrophic Cardiomyopathy 289

significantly impaired. One could speculate that this mutation myocytes, and the percentage of fibrosis, with negative correla-
could result in altered stoichiometry of the thin filament proteins tions with disarray. There was a significantly negative correlation
and lead to dysfunctional interactions between the thick and thin between RFVI and wall thickness, and a significantly positive
filaments and change Ca2+-dependent interactions that would correlation between RFVI and disarray. Multiple regression anal-
ultimately result in reduced activation and relaxation during yses showed that the diameter of myocytes, the percentage of
muscle contraction.17 The data demonstrate that TnT can alter fibrosis, and disarray all correlated significantly with IVRT (r =
the rate of myosin cross-bridge detachment, and thus the tropo- 0.821) and RFVI (r = 0.604). These results indicate that diastolic
nin complex plays a significant role in modulating muscle contrac- dysfunction in HCM is related to the degree of myocardial hyper-
tile performance.18 trophy, increased interstitial fibrosis, and especially myocardial
disarrangement, including disorganization.23,24
a-Tropomyosin
Four HCM-related mutations are known, two of which change
Ca2+ sensitive troponin binding, while the other two alter actin Geometry
binding.6 In transgeneic mice, work performing ex vivo heart Dynamic diastolic pressure-volume (P-V) curves measured
preparations demonstrated dramatically decreased rate of relax- during filling (PVRfill) in patients with HCM are often consider-
ation (−dP/dt) and increased diastolic and end diastolic pres- ably shallower than would be anticipated if one assumed high
sures. Skinned fiber bundle measurements showed an increase in chamber stiffness,25–27 and they markedly deviate from the passive
maximum tension and in Ca2+ sensitivity that corresponded to a end diastolic pressure-volume relationship (EDPVR) recorded
slight increase in +dP/dt and slowing of relaxation as reflected in during balloon catheter obstruction of inferior vena cava inflow.
−dP/dt, respectively.19,20 This is in contrast to the concordance of dynamic and passive
Troponin I curves in normal subjects, hypertensive hypertrophy, and dilated
Five missense mutations were reported, along with a mutation cardiomyopathy.27 The unusual behavior in HCM cannot be
causing the deletion of one codon. Troponin I (TnI) is the attributed directly to increased viscosity, enhanced pericardial
inhibitory component of the troponin complex and is involved in constraint, or preload dependence of isovolumic relaxation.
the Ca2+ regulation of muscle contraction in both skeletal Regional heterogeneity of relaxation may play a role, but
and cardiac muscle.21 HCM TnI mutations result in (1) reduced probably the major mechanism involves the end systolic distal
inhibition of actin-tropomyosin–activated myosin ATPase by chamber being virtually emptied, so that unfolding of the chamber
the troponin complex under relaxing conditions and (2) in early diastole can accommodate substantial volumes by
increased Ca2+ sensitivity of actin-tropomyosin–activated myosin pure shape change without increasing the endocardial surface area
ATPase regulation. These functional differences may manifest and thus without stretching the myocardium.25,26 This may
themselves in vivo as impairment of relaxation of cardiac muscle account for the fact that there was very little change in LV pres-
and may provide a hypertrophic stimulus leading to the disease sure during early filling in HCM hearts, yielding shallow PVRfill.
state.21,22 This in turn may be directly related to the unique fiber and
chamber architecture seen with HCM and possibly to enhanced
Myosin Regulatory Light Chain ventricular interaction. These observations complicate the inter-
Regulatory light chains (RLCs) play an important role in pretation of diastolic P-V data in HCM, as well as conclusions
the maintenance of integrity of the thick filaments and their regarding the influence of therapies based on analysis of single
relaxed, ordered arrangement of myosin heads. Deltoid muscle cardiac cycles.27
biopsies from HCM patients with an RLC substitution mutation
demonstrated increased calcium sensitivity and loss of relaxed
order of thick filaments. The conformational change in Ischemia
peptide shape caused by the mutation may alter the degree to In HCM, exercise-induced ischemia and reduced LV distensibil-
which the RLC can support the partially naked α-helical heavy ity were demonstrated28,29 when studied by stress redistribution
chain core.13 201
Tl myocardial scintigraphy and biventricular cardiac catheter-
ization and echocardiography at rest and during exercise. The
LVEDP was significantly increased in HCM patients with
Tissue Level: Hypertrophy, Fibrosis, and Disarray ischemia, while the end diastolic dimensions did not differ
Microscopically, hypertrophy, fibrosis, and myocardial fiber dis- from patients without it, indicating reduced LV diastolic
array are hallmarks of HCM,5–9 but they also exist in other forms distensibility.28
of cardiac hypertrophy.23 Studies comparing hypertensive hyper- When LVEDP was measured serially,29 two distinct patterns
trophy to HCM correlating histopathology findings to diastolic were shown. In one, LVEDP steadily increased continuously
function showed that in both hypertensive and HCM patients, throughout exercise. In contrast, in the second pattern, LVEDP
IVRT was significantly longer, and the rapid filling volume index exhibited biphasic changes rising until a critical heart rate was
(RFVI) tended to be smaller than in the controls. While the mean achieved, after which it declined. Importantly, the LVEDP at peak
myocyte size and percentage of myocardial interstitial fibrosis did exercise in group 1 was similar to that at the critical heart rate in
not differ significantly, quantitative disarray of myocytes in HCM group 2 patients. Patients with this pattern had less exercise-
was significantly greater than that in hypertensive subjects. Mul- induced filling defects in 201Tl scintigraphy, suggesting a lower
tiple regression analysis showed that the percentage of fibrosis ischemic burden in this group. The biphasic pattern was lost with
was the most significant factor related to diastolic LV dysfunction administration of a beta-blocker prior to exercise. The biphasic
in hypertensive subjects, while disarray was the most significant changes in LVEDP seen during exercise may be related to
in HCM.23,24 In HCM patients, significant positive correlations improved coronary microcirculation in response to beta-
were observed between IVRT and wall thickness, diameter of adrenergic stimulation in patients with mild to moderate HCM.
290 Chapter 23 • Hypertrophic Cardiomyopathy

CLINICAL PRESENTATION AND PROGNOSIS HCM, particularly those that influence the extent of hypertrophy,
including the renin-angiotensin-aldosterone axis, endothelin, and
Phenotypic Heterogeneity of tumor necrosis factor (TNF), have shown conflicting results and
Hypertrophic Cardiomyopathy appear only partially to explain the observed clinical diversity in
The cardiac phenotype of HCM shows great diversity in the the extent of hypertrophy in HCM. Polymorphisms within the
extent and pattern of hypertrophy, which may be asymmetric angiotensin converting enzyme (ACE) gene have been reported
(involving mainly the interventricular septum, with or without to be associated with increased risk for sudden death.43,44 The
LVOT obstruction), concentric, or apical,30 as well as in its pen- complexities of defining genetic modifiers in human HCM popu-
etrance.31,32 The clinical course is also very variable, especially in lations remain considerable, given the substantial heterogeneity of
age of onset, existence of symptoms, disability, and predisposition genetic causes that may independently influence hypertrophy.
to sudden death.33–35 With age, the hearts of affected individuals
undergo further remodeling, manifested by changes in the Origin of Symptoms
chamber size and the extent of hypertrophy. A small subset of
affected individuals progress to LV dilatation associated with Symptoms leading to considerable disability in HCM patients are
end-stage heart failure (usually referred to as “burnt-out” caused by obstruction (LVOT, RVOT, or LV midventricular),
HCM).36,37 diastolic dysfunction with impaired relaxation and elevated filling
Progression of HCM to the burnt-out phase of disease repre- pressures, coronary artery disease, independent mitral regurgita-
sents unfavorable remodeling characterized by loss of function; tion (MR), and arrhythmia.45
wall thinning and chamber dilatation cause combined systolic and Patients with obstructive HCM typically complain of dyspnea,
diastolic dysfunction. Although this progression occurs in only angina, presyncope, syncope on exertion, or a combination thereof.
about 10% of individuals with HCM, there is evidence that Patients with nonobstructive HCM present with these symptoms
certain mutation populations are at greater risk for this clinical less frequently, and usually the symptoms are milder. Congestive
deterioration.37,38 In addition, the burnt-out phase of HCM may heart failure is uncommon in HCM in normal sinus rhythm, but
be evoked by a “second hit” in another gene, as has been reported it may be seen with severe obstruction to outflow or severe systolic
in individuals with both sarcomere protein gene and mitochon- or diastolic dysfunction, and of course it is common in the pres-
drial mutations. ence of atrial fibrillation (AF).
Patients with HCM and impaired relaxation, including those
with apical HCM, develop progressive LA enlargement and AF,
which results in severe hemodynamic deterioration because of
Genotype/Phenotype Relations the importance of atrial systole in the presence of impaired
Variability in the clinical course is explained in part by the differ- relaxation.
ent roles that mutant proteins play in the sarcomere (see Fig. Myocardial ischemia has been repeatedly demonstrated in both
23-2) and the effect of the mutation on protein structure and obstructive and nonobstructive HCM by means of fixed and
function. The β-MHC gene was the first to be identified as a reversible thallium perfusion defects; by measurement of myocar-
cause of familial HCM, and almost 100 disease-causing muta- dial lactate production, particularly during rapid atrial pacing;
tions have been defined to date that are responsible for about 35% and by positron emission tomography. Although the exact cause
of HCM cases.37 Most β-MHC mutations are located in the head of the ischemia is in some doubt, it may be related to small-vessel
and head/rod junction, and some of these mutations are recog- disease with decreased vasodilator capacity. Other factors that
nized as causing severe hypertrophy that presents clinically early could cause or contribute to ischemia are septal perforator artery
in life and demonstrate an increased risk for outflow obstruction, compression, myocardial bridging, decreased coronary perfusion
heart failure, and sudden death. pressure, obstruction to LV outflow, and decreased capillary myo-
Other β-MHC mutations may cause less severe clinical cardial fiber ratio. Impaired relaxation of the myocardium during
disease.37,39 MyBPC mutations (accounting for 15%–30% of the isovolumic and rapid filling periods could impair coronary
HCM cases) are a leading cause of late-onset HCM and are filling and result in ischemia. On the other hand, myocardial
generally associated with a good prognosis.31,32,40 TnT mutations ischemia could act to impair relaxation by a number of mecha-
(∼15% of HCM) generally cause less marked hypertrophy, with nisms. Indeed, a vicious cycle may exist in HCM that relates
poor survival. Near-normal life expectancy has been reported diminished coronary perfusion and myocardial ischemia with
with most α-tropomyosin (∼5% of HCM) and MyBPC muta- impaired diastolic relaxation and vice versa.
tions. Although this variation in clinical consequences most likely In about 20% of patients with subaortic obstruction in HCM,
reflects differences in the biophysical properties of mutant and MR is to a variable extent independent of the systolic anterior
normal peptide, factors other than these structural changes can motion, in which case other abnormalities of the mitral valve are
also influence disease expression. It has been demonstrated that present, such as anomalous papillary muscle attachment to the
the identical sarcomere mutation in different populations can anterior leaflet, mitral valve prolapse, extensive anterior leaflet
cause distinct hypertrophic morphologies and divergent clinical fibrosis due to repeated mitral leaflet/septal contact, mitral
courses.41,42 annular calcification, and other, rarer abnormalities. These inde-
Thus, although HCM-causing mutations can be identified, pendent abnormalities of the mitral valve at times cause pansys-
clinical diversity exists and is probably related to other genetic tolic MR, which is often anteriorly or centrally directed into the
phenotypes, environment, gender, and acquired conditions. These left atrium and is quite different from the late-onset, posteriorly
data also raise the possibility that some (genetic or environmental directed MR that is the result of anterior mitral leaflet systolic
or a combination of both) modifiers account for unfavorable anterior motion.46
cardiac remodeling and predisposition to adverse outcomes in AF in the vast majority of cases of HCM is related to an
HCM. Evaluation of candidate molecules as genetic modifiers of increase in LA size (usually >50 mm). Obstructive HCM with
 Chapter 23 • Hypertrophic Cardiomyopathy 291

concomitant MR is the most common cause of increased LA size curve variables and mean LA pressure were not related in HCM
and AF, but both systolic and diastolic dysfunction may also lead patients, even when the extremes of age were excluded (Figs. 23-3
to significant LA enlargement and atrial arrhythmias. The onset and 23-4).53 This may be due to a dominant influence of impaired
of AF in both obstructive and nonobstructive HCM may result relaxation on mitral inflow that overshadows the effect of increased
in cardiac failure, syncope, and systemic emboli. filling pressures.54 During left-heart catheterization, diastolic
pressures before atrial contraction were weakly related to veloci-
ties of mitral or pulmonary venous flow in HCM patients,54–57
Prognosis whereas they correlated strongly with E/e′ and with E/Vp (e′ is
In an unselected population followed prospectively,47 three dis- the early diastolic longitudinal velocity recorded at the lateral
tinctive modes of death were identified: (1) sudden and unex- mitral annulus; Vp is the flow propagation velocity of ventricular
pected (51%; age 45 ± 20), (2) progressive heart failure (36%; age filling).
56 ± 19), and (3) HCM-related stroke associated with AF (13%;
age 73 ± 14). Sudden death was most common in young patients, Left Atrial Volumes
whereas heart failure and stroke-related deaths occurred more LA volumes have been previously shown to relate to LV filling
frequently in midlife and beyond. However, neither sudden nor pressures.58 A higher incidence of abnormal diastolic filling, a
heart failure–related death showed a disproportionate age distri- higher early diastolic velocity to early diastolic mitral annular
bution. Stroke-related death did occur disproportionately in older velocity ratio, and a higher calculated LA pressure were found in
patients, 91% of whom had AF and 64% of whom had LVOT HCM patients with an LA volume index (LAVI) of at least
obstruction. 34 m3/m2.51 Moreover, LA volumetric remodeling predicts exer-
Even in patients with latent LVOT obstruction and apical cise capacity in nonobstructive HCM and may reflect chronic LV
HCM,48 the most frequent morbid event was AF. LA enlarge- diastolic burden. This simple, noninvasive measure of LA size
ment on baseline echo was identified as the only predictor of AF. may provide a long-term indication of the effects of chronically
Impaired LV relaxation in patients with HCM, including apical, elevated filling pressures in patients with HCM.59
has been previously proposed as a mechanism for progressive LA
enlargement and subsequent AF.49–51 Thus, HCM patients appear Newer Doppler Echocardiographic Indices
to have a four- to sixfold greater likelihood of developing AF
compared with the general population, and it will occur in about Myocardial Velocities by Tissue Doppler Imaging
a third of them. AF prevalence increased progressively with age Patients with HCM demonstrate delayed and reduced longi-
and LA size, which in turn is related to the degree of hypertrophy, tudinal myocardial velocities and time-velocity integrals during
severity of MR, and diastolic dysfunction. It is predominant in early diastole.60 They also have lower velocities during atrial con-
patients older than 60 years, but it is not rare in younger patients traction and prolonged regional deceleration times and IVRTs.
(<50 years), in whom it is associated with higher risk for clinical Larger changes in regional diastolic function were found in
deterioration and HCM-related death.52 patients with mitral inflow E/A ratio below 1,60 and the difference
in duration between mitral inflow and retrograde pulmonary
venous flow during atrial systole (Ar-A) correlates with elevated
Diagnosis LA pressure54 and with abnormal collagen metabolism in patients
Conventional Doppler Echocardiography with HCM.61
Mitral and Pulmonary Venous Flow Velocities Myocardial Velocity Gradient
Estimation of LV filling pressures by flow Doppler echocardio- A reduced myocardial velocity gradient (MVG), defined as the
graphic methods is unreliable in HCM.53–57 Mitral flow velocity difference in myocardial velocity between the endocardium and

E
E
E DT=220 msec
DT=220 msec DT=200 msec
A LV A LV

Mean LAP Mean LAP Mean LAP

9 mmHg 14 mmHg 30 mmHg
DT 220; LAP 9 DT 220; LAP 14 DT 200; LAP 30
Figure 23-3 Hypertrophic cardiomyopathy: deceleration time (DT) and mean left atrial pressure (LAP).53 Mitral inflow Doppler velocities and simultaneous
left ventricular and LA pressure recordings are shown in three patients with similar transmitral early (E) and atrial (A) filling velocities and similar DT. Note
that the mean LAPs are 9, 14, and 30 mmHg, respectively. This demonstrates the limitations of mitral inflow velocities in predicting LAP, since impaired
relaxation overwhelms changes in filling pressures. (From Nishimura R, et al: Noninvasive Doppler echocardiographic evaluation of left ventricular filling pres-
sures in patients with cardiomyopathies: A simultaneous Doppler echocardiographic and cardiac catheterization study. J Am Coll Cardiol 1996;28:1226–1233.)
292 Chapter 23 • Hypertrophic Cardiomyopathy

E¢

A B
Mitral
E = 87 cm/sec
A = 50 cm/sec
E/A = 1.7
S DT = 150 ms
D Annular = E′=8 cm/sec
E/E′=10.9
Pulmonary vein
PVS = 58 cm/sec
PVD = 40 cm/sec
PVAR = 50 cm/sec
AR
C
Figure 23-4 Mitral inflow and tissue annular velocities in apical hypertrophic cardiomyopathy (HCM). This patient with apical HCM complained of dyspnea
on exertion and has Stage 2 diastolic dysfunction using mitral inflow and pulmonary vein flow velocities with a large atrial reversal. The use of E/E′ confirms
an elevated LAP. A, Mitral inflow; B, Annular tissue velocities; C, Pulmonary venous velocities. Estimated LAP: 87/8 × 1.24 + 1.9 = 15 mmHg. DT, deceleration
time; LAP, left atrial pressure.

the epicardium divided by myocardial wall thickness during trols, asynchrony was increased in mid- and late diastole, and
diastole in HCM, reflects prolonged relaxation. It may also reflect regional filling times were prolonged even in nonhypertrophied
an elevated LV EDP (Fig. 23-5).40,62 MVG is less affected segments.
by preload alterations than by mitral inflow velocity pattern.63
During simultaneous LV pressures with tissue Doppler wave-
Myocardial Strain and Strain Rate
forms comparing HCM patients with controls, the peak
The assessment of myocardial muscle shortening (strain) and
negative MVG during rapid filling was lower in HCM, and a
its rate are new tools in cardiac imaging. Strain may be
cutoff value of 3.2/s discriminated well. HCM patients had
evaluated noninvasively by tagging on magnetic resonance imaging
higher EDPs (mean, 19.6 mmHg vs. 6.5 mmHg) and longer time
(MRI) and by echocardiography.68–73 MRI studies have shown
constants of LV pressure decay (Tau, τ); MVG correlated
reduced longitudinal strain and early diastolic strain rate. Circum-
inversely with both.62 In HCM patients, τ has been reported to
ferential strain was less documented and was found to be
inversely correlate with the myocardial peak early diastolic motion
either normal or slightly reduced in HCM.68,69 Strain rate imaging
velocity.64
by tissue Doppler calculates velocity differences between two
adjacent points to generate a strain rate/time curve, which is
Echocardiographic Indices of then integrated to calculate strain (Fig. 23-6). This method is
Mechanical Dyssynchrony restricted mostly to the evaluation of longitudinal indices by the
In HCM, longitudinal velocities around the LV base vary con- alignment of the interrogation beam. By this method, longitudi-
siderably, and a “heterogeneity index” (the average difference nal strain in patients has been shown to be reduced compared
between individual velocity measurements and their means) can with controls.73
be calculated.65 Patients with HCM exhibit increased regional Newer methods analyze two-dimensional B-mode images by
variations or asynchrony in the time to peak systolic velocity and tissue tracking74–78 and allow for direct measurement of regional
in the duration of ejection.66 Diastolic function is also asynchro- tissue displacement, shortening (strain) and strain rate both lon-
nous, since patients with HCM have a high myocardial E/A gitudinally and circumferentially and combining them into a
heterogeneity index67 and more variation in the times from aortic three-dimensional model. Circumferential LV rotation can
valve closure to peak myocardial E velocity in different segments.64 also be calculated. Our data77,78 are in support of the reduction of
These observations are supported by a study of color kinesis in the longitudinal strain shown previously, while the circumferen-
patients with HCM, using time curves of regional LV filling in a tial strain was found to be increased. Longitudinal strain rate E
short-axis view.67 The percent filling fractions at 25%, 50%, was decreased by 23%, and circumferential strain rate E was
and 75% of total filling were averaged for all segments in each increased by 37%, reflecting the decreased longitudinal strain and
patient, and the standard deviation of each mean was used as an strain rate S and their increased circumferential values in HCM
“asynchrony index.” In subjects with HCM compared with con- (Fig. 23-7A). Both longitudinal and circumferential strain rate
 Chapter 23 • Hypertrophic Cardiomyopathy 293

Figure 23-5 Myocardial velocity gradients (MVGs) in hypertrophic cardiomyopathy (HCM) and athletes. Examples of Doppler myocardial M-mode images
taken from the left ventricular (LV) posterior wall with calculated MVG. A, Male patient with HCM (age 36 years) with markedly hypertrophied LV posterior
wall (1.9 cm). B, Male patient with HCM (age 23) with borderline LV posterior wall thickness (1.2 cm). C, Male athlete’s heart (age 25) with mild LV posterior
wall hypertrophy (1.3 cm). Arrows show the peak values of the MVG and the normalized rate of the LV posterior wall systolic thickening during phases of
the cardiac cycle. Asterisks indicate that MVG measured during right ventricular filling was markedly decreased in both HCM hearts (A and B) compared
with the athlete’s heart (C). In contrast, the peak rate of wall thinning, assessed from a digitized grayscale M-mode image, did not show significant changes
during right ventricular filling between the patient with HCM with borderline hypertrophy (B) and the athlete (C). AC, atrial contraction; RVF, rapid ven-
tricular filling; VE, ventricular ejection. (From Palka P, et al: Differences in myocardial velocity gradient measured throughout the cardiac cycle in patients with
hypertrophic cardiomyopathy, athletes and patients with left ventricular hypertrophy due to hypertension. J Am Coll Cardiol 1997;30:760–768.)

E/S ratio decreased significantly, indicating impaired relaxation. timing of motion or contraction), whereas athletes have normal
Functional status (New York Heart Association class greater than or supranormal function.65,79 Tissue Doppler is very helpful for
I) was found to be related to decreased basal and midlongitudinal discriminating between these conditions, and normal longitudinal
strain rate E. The LV twist angle (maximal instantaneous basal function (mean systolic annular velocity <9 cm/sec)65 has a high
to apical angle difference) was similar, but time to peak twist negative predictive value. Individuals with HCM have lower dia-
was decreased by 13%, and untwist time (peak to trough twist) stolic velocities and prolonged isovolumetric relaxation.79 In one
was lengthened by 16%, also implying delayed relaxation (see study, a value of less than 1 for the tissue Doppler E/A ratio was
Fig. 23-7B). shown to be specific but not sensitive for differentiating HCM
from athlete’s heart.80 A peak early diastolic MVG of at least 7 s−1
Differential Diagnosis differentiated well between patients with HCM and athletes, in
a young population (mean age 30) (see Fig. 23-6).40 In athlete’s
Hypertrophic Cardiomyopathy Versus Hypertensive heart, early diastolic velocity at the tricuspid annulus correlates
Left Ventricular Hypertrophy with LV end diastolic diameter, inversely related to septal thick-
Systolic velocities have been shown to be similarly reduced in ness.79 A tricuspid annular e velocity less than 0.16 m/sec differ-
HCM and hypertensive LV hypertrophy (LVH), with longer iso- entiated between HCM and athlete’s heart with 89% sensitivity
volumetric contraction and prolonged pre-ejection times in HCM and 93% specificity.81
compared with hypertensive patients. In HCM, the early diastolic
velocity tends to be lower with increased heterogeneity of annular Identification of Subclinical Disease
systolic velocities. Diastolic function is also more impaired in
HCM, with lower velocities, higher heterogeneity, and longer Subclinical disease implicates a negative phenotype with a positive
IVRT.65,79 The MVG is also reduced in late diastole in HCM HCM genotype. In a transgenic model of HCM,82 myocardial
compared with hypertensive disease.62 These comparisons are velocities were shown to be reduced. Systolic and early diastolic
somewhat confounded by younger mean age of HCM patients. velocities were shown to be significantly lower in subjects with
HCM mutations, whether or not they had LVH when blindly
compared with controls.83 A lateral annular systolic velocity less
Hypertrophic Cardiomyopathy Versus
than 13 cm/sec had excellent sensitivity and specificity for iden-
Athlete’s Heart tifying subjects with mutations but no LVH (see Table 23-1). In
The discrimination between HCM and athlete’s heart is not a similar study comparing controls and patients with proven β-
trivial and may have significant personal implications on an ath- MHC mutations (with and without LVH), the mean myocardial
lete’s career (ending it) and life (risking its end by sudden death). early diastolic velocity was lower in patients with a mutation but
Patients with HCM have impaired systolic and diastolic function no LVH,84 with a substantial overlap with the control group. In
with both heterogeneity (of velocities) and dyssynchrony (of follow-up of 12 patients with β-MHC mutations (7 with MyBPC
294 Chapter 23 • Hypertrophic Cardiomyopathy

Figure 23-6 Reduced longitudinal

strain in hypertrophic cardiomyopathy
(HCM) by Doppler strain rate imaging.
Different strain patterns in control
patients and patients with HCM. Yellow,
green, and red lines represent strain in
basal, mid, and apical segments, respec-
tively. A, Strain in healthy control.
B, Strain in a patient with HCM. Note the
lower maximal strain in HCM (8%) com-
pared with normal (15%). (From Palka P,
et al: Differences in myocardial velocity
gradient measured throughout the
cardiac cycle in patients with hyper-
trophic cardiomyopathy, athletes and
patients with left ventricular hypertrophy
due to hypertension. J Am Coll Cardiol
1997;30:760–768.)

mutations) but no LVH when first examined, septal thickness diastolic velocities of lateral and septal annular motion were
and LV mass had increased after 2 years, and 6 patients met reduced in HCM compared with normal controls, and the E/E′
diagnostic criteria for HCM.85 These studies suggest that tissue ratio correlated with symptomatic class and inversely with peak
Doppler may be very useful for early diagnosis or screening, but oxygen consumption.86,87 Our data also show that the clinical
much larger studies are needed before clear diagnostic criteria can functional class77,78 is related to the early basal and midlongitudi-
be proposed. Troponin T mutations present a major diagnostic nal diastolic strain rate.
challenge because of their very mild LVH and their high risk of The practical approach to echocardiographic assessment of
sudden death. Tissue Doppler findings, especially diastolic veloci- diastolic function in HCM includes the combination of two-
ties, may prove to be of prognostic value in future studies. dimensional, Doppler, and tissue Doppler information. Table 23-1
outlines this approach.
Clinical and Prognostic Correlates
TREATMENT
A high ratio of early diastolic mitral inflow velocity to mitral
septal annular tissue velocity (E/E′) predicted death, cardiac Medical
arrest, or ventricular tachycardia in children observed for 26
months.86 Patients with HCM and LA enlargement had more Beta Blockers and Calcium Channel Blockers
serious cardiovascular events and demonstrated greater LVH, With symptoms it is conventional to initiate pharmacological
more diastolic dysfunction, and higher filling pressures.51 Early therapy with negative inotropic drugs such as β-adrenergic
 Chapter 23 • Hypertrophic Cardiomyopathy 295

STRAIN RATE

Strain rate absolute value (%/s)

Normal
3.5 HCM
3
2.5
2
1.5
1
0.5 S E S E S E S E
0
Base Mid Apex
Longitudinal Circumferential
A
TWIST ANGLE

4.5 Twist
Normal
4 HCM
3.5

Angle (degrees)
3
2.5
Figure 23-7 Strain rate and twist by tissue strain imaging. A, Lon- 2
gitudinal and circumferential systolic and early diastolic strain rate 1.5
in normal controls and hypertrophic cardiomyopathy (HCM) Untwist
patients. Longitudinal systolic and diastolic strain rates are 1
decreased in HCM, whereas circumferential strain rates are 0.5
increased. Diastolic-to-systolic strain rate ratio is decreased in both
planes. S and E denote peak systolic and early diastolic strain rates, 0
respectively. B, Left ventricular twist (instantaneous base to apex 0 20 40 60 80 100
rotation angle difference). Earlier systolic peak twist (solid arrows)
Time (percent cycle length)
and prolonged (dashed arrows) untwist are demonstrated in HCM
patients. B

TABLE 23-1 blockers or verapamil, independent of whether outflow obstruc-

tion is present.88,89 Beta blockers relieve LVOT obstruction, and
A PRACTICAL APPROACH TO ECHOCARDIOGRAPHIC both beta blockers and verapamil influence ventricular diastolic
ASSESSMENT OF DIASTOLIC FUNCTION IN function as well. Propranolol has been shown to shorten relax-
HYPERTROPHIC CARDIOMYOPATHY ation time in a dose-dependent fashion, up to its normalization
at high dosages.90 LV diastolic stiffness in patients with HCM is
ECHOCARDIOGRAPHIC MODALITY PARAMETERS
not affected by propranolol and verapamil.91,92 In tropomyosin
Two-dimensional LA dimension (Tm)-mutated mice (E180G), diastolic dysfunction was abol-
echo ished during β-blockade because propranolol eliminated the effect
LA volume of Tm to slow myocardial relaxation.93
Flow Doppler Mitral inflow E
A Verapamil
IVRT The effect of verapamil on LVOT obstruction is less predict-
Pulmonary veins S
D
able, as it is also a potent vasodilator that can dangerously increase
A reversal the outflow gradient.89 LV diastolic stiffness has been shown to
Tissue Doppler Mitral annular longitudinal E′ remain unchanged in patients with HCM as with propranolol,
velocity and improved LV relaxation and mean diastolic filling were more
Multimodality Left atrial pressure estimation
( E′E × 1.24) + 1.9 consistent with verapamil than with beta blockers. Thus, the ben-
eficial effect of verapamil on diastolic mechanics was found to be
related to improved relaxation and diastolic filling rather than to
LA, left ventricular; E, early diastolic filling; A, late atrial contraction; IVRT, isovolumic changes in LV diastolic stiffness.91,92
relaxation time; S, systolic; D, diastolic.
From Nagueh et al: Doppler tissue imaging: A noninvasive technique for evaluation of L-Type Calcium Channel Blockers
left ventricular relaxation and estimation of filling pressures. JACC 1997;30:1527–33. Diltiazem has been shown to normalize tissue Doppler peak
systolic and early diastolic velocities at the lateral mitral annulus in
asymptomatic patients with MyBPC mutations.94 In TnT mutant
296 Chapter 23 • Hypertrophic Cardiomyopathy

mice stressed by isoproternol, severe diastolic heart failure and

sudden death were prevented by pretreatment with diltiazem.95
Disopyramide
A 1C anti-arrhythmic drug, disopyramide is a potent negative
inotropic agent used in the treatment of obstructive HCM. Few
studies have approached its effect on diastolic function in HCM
patients. Its main effect seems to be improvement in filling
(increased E, E/A ratio, decreased time interval from mitral valve
opening to the O point in the apexcardiogram) that is related to A
the reduction of the LVOT gradient.96–98
Other Drugs
Nicorandil, a potassium channel activator whose main effect is
anti-ischemic, has been shown to improve EDP during stress tests
in HCM patients.99 Recent studies in animal models of HCM
have shown that losartan and simvastatin can reverse the evolving
cardiac phenotype.100,101 Aldosterone is a fundamental “molecular
bridge” between enhanced collagen turnover in HCM and the
cardiac phenotype.102 Therefore spironolactone might also be B
beneficial but its potential benefits remain unproven.

Interventional Procedures
Septal ablation by alcohol and septal myectomy reduce Doppler-
estimated τ, increase mitral annulus Ea velocity, and decrease
pulmonary artery wedge pressure. Moreover, mitral inflow veloc-
ity propagation (Vp) assessed by color Doppler M-mode shows
improvement of LV relaxation after septal reduction by increasing
the intraventricular pressure gradient, or “suction,” during early C
diastole.103–105 Tissue Doppler strain rate imaging has shown
normalization of diastolic dyssynchrony with septal ethanol abla-
tion.106 Decreased afterload and an increased cardiac output due
to the relief of the obstruction may lead to increased coronary
flow and improved myocardial perfusion,107 which may in turn
benefit LV relaxation. Also, the regression of hypertrophy and the
changes in LV geometry that occur after septal reduction therapy,
as shown in the present and previous studies,108,109 may also par-
tially explain the improvement in diastolic function (Fig. 23-8).
D
Figure 23-8 Mitral inflow velocity and propagation velocity before
FUTURE RESEARCH and after septal ethanol ablation (SEA). Representative images of the
improvement in color M-mode Doppler (CMM) and mitral inflow pulsed
Doppler before (A and B, respectively) and after (C and D, respectively)
The origin of diastolic dysfunction in HCM is multifactorial. SEA. Note increasing mitral velocity propagation (panel A vs. C) and nor-
These factors range from molecular abnormalities in sarcomeric malization of restrictive mitral inflow (panel B vs. D) after the procedure. E
proteins and calcium metabolism and sensitivity, to tissue-level and A denote early and late mitral inflow velocities, while Vp is the flow
factors such as hypertrophy, fibrosis, and disarray, to global propagation.
ventricular geometric abnormalities and oxygen demand/supply
mismatch.
Symptoms in HCM are related to systolic obstruction and to REFERENCES
the degree of diastolic dysfunction. Diastolic dysfunction leads
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 Chapter 23 • Hypertrophic Cardiomyopathy 297
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 TRACI L. JURRENS, MD
NASER M. AMMASH, MD
JAE K. OH, MD
24
Pericardial Diseases:
Constriction and
Pericardial Effusion

INTRODUCTION Echocardiography
Chest X-ray, Computed Tomography, and
PATHOPHYSIOLOGY
Magnetic Resonance Imaging
Constrictive Pericarditis Versus Restrictive
Treatment
Cardiomyopathy
Clinical Presentations and Physical CLINICAL RELEVANCE
Examination Findings
SUMMARY AND FUTURE RESEARCH
Electrocardiogram and Brain Natriuretic
Peptide

INTRODUCTION pathophysiology of cardiac tamponade and constrictive pericardi-

tis (CP). Ventricular interdependence within a normal pericar-
Normal pericardium consists of an outer sac, the fibrous pericar- dium is not noticeable clinically but becomes more marked when
dium; and an inner double-layered sac, the serous pericardium. filling pressure becomes high or diastolic filling is limited. Among
The visceral layer of the serous pericardium, or epicardium, covers much pathology involving the pericardium, none is more fascinat-
the heart and proximal great vessels. It is reflected to form the ing than CP in terms of characteristic hemodynamics, clinical
parietal pericardium, which lines the fibrous pericardium (Fig. presentations, physical examination findings, and difficulty of
24-1). The pericardium provides mechanical protection for the diagnosis. This chapter will focus mainly on the underlying patho-
heart and lubrication to reduce friction between the heart and sur- physiology, clinical presentations, characteristic diagnostic fea-
rounding structures. The pericardium also has a significant hemo- tures, various forms, and treatments of CP.
dynamic impact on the atria and ventricles. The nondistendible Acute accumulation of pericardial effusion results in sudden
pericardium limits acute distention of the heart (see Chapter 2). hemodynamic deterioration, as in cardiac rupture or hemoperi-
Ventricular volume is greater at any given ventricular filling cardium. Detection of this acute cardiac tamponade is relatively
pressure with the pericardium removed than with the pericar- easy by characteristic clinical setting (acute myocardial infarction,
dium intact. The pericardium also contributes to diastolic cou- aortic dissection, or invasive cardiac procedure) and two-
pling between two ventricles: The distention of one ventricle dimensional echocardiographic findings of hemopericardium.
alters the filling of the other, an effect that is important in the This entity is not discussed in this chapter. Subacute or chronic
301
302 Chapter 24 • Pericardial Diseases: Constriction and Pericardial Effusion

pericardial effusion may create prominent right-heart failure, the tilage, adherent to its interior so that the blood could scarcely
presentation of which may be similar to CP; and not infrequently, enter the ventricle,”1 illustrating diastolic filling abnormality of
CP presents with varying degrees of pericardial effusion, includ- this disorder. Several hundred years passed before the first publi-
ing a presentation similar to cardiac tamponade, but hemo- cation mentioning the hemodynamics of CP appeared in 1946
dynamic abnormality persists after removal of pericardial effu- from New York University. Cournand and Richards, who received
sion. This condition is called effusive-constrictive pericarditis and the Nobel Prize for their work on cardiac catheterization,
will be discussed at further length at the end of this chapter. described the pressure tracing of CP in a 30-year-old patient,
Interest in the pericardium dates back to antiquity. Hippocrates resembling right ventricular (RV) failure with “certain additional
mentioned the “smooth mantle surrounding the heart and con- features.”2 The additional features include normal ventricular sys-
taining a small amount of fluid resembling urine.”1 In the 17th- tolic pressure, low ventricular pulse pressure, a marked elevation
century, a Cornish clinician, John Mayow, described the gross of mean atrial and ventricular diastolic pressure, and the promi-
appearance of CP in his patient’s heart as “nearly covered by car- nence of early diastolic dip in atrial and ventricular pressure. At
that time, the hemodynamics of restrictive cardiomyopathy (RC)
were not firmly established, and subsequently it was recognized
that the hemodynamic features of CP were similar to those of
RC.3 Sixty years later, the same hemodynamic criteria are still
being used in most cardiac catheterization laboratories to diag-
nose CP, although the criteria lack specificity. More insights into
the pathophysiology and unique hemodynamic features of CP
have established more specific diagnostic criteria for constriction,
which can be demonstrated by noninvasive two-dimensional
Doppler echocardiography, as well as by invasive cardiac hemo-
dynamic measurements.
The diagnosis of CP is often overlooked, since ventricular sys-
tolic function is usually well preserved, and clinical manifestations
can involve other organs, leading to investigation of noncardiac
abnormalities before consideration of a pericardial disease. When
discussing CP, it is impossible not to mention RC as well. Although
CP and RC are two very different entities, they appear similar
Figure 24-1 Normal pericardium consists of an outer sac, the fibrous peri- superficially. The hemodynamic end products of the constriction
cardium, and an inner double-layered sac, the serous pericardium. The and restriction are almost identical, which makes their distinction
visceral layer of the serous pericardium, or epicardium, covers the heart difficult if not impossible by a casual inspection of a patient’s
and proximal great vessels. It is reflected to form the parietal pericardium,
which lines the fibrous pericardium. The pericardium provides mechanical hemodynamic status. It is essential to demonstrate features unique
protection for the heart and lubrication to reduce friction between the to each condition and that are not present in other conditions.
heart and surrounding structures. The pericardium also has a significant This chapter will, therefore, also describe the similarities and
hemodynamic impact on the atria and ventricles. The nondistendible peri- differences between constriction and restriction in their clinical
cardium limits acute distention of the heart. Ventricular volume is greater
at any given ventricular filling pressure with the pericardium removed than
characteristics, hemodynamic profiles, and laboratory data.
with the pericardium intact. The pericardium also contributes to diastolic
coupling between two ventricles: The distention of one ventricle alters the
filling of the other, an effect that is important in the pathophysiology of PATHOPHYSIOLOGY
cardiac tamponade and constrictive pericarditis. Ventricular interdepen-
dence becomes more marked at high ventricular filling pressures. Abnor-
malities of the pericardium can range from the pleuritic chest pain of CP is caused by noncompliant and usually (but not always) thick-
pericarditis to marked heart failure and even death from tamponade or ened pericardium (Fig. 24-2). The pericardium becomes abnor-
constriction. (Courtesy of William D. Edwards, MD). mal because of damage from inflammation, radiation, trauma, or

Figure 24-2 A, Pathology specimen of

typical constrictive pericarditis. The
figure shows a thickened and fibrotic
pericardium, which limits diastolic filling
and can lead to heart failure despite
normal systolic function. Since constric-
tion is a curable entity, it should be con-
sidered in patients with heart failure
and normal systolic function. B, Pathol-
ogy specimen of idiopathic restrictive
cardiomyopathy demonstrating promi-
nent biatrial enlargement with normal-
sized ventricles. (A, Courtesy of William
D. Edwards, MD; B, From Ammash NM
et al: Clinical profile and outcome of idio-
A B pathic restrictive cardiomyopathy. Circu-
lation 2000;101:2490–2496.)
 Chapter 24 • Pericardial Diseases: Constriction and Pericardial Effusion 303

an autoimmune process. A majority of patients with CP do have

an underlying etiology, although this cannot be determined in a
third of patients.4 In regions where tuberculosis is common, this
is still the most frequent etiology for CP,5 but in the current era,
previous cardiac surgery is the most common etiology in the
United States,4 accounting for one third of surgically confirmed
cases of CP, followed by acute pericarditis, radiation, and collagen
vascular disease. Therefore, CP should always be considered if a
patient presents with heart failure, normal ejection fraction, and
history of one of the associated conditions. In CP, the atria and
inferior vena cava are enlarged secondary to limited ventricular
filling and high filling pressure. Ventricular septal thickness is not
increased but shows a characteristic motion with respiratory
septal shift. Figure 24-3 Simultaneous pressure recordings from the left ventricle (LV)
and pulmonary capillary wedge (PCW), together with mitral inflow velocity
on a Doppler echocardiogram. The onset of the respiratory phase is indi-
Constrictive Pericarditis Versus cated at the bottom. With the onset of expiration (Exp), PCW pressure
Restrictive Cardiomyopathy increases much more than LV diastolic pressure, creating a large driving
pressure gradient (large arrowhead). With inspiration (Insp), however, PCW
By definition, RC is a myocardial disease causing primarily dia- pressure decreases much more than LV diastolic pressure, with a very small
stolic dysfunction and heart failure similar to CP (see Chapter driving pressure gradient (three small arrowheads). These respiratory
changes in the LV filling gradient are well reflected by the changes in the
21).6 RC can be idiopathic or secondary to infiltrative disease such mitral inflow velocities recorded on Doppler echocardiography. (From Oh
as amyloidosis or sarcoidosis, or a storage disease such as Fabry’s JK et al: The echo manual, 2nd ed, Lippincott Williams & Wilkins, 1999.)
disease. It has been also reported to occur secondary to hypereo-
sinophilic syndrome, radiation, scleroderma, and medications
such as chloroquine. Idiopathic or primary RC has distinct mor- ventricle and the pulmonary capillary wedge, together with mitral
phologic features that include nondilated, nonhypertrophied ven- inflow velocities (Fig. 24-3).
tricles with biatrial enlargement (see Fig. 24-2B). On the other A thickened or inflamed pericardium prevents full trans-
hand, left ventricular (LV) wall thickness in secondary RC is mission of the intrathoracic pressure changes that occur with
usually increased, and there may be an overlap with the nonob- respiration to the pericardial and intracardiac cavities, creating
structive form of hypertrophic cardiomyopathy. Despite the dif- respiratory variations in the left-sided filling pressure gradient
ferent pathophysiologic mechanisms of CP and RC, they share (the pressure difference between the pulmonary vein and the left
many similar hemodynamic findings when measured by cardiac atrium). With inspiration, intrathoracic pressure falls (3 to
catheterization. Both have increased atrial pressures and equaliza- 5 mmHg normally), and the pressure in other intrathoracic struc-
tion of end diastolic pressures although the equalization is more tures (pulmonary vein, pulmonary capillaries) falls to a similar
common in CP.7 degree. This inspiratory pressure change is not fully transmitted
The “dip and plateau” pattern seen in ventricular diastolic pres- to the intrapericardial and intracardiac cavities. As a result, the
sure tracings has classically been associated with constriction. driving pressure gradient for LV filling decreases immediately
This finding, which reflects rapid early diastolic filling of the ven- after inspiration and increases with expiration.
tricles, followed by an abrupt cessation of filling in mid- and late
diastole, is also found in RC, which is characterized by the non-
compliant myocardium and limited ventricular filling during the Interventricular Dependence
mid- and late diastolic period. Therefore, there is a substantial Diastolic filling (or distensibility) of the left and right ventricles
overlap in hemodynamic features between CP and diastolic heart is interdependent because the overall cardiac volume is relatively
failure due to myocardial diseases. To distinguish one from the fixed within the thickened or noncompliant (adherent) pericar-
other condition, which is critical in providing an appropriate man- dium. Hence, reciprocal respiratory changes occur in the filling of
agement, diagnostic features specific to a condition should be both ventricles. With inspiration, decreased LV filling allows
identified. There are two unique features in CP: (1) dissociation increased filling in the right ventricle. As a result, the ventricular
between intrathoracic and intracardiac pressures, which vary with septum shifts to the left, and tricuspid inflow E velocity and
respiration, and (2) increased interventricular coupling or depen- hepatic vein diastolic forward-flow velocity increase (Fig. 24-4).
dence due to a relatively fixed combined volume of the left and With expiration, LV filling increases, causing the ventricular
right ventricles within the constrictive pericardium. These unique septum to shift to the right, which limits RV filling. Tricuspid
features result in characteristic respiratory variation in diastolic inflow decreases and hepatic vein diastolic forward flow decreases,
filling, ventricular pressures, and Doppler velocities representing with increased flow reversals during diastole. Usually, diastolic
diastolic filling.8 forward-flow velocity is higher than systolic forward-flow velocity
in the hepatic vein, which corresponds to the Y and X waves,
respectively, of systemic venous pressure. It needs to be empha-
Intrathoracic-Intracardiac Dissociation sized that the respiratory variation in ventricular filling is initiated
The dissociation between intrathoracic and intracardiac pressures from the left side, which is also evident from careful inspection of
in constriction causes respiratory variation in pressure difference simultaneous pressure tracings from the left and right ventricles.
between pulmonary capillary wedge pressure (PCWP) and LV In CP, the fluctuation in the PCWP is more marked in parallel
diastolic pressure. This characteristic hemodynamic pattern is with intrathoracic pressure changes than fluctuation in left atrial
best illustrated by simultaneous pressure recordings from the left (LA) and LV diastolic pressure. Ventricular interdependence also
304 Chapter 24 • Pericardial Diseases: Constriction and Pericardial Effusion

is observed in simultaneous recordings of LV and RV pressures. there is a large overlap of the hemodynamic values between con-
With inspiration, which induces less filling of the left ventricle, striction and restriction.8 If cardiac catheterization is performed
LV peak systolic pressure decreases; the opposite changes occur for evaluation of CP, the discordant respiratory change between
in the right ventricle, so that RV peak systolic pressure increases RV and LV pressures during inspiration should be looked for as
with inspiration.9 Their ejection time also varies with respiration a sign of interdependence of ventricular filling.9
in opposite directions in the left and right ventricles. This discor-
dant pressure change between the ventricles in CP does not occur
in RC (Fig. 24-5). Clinical Presentations and Physical
Therefore, invasively or noninvasively, the diagnostic criteria of Examination Findings
restriction and constriction should be based on the respiratory Clinical presentations of CP are protean and nonspecific, but
changes of ventricular filling and hemodynamic features instead almost all patients do have symptoms and signs of heart failure.
of previously proposed criteria using the level of systolic RV pres- Dyspnea, edema, ascites, and fatigue are common symptoms. Less
sure or equalization of ventricular end diastolic pressures, because common symptoms, but important to remember, are chest
pain, gastrointestinal adversities, hypotension with tamponade
(effusive-constrictive), arrhythmia, and right upper quadrant pain
from hepatic congestion. Two thirds of the patients with CP do
S D have an underlying etiology, as we have noted. On physical exami-
HV PV
nation, jugular venous pressure ( JVP) is almost always elevated
with rapid “y” descent. However, JVP rises further with inspira-
tion in CP (which is called Kussmaul sign). Systemic and pulmo-
nary venous congestion are parts of clinical presentations in both
LA
LA

constriction and restriction. Ascites and hepatomegaly are more

A
A

common in CP, and this may lead a physician to evaluate an

R
R

abnormality in the liver or abdomen.

LV
LV

Among patients who were referred to our medical center and

RV

Thickened found to have CP, more than a third of them had undergone a
RV

pericardium gastrointestinal procedure or liver biopsy or sometimes both prior

to their referral. If JVP is found to be elevated in patients with
hepatomegaly or ascites, right-heart failure as an underlying
Inspiration Expiration
PCW cardiac abnormality, including CP, should be strongly considered.
Pulsus paradoxus may be present in patients with CP but is less
IP common than in cardiac tamponade. Pulmonary venous conges-
Figure 24-4 Schematic diagram of differential ventricular filling varying tion is more common in RC than in CP, and this is a poor prog-
with respiration. Pulmonary capillary wedge (PCW) pressure changes with nostic sign. Characteristically, a third heart sound is heard in both
respiration while intrapericardial (IP) or left ventricular (LV) diastolic pres-
sure changes minimally with respiration. Diastolic filling (or distensibility) constriction and restriction, and it is difficult to distinguish them
of the left and right ventricles is interdependent because the overall based on cardiac auscultation. The third heart sound corresponds
cardiac volume is relatively fixed within the thickened or noncompliant to the time of the end of early rapid filling and the nadir of the
pericardium. Hence, reciprocal respiratory changes occur in the filling of “y” descent in atrial pressure tracings. In CP, this diastolic gallop
both ventricles. With inspiration, decreased LV filling allows increased
filling in the right ventricle. As a result, the ventricular septum shifts to the
sound is called a pericardial knock.
left, and tricuspid inflow E velocity and hepatic vein diastolic forward-flow
velocity increase. With expiration, LV filling increases, causing the ventricu-
lar septum to shift to the right, which limits RV filling. Tricuspid inflow Electrocardiogram and Brain Natriuretic Peptide
decreases, as does hepatic vein diastolic forward flow, with significant flow Electrocardiography is nonspecific for both CP and RC, although
reversals during diastole. Usually, diastolic forward-flow velocity is higher
than systolic forward-flow velocity in the hepatic vein, which corresponds low QRS voltage in the setting of increased LV wall thickness
to the Y and X waves, respectively, of systemic venous pressure. (From Oh strongly suggests cardiac amyloidosis. Brain natriuretic peptide
JK et al: The echo manual, 2nd ed, Lippincott Williams & Wilkins, 1999.) (BNP) is usually elevated in patients with RC and relatively

RCM CONSTRICTION
Figure 24-5 Simultaneous recordings
100 INSP of left ventricular (LV) and right
ventricular (RV) pressures in restrictive
EXP
150 cardiomyopathy and constrictive peri-
LV LV carditis. Ventricular interdependence is
shown with constriction. On inspira-
100 tion, there is less filling of the left
ventricle, so LV peak systolic pressure
50 decreases. The opposite changes occur
RV 50
AV in the right ventricle during inspiration
so that RV peak systolic pressure
increases with inspiration. This causes a
0 mmHg discordant pressure change between
the left and right ventricles, as seen by
the arrows pointing together. This
0 INSP EXP change is not seen in restriction.
 Chapter 24 • Pericardial Diseases: Constriction and Pericardial Effusion 305

3.25

3.00

2.75
Log10BNP (ng/L)

2.50

2.25

2.00

1.75
Figure 24-7 M-mode echocardiogram of a patient with constrictive peri-
1.50 carditis. Ventricular septal motion is characteristically abnormal in patients
with constrictive pericarditis due to the differential ventricular filling with
1.25 respiration and increased interventricular dependence. The cardiac volume
CP idiopathic CP secondary RCMP is relatively fixed within the noncompliant pericardium, thus diastolic
filling of the left and right ventricles are reliant on each other. With inspira-
Diagnosis tion, there is decreased filling of the left ventricle and increased filling in
Figure 24-6 Log 10 of brain natriuretic peptide (BNP) is compared in idio- the right ventricle. To allow for this, the ventricular septum shifts to the left.
pathic constrictive pericarditis, secondary constrictive pericarditis, and With expiration, left ventricular (LV) filling increases, causing the ventricu-
restrictive cardiomyopathy. BNP is significantly lower in patients with idio- lar septum to shift to the right, thus limiting right ventricular (RV) filling.
pathic constrictive pericarditis than restrictive cardiomyopathy; however,
BNP is not significantly different in patients with secondary constrictive
pericarditis (previous cardiac surgery or radiation) compared with restric-
tive cardiomyopathy. A relatively normal BNP in the setting of elevated respiration and increased interventricular dependence (Fig. 24-7).
jugular venous pressure should alert the physician toward constrictive Although the atria are generally larger in RC than in constriction,
pericarditis. (From Babuin L et al: Brain natriuretic peptide levels in constrictive
pericarditis and restrictive cardiomyopathy. JACC 2006;47:1489–1491.)
this feature cannot be used to differentiate one condition from the
other. In RC, LA pressure is usually higher than right atrial (RA)
pressure, and the atrial septum is curved toward the right atrium.
The atrial septum has respiratory movement in patients with CP.
normal in CP,10–11 especially when constriction is idiopathic (Fig.
The pericardial thickness is usually, but not always, increased in
24-6). When constriction is related to coronary bypass surgery or
CP and can be measured by transthoracic and, better still, by
radiation, BNP is higher than in idiopathic CP because of the
transesophageal echocardiography (TEE).13 When calcified, it
underlying concomitant myocardial disease in those conditions.11
appears as a bright echo dense structure, and when inflamed with
Therefore, relatively normal BNP in patients with clear evidence
edema, it appears as a dark soft tissue or a rind. The inferior vena
of heart failure suggests CP. The patients with cardiac amyloidosis
cava, hepatic vein, and pulmonary veins are dilated in both RC
usually have systemic amyloid with monoclonal gammopathy,
and CP, unless patients are well treated with a diuretic agent. In
positive fat aspirate, and other systemic manifestations of the
constriction, the atrioventricular groove may be indented with
disease. However, in a minority of patients, all these studies can
their characteristic appearance.
be negative and may require RV endomyocardial biopsy for a
definitive diagnosis.
Pulsed Doppler
Echocardiography Since atrial and diastolic filling pressures are elevated in symp-
tomatic patients with both CP and RC, mitral and tricuspid
Two-Dimensional Echocardiography inflow velocities are expected to be restrictive, with E/A ratios
Ventricular dimensions and ejection fractions are usually normal greater than 1.5 and E-velocity deceleration times shorter than
in both CP and RC. Ventricular wall thickness can be increased in 160 msec. Additionally, in CP, there is a characteristic variation
some secondary forms of RC and markedly increased in the cases in mitral early diastolic E velocity with respiration.8,14 The varia-
of infiltrative cardiomyopathy. The most common infiltrative car- tion in mitral E velocity is a result of preventing the full transmis-
diomyopathy is cardiac amyloid, but rare conditions such as glyco- sion of intrathoracic pressure change that occurs with respiration
gen storage disease, hyperoxalosis, and hydroxychloroquine into intracardiac cavities. This unique feature of CP produces
myopathy12 should be considered. The RV wall thickness is also diagnostic Doppler echocardiographic recordings. Optimally, a
characteristically increased in most infiltrative cardiomyopathy. respiratory variation of 25% or greater in the mitral inflow E
When the myocardium is infiltrated by amyloid deposits, the velocity and increased diastolic flow reversal with expiration in
valves, atrial wall, and ventricular walls are affected, providing a the hepatic vein need to be demonstrated to establish the diagno-
characteristic granular or speckled appearance on echocardiogra- sis of CP (Fig. 24-8). This observation was initially based on the
phy. Other forms of secondary restrictive cardiomyopathy can seven patients with CP.8 Further clinical observations, however,
also have characteristic echocardiographic features, such as areas found that up to 50% of patients with CP demonstrate less than
of myocardial thinning or unusual regional wall motion abnor- 25% of respiratory variation in mitral E velocity14 because of
malities that do not follow a coronary distribution in sarcoidosis (a) mixed constriction and restriction, (b) marked increase of
or apical endocardial thickening due to thrombus deposition in atrial pressures, or (c) more clinical experience of using two-
hypereosinophilic syndrome. dimensional/Doppler echocardiography in the diagnosis of CP.
Ventricular septal motion is characteristically abnormal in If LA pressure is markedly increased, mitral valve opening
patients with CP because of differential ventricular filling with occurs at a steep portion of the LV pressure curve, and the
306 Chapter 24 • Pericardial Diseases: Constriction and Pericardial Effusion

A Figure 24-9 In both restrictive cardiomyopathy and constriction, diastolic

forward flow in the hepatic vein flow is accentuated. However, the diastolic
flow reversals between the two are different, however. This figure shows
hepatic vein flow in a patient with restrictive cardiomyopathy. Hepatic vein
reversal is mostly during inspiration in restrictive cardiomyopathy due to
the increase in systemic venous return with inspiration exceeding filling
capacity of the diseased myocardium. Thus, both forward and reverse flow
in the hepatic vein increase with inspiration and decrease with expiration.
In constriction (see Fig. 24-8), the right ventricular (RV) cavity size increases
with inspiration secondary to decreased left ventricular (LV) filling and
ventricular septal shift to the left, resulting in little diastolic reversal on
inspiration. During expiration, the RV cavity size decreases with the ven-
tricular septal shift to the right, resulting in increased diastolic reversal on
expiration.
B
Figure 24-8 A, Mitral inflow velocity of a patient with constrictive pericar-
ditis. Optimally, a respiratory variation of 25% or greater is seen in mitral fore, both forward and reversal flows in the hepatic vein increase
inflow E velocity, as shown, where EI is the mitral inflow velocity on inspira- with inspiration and decrease with expiration and RC (Fig. 24-9).
tion and Ee is the mitral inflow on expiration. This observation was based In constriction, RV cavity size becomes larger during inspiration
on a small number of patients with constrictive pericarditis.8 Larger obser- because of decreased LV filling and the ventricular septal shift to
vations indicate that up to 50% of patients with constrictive pericarditis
have less than 25% respiratory variation in mitral E velocity.14 B, Pulsed-
the left, resulting in little diastolic flow reversals. With expiration,
wave Doppler recording of hepatic vein velocity in a patient with constric- however, the right ventricle becomes smaller with the ventricular
tive pericarditis. In constriction, right ventricular (RV) cavity size becomes septal shift to the right because of increased filling to the left
larger during inspiration because of decreased left ventricular filling and ventricle, resulting in increased diastolic flow reversal, as well as a
the ventricular septal shift to the left, resulting in little diastolic flow rever- decreased forward-flow velocity (see Fig. 24-8B). This is com-
sals (arrowhead). With expiration, the right ventricle becomes smaller and
the ventricular septum shifts to the right, resulting in increased diastolic pletely paradoxical to respiratory phasic changes of hepatic venous
flow reversal (arrow), as well as a decreased forward-flow velocity. flow pattern seen in RC.7 This characteristic hepatic venous flow
velocity pattern in constriction has been observed even in the
concomitant presence of atrial fibrillation or with severe tricuspid
respiratory change has little effect on the transmitral pressure valve regurgitation.
gradient. In this case, Doppler echocardiographic examination The sensitivity of two-dimensional and Doppler echocardiog-
may be repeated after an attempt to reduce preload (i.e., head-up raphy using these criteria for detecting constriction was found to
tilt or sitting position).15 In any event, the lack of respiratory be more than 80% and has been enhanced by additional tissue
variation in mitral inflow velocities should not exclude the diag- Doppler imaging (TDI) data.16 The respiratory variation of
nosis of CP as long as mitral inflow is restrictive and other fea- mitral inflow velocity is also observed in patients with increased
tures of constriction are present. In contrast to myocardial disease, respiratory effort, as seen with severe chronic obstructive pulmo-
the deceleration time of mitral E velocity becomes shorter in CP, nary disease, because the exaggerated pressure decrease in the
and shorter still with a reduced E velocity with inspiration. There thorax is not fully transmitted to the intracardiac cavities. There-
is a corresponding respiratory variation in pulmonary venous dia- fore, with inspiration, the LV filling pressure gradient decreases,
stolic forward-flow velocities in CP while maintaining a larger as in CP, and increases with expiration. However, patients with
forward-flow velocity during diastole compared with systolic increased respiratory effort resulting in the respiratory variation
forward-flow velocity as in RC. Respiratory variation in tricuspid of mitral inflow velocity have typical superior vena cava (SVC)
inflow velocity is completely opposite to that of mitral inflow flow velocities that are not observed in patients with CP. Because
velocity. Hepatic vein flow velocity has more predominant dia- of the marked intrathoracic pressure decrease with inspiration,
stolic forward-flow velocity and diastolic flow reversals in both there is an increase forward flow from the SVC to the right
RC and constriction. atrium with inspiration,17 and the forward flow is markedly
However, in RC, hepatic vein diastolic flow reversal is mostly reduced or even absent during the expiratory phase (Fig. 24-10).
during inspiration, when systemic venous return is increased and However, in CP, there is little respiratory change in RA pressure
exceeds the filling capacity of the diseased myocardium. There- and the flow from the SVC to the right atrium; therefore, respira-
 Chapter 24 • Pericardial Diseases: Constriction and Pericardial Effusion 307

Figure 24-10 Pulsed-wave Doppler and color M-mode recordings from the superior vena cava (SVC) in a patient with chronic obstructive lung disease,
showing marked increase in SVC flow velocity with inspiration (arrows on left by pulsed-wave Doppler and arrowheads on right by color M-mode) and
diminution with expiration. Patients with increased respiratory effort can also have respiratory variation of mitral inflow velocity, but they also have typical
SVC flow velocities, which are not observed in patients with constrictive pericarditis. Patients with increased respiratory effort, such as in chronic obstruc-
tive pulmonary disease, have an exaggerated intrathoracic pressure decrease with inspiration causing an increased flow from the SVC to the right atrium.
This flow is markedly reduced or absent during expiration. In constriction, however, there is little respiratory change in the right atrial pressure and the
flow from the SVC to the right atrium; therefore, respiratory change in systolic forward-flow velocity in the SVC is usually <20 cm/sec in patients with con-
strictive pericarditis.

A B
Figure 24-11 Tissue Doppler imaging (TDI) of mitral annulus to differentiate restriction from constriction. The lack of respiratory variation in mitral inflow
velocities does not exclude the diagnosis of constrictive pericarditis, and other features of constriction should be looked for, such as hepatic vein velocity
changes or early diastolic mitral septal annulus velocity (E′) of >7 cm/sec, especially when the mitral inflow profile indicates high filling pressure (i.e.,
restrictive filling with E/A ratio of >1.5 and deceleration time of <160 msec). The mitral annulus velocity E′ recorded by TDI has become a valuable Doppler
parameter in the establishment of the diagnosis of constriction and in differentiating it from myocardial disease with restrictive filling. A, In myocardial
disease, E′ is reduced (<7 cm/sec), since myocardial relaxation is abnormal. In constrictive pericarditis, it (and especially the septal annulus velocity) is rela-
tively normal or even increased. B, This finding occurs because the constrictive pericardium limits ventricular filling by lateral expansion of the heart. Since
myocardial relaxation is relatively well preserved in constriction (unless the myocardium is also involved, as seen in radiation injury to the heart), much of
ventricular filling results instead from exaggerated longitudinal motion of the heart.

tory change in systolic forward-flow velocity is usually less than Tissue Doppler Imaging
20 cm/sec in the SVC in patients with CP.
TEE has also been shown to be helpful in the differentiation Mitral annulus velocity recorded by TDI has become a valuable
of occult CP from RC by Doppler interrogation of the pulmonary Doppler parameter in establishing the diagnosis of constric-
veins. Abdalla et al. found that rapid volume loading patients with tion19,20 and in differentiating it from a myocardial disease or RC
occult constriction could enhance diastolic pressure equalization. (Fig. 24-11). The application of this modality for the evaluation
Pulsed-Doppler TEE of the left or right pulmonary vein and of diastolic function is reviewed at length in Chapter 12. All
mitral inflow performed after giving volume load can unmask a patients with myocardial disease have abnormal relaxation of the
greater respiratory variation of diastolic flow velocity in patients heart, which can be detected reliably by TDI, since early diastolic
with CP.18 velocity (E′) of the mitral annulus has a good correlation with
308 Chapter 24 • Pericardial Diseases: Constriction and Pericardial Effusion

myocardial relaxation. In myocardial disease, mitral septal annulus A calcified pericardium (Fig. 24-12) is seen in 24% of patients
velocity is reduced (<7 cm/sec), since myocardial relaxation is with constriction and is best visualized from the lateral view.4
abnormal, but in CP, mitral annulus velocity is relatively normal Pericardial calcification occurs more commonly over the right
or even increased (see Fig. 24-11). It is related to the limitation ventricle and diaphragmatic surface. Pericardial calcification in
of ventricular filling by lateral expansion of the heart due to the patients with heart failure strongly suggests CP, but its presence
constrictive pericardium, and most ventricular filling is accom- is not always indicative of symptomatic CP. Computed tomogra-
plished by exaggerated longitudinal motion of the heart. Myocar- phy (CT) and magnetic resonance imaging (MRI) can be used in
dial relaxation is relatively well preserved in constriction unless the evaluation of constriction versus restriction.26–27 CT and MRI
the myocardium is also involved, as seen in radiation heart injury. are the best imaging modalities to measure pericardial thickness
The longitudinal motion, hence mitral septal annulus velocity, and calcification (see Fig. 24-12). Gadolinium administration
becomes more increased as the constriction gets worse with higher during MRI highlights the area of pericardial inflammation and
filling pressure, paradoxical to its change in myocardial disease. is useful in identifying reversible components of increased peri-
The phenomenon has been termed annulus paradoxus.21 The E/E′ cardial thickness. Pericardial thickness exceeding 4 mm is highly
ratio is therefore inversely proportional to PCWP, whereas E/E′ suggestive of CP. However, a thickened pericardium, defined
is positively related to PCWP in myocardial disease. More as greater than 4 mm, is found in 72% and calcification in 25%
recently, Sohn et al. reported that E′ also varies with respiration.22 of patients with surgically confirmed constriction.13 Therefore, a
Strain imaging in CP is similar to that of normal individuals, but normal appearance or normal thickness of the pericardium does
negative peak strain is markedly reduced in myocardial disease.23 not rule out CP. Cine imaging of CT and MRI can demonstrate
Doppler myocardial velocity gradients (MVGs) measured the abnormal ventricular septal motion, a characteristic of CP.
from the posterior LV wall may be useful in discriminating con- Patients who have had radiation or open-heart surgery may have
striction versus restriction. Palka et al. found that MVG was patchy areas of thickened pericardium, as seen on imaging studies,
lower in restriction compared with constriction and normal con- but no hemodynamic compromise. Thus, CT and MRI can add
trols during ventricular ejection and rapid ventricular filling.24 information but should not be used alone in the diagnosis of
constriction.
Doppler Echocardiographic Assessment in Patients
with Atrial Fibrillation Treatment
Although respiratory variations in mitral inflow Doppler veloci- The differentiation of CP from RC is critical because the treat-
ties are helpful in differentiating constriction from restriction, ments are distinctly different. While there is no cure for most
atrial fibrillation can make interpretation of respiratory variation myocardial diseases, CP is potentially curable by surgical pericar-
in Doppler patterns difficult. In patients with atrial fibrillation, diectomy. A recent review of 135 patients with constriction found
mitral valve E (MV-E) velocities and pulmonary vein diastolic decreased perioperative mortality compared with earlier studies,
(PVD) velocities become greater with longer filling intervals. but late survival was still inferior to that of age- and sex-matched
Thus, one would expect in patients with atrial fibrillation and CP controls.28 Long-term outcome was predicted by three variables:
that filling intervals would be an equally important factor in MV- age, New York Heart Association (NYHA) functional class, and
E and PVD velocities. On the other hand, constrictive physiology postradiation, with the last having the worst prognosis. Surgery
and hemodynamics should also affect Doppler flow velocities alleviated or improved symptoms in a majority of late survivors,
with respect to the respiratory cycle. Tabata et al. found a decrease but one third eventually experienced new or recurrent NYHA
in MV-E and PVD velocities after onset of inspiration, even class III or IV symptoms. In a subset with a recent onset (within
during long filling intervals.25 The decrease in pressure gradient 3 months) of CP, patients may respond to nonsteroidal anti-
during inspiration reduces flow from the pulmonary vein to the inflammatory drugs (NSAIDs) or steroids. This “transient
left ventricle, and despite the longer cardiac cycle length, the blood constriction” is not uncommon (see Case 4). Much effusive-
volume is not available to cause increased flow during diastole. constrictive pericarditis belongs to this category of transient
Conversely, there is an increase in velocities even during short constriction.
filling intervals at the onset of expiration.
Doppler velocities may need to be monitored for longer periods
of time to appreciate the respiratory variations. Hepatic vein dia- CLINICAL RELEVANCE
stolic flow reversal with expiration is an important Doppler
finding in patients with constriction, especially when mitral inflow Early reliable diagnosis of CP avoids unnecessary diagnostic
velocity is nondiagnostic, as it is in many patients. Occasionally, a investigations for other diseases, frequently noncardiac, and pro-
temporary pacemaker may be required to regularize the patient’s vides a potentially curable treatment for the condition. CP can
rhythm to interpret the respiratory variation of Doppler veloci- present in a variety of forms, some of which may be treatable
ties. Whether E′ velocity can distinguish constriction from restric- medically. Understanding of characteristic hemodynamics and
tion in patients with atrial fibrillation requires further clinical diagnostic features will be able to differentiate heart failure due
observations. to myocardial dysfunction from that due to CP. These relevant
clinical points will be discussed in this section using several case
examples.
Chest X-Ray, Computed Tomography, and
Magnetic Resonance Imaging
Chest x-ray findings can be helpful in a minority of patients. Case 1
Biatrial enlargement is common, and pulmonary venous conges- A 58-year-old female was originally referred for evaluation of
tion as well as pleural effusion may be seen in both RC and CP. ascites. She complained of shortness of breath and abdominal
 Chapter 24 • Pericardial Diseases: Constriction and Pericardial Effusion 309

A
Figure 24-12 Typical chest x-ray (A)
and CT (B) of constrictive pericarditis
showing pericardial calcification
(arrows). Pericardial calcification on
chest x-ray is helpful but is present in
only 25% of cases of constrictive peri-
carditis.13 It is best seen from the lateral
view over the right ventricle and across
the diaphragmatic surface of the heart.
Pericardial calcification reflects chronic-
ity of constrictive pericarditis and is
associated with a higher surgical mor-
tality. CT and MRI are the best imaging
modalities to determine the thickness
of the pericardium. However, a thick-
ened pericardium, defined as greater
than 4 mm, is found in 72% and calcifi-
cation in 25% of patients with surgically
confirmed constriction.13 Therefore, a
normal appearance or normal thickness
of the pericardium does not rule out
constrictive pericarditis. B

distention. At a different institution, she underwent an extensive undergo noncardiac procedures, including liver biopsy, endoscopy,
diagnostic evaluation that included multiple hepatic ultrasounds abdominal exploration, lymph node biopsy, etc. This case example
and a liver biopsy, the results of which were unremarkable. She points out the importance of assessing filling pressure in patients
described a pleuritic chest pain a few years prior to symptoms. presenting with abdominal or gastrointestinal complaints. Gas-
On physical exam, she had elevation of her JVP with Kussmaul trointestinal and hepatology colleagues are frequent referral
sign, and ascites was present. She was sent to cardiology for pos- physicians of their patients for an evaluation of CP, or at least a
sible pericardial disease as a primary cause of symptoms. Echo- cardiac cause. It is also important to emphasize that echocardiog-
cardiogram revealed normal systolic function and characteristic raphy is usually the first diagnostic study in such a clinical situa-
mitral and hepatic inflow velocities for CP as described in this tion, and all sonographers and echocardiologists should be thor-
chapter. Subsequent left- and right-heart catheterization demon- oughly familiar with echocardiographic diagnostic features of CP
strated marked elevation and equalization in diastolic filling pres- as described. It is possible that patients can proceed with pericar-
sures, as well as dissociation of intrathoracic and intracavitary diectomy based on the diagnostic echocardiographic findings.
pressures. She underwent pericardiectomy successfully and When the diagnosis is not certain after echocardiography, but
improved markedly. suggestive, or other physicians involved in patient care are not
This case illustrates the difficulty in early detection and diag- fully comfortable with an echocardiographic diagnosis of con-
nosis of CP. Unless it is clinically suspected, no appropriate diag- striction, further imaging tests or cardiac catheterization may be
nostic procedure can be ordered or performed. This patient had performed.
markedly elevated JVP with Kussmaul sign, which should have
alerted her physician to a possibility of cardiac pathology, even
CP. Instead, her ascites was the main point of investigation,
Case 2
leading to various hepatic procedures. In our experience, almost A 40-year-old male who underwent aortic valve replacement
a third of patients with an ultimate diagnosis of constriction presented 5 years later with dyspnea on exertion and decreased
310 Chapter 24 • Pericardial Diseases: Constriction and Pericardial Effusion

exercise tolerance. On physical examination, he had marked eleva- in the left and right ventricles would have been helpful, along with
tion of JVP with dramatic x and y descent. His lungs were clear evidence of interventricular dependence. Echocardiography may
and liver was enlarged. Echocardiogram showed typical respira- have revealed the appearance of cardiac amyloid. Appearance of
tory variation of mitral inflow and hepatic vein velocities for CP. LV hypertrophy was because of increased wall thickness. Myo-
Mitral annulus early diastolic velocity was 15 cm/sec. Cardiac cardial tissue imaging of the mitral annulus would have shown
catheterization at a home hospital also showed hemodynamic marked reduction in E′ velocity.
changes consistent with CP. The CT scan, however, showed a Endomyocardial biopsy may be performed in patients sus-
normal-appearing pericardium. A few months later, the patient pected of having RC. Biopsy is usually done to exclude specific
had a pericardiectomy. He had a thin and tightly adherent peri- heart muscle diseases such as cardiac amyloid, sarcoidosis, or
cardium laterally and inferiorly with multiple areas of thickening. eosinophilic myocarditis. In idiopathic RC, the myocardial biopsy
His symptoms improved after pericardiectomy. demonstrates nonspecific fibrosis with increased collagen deposi-
CT and MRI can be used in the evaluation of constriction tion, myocellular hypertrophy without necrosis, or disarray. On
versus restriction26–27 since their efficacy is the best in imaging the other hand, the myocardial biopsy is typically normal in CP
pericardial thickness and calcification. unless the two conditions coexist.
This case also illustrates the diagnostic importance of measur-
ing mitral annulus velocity by TDI. If a patient has heart failure,
and E′ is greater than 8 cm/sec, CP should be strongly considered Case 4
and confirmed by other characteristic Doppler features, such as A 54-year-old man with a history of acute myocardial infarction
restrictive mitral inflow with or without respiratory variation and (AMI) presented one month after AMI with pleuritic chest pain.
hepatic vein Doppler recording of diastolic flow reversals with He was treated with anti-inflammatory medications, and pain
expiration. resolved but returned with shortness of breath, requiring admis-
sion. Echo findings were consistent with CP. CT of the chest
revealed uniform thickening of the pericardium. He was placed
Case 3 on prednisone, with significant improvement of symptoms. A
A 60-year-old patient was transferred for treatment of his amyloid repeat CT scan one week later showed resolution of pericardial
cardiomyopathy. His original workup started a little over one year thickness with normal-appearing pericardium (Fig. 24-13). The
ago. He went to his physician complaining of shortness of breath patient is diagnosed as having transient CP.
and weakness. Echocardiogram showed LV hypertrophy, and his CP may be transient because of inflammation of the pericar-
LV ejection fraction was 40%. His coronary angiogram revealed dium. There is a subgroup of patients who, after a recent episode
no clinically significant coronary artery disease, and right-heart of acute pericarditis, present with constrictive physiologic features
catheterization showed elevated filling pressures with equaliza- that resolve with medical treatment alone. In a review of 212
tion. He was sent to surgery for pericardiectomy for a presumed patients with echocardiographic findings of CP at our institution,
diagnosis of CP, but at surgery there was no evidence for abnor- 36 had echocardiographic resolution of constrictive hemodynam-
mal pericardium. There was, however, a nodule that was biopsied ics without pericardiectomy.29 The most common cause of tran-
and showed deposits consistent with amyloid. He was then sient CP was again cardiac surgery. The average time for resolu-
referred to our institution for subsequent management. tion was 8.3 weeks after initial diagnosis.
This case is an example of the difficulty in distinguishing CP The implication of this finding is that patients with symptoms
from RC. The right-heart catheterization results of the patient and physiologic features consistent with CP who are hemody-
can be seen in both constriction and restriction but are classically namically stable with a recent onset can be managed with a trial
associated with constriction, thus many may not pursue further of medical treatment up to 3 months prior to consideration of
workup for restriction. In this case, respiratory variation in ven- surgical pericardiectomy. Medical therapy is aimed at acute
tricular systolic pressures as well as discordant pressure changes inflammation of the pericardium and can include NSAIDs,

Figure 24-13 Chest computed tomog-

raphy (CT) image of 54-year-old man
with constrictive pericarditis before (left)
and after (right) treatment with predni-
sone. The pericardium is thick (arrows on
left) at baseline. Repeat CT scan was
done one week later and showed resolu-
tion of pericardial inflammation (arrows
on right).
 Chapter 24 • Pericardial Diseases: Constriction and Pericardial Effusion 311

steroids, antibiotics, or chemotherapy, depending on the etiology present in cardiac tamponade with respiratory variation in mitral
of CP. and hepatic vein flow velocities as seen in CP.
Clinically, effusive-constrictive pericarditis should be suspected
if JVP remains elevated after successful pericardiocentesis. Hemo-
Case 5 dynamically, all intracardiac diastolic pressures remain elevated in
A 66-year-old male has a history of aortic valve replacement for this condition, even after intrapericardial pressure returns to
a bicuspid aortic valve, and mitral valve repair for mitral valve normal with pericardiocentesis. A significant subset of these
prolapse. His hospital course was uneventful. Two weeks after patients do have inflammation of the pericardium, which can be
discharge, he complained of profound fatigue and was eventually demonstrated by delayed enhancement by gadolinium on MRI.
readmitted for a syncopal event. Chest x-ray showed a large Most effusive-constrictive pericarditis belongs to transient con-
cardiac silhouette suggestive of pericardial effusion. Echocardio- striction since it can be treated medically (with nonsteroidal or
gram not only confirmed the effusion, but showed evidence of steroidal anti-inflammatory agents) in most patients.
tamponade physiology. Pericardiocentesis successfully removed
750 cc of fluid. Repeat echocardiography after pericardiocentesis
showed a tiny pericardial effusion but persistent constrictive SUMMARY AND FUTURE RESEARCH
physiology, and the pericardium appeared inflamed.
This is a typical presentation of effusive-constrictive pericardi- CP is the result of loss of elasticity of the pericardium surround-
tis, a rare syndrome in which constriction from the visceral surface ing the heart. This lack of distensibility of the pericardium causes
of the heart is accompanied by a hemodynamically significant diastolic dysfunction that is clinically evident as congestive heart
effusion in the pericardial space. The hallmark of this phenome- failure with increased pulmonary and jugular venous pressures,
non is persistently elevated RA pressure after adequate pericar- including hepatomegaly, ascites, and peripheral edema. Systolic
diocentesis. In one study, the prevalence of this disorder was 1.3% ventricular function may be well preserved, thus investigation of
among patients with pericardial disease of any type and 6.9% other organ systems is often pursued prior to pericardial disease.
among patients with clinical tamponade.30–31 The most common Once a cardiac abnormality is suspected, the difficulty is in dis-
etiology was idiopathic and history of radiation therapy, but any tinguishing CP from RC, which have similar clinical and hemo-
cause of pericarditis can lead to effusive-constrictive pericarditis. dynamic profiles. But because of their differing causes and
The diagnosis requires hemodynamic criteria from a right-heart treatments, it is important to distinguish between the two.
catheterization or echocardiography soon after pericardiocentesis. To understand the difference, one must remember the patho-
One must recognize the hemodynamics of both tamponade and physiologic mechanisms causing the diastolic dysfunction. In CP,
constriction to understand effusive-constrictive pericarditis. the noncompliant pericardium causes the limitation of diastolic
Cardiac tamponade and CP are similar in that they both restrict filling, but in RC, the pericardium is normal but the myocardium
filling of the ventricles. is stiff and noncompliant. This difference in etiology allows us to
Tamponade can occur when the pericardial space is filled with observe unique hemodynamic features between the two entities.
fluid. An echo free space persists throughout the cardiac cycle CP has distinct hemodynamic characteristics, which include dis-
when the effusion reaches 25 ml. As the pericardial effusion sociation between intrathoracic and intracardiac pressures and
increases, the movement of the parietal pericardium decreases. exaggerated ventricular interdependence in diastolic filling, which
Even larger amounts of fluid can cause the heart to actually swing can be seen either invasively or noninvasively. Imaging modalities
in the pericardium. Echocardiographic features of tamponade such as MRI and CT may be helpful in the diagnosis of constric-
include early diastolic collapse of the right ventricle, late diastolic tion and restriction.
inversion of the right atrium, abnormal ventricular septal motion, Despite these tools, distinguishing between the two can be a
and respiratory variation in ventricular size. These features may clinical challenge, but it is important in deciding on treatment. CP
not be present if the patient also has pulmonary hypertension and is a treatable condition. Treatment depends on the form of the
may not be specific since increased interventricular dependence, condition. Most patients will have chronic CP, with previous
which is responsible for respiratory variation in ventricular filling, cardiac surgery being the most common cause. A small propor-
and abnormal ventricular septal motion can occur with increased tion, however, may have transient CP, which can be treated
respiratory efforts and no pericardial effusion. Therefore, hemo- medically. The diagnostic approach and treatment must be indi-
dynamic evidence of cardiac tamponade needs to be identified to vidualized for each patient, and the most important diagnostic
make a definitive diagnosis of tamponade as well as of CP. Doppler tool is clinical suspicion.
echocardiographic features of tamponade are due to respiratory
variation in intrathoracic and intracardiac hemodynamics, just as
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NY, Futura, 1985:1–17.
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carditis, and restrictive cardiomyopathy. Am J Cardiol 1976;38:547–
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2496. ity for constrictive pericarditis in the absence of respiratory variation in
7. Vaitkus PT, Kussmaul WG: Constrictive pericarditis versus restrictive car- mitral inflow velocity. J Am Soc Echocardiogr 2002;15:1468–1471.
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10. Babuin L, Alegria JR, Oh JK, et al: Brain natriuretic peptide levels in con- annulus velocity in constrictive pericarditis. J Am Soc Echocardiogr
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 BENJAMIN W. EIDEM, MD
25
Congenital Heart Disease

INTRODUCTION Left Ventricular Hypertrophy

Hypertrophic and Dilated Cardiomyopathies
PATHOPHYSIOLOGY OF DIASTOLIC
in Children
DYSFUNCTION IN CHILDREN
Tetralogy of Fallot
Normal Diastolic Function in Children
Single Ventricle Palliation
CLINICAL RELEVANCE: CONGENITAL HEART Postoperative Congenital Heart Disease
DISEASE AND DIASTOLIC DYSFUNCTION
FUTURE DIRECTIONS
Ventricular Volume Overload
Ventricular Pressure Overload

INTRODUCTION stolic disease processes, with increases in collagen content and

altered extracellular matrix composition leading to altered
As invasive and noninvasive methods of assessment of ventricular chamber compliance.
performance evolve, the clinical importance of diastolic function The rate of pressure decline within the ventricular chamber can
in both children and adults with congenital heart disease has be determined by invasive methods. Tau (τ), or pressure half-time,
become better appreciated. Alterations in ventricular geometry is the period of time for pressure to fall by 50% of its initial mea-
and loading conditions are the hallmark of congenital heart sured value. Impaired relaxation leads to a decreased rate of ven-
disease and further complicate the quantitative evaluation of dia- tricular pressure decline. Lengthening of isovolumic relaxation
stolic function. Additional intrinsic and extrinsic factors also may time (IVRT) (defined as the time interval between aortic valve
affect diastolic performance, significantly altering this phase of the closure and mitral valve opening) is also characteristic of abnor-
cardiac cycle. Systolic ventricular function, atrial and ventricular mal diastolic filling and can be evaluated noninvasively by M-
compliance, ventricular filling pressure, pericardial constraint, and mode or pulsed-wave Doppler echocardiography. However,
ventricular interaction may each have a significant effect on overall neither IVRT nor τ elucidates whether dysfunction occurs in
diastolic performance. This chapter will discuss current concepts active or passive relaxation, which act in concert to cause a fall
in diastolic function in children and adults with congenital heart in ventricular pressure and augment filling. As diastolic disease
disease and detail ongoing clinical efforts regarding the assess- progresses, increased ventricular end diastolic pressure further
ment of diastolic performance in this population. increases τ and pressure halt time, while concomitant changes
in atrial compliance and filling pressure act to shorten IVRT
duration.
PATHOPHYSIOLOGY OF DIASTOLIC Echocardiography, and in particular Doppler echocardiogra-
DYSFUNCTION IN CHILDREN phy, historically has been an essential noninvasive tool in the
quantitative assessment of left ventricular (LV) diastolic function.
Diastole is a complex process involving both active and passive Abnormalities of ventricular compliance and relaxation can be
components. Abnormalities of relaxation and early rapid filling demonstrated by characteristic changes in mitral inflow and pul-
are often manifested by changes in the rate of relaxation and the monary venous Doppler patterns.1–4 The addition of newer meth-
amount of early rapid filling. Diastolic dysfunction also is mani- odologies including tissue Doppler echocardiography5–15 and flow
fested by changes in chamber stiffness or compliance. Adverse propagation velocities16–20 enhanced the ability of echocardiogra-
changes within the myocardial cytoskeleton are common in dia- phers to define and quantitate these adverse changes in diastolic
313
314 Chapter 25 • Congenital Heart Disease

performance. Because diastolic dysfunction often precedes sys- tion of diastolic dysfunction using these parameters alone very
tolic dysfunction, careful assessment of diastolic function is essen- challenging in patients with congenital heart disease.27
tial in the noninvasive characterization and evaluation of patients
with congenital heart disease.
Mitral Inflow Doppler
Mitral inflow Doppler represents the diastolic pressure gradient
Normal Diastolic Function in Children between the left atrium and the left ventricle (Fig. 25-1) (see
Normal maturation of the neonatal myocardium occurs over the Chapter 10). The early diastolic filling wave, or E wave, is the
first year of life, resulting in improved ventricular compliance with dominant diastolic wave in children and young adults and repre-
aging. Noninvasive evaluation of normal diastolic function in sents the peak left atrial (LA)-to-LV pressure gradient at the
infants and children is influenced by several factors, including age, onset of diastole. The deceleration time (DT) of the mitral E wave
heart rate, and the respiratory cycle.21–26 Researchers have estab- reflects the period of time needed for equalization of LA and LV
lished reference values detailing both mitral and pulmonary pressures. The late diastolic filling wave, or A wave, represents the
venous Doppler velocities in a large cohort of children with unim- peak pressure gradient between the left atrium and the left ven-
paired hearts (Tables 25-1, 25-2, and 25-3).27 Similar to many tricle in late diastole at the onset of atrial contraction. Normal
echocardiographic parameters, these Doppler velocities also are mitral inflow Doppler is characterized by a dominant E wave, a
significantly affected by loading conditions, making determina- smaller A wave, and a ratio of E and A waves (E/A ratio) between

TABLE 25-1
NORMAL DOPPLER DATA (N = 233): MITRAL VALVE FLOW VARIABLES AND LEFT VENTRICULAR ISOVOLUMIC
RELAXATION TIME (STRATIFIED BY AGE GROUP)
3–8 yrs 9–12 yrs 13–17 yrs
(N = 75) (N = 72) (N = 76)

FACTOR Mean 1 SD Mean 1 SD Mean 1 SD

E velocity (cm/sec) 92 14 86 15 88 14
E TVI (cm) 12.0 2.6 12.3 2.9 14.0 2.9
A velocity (cm/sec) 42 11 41 9 39 8
A TVI (cm) 3.7 1.1 3.7 1.0 3.7 1.1
A duration (msec) 136 22 142 21 141 22
E at A velocity (cm/sec) 16 7 14 5 12 4
E to A velocity ratio 2.4 0.7 2.2 0.6 2.3 0.6
E to A TVI ratio 3.7 2.0 3.7 1.5 4.2 1.7
Deceleration time (msec) 145 18 157 19 172 22
End mitral A to R wave interval (msec) 34 16 29 15 27 19
LV IVRT (msec) 62 10 67 10 74 13

A, atrial filling wave; E, early filling wave; IVRT, isovolumic relaxation time; LV, left ventricular; SD, standard deviation; TVI, time velocity integral.
From O’Leary PW et al: Diastolic ventricular function in children: A Doppler echocardiographic study establishing normal values and predictors of increased ventricular end diastolic
pressure. Mayo Clin Proc 1998;73:616–628.

TABLE 25-2
NORMAL DOPPLER DATA (N = 223): PULMONARY VEIN FLOW VARIABLES
3–8 yrs 9–12 yrs 13–17 yrs
(N = 75) (N = 72) (N = 76)

FACTOR Mean 1 SD Mean 1 SD Mean 1 SD

Systolic velocity (cm/sec) 46 9 45 9 41 10

Systolic TVI (cm) 11.1 2.3 11.5 2.2 10.8 2.8
Diastolic velocity (cm/sec) 59 8 54 9 59 11
Diastolic TVI (cm) 8.8 1.8 9.2 2.5 12.1 3.1
Ratio of systolic to diastolic velocity 0.8 0.2 0.8 0.2 0.7 0.2
Ratio of systolic to diastolic TVI 1.3 0.3 1.3 0.4 0.9 0.3
Atrial reversal velocity (cm/sec) 21 4 21 5 21 7
Atrial reversal duration (msec) 130 20 125 20 140 28
Atrial reversal TVI (cm) 1.7 0.5 1.6 0.6 2.0 0.9

SD, standard deviation; TVI, time velocity integral.

From O’Leary PW et al: Diastolic ventricular function in children: A Doppler echocardiographic study establishing normal values and predictors of increased ventricular end diastolic
pressure. Mayo Clin Proc 1998;73:616–628.
 Chapter 25 • Congenital Heart Disease 315

TABLE 25-3
INFLUENCES OF AGE AND HEART RATE ON DIASTOLIC DOPPLER VARIABLES IN CHILDREN
BIVARIATE PARTIAL
UNIVARIATE ASSOCIATIONS ASSOCIATIONS*

VARIABLE Age RR Age RR

Mitral E velocity — ↑ ↓ ↑
Mitral A velocity ↓ ↓↓ ↑ ↓↓
End A to R interval ↑ — ↑ —
Duration of A wave — ↑ — —
Mitral deceleration time ↑↑↑ ↑↑↑ ↑ ↑
Mitral E wave TVI ↑↑ ↑↑↑ — ↑↑↑
Mitral A wave TVI — ↓ ↑ ↓
Mitral E at A velocity ↓ ↓↓ — ↓↓
Mitral E to A ratio (velocity) — ↑↑↑ ↓ ↑↑↑
Mitral E to A ratio (TVI) ↑ ↑↑↑ ↓ ↑↑↑
LV IVRT ↑↑ ↑↑ ↑ ↑
PV systolic peak velocity ↓ — ↓ —
PV diastolic peak velocity — ↑ — ↑
Peak PVAR velocity — — — —
PVAR duration ↑ ↑↑ — ↑↑
PV systolic TVI — ↑ — ↑
PV diastolic TVI ↑↑↑ ↑↑↑ ↑ ↑
PVAR TVI ↑ ↑ — ↑
PV systolic to diastolic ratio (velocity) ↓ — — —
PV systolic to diastolic ratio (TVI) ↓↓ ↓ ↓ ↓
Ratio of PVAR to mitral A wave duration — — — —
Ratio of PVAR to mitral A wave TVI ↓ ↓↓ — ↓↓

*Univariate associations column demonstrates the association between age or heart rate (RR interval) and each dependent variable without accounting for other influences. Bivariate
partial associations column demonstrates the effect of age or heart rate on each dependent variable after controlling for the influence of the other independent variable (age or heart
rate). Upward arrows indicate positive associations between age or RR interval and the measured variable; downward arrows indicate negative associations. The number of arrows
shown increases as the degree of association increases.
A, atrial; E, early; IVRT, isovolumic relaxation time; LV, left ventricular; PV, pulmonary vein; PVAR, pulmonary vein atrial reversal; RR, RR interval; TVI, time velocity integral; — = no
effect; ↑ = weak association (R2 < 0.10); ↑↑ = moderate association (0.10 < R2 < 0.20); ↑↑↑ = strong association (R2 > 0.20).
From O’Leary PW et al: Diastolic ventricular function in children: A Doppler echocardiographic study establishing normal values and predictors of increased ventricular end diastolic
pressure. Mayo Clin Proc 1998;73:616–628.

Impaired relaxation

Normal Abnormal Decrease in

relaxation compliance
Children Adults
Velocity E Mild to Severe
moderate
AV valve

A
Venous flow

D
S
Figure 25-1 Spectrum of diastolic flow patterns in
diastolic dysfunction in children. (From Olivier M et al:
Serial Doppler assessment of diastolic function before and
after the Fontan operation. J Am Soc Echocardiogr
2003;16:1136–1143.) VAR I II III and IV
316 Chapter 25 • Congenital Heart Disease

1 and 3.1,27 Normal durations of mitral DT and IVRT vary with

age and have been reported in both pediatric and adult popula- ECG
tions.1–3,27–29 Mitral inflow Doppler velocities are affected not
only by changes in LV diastolic function but also by a variety of
additional hemodynamic factors, including age, altered loading Velocity E
conditions, heart rate, and changes in atrial and ventricular com-
pliance.1–3,28,30 Interpretation of characteristic patterns of mitral

MV
A
inflow must be carefully evaluated with particular attention paid
to the potential impact of each of these hemodynamic factors on
mitral inflow Doppler velocities.
As in the adult population, the earliest stage of LV diastolic
dysfunction demonstrated by mitral inflow Doppler in children DT A-d
is abnormal relaxation. This Doppler pattern is characteristic of
normal aging in adults and represents a mild decrease in the rate
of LV relaxation with continued normal LA pressure. It is char- D
S

PV
acterized by a reduced E-wave velocity, increased A-wave velocity,
decreased E/A ratio less than 1, and a prolonged mitral DT and PVAR-d
IVRT. sTVI dTVI
As diastolic dysfunction progresses, further changes in ven-
tricular relaxation and compliance occur, leading to an increase in
LA pressure. Increased LA pressure normalizes the initial trans- PVAR
mitral gradient between the left atrium and the left ventricle, A Time
producing a “pseudonormalized” mitral inflow Doppler pattern
2.00
with increased E-wave velocity and E/A ratio and normalized
mitral DT and IVRT intervals. This pseudonormal Doppler 1.8
pattern may be difficult to distinguish from normal mitral inflow
Doppler; however, maneuvers that decrease ventricular preload, 1.6
like the Valsalva maneuver, as well as additional evaluation of
and MV-A duration

pulmonary venous inflow Doppler can help unmask this advanced 1.4
Ratio of PVAR

degree of LV diastolic dysfunction.

Further deterioration of LV diastolic function results in restric- 1.2
tive ventricular filling with an additional increase in LA pressure
and a concomitant decrease in ventricular compliance. The 1.0
Doppler pattern of restrictive LV filling is characterized by addi-
0.8
tional increases in E-wave velocity, reduction in A-wave velocity,
an increased E/A ratio greater than 3, and significant shortening 0.6
of both mitral DT and IVRT.
0.4
Pulmonary Venous Doppler B Normal EDP High EDP
Figure 25-2 A, Diagram depicting mitral valve and pulmonary vein
Pulmonary venous Doppler combined with mitral inflow Doppler Doppler flow tracings. B, Detecting elevated end diastolic pressure
provides a more comprehensive assessment of LA and LV filling >18 mmHg (EDP) with use of ratio of pulmonary vein atrial reversal (PVAR)
pressures (see Fig. 25-1).27,31–34 Pulmonary venous inflow consists to mitral valve (MV) atrial filling wave (A) duration. A, atrial filling wave; A-d,
of three distinct Doppler waves: a systolic wave (S wave), a dia- duration of atrial filling wave; D, pulmonary vein diastolic flow wave; DT,
mitral deceleration time; dTVI, time velocity integral of pulmonary vein
stolic wave (D wave), and a reversal wave with atrial contraction diastolic flow wave; E, early filling wave; ECG, electrocardiogram; PVAR,
(Ar wave). In adolescents and adults with normal hearts, the pulmonary vein atrial reversal wave; PVAR-d, duration of pulmonary vein
characteristic pattern of pulmonary venous inflow consists of a atrial reversal flow; S, pulmonary vein systolic flow wave; sTVI, time velocity
dominant S wave, a smaller D wave, and a small Ar wave of low integral of pulmonary vein systolic flow wave. (From O’Leary PW et al: Dia-
stolic ventricular function in children: A Doppler echocardiographic study
velocity and brief duration. In neonates and younger children, establishing normal values and predictors of increased ventricular end-
a dominant D wave is often present with a similar brief low- diastolic pressure. Mayo Clin Proc 1998;73:616–628.)
velocity, or even absent, Ar wave.
With worsening LV diastolic dysfunction, LA pressure rises,
leading to diminished systolic forward flow into the left atrium
from the pulmonary veins with relatively increased diastolic
forward flow, resulting in a diastolic dominance of pulmonary
Tissue Doppler Imaging
venous inflow. More importantly, both the velocity and the dura- Tissue Doppler imaging is particularly well suited to the quantita-
tion of the pulmonary venous Ar wave are increased. Pediatric tive evaluation of LV diastolic function (Fig. 25-3) (see Chapter
and adult studies have demonstrated that an Ar-wave duration 12). Both early (Ea) and late (Aa) annular diastolic velocities can
more than 30 msec longer than the corresponding mitral A-wave be readily obtained by tissue Doppler echocardiography. Similar
duration or a ratio of pulmonary venous Ar-wave duration to to systolic tissue Doppler velocities, differences in diastolic veloci-
mitral A-wave duration greater than 1.2 is predictive of elevated ties exist (1) between the subendocardium and the subepicar-
LV filling pressure (Fig. 25-2).27,35–36 dium, (2) from cardiac base to apex, and (3) among various
 Chapter 25 • Congenital Heart Disease 317

S
ICT
S S ICT
ICT
IRT

A IRT IRT A
A
A E B E C E
Figure 25-3 Longitudinal tissue Doppler imaging velocities obtained at lateral mitral annulus (A), interventricular septum (B), and lateral tricuspid annulus
(C). Tissue Doppler velocities include systolic (S), early diastolic (E), and late diastolic (A) myocardial velocities. Isovolumic contraction time (IVCT) and iso-
volumic relaxation time (IVRT) are also demonstrated. (From Eidem BW et al: Impact of chronic left ventricular preload and afterload on Doppler tissue imaging
velocities: A study in congenital heart disease. J Am Soc Echocardiogr 2005;18:830–838.)

myocardial wall segments.5,6,8,9,12,37–41 Previous studies have IMPAIRED

reported an excellent correlation between early annular diastolic NORMAL RELAXATION PSEUDONORMAL
mitral velocity and simultaneous invasive measures of diastolic Mitral inflow Mitral inflow Mitral inflow
function at cardiac catheterization.42 Early annular diastolic veloc-
ities also appear to be less sensitive to changes in ventricular
E E
preload compared with corresponding early transmitral Doppler A
A A
inflow velocities.42–44 Significant alterations in preload, however,
have been shown to affect these diastolic tissue Doppler veloci- E 50 cm/sec
ties.45–47 The effect of afterload on tissue Doppler velocities is less
controversial, with many studies documenting significant changes
in systolic and diastolic annular velocities with changes in ven-
tricular afterload.48–50 Therefore, the clinical use of tissue Doppler
velocities in patients with valvular stenosis or other etiologies of
altered ventricular afterload need to be interpreted carefully in DTI DTI DTI
light of this limitation.
Tissue Doppler velocities are helpful in the discrimination Sa
between normal and pseudonormal transmitral Doppler filling Sa Sa
5 cm/sec
patterns (Fig. 25-4).7,43,51–52 In addition to changes incurred by
loading conditions, alterations in LA pressure and LV end dia-
stolic pressure also affect the early transmitral diastolic velocity. 5 cm/sec

However, the corresponding tissue Doppler velocity is typically Ea

Ea A
Aa a
decreased in patients with pseudonormal filling, allowing Aa
Ea
differentiation of this abnormal filling pattern from one of
normal transmitral Doppler inflow. Clinical reports have sug- Figure 25-4 Representative transmitral Doppler and tissue Doppler veloc-
gested a ratio of the early transmitral inflow Doppler signal to the ities in normal and diastolic dysfunction. Note significantly decreased
lateral mitral annular early diastolic velocity (mitral E/Ea) as a tissue Doppler velocities with pseudonormal pattern. (From Nagueh SF
noninvasive measure of LV filling pressure. Nagueh and et al: Doppler tissue imaging: a noninvasive technique for evaluation of left
ventricular relaxation and estimation of filling pressures. J Am Coll Cardiol
colleagues demonstrated a significant correlation of mitral 1997;30:1527–1533.)
E/Ea with invasively measured mean pulmonary capillary
wedge pressure,43 while subsequent studies have further validated
this ratio and reported its applicability in a variety of hemo-
dynamic settings (Fig. 25-5).53–57 Additional novel indices of myocardium in patients with constrictive pericarditis is com-
LV diastolic function using tissue Doppler echocardiography monly normal, the corresponding tissue Doppler velocities are
have recently been reported that may further expand the role of also normal. However, patients with restrictive cardiomyopathy
this modality in the clinical evaluation of LV filling have significantly decreased early diastolic and systolic tissue
pressures.52,58 Doppler velocities, allowing separation of these two distinct clini-
Tissue Doppler also is of considerable clinical value in the dif- cal entities.
ferentiation of constrictive from restrictive LV filling (see Chapter
24).59–62 Evaluation of patients with constrictive pericarditis and Tissue Doppler Studies in Children with
restrictive cardiomyopathy with two-dimensional echocardiogra- Healthy Hearts
phy and even invasive cardiac catheterization may fail to confi- To date, a number of studies have established baseline reference
dently differentiate between these two disease states. Because the values of tissue Doppler velocities in children (Tables 25-4 and
318 Chapter 25 • Congenital Heart Disease

25-5).13–15,63–66 Similar to previously published adult reports, (Fig. 25-7).63 In a recently published large study of infants and
pediatric tissue Doppler velocities vary with age,15,63,66 heart children, tissue Doppler velocities did not correlate significantly
rate,15,63 wall location,63 and myocardial layer (Fig. 25-6).67 In with other more commonly utilized measures of systolic and dia-
addition, pulsed-wave tissue Doppler velocities are highly corre- stolic ventricular performance, including LV shortening fraction,
lated with parameters of cardiac growth, most notably LV end LV and RV myocardial performance indices, and transmitral
diastolic dimension and LV mass, with the most significant inflow Doppler.63 This lack of correlation is likely due in part to
changes in these velocities occurring during the first year of life pulsed-wave tissue Doppler assessments of longitudinal ventricu-
lar function, while other, more traditional, two-dimensional and
45 Doppler methods assess radial and global measures of ventricular
y = 1.9 + 1.24x performance.
r = 0.87
40 n= 60
Normative data for the E/Ea ratio, similar to those previously
published for adults, have also been reported for children43–44,53–56
35
(Fig. 25-8).63 These values are significantly altered by age, heart
rate, ventricular wall location, and LV dimensions and mass.63
Values for E/Ea are highest in neonates and decrease with advanc-
PCWP mmHg

30
ing age due primarily to increased Ea velocity. Simultaneous cath-
eterization/echocardiographic measurements correlating the E/
25 Ea ratio in children with invasive measures of LV filling pressure
are lacking to date. In a small cohort of children, invasive cardiac
20 catheterization measures of LV function were compared with
simultaneously obtained color M-mode and Doppler parameters
15 of LV performance.68 The ratio of early diastolic mitral inflow
Doppler velocity to flow propagation velocity (E/Vp) correlated
10 closely with invasive LV end diastolic pressure, while the septal
Ea velocity correlated with the time constant of relaxation (τ).
5 Additional studies using tissue Doppler have established normal
0 5 10 15 20 25 30 35 atrioventricular electromechanical coupling intervals.65
E/Ea
Figure 25-5 Relation of E/EA to pulmonary capillary wedge pressure. Color M-Mode Flow Propagation Velocity
(From Nagueh SF et al: Doppler tissue imaging: a noninvasive technique for
evaluation of left ventricular relaxation and estimation of filling pressures. Flow propagation of early diastolic filling from the mitral annulus
J Am Coll Cardiol 1997;30:1527–1533.) to the cardiac apex can be quantitated by color M-mode (see

TABLE 25-4
DEMOGRAPHICS AND ECHOCARDIOGRAPHIC DATA IN STUDY PATIENTS
DEMOGRAPHICS <1 yr 1–5 yrs 6–9 yrs 10–13 yrs 14–18 yrs TOTAL

N 63 68 55 58 81 325
Male 29 39 27 38 44 177
Age (y) 0.40 ± 0.30 3.05 ± 1.51 7.91 ± 1.12 11.99 ± 1.11 16.0 ± 1.40 7.8 ± 6.0
Weight (kg) 6.6 ± 2.7 15.1 ± 5.4 33.8 ± 14.9 47.2 ± 16.3 66.1 ± 15.5 33.3 ± 25.2
BSA (m2) 0.34 ± 0.08 0.62 ± 0.14 1.07 ± 0.27 1.37 ± 0.29 1.73 ± 0.25 1.0 ± 0.6
HR (bpm) 124 ± 16 105 ± 17 80 ± 11 75 ± 12 69 ± 16 90 ± 26
Echocardiographic
LV EDD (cm) 2.3 ± 0.3 3.1 ± 0.4 3.9 ± 0.4 4.3 ± 0.4 4.7 ± 0.4 3.6 ± 1.0
LV ESD (cm) 1.4 ± 0.2 1.9 ± 0.3 2.4 ± 0.3 2.7 ± 0.3 3.0 ± 0.4 2.3 ± 0.6
LV PWT (cm) 0.4 ± 0.1 0.6 ± 0.1 0.7 ± 0.1 0.8 ± 0.1 0.9 ± 0.2 0.7 ± 0.2
LV SWT (cm) 0.5 ± 0.1 0.6 ± 0.1 0.8 ± 0.1 0.8 ± 0.2 1.0 ± 0.2 0.7 ± 0.2
LV mass (g/m2) 18.9 ± 6.5 43.6 ± 16.4 82.3 ± 28.3 110.1 ± 32.9 158.4 ± 48.5 81.8 ± 58.9
Mitral E velocity 79.7 ± 18.8 95.2 ± 19.5 94.4 ± 14.8 94.5 ± 16.0 90.3 ± 17.8 90.8 ± 18.5
Mitral A velocity 65.3 ± 13.3 61.3 ± 12.1 49.4 ± 12.5 49.5 ± 13.8 45.5 ± 13.2 54.4 ± 15.0
Mitral E/A ratio 12.4 ± 0.30 1.60 ± 0.46 1.99 ± 0.51 2.02 ± 0.58 2.13 ± 0.65 1.79 ± 0.61
PV S-wave velocity 44.6 ± 10.3 48.0 ± 8.9 50.7 ± 11.3 49.0 ± 11.1 47.7 ± 7.3 48.7 ± 9.2
PV D-wave velocity 46.0 ± 9.5 54.5 ± 11.0 53.3 ± 11.4 58.4 ± 12.1 57.9 ± 15.0 54.6 ± 12.9
PV A-reversal velocity 16.4 ± 6.3 20.6 ± 4.3 20.2 ± 3.8 21.2 ± 4.9 20.0 ± 5.2 20.5 ± 5.1
Tricuspid E velocity 53.3 ± 12.3 61.6 ± 12.5 60.5 ± 13.9 59.6 ± 11.4 60.4 ± 10.9 59.2 ± 12.4
Tricuspid A velocity 53.2 ± 13.0 48.3 ± 12.3 42.4 ± 10.8 39.2 ± 11.3 34.5 ± 11.2 43.3 ± 13.5
Tricuspid E/A ratio 1.01 ± 0.38 1.27 ± 0.31 1.49 ± 0.40 1.61 ± 0.47 1.88 ± 0.56 1.47 ± 0.53
SF (%) 38.9 ± 4.1 38.0 ± 3.6 37.4 ± 3.8 37.4 ± 4.2 36.4 ± 4.3 37.6 ± 4.1
LV MPI 0.33 ± 0.08 0.34 ± 0.07 0.32 ± 0.06 0.34 ± 0.06 0.34 ± 0.08 0.33 ± 0.08
RV MPI 0.29 ± 0.09 0.28 ± 0.07 0.29 ± 0.08 0.28 ± 0.08 0.29 ± 0.08 0.28 ± 0.08

From Eidem BW et al: Impact of cardiac growth on Doppler tissue imaging velocities: A study in healthy children. J Am Soc Echocardiogr 2004;17:212–221.
 Chapter 25 • Congenital Heart Disease 319

TABLE 25-5
PULSED-WAVE DOPPLER TISSUE VELOCITIES AND TIME INTERVALS IN HEALTHY CHILDREN BY AGE GROUP
AGE GROUP N E*-WAVE VELOCITY A*-WAVE VELOCITY S*-WAVE VELOCITY ICT IRT E/E* RATIO

Mitral annular
<1 yr 63 9.7 ± 3.3 5.7 ± 1.8 5.7 ± 1.6 77.4 ± 18.4 57.0 ± 14.8 8.8 ± 2.7
(8.8–10.5) (5.3–6.2) (5.3–6.1) (72.7–82.0) (53.1–60.8) (8.1–9.5)
1–5 yrs 68 15.1 ± 3.4† 6.5 ± 1.9 7.7 ± 2.1† 76.9 ± 15.9 62.1 ± 13.2 6.5 ± 2.0†
(14.3–15.4) (6.1–7.0) (7.2–8.2) (72.8–80.9) (58.9–65.4) (6.0–7.0)
6–9 yrs 55 17.2 ± 3.7† 6.7 ± 1.9 9.5 ± 2.1† 77.9 ± 18.9 62.9 ± 11.9 5.8 ± 1.9
(16.2–18.3) (6.2–7.3) (8.9–10.1) (72.4–83.4) (59.5–66.3) (5.3–6.4)
10–13 yrs 58 19.6 ± 3.4† 6.4 ± 1.8 10.8 ± 2.9* 76.6 ± 16.2 62.6 ± 12.4 4.9 ± 1.3
(18.7–20.5) (5.9–6.9) (10.0–11.5) (72.4–80.9) (59.4–65.9) (4.6–5.2)
14–18 yrs 81 20.6 ± 3.8 6.7 ± 1.6 12.3 ± 2.9† 78.9 ± 15.4 69.5 ± 15.5* 4.7 ± 1.3
(19.7–21.4) (6.3–7.1) (11.6–12.9) (75.4–82.3) (66.1–73.0) (4.4–5.0)
Total 325 16.5 ± 5.3 6.4 ± 1.9 9.3 ± 3.4 77.5 ± 16.7 63.2 ± 14.4 6.1 ± 2.4
(16.0–17.1) (6.2–6.6) (8.9–9.7) (75.7–79.5) (61.7–64.9) (5.9–6.4)
Septal
<1 yr 63 8.1 ± 2.5 6.1 ± 1.5 5.4 ± 1.2 77.5 ± 17.5 53.0 ± 11.7 10.3 ± 2.7
(7.5–8.7) (5.7–6.4) (5.1–5.7) (73.0–82.0) (50.0–56.0) (9.7–11.0)
1–5 yrs 68 11.8 ± 2.0† 6.0 ± 1.3 7.1 ± 1.5† 80.1 ± 15.5 59.8 ± 12.0 8.1 ± 1.8†
(11.3–12.3) (5.7–6.4) (6.8–7.5) (76.3–83.9) (56.9–62.7) (7.7–8.5)
6–9 yrs 55 13.4 ± 1.9† 5.9 ± 1.3 8.0 ± 1.3 82.8 ± 15.3 65.6 ± 10.7 7.2 ± 1.6
(12.8–13.9) (5.5–6.3) (7.6–8.4) (78.4–87.2) (62.5–68.7) (6.8–7.7)
10–13 yrs 58 14.5 ± 2.6 6.1 ± 2.3 8.2 ± 1.3 87.9 ± 16.4* 72.5 ± 12.3 6.6 ± 1.4
(13.8–15.2) (5.6–6.7) (7.9–8.5) (83.6–92.2) (69.3–75.8) (6.3–7.0)
14–18 yrs 81 14.9 ± 2.4 6.2 ± 1.5 9.0 ± 1.5 88.4 ± 15.6 77.5 ± 14.5 6.4 ± 1.5
(14.3–15.4) (5.9–6.6) (8.7–9.3) (84.9–91.9) (74.3–80.8) (6.1–6.8)
Total 325 12.6 ± 3.4 6.1 ± 1.6 7.6 ± 1.9 83.5 ± 16.5 66.1 ± 15.3 7.7 ± 2.3
(12.2–13.0) (5.9–6.3) (7.4–7.8) (81.7–85.4) (64.4–67.9) (7.5–8.0)
Tricuspid annular
<1 yr 63 13.8 ± 8.2 9.8 ± 2.4 10.2 ± 5.5 68.7 ± 18.2 52.0 ± 12.9 4.4 ± 2.3
(11.7–15.9) (9.1–10.5) (8.8–11.7) (63.9–73.5) (48.5–55.4) (3.8–5.0)
1–5 yrs 68 17.1 ± 4.0† 10.9 ± 2.7 13.2 ± 2.0† 77.7 ± 15.0 59.0 ± 13.9 3.8 ± 1.1
(16.1–18.1) (10.2–11.6) (12.7–13.7) (73.9–81.5) (55.4–62.5) (3.5–4.1)
6–9 yrs 55 16.5 ± 3.0 9.8 ± 2.7 13.4 ± 2.0 91.8 ± 21.5† 58.5 ± 17.5 3.6 ± 0.8
(15.7–17.4) (9.0–10.6) (12.8–14.0) (85.5–98.0) (53.4–63.6) (3.4–3.9)
10–13 yrs 58 16.5 ± 3.1 10.3 ± 3.4 13.9 ± 2.4 98.1 ± 21.7 61.7 ± 19.9 3.5 ± 1.4
(15.7–17.4) (9.3–11.2) (13.2–14.5) (92.2–103.9) (56.4–67.1) (3.2–3.9)
14–18 yrs 81 16.7 ± 2.8 10.1 ± 2.6 14.2 ± 2.3 101.9 ± 20.4 62.9 ± 18.9 3.7 ± 1.0
(16.0–17.3) (9.5–10.7) (13.7–14.7) (97.2–106.6) (58.5–67.3) (3.5–3.9)
Total 325 16.1 ± 4.7 10.2 ± 2.8 13.0 ± 3.4 88.2 ± 23.1 59.0 ± 17.2 3.8 ± 1.4
(15.6–16.7) (9.9–10.5) (12.6–13.4) (85.6–90.8) (57.0–60.9) (3.6–4.0)

*P < .05; †P < .01 compared with proceeding age group.

Data expressed as mean ± SD (95% confidence interval). Doppler tissue imaging velocities are expressed in cm/sec. Time intervals are expressed in milliseconds.
A, Late diastolic velocity; A*, late diastolic annular velocity; ICT, isovolumic contraction time; E, early diastolic inflow Doppler velocity; E*, early diastolic annular velocity;
IRT, isovolumic relaxation time; S, systolic velocity; S*, systolic annular velocity.
From Eidem BW et al: Impact of cardiac growth on Doppler tissue imaging velocities: A study in healthy children. J Am Soc Echocardiogr 2004;17:212–221.

Chapter 11).52,54 As opposed to mitral inflow Doppler, the propa- peak early transmitral Doppler flow velocity to flow propagation
gation velocity is significantly less affected by changes in heart velocity (E/Vp) (Fig. 25-9).
rate, LA pressure, and loading conditions and may therefore more
accurately reflect changes in myocardial relaxation. Numerous
studies have demonstrated a significant decrease in flow propaga- CLINICAL RELEVANCE: CONGENITAL HEART
tion velocity in patients with diastolic dysfunction of varying eti- DISEASE AND DIASTOLIC DYSFUNCTION
ology.53–56 In addition, the ratio of the mitral annular Doppler
tissue E-wave velocity to flow propagation velocity is a significant
Ventricular Volume Overload
predictor of congestive heart failure and outcome in patients after Altered ventricular geometry and loading conditions are the hall-
myocardial infarction.69–70 This ratio of flow propagation and marks of congenital heart disease. However, the majority of non-
Doppler tissue imaging velocity also may be helpful in distin- invasive measures of systolic and diastolic ventricular performance
guishing a normal mitral inflow pattern from one of pseudonor- are significantly affected by changes in loading conditions. Tradi-
malized mitral inflow. In a small cohort of children undergoing tional echocardiographic measures of systolic function, including
simultaneous cardiac catheterization and transthoracic echocar- LV shortening and LV ejection fraction (LVEF), as well as
diography, Border et al.68 showed a significant correlation between Doppler measures of LV diastolic function, namely pulmonary
invasively measured LV end diastolic pressure and the ratio of venous and mitral inflow Doppler, are significantly affected by
320 Chapter 25 • Congenital Heart Disease

35 y = 11.778 + 0.615x 20 y = 6.059 + 0.050x 30 y = 6.186 + 0.405x

Mitral annular S-wave

Mitral annular E-wave
r2 = 0.487, p < 0.001 r2 = 0.025, p = 0.005 r2 = 0.512, p < 0.001

Mitral annular A-wave

30 25

velocity (cm/sec)
velocity (cm/sec)

velocity (cm/sec)
SEE = 3.8 SEE = 1.9 SEE = 2.4
25 15
20
20
10 15
15
10
10 5
5 5
0 0 0
0 4 8 12 16 20 0 5 10 15 20 0 4 8 12 16 20
Age (yrs) Age (yrs) Age (yrs)

30 y = 9.629 + 0.380x 15 y = 5.949 + 0.021x 20 y = 6.037 + 0.204x

r2 = 0.450, p < 0.001 r2 = 0.006, p = 0.18 r2 = 0.419, p < 0.001
25

velocity (cm/sec)
velocity (cm/sec)

velocity (cm/sec)
SEE = 2.5 SEE = 1.6 SEE = 1.4
Septal E-wave

Septal A-wave

Septal S-wave
15
20 10
15 10
10 5
5
5
0 0 0
0 4 8 12 16 20 0 4 8 12 16 20 0 4 8 12 16 20
Age (yrs) Age (yrs) Age (yrs)

40 y = 15.363 + 0.102x 25 y = 10.303 – .013x y = 11.543 + 0.191x

Tricuspid annular E-wave

Tricuspid annular A-wave

30

Tricuspid annular S-wave

35 r2 = 0.016, p = 0.02 r2 = 0.001, p = 0.65 r2 = 0.112, p < 0.001
20
velocity (cm/sec)

velocity (cm/sec)

SEE = 4.7 SEE = 2.8 25 SEE = 3.2

velocity (cm/sec)
30
25 15 20
20 15
15 10
10
10
5 5
5
0 0 0
0 4 8 12 16 20 0 4 8 12 16 20 0 4 8 12 16 20
Age (yrs) Age (yrs) Age (yrs)
Figure 25-6 Effect of age on tissue Doppler velocities in healthy children. Data are expressed as mean ± SD and 95% confidence interval. A, late diastolic
velocity; E, early diastolic velocity; S, systolic velocity. (From Eidem BW et al: Impact of cardiac growth on Doppler tissue imaging velocities: A study in healthy
children. J Am Soc Echocardiogr 2004;17:212–221.)

altered LV preload and afterload.27,31,71–81 While the distortion septal defects (VSDs) or patent ductus arteriosi (PDAs) with
in ventricular geometry and loading are significant limitations increased LV preload using both tissue Doppler and conventional
in routine two-dimensional and Doppler echocardiography in Doppler methodologies compared with simultaneous cardiac
patients with these congenital heart lesions, tissue Doppler echo- catherization-derived hemodynamic data.82 In their cohort,
cardiography is ideally suited to this quantitative evaluation routine transmitral early diastolic velocities (E) were significantly
because of its relative independence from these geometric increased and correlated directly with increases in LA pressure
constraints. and pulmonary-to-systemic flow ratios. However, the correspond-
Tissue Doppler has been reported to be relatively independent ing early (Ea) and late (Aa) tissue Doppler velocities were not
of changes in ventricular loading in adults with and without asso- different compared with controls despite increased LV preload.
ciated heart disease. Sohn et al. reported the relative preload inde- The E/Ea ratio was significantly elevated in children with both
pendence of mitral annular tissue Doppler velocities in adults VSDs and PDAs and correlated well with invasive LA pressure
with unimpaired hearts as well as those with abnormal LV relax- measurement. Postrepair, in a small number of children, tissue
ation.42 These findings were challenged by Firstenberg et al., Doppler velocities remained unchanged despite the removal of
who reported significantly altered early diastolic myocardial this chronic LV volume overload.82 We reported similar findings
velocities in dogs with decreased ventricular preload.45 Pulsed- in 94 children with varying sizes of VSDs.83 In our series, tissue
wave tissue Doppler, however, appears to be less influenced by Doppler velocities at both the lateral mitral and tricuspid annuli
similar alterations in ventricular preload compared with trans- were unaffected by significantly increased ventricular preload
mitral Doppler velocities. (Table 25-6). Isolated small differences in systolic and early dia-
Studies in children with congenital heart disease and associ- stolic velocities were demonstrated at the septal annulus and were
ated chronic increases in LV preload have documented minimal thought to be related more to altered cardiac translation second-
changes in tissue Doppler velocities compared with pediatric con- ary to ventricular dilatation than to changes attributable to
trols. Harada et al. evaluated 33 children with either ventricular increased ventricular preload. In children with VSDs, the E/Ea
 Chapter 25 • Congenital Heart Disease 321

35 y = 1.831 + 4.049x 20 y = 5.582 + 0.227x 25 y = 0.190 + 2.506x

Mitral annular S-wave

Mitral annular E-wave r2 = 0.538, p < 0.001 r2 = 0.014, p = 0.035 r2 = 0.505, p < 0.001

Mitral annular A-wave

30

velocity (cm/sec)
velocity (cm/sec)

velocity (cm/sec)
SEE = 3.6 SEE = 1.8 20 SEE = 2.4
25 15
20 15
10
15 10
10 5 5
5
0 0 0
1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 6
LV EDD (cm) LV EDD (cm) LV EDD (cm)

25 y = 3.586 + 2.466x 15 y = 5.748 + 0.091x 20 y = 2.776 + 1.325x

r2 = 0.483, p < 0.001 r2 = 0.003, p = 0.34 r2 = 0.464, p < 0.001

velocity (cm/sec)
velocity (cm/sec)

velocity (cm/sec)
20 SEE = 2.5 SEE = 1.6 SEE = 1.4
Septal E-wave

Septal A-wave

Septal S-wave
15
10
15
10
10
5
5
5

0 0 0
1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 6
LV EDD (cm) LV EDD (cm) LV EDD (cm)

40 y = 13.180 + 0.809x 25 y = 10.508 – 0.090x

Tricuspid annular E-wave

Tricuspid annular A-wave

25

Tricuspid annular S-wave

r2 = 0.026, p = 0.004 r2 = 0.001, p = 0.61 y = 7.945 + 1.385x
35 r2 = 0.150, p < 0.001
SEE = 4.7 SEE = 2.8
velocity (cm/sec)

20
velocity (cm/sec)

velocity (cm/sec)
30 20 SEE = 3.1
25 15 15
20
15 10 10
10
5 5
5
0 0 0
1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 6
LV EDD (cm) LV EDD (cm) LV EDD (cm)
Figure 25-7 Effect of left ventricular end diastolic dimension (LV EDD) on tissue Doppler velocities in healthy children. Data are expressed as mean ± SD
and 95% confidence interval. A, late diastolic velocity; E, early diastolic velocity; S, systolic velocity. (From Eidem BW et al: Impact of cardiac growth on Doppler
tissue imaging velocities: A study in healthy children. J Am Soc Echocardiogr 2004;17:212–221.)

25 y = 7.899 – 0.230x 25 y = 1.451 + 0.051x

Mitral annular E/E′ ratio

Mitral annular E/E′ ratio

r2 = 0.327, p < 0.001 r2 = 0.294, p < 0.001

20 SEE = 2.0 20 SEE = 2.0

15 15

10 10

5 5

0 0
0 4 8 12 16 20 40 60 80 100 120 140 160 180
Age (years) Heart rate (BPM)

25 y = 11.458 – 1.467x y = 7.733 – 0.020x

25
Mitral annular E/E′ ratio

Mitral annular E/E′ ratio

r2 = 0.339, p < 0.001 r2 = 0.233, p < 0.001

20 SEE = 2.0 SEE = 2.1
20
15 15
Figure 25-8 Effect of age, heart rate, left ventricular end
diastolic dimension (LV EDD) and LV mass on mitral 10 10
inflow Doppler early diastolic velocity (E)/early mitral
annular diastolic tissue Doppler imaging velocity (E′) 5 5
ratio in healthy children. Data are expressed as mean ±
SD and 95% confidence interval. (From Eidem BW et al: 0 0
Impact of cardiac growth on Doppler tissue imaging veloci- 1 2 3 4 5 6 0 100 200 300
ties: A study in healthy children. J Am Soc Echocardiogr
2004;17:212–221.) LV EDD (cm) LV mass (gm/m2)
322 Chapter 25 • Congenital Heart Disease

20
y = 0.14 + 5.5x

LV end-diastolic pressure (mmHg)

18 r = 0.71
16 p < 0.001

14
12
10
8
6
4
2
0
0.0 0.5 1.0 1.5 2.0 2.5 3.0
A B E/Vp ratio
Figure 25-9 A, Measurement of flow propagation velocity (Vp) from color M-mode Doppler: Vp is determined by the slope (white line) of the first clearly
demarcated aliasing velocity (red-yellow interface) during early left ventricular filling. B, Relationship between dimensionless index ratio of peak early
transmitral flow ventricular velocity to flow propagation velocity (E/Vp) to invasively determined left ventricular (LV) end diastolic pressure. (From Border
WL et al: Color M-mode and Doppler tissue evaluation of diastolic function in children: Simultaneous correlation with invasive indices. J Am Soc Echocardiogr
2003;16:988–994.)

TABLE 25-6
EFFECT OF INCREASING PRELOAD ON DOPPLER TISSUE IMAGING VELOCITIES IN PATIENTS WITH VENTRICULAR
SEPTAL DEFECTS
SMALL VSD CONTROL SUBJECTS P VALUE MODERATE-LARGE VSD CONTROL SUBJECTS P VALUE

N 56 56 — 38 38 —
Male 22 25 — 18 21 —
Doppler tissue
Mitral
MV-E 14.6 ± 5.7 14.0 ± 4.8 .55 11.8 ± 4.0 13.1 ± 4.7 .22
MV-A 6.6 ± 1.8 6.4 ± 1.9 .53 6.6 ± 2.1 6.2 ± 2.6 .45
MV-S 7.7 ± 2.9 7.6 ± 2.5 .87 6.9 ± 2.1 7.3 ± 3.1 .50
Septal
IVS-E 11.0 ± 3.8 11.4 ± 3.1 .49 9.7 ± 3.1 10.9 ± 2.9 .09
IVS-A 6.3 ± 1.5 6.0 ± 1.3 .29 6.7 ± 1.9 5.8 ± 1.2 .015
IVS-S 6.5 ± 1.6 7.0 ± 1.5 .10 6.2 ± 1.6 6.6 ± 1.4 .26
Tricuspid
TV-E 16.1 ± 4.6 15.6 ± 4.8 .70 16.7 ± 4.4 15.1 ± 4.9 .15
TV-A 10.2 ± 2.4 10.4 ± 2.8 .65 10.5 ± 2.2 9.9 ± 2.5 .30
TV-S 12.2 ± 3.0 12.0 ± 2.7 .74 11.8 ± 2.6 11.5 ± 3.0 .63
Mitral E/Ea ratio 7.0 ± 2.7 6.8 ± 2.4 .68 8.9 ± 3.7 8.1 ± 3.0 .32
Septal E/Ea ratio 9.0 ± 2.7 8.0 ± 2.3 .04 10.8 ± 4.4 9.2 ± 2.5 .07
Tricuspid E/Ea ratio 3.7 ± 1.5 3.8 ± 1.0 .70 3.7 ± 1.5 4.0 ± 1.4 .34
Echocardiographic
Qp : Qs 1.5 ± 0.4 — — 2.4 ± 0.6 — —
LV SF (%) 38.0 ± 4.6 37.6 ± 3.9 .56 38.7 ± 4.7 38.7 ± 3.9 .95
LV MPI 0.35 ± 0.08 0.33 ± 0.07 .12 0.34 ± 0.08 0.29 ± 0.08 0.07

Doppler tissue imaging velocities are expressed in cm/s.

Values expressed as mean ± SD.
A, Late diastolic velocity; E, early diastolic velocity; IVS, septal annulus; LV, left ventricular; MPI, myocardial performance index; MV, lateral mitral annulus; Qp, total pulmonary blood
flow; Qs, total systemic blood flow; S, systolic velocity; SF, shortening fraction; TV, lateral tricuspid annulus; VSD, ventricular sepatal defect.
From Eidem BW et al: Impact of chronic left ventricular preload and afterload on Doppler tissue imaging velocities: A study in congenital heart disease. J Am Soc Echocardiogr
2005;18:830–838.

ratio at both the lateral mitral and septal annuli were minimally VSDs with otherwise normal LV systolic and diastolic
increased compared with controls; however, when divided function.84
into subgroups based on VSD size, no significant change in this Congenital heart lesions involving the right ventricle frequently
ratio was demonstrated with increasing LV preload. These data have concomitant changes in ventricular loading conditions.
were consistent with previously published invasive hemodynamic Quantitative noninvasive assessment of right ventricular (RV)
data demonstrating normal LV filling pressures in patients with function has been challenging because of the geometric shape of
 Chapter 25 • Congenital Heart Disease 323

the right ventricle. Tissue Doppler imaging allows quantitative load may lead to more definitive changes in myocardial architec-
nongeometric evaluation of longitudinal RV function along its ture, resulting in decreased ventricular compliance or even a
primary axis of contraction and relaxation. The validity of tissue restrictive filling pattern.109
Doppler velocities in this setting is the topic of many recent Pacileo et al. reported the effect of increased afterload on LV
reports. Pauliks et al. evaluated 39 children with atrial septal geometry and function in 22 children with moderate aortic valve
defects (ASDs) before and after interventional device closure.85 stenosis.110 In their study, routine measures of LV systolic and
At baseline, children with ASDs had increased tricuspid and diastolic function were normal despite increased intensity of inte-
mitral annular velocities compared with controls, while RV iso- grated backscatter, suggesting altered myocardial architecture with
volumic acceleration (IVA) was similar between the two groups. concomitant fibrosis. The clinical effect of these potential ana-
Following ASD closure, a transient immediate decrease in tissue tomic changes on long-term ventricular pump function and relax-
Doppler velocities in all myocardial segments was demonstrated, ation suggests that more sensitive methods of regional functional
while no change was evident in IVA. Tissue Doppler velocities assessment, such as tissue Doppler echocardiography, may help
normalized at 24 hours postprocedure, while IVA remained identify early subclinical changes in ventricular performance.
unchanged, demonstrating the probable load dependence of tissue Kiraly et al. have published data on 24 children with aortic valve
Doppler velocities and the relative load independence of IVA in stenosis and demonstrated decreased systolic and diastolic
children undergoing ASD device closure. Other studies have sug- tissue velocities and strain rate velocities in the lateral and poste-
gested that the load dependence of tissue Doppler velocities in rior LV walls, with longitudinal velocities more significantly
children with ASD depends upon RV size and relative compli- affected than radial velocities.111 We have recently detailed a
ance.86 Cheung et al. evaluated RV function with tissue Doppler study of 96 children with varying severities of aortic valve steno-
imaging and showed improved global and regional indices of RV sis.83 In this pediatric cohort, children with aortic stenosis had
function after interventional device closure of ASDs but not with significantly decreased systolic and early diastolic annular veloci-
surgical closure of these defects.87 Other tissue Doppler studies ties at both the septal and lateral mitral annuli despite normal
have demonstrated improvement in LV diastolic function after outcomes of traditional measures of systolic and diastolic ventric-
ASD closure likely related to improved ventricular interaction ular performance (Table 25-7). Patients with the highest aortic
with decreased RV dilatation and volume overload.88 valve gradients had the most significant decreases in tissue Doppler
velocities, suggesting that afterload plays a key role in these myo-
cardial velocities. In addition, both lateral mitral and septal E/Ea
Ventricular Pressure Overload ratios were elevated in children with aortic stenosis and correlated
Children with congenital heart disease commonly have myocar- with disease severity consistent with previously published invasive
dial hypertrophy due to increased afterload. Previous studies in studies suggesting increased LV filling pressures in these
both adults and children with ventricular hypertrophy caused by patients.101,112–114
chronic elevation of afterload have shown variable effects on LV
systolic function.89–97 In children, studies utilizing endocardial
indices such as EF and velocity of circumferential fiber shortening Left Ventricular Hypertrophy
have shown increased LV function, while those corrected for The presence of ventricular hypertrophy in children may be due
afterload tend to show normal contractility.95–96 to a primary myopathy such as hypertrophic cardiomyopathy
Patients with ventricular hypertrophy may present with an (HCM) secondary to altered hemodynamics and ventricular
abnormality of diastolic function prior to overt changes in systolic loading conditions, or to a compensatory response to intense ath-
performance. In adults with chronic pressure overload, conflicting letic training. Pathologic hypertrophy leads to diastolic dysfunc-
data exist regarding the effect of increasing wall thickness on tion with characteristic changes in mitral inflow Doppler of
active and passive properties of diastolic function,98–102 with abnormal relaxation or pseudonormal filling. Tissue Doppler can
increased fibrosis noted in some studies.103–104 Children with be quite helpful in characterizing abnormal diastolic function in
chronic hypertrophy secondary to aortic stenosis105 or hyperten- the hypertrophied left ventricle, including decreased early dia-
sion106 have distinct abnormalities of LV diastolic function, espe- stolic velocity and increased E/E′ ratio in the affected myocardial
cially impaired LV filling when evaluated noninvasively. Invasive segments. Numerous additional applications of tissue Doppler in
evaluation of diastolic performance, utilizing the time constant of adults with heart disease continue to become evident. Systolic and
relaxation (τ) or myocardial stiffness constant, is rarely performed diastolic abnormalities of myocardial function have been charac-
in these patients, but these parameters have also been shown to terized extensively in patients with HCM.115–121 Mutation car-
be abnormal.107 Banerjee et al. evaluated ten patients with riers of HCM that lack the hallmark phenotypic expression of
congenital obstruction of the left ventricular outflow tract ventricular hypertrophy also have been identified utilizing this
(LVOT) (valvular aortic stenosis in seven children, coarctation of modality.115–118 Differentiation of pathologic etiologies of second-
the aorta in two patients, and supravalvular aortic stenosis in ary ventricular hypertrophy (such as hypertension or infiltrative
one).108 Both noninvasive and invasive parameters of LV function diseases), as well as physiologic adaptations of myocardial hyper-
were evaluated in these children and compared with normal con- trophy, in highly trained athletes from those with definitive HCM
trols. While systolic parameters, including fractional shortening also has been reported.121–124 The effect of medical and surgical
and end systolic fiber elastance, were normal, children with LVOT interventions upon myocardial performance and cardiovascular
obstruction had prolonged IVRT and time constants of relax- hemodynamics in adults with HCM also has been detailed using
ation. While active relaxation was impaired, passive diastolic tissue Doppler echocardiography.69–70,125 The role of cardiac
properties, including both chamber stiffness and myocardial stiff- resynchronization in patients with heart failure, as well as its
ness, were normal in this small cohort. These studies suggest that applications in patients with cardiomyopathies, has broadened
early detrimental changes secondary to hypertrophy lead to the appeal of tissue Doppler modalities in heart failure manage-
abnormal relaxation, while prolonged chronic elevation of after- ment strategies.126–132
324 Chapter 25 • Congenital Heart Disease

TABLE 25-7
EFFECT OF INCREASING AFTERLOAD ON DOPPLER TISSUE IMAGING VELOCITIES IN PATIENTS WITH AORTIC
VALVE STENOSIS
CONTROL MODERATE TO CONTROL
MILD AS SUBJECTS P VALUE SEVERE AS SUBJECTS P VALUE

N 59 59 — 37 37 —
Male 39 36 — 23 25 —
Doppler tissue
Mitral
MV-E 17.4 ± 4.3 18.7 ± 4.7 .12 15.3 ± 5.1 17.4 ± 4.8 .03
MV-A 6.7 ± 1.9 6.8 ± 2.0 .67 6.0 ± 2.5 6.6 ± 2.2 .27
MV-S 9.6 ± 2.6 10.4 ± 3.3 .12 8.5 ± 2.7 10.5 ± 3.5 .006
Septal
IVS-E 12.7 ± 2.8 13.8 ± 2.6 .025 11.0 ± 3.0 13.4 ± 8.2 .001
IVS-A 6.4 ± 1.7 6.0 ± 1.50 .17 6.5 ± 1.3 6.5 ± 1.7 .83
IVS-S 7.9 ± 1.6 8.3 ± 1.8 .19 7.2 ± 1.4 8.4 ± 1.9 .003
Tricuspid
TV-E 16.5 ± 4.1 16.6 ± 3.4 .88 15.3 ± 4.0 16.4 ± 4.5 .28
TV-A 10.2 ± 2.8 10.1 ± 2.8 .81 10.3 ± 2.8 10.2 ± 2.3 .92
TV-S 13.3 ± 2.4 16.9 ± 2.4 .34 12.7 ± 2.5 13.2 ± 2.5 .34
Mitral E/Ea ratio 6.7 ± 2.9 5.5 ± 1.7 .02 7.5 ± 2.5 5.7 ± 2.1 .004
Septal E/Ea ratio 8.6 ± 2.1 7.2 ± 1.8 .001 9.8 ± 2.9 7.2 ± 2.0 .0001
Tricuspid E/Ea ratio 4.0 ± 1.2 3.7 ± 0.9 .12 4.2 ± 1.5 4.0 ± 1.1 .54
Echocardiographic
Mean gradient (mmHg) 11.6 ± 4.0 — — 31.7 ± 3.9 — —
LV SF (%) 39.3 ± 3.5 37.7 ± 3.5 .01 43.6 ± 5.8 38.0 ± 4.9 .0002
LV MPI 0.34 ± 0.06 0.33 ± 0.07 .38 0.33 ± 0.10 0.33 ± 0.07 .96

Values expressed as mean ± SD.

Doppler tissue imaging velocities are expressed in cm/s.
A, Late diastolic velocity; AS, aortic valve stenosis; E, early diastolic velocity; IVS, septal annulus; LV, left ventricular; MPI, myocardial performance index; MV, lateral mitral annulus;
S, systolic velocity; SF, shortening fraction; TV, lateral tricuspid annulus.
From Eidem BW et al: Impact of chronic left ventricular preload and afterload on Doppler tissue imaging velocities: A study in congenital heart disease. J Am Soc Echocardiogr
2005;18:830–838.

Hypertrophic and Dilated Cardiomyopathies Tetralogy of Fallot

in Children There is considerable evidence that altered RV compliance occurs
The use of tissue Doppler to predict clinical outcomes has emerged in the immediate postoperative period as well as in the long-term
as a potentially important clinical application in children with in patients following repair of tetralogy of Fallot.135 These changes
cardiomyopathies. McMahon et al.133 prospectively evaluated 54 in RV compliance are not secondary to residual RVOT obstruc-
children with dilated cardiomyopathy (DCM) with both conven- tion or elevated pulmonary arterial pressures but are thought to
tional echocardiographic indices and tissue Doppler velocities to be more likely related to myocardial injury at the time of cardio-
determine predictors of adverse clinical outcomes (defined as pulmonary bypass. Norgard et al. evaluated 34 children after
death, cardiac transplantation, or hospitalization). While tissue repair of tetralogy of Fallot. In their series, almost half of their
Doppler velocities, LV and RV Tei indices, RV fractional area patients had Doppler evidence of restrictive physiology in the
change, and LVEF were all abnormal in DCM patients, only immediate postoperative period, with restrictive changes resolv-
tricuspid Ea velocity less than 8.5 cm/sec and LVEF less than ing prior to hospital discharge in most children. Children who
30% were multivariate predictors of poor clinical outcome. had a transannular patch as part of their repair were most likely
Similarly, McMahon et al.134 evaluated LV diastolic function in to have restrictive RV physiology postoperatively and to manifest
children with HCM using tissue Doppler echocardiography this abnormality again at midterm follow-up. Only those children
compared with traditional echocardiographic parameters, who had restrictive physiology in the immediate postoperative
exercise stress testing, and ambulatory Holter monitoring to period had similar findings present at midterm serial follow-up.
determine their clinical utility in predicting adverse outcome Findings from previous studies showing decreased QRS duration
(death or ventricular tachycardia), and significant cardiac symp- on surface electrocardiography (ECG) or decreased incidence of
toms. In all, 80 children were prospectively evaluated, with the ventricular arrhythmias in patients with tetralogy who also had
ratio of transmitral E to septal Ea found to be significantly predic- restrictive physiology were not duplicated in Norgard’s series.136
tive of adverse clinical outcomes. In addition, this ratio correlated Restrictive RV physiology at midterm follow-up, in contrast to
inversely with peak oxygen consumption obtained during exercise the acute postoperative setting, may be beneficial, limiting RV
stress testing (Fig. 25-10). While LVEF, Tei index, maximal LV dilatation secondary to long-standing pulmonary regurgitation,
wall thickness, and LA volume were all significantly different and has been associated with improved exercise performance in
compared with controls, none were predictive of the primary these patients. The hallmark Doppler echocardiographic finding
clinical endpoint. is antegrade diastolic flow in the pulmonary artery with atrial
 Chapter 25 • Congenital Heart Disease 325

10 Sa
70
y = 54 – 2x
cm/sec

0 r = 0.74
60 p < 0.001

VO2 Max (ml/min/kg)

Ea Aa
–10 50
A
40
20
Sa 30
cm/sec

0
20

Aa
Ea 10
–20
0 4 8 12 16 20 24
B Septal E/Ea
Figure 25-10 On the left is a tissue Doppler profile demonstrating significantly reduced mitral septal Ea velocities in (A) child with hypertrophic cardio-
myopathy (HCM) and ventricular tachycardia and (B) asymptomatic child with HCM. On the right is a graph correlating maximum VO2 and transmitral E/Ea
septal ratio. There is a strong inverse relationship between maximal VO2 and E/septal Ea ratio. Aa, late diastolic velocity; Ea, early diastolic velocity;
Sa, systolic velocity. (From McMahon CJ et al: Characterization of left ventricular diastolic function by tissue Doppler imaging and clinical status in children
with hypertrophic cardiomyopathy. Circulation 2004;109:1756–1762.)

contraction. This echocardiographic finding suggests that second-

ary to decreased RV compliance, the right ventricle acts like a
passive conduit, directing blood from the right atrium to the pul-
monary artery during atrial systole (Fig. 25-11).
Long-term follow-up of patients with tetralogy can be particu-
larly challenging because of the common presence of significant
pulmonary regurgitation and RV dilatation leading to late mor-
bidity and mortality. Studies to date have been mixed in their
results concerning the effect of chronic pulmonary regurgitation
and RV dilatation on RV systolic function.137–140 Geva et al. evalu-
ated 100 patients after tetralogy repair with cardiac magnetic
resonance imaging (MRI) with hopes of identifying independent
factors associated with impaired clinical status.141 Interestingly,
neither the degree of pulmonary regurgitation nor the indexed
RV end diastolic volume were predictive of clinical status; however,
the presence of either moderate to severe RV or LV systolic dys-
function and older age at repair were found to be independently
associated with impaired clinical status. This study and others Figure 25-11 Pulsed-wave Doppler from a parasternal short-axis scan in
suggest that clinical outcomes in tetralogy of Fallot may be more a patient postoperative of tetralogy of Fallot demonstrating antegrade
complex, with the interaction between the right and left ventricles pulmonary artery flow with atrial contraction (arrow).
playing an important role in patient outcome.142
Quantitative assessment of RV performance with tissue
Doppler echocardiography after repair of tetralogy of Fallot
also has been the subject of considerable investigation.143–146 Single Ventricle Palliation
Tissue Doppler velocities are decreased in patients with tetralogy When assessed serially, patients with complex congenital heart
post-repair, and these velocities correlate with the degree of disease who have undergone the Fontan operation are shown to
pulmonary regurgitation.143–144 RV contractile reserve has have abnormalities of diastolic ventricular function. Preopera-
been shown to be decreased during submaximal exercise and cor- tively, these patients often have evidence of both systolic and dia-
relates with decreased tricuspid annular velocities, degree of pul- stolic ventricular dysfunction that is likely secondary to chronic
monary regurgitation, and increased brain natriuretic peptide in volume overload and cyanosis. While the systolic abnormalities
these children.146 RV isovolumic myocardial acceleration shows may improve postoperatively,147–148 diastolic filling abnormalities
promise in the evaluation of children with tetralogy of Fallot often persist and may worsen over time.149 In fact, in a large series
and has correlates with the degree of pulmonary regurgitation of patients with a double inlet left ventricle from the Mayo Clinic,
postrepair.145 diastolic dysfunction (i.e., elevated LV end diastolic pressure) was
326 Chapter 25 • Congenital Heart Disease

one of two independent risk factors for late death after the Fontan strated in other cardiac anomalies with similar alterations in
operation.150 loading conditions.163 The most common abnormality of diastolic
Gewillig et al. have evaluated the effect of altered loading con- function in these patients is abnormal relaxation with decreased
ditions on LV size and function after the Fontan operation. In early diastolic filling and increased compensatory late filling with
their study, normalization of LV end diastolic volume and of atrial contraction. The additional presence of wall motion abnor-
ventricular hypertrophy was demonstrated on serial follow-up of malities, which are common in these patients, likely contributes
patients with tricuspid atresia after Fontan palliation.151 This nor- to this altered diastology. Characteristic Doppler findings in
malization of mass-to-volume ratio was associated with improved patients after the Fontan operation are consistent with decreased
LV contractility indices (stress-velocity index). Sluysmens et al. ventricular compliance and include systolic dominance of pulmo-
also have evaluated children with single ventricle morphology to nary venous inflow, prolonged IVRT,161,164 and decreased peak
assess the effect of the Fontan circulation on ventricular geometry early filling velocities161,164,165 and mitral DT. Additional findings
and function.152 In their study of 84 children with double inlet of middiastolic mitral inflow149 and intracavitary flow during
left ventricles or tricuspid atresia, ventricular volumes were twice IVRT in Fontan patients also suggest abnormal diastolic func-
to three times normal for the age group, with an associated shift tion.149,164 The presence of abnormalities of ventricular relaxation
in ventricular geometry from an ellipsoidal to a spherical shape. and compliance, if significant, are poorly tolerated in the long term
Ventricular afterload became abnormal after 2 years of age because in patients with Fontan physiology.
of abnormally decreased wall thickness-to-dimension and mass- Conversely, in a younger cohort of patients evaluated both
to-volume ratios. Indices of LV function and contractility, includ- before and at intervals following the Fontan operation, Olivier et
ing fractional shortening, EF, and velocity of circumferential fiber al. demonstrated only very mild abnormalities of Doppler dia-
shortening, all became abnormal with advancing age, likely because stolic dysfunction, which were present both before and after sur-
of a combination of altered afterload and decreased myocardial gical palliation.166 In their group of 55 children and young adults
contractility. More severely impaired systolic performance also with normal invasive measurement of LV end diastolic pressure,
was correlated with higher oxygen saturation, indicating the Doppler inflow from the mitral valve and pulmonary veins dem-
detrimental effect of prolonged ventricular volume load on LV onstrated a transitional pattern between that of children with
function. Similar to previous studies, age at repair was also a sig- normal relaxation and those with abnormal relaxation (Fig.
nificant factor, with children who underwent Fontan palliation 25-12). Lack of improvement in these Doppler parameters after
before 10 years of age achieving normalization of afterload and a successful Fontan palliation was thought to be due to reduced
improved contractility at serial follow-up.151,153–157 ventricular preload after the Fontan operation and not to progres-
A high LV mass-to-volume ratio in the immediate postopera- sive impairment of diastolic relaxation or compliance.
tive period in children following Fontan palliation may be an
indicator of increased early morbidity with pericardial or pleural
effusions.158–160 Normalization of mass-to-volume ratio in Fontan Postoperative Congenital Heart Disease
patients may not lead to improved diastolic performance.147,161–162 Measurement of systolic and diastolic function in children under-
Increased collagen deposition within the hypertrophied ventricu- going surgical repair can be quite challenging due to altered ven-
lar myocardium likely leads to decreased compliance, as demon- tricular geometry and preoperative loading conditions. Children

Echo I Echo II Echo III

E/A ratio: 1.3 E/A ratio: 1.2 E/A ratio: 1.2
DT: 167 msec DT: 148 msec DT: 183 msec

100
E E E
AV (cm/sec)

A A A
50

msec
80 D D
S
PV (cm/sec)

D S
S
40

Figure 25-12 Ventricular filling patterns before

and after Fontan operation. Echo I, preoperative
FFxdias: 0.5 FFxdias: 0.6 FFxdias: 0.6 echo; Echo II, immediate postoperative echo;
Echo III, long-term (>6 months) follow–up.
PVAR (From Olivier M et al: Serial Doppler assessment
PVAR
of diastolic function before and after the Fontan
PVAR
operation. J Am Soc Echocardiogr 2003;16:
msec 1136–1143.)
 Chapter 25 • Congenital Heart Disease 327

FUTURE DIRECTIONS

Medical and surgical management techniques for diagnosis and

treatment of congenital heart disease in children and adults con-
tinue to evolve. A limited number of studies evaluating diastolic
dysfunction in these populations have been performed to date;
however, newer noninvasive modalities such as tissue Doppler
echocardiography and strain rate imaging169 continue to broaden
the ability of the clinician to identify ventricular dysfunction at
an early stage and will likely provide opportunities to institute
more effective therapies in these patients. Exciting new modalities
such as cardiac resynchronization therapy show promising results
in adults with heart failure and may offer similar benefits to
patients with congenital cardiac anomalies with abnormal ven-
tricular performance. As our tools to identify hemodynamic
Figure 25-13 Mitral valve Doppler inflow from transesophageal 4- and functional myocardial abnormalities continue to improve,
chamber view showing middiastolic flow reversal (arrow). (From Li JS et al: researchers must critically evaluate the effectiveness of novel
Abnormal left ventricular filling after neonatal repair of congenital heart medical and surgical treatment strategies on diastolic ventricular
disease: Association with increased mortality and morbidity. Am Heart J
1998;136:1075–1080.)
performance with the result being improved long-term clinical
outcome in children and adults with congenital heart disease.

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160. Mayer JE Jr, Helgason H, Jonas RA, et al: Extending the limits of the modi- mortality and morbidity. Am Heart J 1998;136:1075–1080.
fied Fontan procedures. J Thorac Cardiovasc Surg 1986;92:1021–1028. 169. Weideman F, Eyskens B, Jamal F, et al: Quantification of regional left and
161. Frommelt PC, Snider AR, Meliones JN, et al: Doppler assessment of pul- right ventricular radial and longitudinal function in healthy children using
monary artery flow patterns and ventricular function after the Fontan opera- ultrasound based strain rate and strain imaging. J Am Soc Echocardiogr
tion. Am J Cardiol 1991;68:1211–1215. 2002;15:20–28.
 LIVIU KLEIN, MD, MS
ROBERT O. BONOW, MD
26
Diabetes Mellitus

INTRODUCTION Interaction with Other Major

Comorbidities
PATHOPHYSIOLOGY
Metabolic Disturbances CLINICAL RELEVANCE
Myocardial Fibrosis
FUTURE RESEARCH
Small Vessel Disease
Cardiac Autonomic Dysfunction
Insulin Resistance

INTRODUCTION The Framingham Heart Study was the first to demonstrate an

increased risk for heart failure in patients with diabetes. The
Diabetes mellitus has reached epidemic proportions, affecting incidence of heart failure in these men and women was increased
more than 170 million individuals worldwide. Global estimates two- and fivefold, respectively, compared with men and women
for the year 2025 predict a further increase of almost 50%, with without diabetes.6 The association was even stronger in patients
the greatest increases in the developing countries of Africa, Asia, younger than 65 years of age, being fourfold higher in diabetic
and South America.1 This trend is particularly ominous, as those men and eightfold higher in diabetic women than in nondiabetic
in developing nations tend to develop diabetes earlier in life (ages subjects.6 Since then, additional studies, including the Studies of
40–64 years) than their counterparts in the developed world (≥65 Left Ventricular Dysfunction (SOLVD),7 the Heart Outcomes
years), implying a longer duration of exposure during the most Prevention Evaluation (HOPE) study,8 and the Cardiovascular
productive years and therefore a potentially greater risk of Health Study (CHS),9 have identified diabetes as a major risk
diabetes-associated morbidity and mortality.2 factor for the development of heart failure. In a large registry of
Of the estimated 20 million persons in the United States almost 50,000 diabetic individuals, poor glycemic control was
who have diabetes mellitus, 90% to 95% have type II diabetes. associated with an increased risk of developing heart failure: each
Among those, 6 million are unaware of their condition.3 An 1% increase in the level of glycosylated hemoglobin (HbA1c) was
additional 40 million show signs of insulin resistance and are at associated with an 8% increase in the risk of heart failure.10
high risk of developing type II diabetes.3,4 Even more alarmingly, Conversely, the presence of heart failure was identified as a
among obese white adolescents, 4% have type II diabetes and possible risk factor for diabetes. During a three-year follow-up of
25% have abnormal glucose tolerance,5 markedly increasing their nondiabetic heart failure Italian patients, diabetes developed in
likelihood of developing future premature cardiovascular 29% compared with 18% of matched controls; multivariate analy-
complications. sis showed heart failure to be an independent risk factor for the
Cardiovascular disease is the leading cause of death among development of diabetes.11 Moreover, diabetic patients make up
patients with diabetes, accounting for over 60% of mortalities.3 to 25% to 30% of all patients enrolled in large-scale heart failure
While diabetes is uniformly recognized as an important risk clinical trials.12–14
factor for the development of atherosclerosis and its complica- The dire prognosis of diabetic heart failure patients is well
tions, it is perhaps less well acknowledged that diabetes is a pow- established. In SOLVD,7 diabetes was a major risk factor for
erful and independent risk factor for the development of heart cardiovascular and all-cause mortality, and in the Diabetes Insulin
failure. Glucose in Acute Myocardial Infarction (DIGAMI) study, heart
333
334 Chapter 26 • Diabetes Mellitus

failure was the most frequent cause of mortality in diabetics, bolic control, these pathological mechanisms are potentially
accounting for 66% of deaths in the year following the first myo- reversible in the early phases, with normalization of the cardiac
cardial infarction.15 function.

PATHOPHYSIOLOGY Free Fatty Acid Metabolism

Abnormalities in free fatty acid metabolism caused by insulin
The term diabetic cardiomyopathy was first coined in 1972 by resistance may be important contributors to the abnormal myo-
Rubler et al., who described four diabetic patients presenting with cardial function in diabetes. High levels of free fatty acids lead
heart failure without evidence of coronary artery disease, hyper- to an inhibition of glucose oxidation, resulting in reduced myo-
tension, or valvular or congenital heart disease.16 Although ini- cardial ATP availability.22 In addition, abnormally high oxygen
tially controversial, the existence of diabetic cardiomyopathy has requirements associated with increased fatty acid metabolism
been confirmed in the past three decades by epidemiological, cause an intracellular accumulation of potentially toxic intermedi-
clinical, and laboratory studies, which have shed light on the bio- ates, leading to impaired myocardial performance and severe mor-
chemical and pathological mechanisms involved (Fig. 26-1). The phological changes.24 These metabolic changes are coupled with a
development of diabetic cardiomyopathy is likely multifactorial, relative carnitine deficiency that is common in diabetes25 and are
with putative mechanisms including metabolic disturbances, potentially reversible once glycemic control is improved.
myocardial fibrosis, small vessel disease, autonomic dysfunction,
and insulin resistance (Fig. 26-2).
Abnormalities in Regulation of
Calcium Homeostasis
Metabolic Disturbances The abnormal myocardial metabolism in diabetes leads to an
Isolated diabetic cardiomyocytes17 in diabetic patients18 exhibit a accumulation of toxic molecules (e.g., long-chain acylcarnitines,
significant decrease in myocardial glucose supply and utilization, free radicals), which in turn results in alterations in the function
with the net effect of reduced adenosine triphosphatase (ATP) of regulatory and contractile proteins and decreased calcium
availability. The slow rate of glucose transport across the sarco- sensitivity.26 The diminished calcium sensitivity along with
lemmal membrane is probably due to the cellular depletion of shifts in cardiac myosin heavy chains (V1 to V3),27 reduction
glucose transporters 1 and 4,19,20 which can be corrected by insulin of sarcoplasmic reticulum calcium-ATPase (SERCA2a), and
therapy.20,21 The reduced glucose oxidation in turn is caused by decreased SERCA2a pump gene expression28 may all contribute
the inhibitory effect of fatty acid oxidation on pyruvate dehydro- to impaired ventricular function.29 Finally, alterations in the
genase complex, due to high levels of circulating free fatty acids.22 expression of myosin isoenzymes and regulatory proteins and
Experimental models have demonstrated that these metabolic myosin phosphorylation have been demonstrated to contribute to
abnormalities are associated with contractile dysfunction mani- the development of myofibrillar remodeling in the diabetic heart30
fested by increased left ventricular (LV) end diastolic pressure and are closely associated with abnormalities in diastolic
and reduced cardiac output.23 Importantly, with improved meta- function.31

Type I Type II
Diabetes mellitus Diabetes mellitus

↑ Acyl CoA ↓ Ca++

↑ NEFA
↑ TNFα /Ceramide ↑ Apoptosis

Cellular insulin
resistance

↑ LV mass
Hyper-insulinemia LVH
↑ Fibrosis

Diastolic
dysfunction Figure 26-1 Proposed hypothesis for the
β-cell failure pathophysiology of diabetic cardiomyopa-
thy. ATP, adenosine triphosphate; CoA,
LV systolic fatty acyl coenzyme A; LV, left ventricle;
dysfunction LVH, left ventricular hypertrophy; NEFA,
nonesterified fatty acids; RyR2, ryanodine
Hypo-insulinemia ↓ SERCA 2a receptor 2; SERCA2a; sarco(endo)plasmic
↓ RyR2 reticulum calcium ATPase 2a; TNFa,
↓ Na+/K+ ATPase tumor necrosis factor α. (From Poornima
↓ Myofibrillar ATPase IG et al: Diabetic cardiomyopathy: The
↓ Microvascular search for a unifying hypothesis. Circ Res
Hyperglycemia flow reserve 2006;98:596–605.)
 Chapter 26 • Diabetes Mellitus 335

TRIGGERS MEDIATORS EFFECTORS TARGETS

↑ Acyl CoA ↑ K+ATP channel ↓ Activator Ca++

↑ Atypical PKC ↓ Akt-1 Insulin

NEFA
↑ PTEN activation resistance
Figure 26-2 Cellular mechanisms in-
volved in the pathophysiology of diabe- ↑ TNFα ↑ Ceramide Myocyte
tic cardiomyopathy. AGE, advanced apoptosis
glycation end products; ATP, adenosine
triphosphate; CoA, fatty acid coenzyme
A; GADPH, glyceraldehyde-3-phosphate ↓ GSK-3β Myocyte
PI 3K/Akt-1
dehydrogenase; GSK-3b, glycogen syn- ↑ mTOR hypertrophy
thase kinase-3b; MAP, mitogen-activated Hyperinsulinemia
protein; mTOR, mammalian target of ↑ MAP kinase ↑ Ras/↑ Rho ↑ Protein synthesis
rapamycin; NEFA, nonesterified fatty
acids; PARP, poly (ADP-ribose) poly-
merase; PI 3K, phosphatidylinositol 3- ↑ PKC Calcium
kinase; PKC, protein kinase C; PTEN, homeostasis
phosphatase and tensin homolog deleted Hyperglycemia
↑ ROS → ↑ PARP ↑ Hexosamine
on chromosome 10; ROS, reactive oxygen ↓
species; TNFa, tumor necrosis factor α. Contractile
↓ GAPDH ↑ Polyol flux proteins
(From Poornima IG et al: Diabetic cardio-
myopathy: The search for a unifying ↑ Age Matrix proteins
hypothesis. Circ Res 2006;98:596–605.)

A magnetic resonance imaging (MRI) study of asymptomatic, more pronounced in symptomatic patients and in those with car-
normotensive, nonobese, well-controlled diabetic patients (mean diomegaly.41,42 The role of fibrosis in myocardial dysfunction
HbA1c, 6.1 g/dL) showed ventricular diastolic dysfunction com- is also supported by studies showing reversal of cardiac fibrosis
pared with control subjects who were matched for age, gender, by short-term pirfenidone and spironolactone treatment, with
body mass index (BMI), and blood pressure.32 These findings improvement in diastolic stiffness in diabetic rats.43 Alterations in
were associated with a significantly lower ratio of myocardial myocardial structure are usually minimal in the early stages of
phosphocreatine to ATP in diabetic patients compared with con- diabetes and may be reversible or partially reversible. As diabetes
trols.32 Previous studies suggested that the lower phosphocreatine progresses, accumulation of collagen becomes obvious and may
content and the switch in substrate preference from glucose to play a major role in the development of diastolic dysfunction.
fatty acids may lead to lower levels of ATP in the sarcomeres, for
which increased mitochondrial ATP production does not com-
pensate.33 Lower cytosolic ATP concentration is associated with Small Vessel Disease
impaired calcium sequestration by the sarcoplasmic reticulum Structural Abnormalities of Vessels
and impaired relaxation of cardiomyocytes.32
Although the contribution of small vessel disease to diabetic car-
diomyopathy is controversial, there are several structural abnor-
Myocardial Fibrosis malities of small vessels that are evident in the diabetic
Myocardial fibrosis and myocyte hypertrophy are among the most myocardium. The capillary basement membrane is thicker in
frequently proposed mechanisms to explain cardiac changes in patients with diabetes, and its thickness seems to be greater com-
diabetic cardiomyopathy. Collagen accumulation in the diabetic pared with patients with glucose intolerance and those without
myocardium may be due in part to impaired collagen degradation diabetics.44 In addition, diabetes patients exhibit capillary micro-
resulting from glycosylation of the lysine residues on collagen.34 aneurysms with reduced capillary density, focal subendothelial
Hyperglycemia also results in the production of reactive oxygen proliferation, and interstitial fibrosis with myocyte atrophy.45–47
and nitrogen species, which increases oxidative stress and causes
abnormal gene expression, altered signal transduction, and activa-
tion of the pathways leading to programmed myocardial cell death Functional Abnormalities of Vessels
or apoptosis.35 This process is associated with the glycosylation of It has been proposed that diabetic cardiomyopathy is a conse-
p53, resulting in an increment in angiotensin II synthesis36 that quence of repeated episodes of myocardial ischemia resulting from
has dose-dependent effects on collagen secretion and production both structural and functional abnormalities in small vessels or
in cardiac fibroblasts.37 In addition, chronic metabolic abnormali- from microvascular spasm during periods of increased myocardial
ties present in diabetes (postprandial hyperglycemia, hyperinsu- demand.48,49 Such processes would lead to focal cell loss due to
linemia, insulin resistance) lead to alterations in endothelin-1 and microvascular spasm and reperfusion injury, with the subsequent
its receptors,38 decreased levels of insulin-like growth factor-I,39 development of focal fibrosis and reactive hypertrophy in response
and increased production of transforming growth factor-β140 that to myocardial necrosis. The myocardial blood flow is not only
result in promotion of angiotensin II activity with an increase in reduced in diabetic patients but also correlates significantly with
myocardial collagen content. fasting glucose concentration and average levels of HbA1c.50,51
The functional abnormalities in diabetic myocardium are asso- Endothelium-dependent responses of both small and large
ciated with myocardial structural changes. Several studies using vessels are impaired in diabetic patients, including those with an
endomyocardial biopsies have shown a correlation between histo- otherwise low likelihood of atherosclerosis.52,53 The half-life of
logical and clinical features in diabetes, with myocardial changes nitric oxide is reduced due to increased oxidative stress,54–57 and
336 Chapter 26 • Diabetes Mellitus

its activity is attenuated by accumulated glycosylation end prod- cardiomyopathy. Furthermore, the presence of silent ischemia in
ucts.58 In addition, diabetic endothelium manifests increased pro- diabetic patients makes the diagnosis of diabetic cardiomyopathy
duction of vasoconstrictor prostanoids59 and increased expression more complicated.
of protein kinase C activity.60 Protein kinase C activation is associ-
ated with abnormal retinal and renal hemodynamics in diabetic Interaction with Hypertension
animals, and overexpression of the myocardial β-isoform is asso-
ciated with cardiac hypertrophy and failure,61 implying that this The prevalence of hypertension is approximately doubled in dia-
may play a role in the development of diabetic cardiomyopathy betic patients compared with nondiabetic controls,82 and the clini-
by affecting the small vasculature. cal and morphological features of heart disease in hypertensive
diabetic patients are more severe than those of hypertensive
patients or diabetic patients alone. Myocardial fibrosis and inter-
Cardiac Autonomic Dysfunction stitial collagen deposition are greater when hypertension is associ-
Studies in which sympathetic innervation was assessed quan- ated with diabetes than when either entity exists in isolation,83 and
titatively using 123 I-metaiodobenzylguanidine or 11 C- these synergistic effects on neurohormonal activation and oxida-
hydroxyephedrine have shown a decreased myocardial uptake in tive stress may promote apoptotic myocyte loss, initiating a transi-
40% to 50% of diabetes patients, indicating the presence of cardiac tion from a subclinical, compensated/hypertrophied state to overt
autonomic dysfunction.62,63 It appears that this is a regional cardiomyopathy.84 At least one study has documented an associa-
process, with the posterior myocardium being predominantly tion between diabetes, hypertension, and the development of
affected64–66 and with areas of proximal hyperinnervation compli- dilated cardiomyopathy.85 In addition, patients with diabetes and
cating distal denervation.67 Myocardial autonomic dysfunction is hypertension in combination have more severe abnormalities of
associated with altered myocardial blood flow, with the regions of ventricular relaxation than those with either condition alone.86
persistent sympathetic innervation exhibiting the greatest deficits
of vasodilator reserve.68 Decreased myocardial perfusion reserve Interaction with Coronary Artery Disease
may be in part responsible for the abnormal response to exercise
in the early phases of diabetic cardiomyopathy69,70 and may explain Although lipid metabolism abnormalities associated with diabe-
its association with impairments of diastolic function.71–74 tes do not have direct influence on the development of diabetic
cardiomyopathy, they are at least partly responsible for enhanced
coronary atherosclerosis in these patients. Enhanced coronary
Insulin Resistance atherosclerosis is directly related to myocardial ischemia, increased
Cellular insulin resistance may precede frank diabetes by a decade oxidative stress, and vascular endothelial dysfunction. Compared
or more and is associated with requisite compensatory increases with nondiabetic patients, those patients with diabetes demon-
in plasma insulin levels to maintain glucose homeostasis in the strate impaired recruitment of contractile reserve in noninfarct
face of impaired cellular insulin action, principally in skeletal segments and greater reduction in global systolic function imme-
muscle and liver.75 The nature and extent of the insulin resistance diately following myocardial infarction,87,88 changes that may be
may be selective to certain organ systems and may vary in terms related to diminished coronary flow reserve and microvascular
of their metabolic, mitogenic, pro-survival, and vascular actions. dysfunction.89 Over the long term, these acute changes do not
Insulin may act as a growth factor in the myocardium, a concept appear to be associated with a greater propensity for ventricular
that is supported by the experimental observation that sustained cavity dilation or progressive systolic dysfunction,90 and the
hyperinsulinemia leads to increased myocardial mass and increased incidence of heart failure in diabetic patients appears to
decreased cardiac output in rats.76 Hyperinsulinemia leads to be related to primary abnormalities of diastolic function.
sodium retention, which may contribute to decompensation in The progression of diabetic cardiomyopathy is a dynamic
persons with otherwise subclinical myocardial dysfunction due to process and takes several years to develop (Table 26-1). In the
volume expansion.77 Hyperinsulinemia also leads to sympathetic initial phase, there is a short-term physiological adaptation to
nervous system activation,78 which is related to an increased metabolic alterations that is potentially reversible once glycemic
response to angiotensin II79 and increases the stimulating effects control has been restored. Thus, therapies during the early stages
of angiotensin II on cellular hypertrophy and collagen produc- of diabetes can potentially prevent or delay the progression to
tion,80 leading to myocardial hypertrophy and fibrosis and likely more permanent sequelae. The late stage represents degenerative
subsequent heart failure. changes for which the myocardium has only limited capacity for
A very elegant recent study has shown that in a community- repair. However, many factors, such as treatments, metabolic
based sample of men free of heart failure and valvular disease at characteristics, lipid profile, blood pressure, and other individual
baseline, insulin resistance predicted heart failure incidence inde- differences, may affect the process of development of diabetic car-
pendently of diabetes and other established risk factors for heart diomyopathy, and not all diabetic patients are affected by the same
failure.81 Furthermore, this study indicated that the previously factors or to the same degree, which may result in marked vari-
described association between obesity and subsequent heart ability in the clinical manifestations of diabetic cardiomyopathy.
failure may be mediated, at least in part, by insulin resistance.
CLINICAL RELEVANCE
Interaction with Other Major Comorbidities
With the addition of untreated hypertension, myocardial isch- LV diastolic dysfunction may be the first stage of diabetic cardio-
emia, or both, the mild subclinical cardiomyopathy of diabetes myopathy.91,92 In the Olmsted County study, close to 50% of par-
may rapidly advance to clinical diastolic and systolic dysfunction. ticipants with diabetes had echocardiographic evidence of diastolic
In clinical practice, it is difficult to distinguish the concurrent dysfunction, compared with 27% of nondiabetic subjects.93
roles of hypertension and ischemia in the development of diabetic Almost none of these participants had a prior diagnosis of heart
 Chapter 26 • Diabetes Mellitus 337

TABLE 26-1
STAGES OF DIABETIC CARDIOMYOPATHY
STAGES CHARACTERISTICS FUNCTIONAL FEATURES STRUCTURAL FEATURES DIAGNOSIS

Early Depletion of glucose transporter 4 No overt functional Normal ventricular size, wall Sensitive methods such as
Increased free fatty acids abnormalities or possible thickness, and mass strain, strain rate, and
Carnitine deficiency overt diastolic dysfunction myocardial tissue
Calcium homeostasis changes but normal ejection fraction velocity
Insulin resistance

Intermediate Apoptosis and necrosis Abnormal diastolic function Slightly increased Conventional
Increased angiotensin II and normal or slightly ventricular mass, wall echocardiography or
Reduced insulin-like growth factor-I decreased ejection fraction thickness, or size sensitive methods such
Increased production of as strain, strain rate,
transforming growth factor-β1 and myocardial tissue
Mild cardiac autonomic velocity
dysfunction

Late Microvascular changes Abnormal diastolic function Significantly increased Conventional

Hypertension and ejection fraction ventricular size, wall echocardiography
Coronary artery disease thickness, and mass
Severe cardiac autonomic
dysfunction

From Fang ZY et al: Diabetic cardiomyopathy: Evidence, mechanisms, and therapeutic implications. Endocr Rev 2004;25:543–567.

failure. Remarkably, this observational study showed that even before clinical diabetes is diagnosed and may have distinct char-
mild impairment in diastolic function is associated with an eight- acteristics among different gender and ethnic groups.
fold risk of all-cause mortality compared with normal diastolic Several studies have shown that the first clinical manifestation
function.93 In the same study, 14% of diabetic patients also had of diastolic dysfunction is limited exercise tolerance. Poirier et al.
an LV ejection fraction (LVEF) below 0.50 compared with only reported that patients with well controlled diabetes and without
5% of nondiabetic patients, providing evidence that diabetes can overt coronary artery disease, hypertension, or heart failure had
affect both systolic and diastolic function. lower exercise performance on maximal treadmill testing than
In a study of 86 patients with diabetes (43% of whom were age-matched controls. The exercise limitation correlated with the
women), more than 40% had diastolic dysfunction: 26% had severity of diastolic dysfunction as assessed by Doppler
impaired relaxation and 17% had pseudonormalization on echocardiography.96
Doppler echocardiogram.94 These findings are noteworthy, as Microalbuminuria appears to be an independent risk factor for
these subjects were young (mean age, 43 years), normotensive the development of diastolic dysfunction, perhaps being a marker
(mean blood pressure, 125/80 mmHg), and under excellent dia- for intramyocardial microangiopathy. In the Strong Heart Study,
betic control (mean HbA1c, 6.5 g/dL). after adjusting for age, gender, BMI, systolic blood pressure, dura-
In the Strong Heart Study, enrolling 2411 Native Americans, tion of diabetes, coronary artery disease, and LV mass, the pre-
diabetic participants had evidence of impaired LV relaxation on valence of LV diastolic dysfunction increased as a function of
Doppler echocardiography. The association between diabetes and increasing urinary albumin excretion.97 Further studies should
abnormal LV relaxation was independent of age, blood pressure, address whether routine testing for microalbuminuria is indicated
LV mass, and systolic function.86 These abnormalities were more to identify diabetic patients with impaired LV relaxation.97
severe in the group with both diabetes and hypertension, showing The influence of diabetic complications on diastolic function
the additive deleterious effects on active LV relaxation when both has been investigated in several other studies. Most of these
these conditions are present.86 studies showed that patients with diabetic retinopathy,98–101
In the Multi-Ethnic Study of Atherosclerosis, 6800 men and nephropathy,102–104 or neuropathy105–107 had significantly more
women from four ethnic groups (Americans of African, Chinese, abnormalities in diastolic function compared with diabetic
European, and Hispanic descent) underwent cardiac MRI at patients without microvascular disease or with nondiabetic
enrollment. Diabetic patients manifested increased LV mass and patients. In addition, the severity of diastolic dysfunction was
lower end diastolic and stroke volumes compared with partici- related to the number of microvascular complications,100,108 glyce-
pants with impaired fasting glucose and with nondiabetic mic control,86,109,110 or duration of diabetes.111–113
patients.95 These findings were independent of traditional risk Despite growing awareness of the burden of diastolic heart
factors and other measures of subclinical atherosclerosis (such as failure (DHF), there have been few randomized clinical trials of
coronary artery calcium or carotid artery intima-media thickness) drug therapies for these patients (see Chapters 32 and 34), and
and were especially significant in African Americans and Hispan- no trial that specifically assessed the unique role of diabetes.
ics. Although LVEF was not different among diabetic and non- The Digitalis Investigation Group ancillary study randomized
diabetic women, diabetic men had a significantly lower LVEF 988 patients with chronic heart failure who were in sinus rhythm
compared with nondiabetic men, albeit within the normal range.95 and had an LVEF greater than 45% to digoxin or placebo, in
These results strengthen the evidence in favor of a diabetic car- addition to standard therapy.114 Although there were no differ-
diomyopathy and suggest that this condition may start even ences in all-cause mortality (23.4% in both groups after a mean
338 Chapter 26 • Diabetes Mellitus

follow-up of 37 months) or in the endpoint of death or hospital- evaluated the effect of a selective beta blocker with additional
ization for worsening heart failure (24% and 21% in the placebo vasodilating properties in 2128 patients 70 years of age or older.14
and digoxin groups, respectively; p = 0.136), there was a trend Twenty percent of the study population had LVEFs above 45%.
toward benefit in the digoxin group for heart failure hospitaliza- As with CHARM-Preserved, the characteristics of the overall
tions (22% and 18% in the placebo and digoxin groups, respec- population were quite different from those of populations with
tively; p = 0.094).114 This study is the basis for the level C DHF in epidemiology studies, in that 63% were men and 76%
recommendation for the use of digoxin to reduce symptoms of had ischemic heart disease as the etiology of heart failure. Nebivo-
heart failure in patients with DHF.115 lol produced a significant reduction in the primary endpoint of
The Candesartan in Heart Failure Assessment of Reduction in death or cardiovascular hospitalization, with 31.1% of patients in
Mortality and Morbidity (CHARM)–Preserved arm is the first of the nebivolol and 35.3% in the placebo group experiencing an
several trials designed to study patients with DHF initiated in the event (HR, 0.86; 95% CI, 0.73–0.99).14 There was a modest
last 5 years to have published its full results. The design of the trend toward an improvement in mortality (HR, 0.88; 95% CI,
study, in the context of the entire CHARM program, dictated 0.71–1.08). The results in the group with LVEFs of 45% or
the selection of patients with LVEF greater than 40%, allowing the greater were not presented separately. Patients without diabetes
inclusion of some patients with at least mild systolic dysfunction. showed a significant benefit with nebivolol for the primary com-
The primary endpoint of cardiovascular death or heart failure posite endpoint, while those with diabetes did not.14
hospitalization occurred in 22% of patients in the candesartan arm With the exception of candesartan and perhaps digoxin, which
and 24% of those in the placebo arm (hazard ratio [HR], 0.89; have been shown to reduce the incidence of hospitalizations, the
95% CI, 0.77–1.03).12 Cardiovascular deaths were identical in management of DHF is based largely on clinical experience, with
number in the two groups, but fewer patients in the candesartan the goal of controlling the deleterious processes that are known
group than the placebo group experienced heart failure hospital- to exert important effects on ventricular relaxation (i.e., hyperten-
izations (15.2% vs. 18.5%, p = 0.017).12 Although candesartan was sion, diabetes, ischemia, tachycardia, and atrial fibrillation) (see
associated with a reduction in the incidence of new-onset diabetes Chapter 32).118
when compared with placebo,116 the authors did not present a The first treatment goal is to provide symptomatic relief by
separate analysis of its effect on mortality or heart failure hospital- decreasing pulmonary congestion at rest and during exercise. This
izations in the diabetic patients in the study. can be achieved by a reduction in LV diastolic volume (with the
The Perindopril for Elderly Persons with Chronic Heart goal of reducing LV diastolic pressure), maintaining synchronous
Failure (PEP-CHF) trial was a study of heart failure in elderly atrial contraction (by maintaining sinus rhythm), and increasing
patients rather than a study of DHF.117 All 852 patients were the duration of diastole (by reducing heart rate).118
older than 70 years and had evidence of chronic heart failure Reduction in LV diastolic volume can be done by reducing
confirmed by clinical and echocardiographic criteria (LVEF total blood volume (through sodium and water restrictions and
greater than 40%). At the end of the 26 months of follow-up, use of diuretics), decreasing central blood volume (through
there was no difference in the primary outcome of all-cause mor- preload reduction with nitrates), and inhibiting the activation of
tality or heart failure hospitalizations between the placebo and the renin-angiotensin-aldosterone system (through ACE inhibi-
the perindopril groups (25.1% vs. 23.6%, p = 0.545). Perindopril tors, angiotensin-receptor blockers, and aldosterone antagonists,
decreased heart failure hospitalizations during the first year (HR, or a combination thereof ) (Table 26-2).118
0.63; 95% CI, 0.41–0.97) but not at the end of the follow-up LV filling in DHF occurs primarily in late diastole and is more
(HR, 0.86; 95% CI, 0.6–1.20).117 In the authors’ opinion, the dependent on atrial contraction than is filling in unimpaired
main reasons for the negative results were the enrollment of fewer hearts. Restoration and maintenance of sinus rhythm is preferred
patients (N = 1000) than anticipated, a lower event rate than when atrial fibrillation occurs in the setting of DHF. If this cannot
predicted, and the use of open-label angiotensin-converting- be achieved, rate control is paramount.118
enzyme (ACE) inhibitors in these patients after the first year of Tachycardia can cause an exacerbation of diastolic dysfunction
follow-up.117 by increasing myocardial oxygen demand (leading to ischemia)
The Study of Effects of Nebivolol Intervention on Outcomes and by causing incomplete relaxation.118 Maintaining a resting
and Rehospitalizations in Seniors with Heart Failure (SENIORS) heart rate around 60–70 bpm and blunting exercise-induced

TABLE 26-2
EFFECTS OF ANGIOTENSIN-CONVERTING-ENZYME INHIBITORS ON MORTALITY FROM SYSTOLIC HEART FAILURE
IN DIABETIC AND NONDIABETIC PATIENTS
TOTAL NONDIABETIC DIABETIC RR, NONDIABETIC RR, DIABETIC
Study Name N N N (95% CI) (95% CI)

CONSENSUS 253 197 56 0.64 (0.46–0.88) 1.06 (0.65–1.74)

SAVE 2231 1739 492 0.82 (0.68–0.99) 0.89 (0.68–1.16)
SMILE 1556 1253 303 0.79 (0.54–1.15) 0.44 (0.22–0.87)
SOLVD-Prevention 4228 3581 647 0.97 (0.83–1.15) 0.75 (0.55–1.02)
SOLVD-Treatment 2569 1906 663 0.84 (0.74–0.95) 1.01 (0.85–1.21)
TRACE 1749 1512 237 0.85 (0.74–0.97) 0.73 (0.57–0.94)
Random effects pooled estimate 10188 2398 0.85 (0.78–0.92) 0.84 (0.70–1.00)

RR, risk reduction; CI, confidence interval; CONSENSUS, Cooperative North Scandinavian Enalapril Survival Study; SAVE, Survival and Ventricular Enlargement; SMILE, Survival of
Myocardial Infarction Long-Term Evaluation; SOLVD, Studies of Left Ventricular Dysfunction; TRACE, Trandolapril Cardiac Evaluation.
From Zile MR, Brutsaert DL: New concepts in diastolic dysfunction and diastolic heart failure: Part II: Causal mechanisms and treatment. Circulation. 2002;105:1503–1508.
 Chapter 26 • Diabetes Mellitus 339

TABLE 26-3
EFFECTS OF BETA BLOCKERS ON MORTALITY FROM SYSTOLIC HEART FAILURE IN DIABETIC AND
NONDIABETIC PATIENTS
TOTAL NONDIABETIC DIABETIC RR, NONDIABETIC RR, DIABETIC
Study Name N N N (95% CI) (95% CI)

CIBIS II 2647 2335 312 0.66 (0.54–0.81) 0.81 (0.52–1.27)

COPERNICUS 2287 1701 586 0.67 (0.52–0.85) 0.68 (0.47–1.00)
MERIT-HF 3991 3006 985 0.62 (0.48–0.79) 0.81 (0.57–1.15)
Random effects pooled estimate 7042 1883 0.65 (0.57–0.74) 0.77 (0.61–0.96)

RR, risk reduction; CI, confidence interval; CIBIS, Cardiac Insufficiency Bisoprolol Study; COPERNICUS, Carvedilol Prospective Randomized Cumulative Survival; MERIT-HF, Metoprolol
CR/XL Randomized Intervention Trial in Heart Failure.
From Zile MR, Brutsaert DL: New concepts in diastolic dysfunction and diastolic heart failure: Part II: Causal mechanisms and treatment. Circulation 2002;105:1503–1508.

tachycardia by using beta blockers and calcium channel antago- Several trials evaluating established and novel treatment
nists may have beneficial effects and prevent elevated LV pres- options in patients with DHF have been completed (e.g., PEP-
sures and pulmonary congestion (Table 26-3).118 CHF and CHARM-preserved) and two trials are ongoing
After symptom control, treatment should target the underlying (Irbesartan in Heart Failure with Preserved Ejection Fraction
disorders that caused DHF. Blood pressure should be maintained [I-PRESERVE]124 and the Trial of Aldosterone Antagonist
below 130/80, in keeping with current guidelines, and all patients Therapy in Adults with Preserved Ejection Fraction Congestive
with suspected ischemic etiology should undergo evaluation and Heart Failure [TOPCAT]). The I-PRESERVE trial is a large
revascularization.115 Regression of LV hypertrophy with beta trial designed specifically to examine patients with DHF. To more
blockers, calcium channel antagonists, and renin-angiotensin- closely approximate the population of patients with DHF, only
aldosterone system blockers can improve diastolic function.119 those 60 years or older and with LVEF 45% or greater are being
Although tight glycemic control decreases the risk of heart entered. Furthermore, patients who have had prior documented
failure in persons with diabetes,10 the effects of different diabetic moderate or severe systolic dysfunction, as evidenced by LVEF
treatment regimens on DHF in this population are unknown. less than 40%, are excluded. Enrollment of 4128 patients has been
While diabetes is an important contributor to diastolic dys- completed. The mean age is older than 70 years, approximately
function and DHF, a significant proportion of patients with heart 60% are women, and hypertension is the primary etiology of heart
failure and impaired systolic function also have diabetes. A recent failure, with only approximately one quarter having known coro-
meta-analysis has shown that the traditional therapies for systolic nary disease. The primary endpoint of I-PRESERVE reflects the
dysfunction with angiotensin-receptor inhibitors and beta critical outcomes that affect this population, including death from
blockers have the same beneficial effect in the diabetic popula- all causes, nonfatal myocardial infarction and stroke, and hospi-
tion.120 In addition, eplerenone, a selective aldosterone blocker, is talizations for worsening heart failure, unstable angina, and
as effective in preventing all-cause or cardiovascular mortality and arrhythmias. Follow-up will be completed in early 2008 when the
cardiovascular events in diabetic patients as it does in nondiabetic target of 1440 primary endpoint events will have occurred.
subjects who have suffered a myocardial infarction and have The National Heart, Lung, and Blood Institute sponsored the
decreased LVEF.121 TOPCAT study, which is enrolling 4500 patients 50 years of age
and older with symptoms of heart failure and LVEF greater than
45%. Patients will be randomized to spironolactone or placebo
FUTURE RESEARCH and followed up for at least 3 years. Enrollment started in summer
2006 and the trial is expected to complete in 2011.
DHF is a major contributor to mortality, hospitalization, and The Japanese Diastolic Heart Failure Study ( J-DHF) is a mul-
medical costs in the United States. Two recent studies have shown ticenter, prospective, randomized trial designed to assess effects
that the percentage of patients hospitalized for decompensated of beta blockers in patients with DHF. A total of 800 patients
heart failure with preserved systolic function (LVEF >50%) has will be enrolled and followed for at least 2 years. The primary
increased over time and that their prognosis is as grim as that of outcome is a composite of cardiovascular death and unplanned
those with impaired systolic function.122,123 The one-year mortal- admission to hospital for congestive heart failure. Other outcomes
ity rates are in the 20% range, and the readmission rate for heart include all-cause mortality, worsening of the symptoms of heart
failure in the first year after discharge is around 13%.123 failure, and a need for modification of the treatment for heart
DHF is usually associated with hypertension, atherosclerosis failure.125
(involving the coronary arteries and aorta), and atrial fibrillation, Glucose cross-link breakers (e.g., alagebrium chloride) are
conditions that are common in the elderly. Thirty percent of novel therapies for DHF. A small open-label study in patients
patients with DHF have diabetes, and the proportion of diabetic older than 65 years of age showed that administration of alage-
patients with preserved EF has increased significantly over time.122 brium chloride for 16 weeks led to regression of LV mass and
Recent studies in experimental animal models and in humans improvements in echocardiographic diastolic parameters and
suggest that diabetes results in functional, biochemical, and quality-of-life questionnaires (see Chapter 34).126 These encour-
morphological myocardial abnormalities independent of coro- aging results are likely to be followed by a larger, placebo-
nary atherosclerosis and hypertension. These abnormalities lead controlled trial.
to a specific diabetic cardiomyopathy that manifests mainly by As of yet, no trials have addressed the unique contribution of
impaired diastolic function. diabetes to diastolic dysfunction and heart failure. Small studies
340 Chapter 26 • Diabetes Mellitus

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dysfunction after kidney-pancreas transplantation in type 1 diabetic uremic 126. Little WC, Zile MR, Kitzman DW, et al: The effect of alagebrium chloride
patients. Diabetes Care 2000;23:1804–1810. (ALT-711), a novel glucose cross-link breaker, in the treatment of elderly
111. Vanninen E, Mustonen J, Vainio P, et al: Left ventricular function and patients with diastolic heart failure. J Card Fail 2005;11:191–195.
dimensions in newly diagnosed non-insulin-dependent diabetes mellitus. 127. Essop MF, Opie LH: Metabolic therapy for heart failure. Eur Heart J
Am J Cardiol 1992;70:371–378. 2004;25:1765–1768.
112. Celentano A, Vaccaro O, Tammaro P, et al: Early abnormalities of cardiac 128. Nikolaidis LA, Levine TB: Peroxisome proliferator activator receptors
function in non-insulin-dependent diabetes mellitus and impaired glucose (PPAR), insulin resistance, and cardiomyopathy: Friends or foes for the
tolerance. Am J Cardiol 1995;76:1173–1176. diabetic patient with heart failure? Cardiol Rev 2004;12:158–170.
 RICHARD W. TROUGHTON, MB, ChB, PhD
JAY RITZEMA-CARTER, BM
M. GARY NICHOLLS, MB, ChB
27
Role of Neurohormones
INTRODUCTION Assessment of Prognosis
Prediction of Heart Failure Events after
PATHOPHYSIOLOGY
Myocardial Infarction
Neurohormonal Regulation of the
Monitoring Heart Failure and Optimizing
Circulation: Normal Versus Heart Failure
Therapy
Neurohormones and the Transition from
Exogenous Administration of B-Type
Hypertrophy to Heart Failure
Natriuretic Peptide
Neurohormonal Factors Contributing to
Differentiation of Constrictive Pericarditis
Heart Failure Pathophysiology
from Restrictive Cardiomyopathy
Pattern of Neurohormonal Activation in
Cardiac Amyloid
Heart Failure with Normal Left Ventricular
Chronic Renal Failure
Ejection Fraction
Valvular Heart Disease
CLINICAL RELEVANCE Hypertrophic Cardiomyopathy
Neurohormones as Treatment Targets for Hypertensive Subjects
Hypertension and Diastolic Heart Failure
SUMMARY
Natriuretic Peptides and Screening for
Cardiac Dysfunction FUTURE RESEARCH
Diagnosis of Acute Heart Failure

INTRODUCTION tides, endothelin (ET), and adrenomedullin (AM) has now

become a major focus of study.16–18 The discovery of these and
The critical role of neurohormonal factors in regulating circula- additional neurohormonal systems and clarification of their roles
tion and volume status has been known for over a century. The in heart failure has opened up exciting new opportunities to
importance of neurohormonal activation in heart failure patho- better define the pathophysiology of heart failure and to develop
physiology was identified in the middle and latter part of the 20th new therapies.19–23
century and formed the basis for the neurohormonal model of The importance of the neurohormonal model of heart failure
heart failure.1,2 Major contributions to this understanding came cannot be understated when considering the recent advances in
from observational data in large, well-characterized populations, heart failure treatment. Awareness that activation of the RAS,
often participating in studies of systolic heart failure treatments.2,3 aldosterone, and the SNS leads to vasoconstriction, sodium
In these studies, plasma levels of vasoactive hormones involved in retention, and adverse effects on cardiac and vascular remodeling,
regulation of circulation and renal function—such as vasopressin, thereby contributing to morbidity and mortality in systolic heart
renin, angiotensin II (A-II), aldosterone, the cardiac natriuretic failure, has led to the development of successful therapies through
peptides, and norepinephrine (NE)—were not only shown to be blockade of these systems.10–15,24 Whether blockade of additional
significantly elevated compared with normal controls, but also neurohormonal systems can be tolerated and offers additional
clearly provided prognostic information.2–5 These seminal obser- benefit is unclear but remains the focus of several current
vations have since been confirmed by multiple studies in a variety studies.25–28 Likewise, it remains to be seen whether administra-
of settings.6–8 Early attention was focused on the pathophysiologi- tion of vasodilator hormones such as the natriuretic peptides,
cal roles of the sympathetic nervous system (SNS), the renin- urocortin, and AM or synthetic compounds acting as agonists
angiotensin system (RAS), and aldosterone.2,3,9 A large body of on their specific receptors produce beneficial effects on
evidence, much of it emanating from studies using targeted block- cardiovascular and renal functions.20,29,30 In the case of B-type
ade of neurohormones, attests to the pivotal role of these systems natriuretic peptide (BNP), this has led to a potential therapeutic
in established heart failure.2,3,9–15 The role of more recently dis- application,31 an option that might also be possible for other
covered systems such as those involving cardiac natriuretic pep- peptides.
345
346 Chapter 27 • Role of Neurohormones

Recent interest has focused on the potential role of neurohor- Cardiac Natriruetic Peptides Increasing severity
mones as markers of cardiac dysfunction and heart failure. In Adrenomedullin
Prostaglandins
of heart failure
(NYHA I-IV)
particular, BNP has been validated as a diagnostic marker for Nitric oxide
heart failure,32–35 and its role in monitoring and guiding therapy NYHA IV Bradykinin NYHA I
is being studied actively.36–38
A significant limitation of the current understanding of neu-
rohormonal factors in heart failure is that there is relatively scant
data describing the pattern and role of neurohormonal activation
for patients in whom left ventricular ejection fraction (LVEF) is
preserved.39,40 The available neurohormonal model of heart failure
is based largely on observations from patients with systolic heart NYHA I NYHA IV
Sympathetic system
failure or in whom left ventricular (LV) function was not well RA system
Vasodilator Vasoconstrictor
described. Based on the known differences in the epidemiology Natriuretic/diuretic
Aldosterone
Anti-natriuretic
Endothelin
of heart failure with preserved versus impaired systolic func- Anti-mitotic
Anti-hypertrophic
TNF
Mitotic
Hypertrophic
tion,41–44 it is likely that neurohormonal profiles will also differ.
Available data suggest that this is indeed the case.39,40 A greater Figure 27-1 Heart failure is characterized by an imbalance in the neuro-
understanding of neurohormonal profiles can potentially lead to hormonal factors that regulate the circulation and volume status. Vaso-
new and more effective therapy for heart failure in the setting of constrictor systems overpower vasodilator systems, leading to sodium
preserved LVEF. retention and cardiovascular remodeling.

lated gene expression in response to various stimuli, including

PATHOPHYSIOLOGY cardiac injury, reduced organ or tissue perfusion, and fluid over-
load.21,50,54,55 Neurohormonal activation may precede the onset of
Neurohormonal Regulation of the Circulation: frank clinical heart failure and is a feature of asymptomatic LV
Normal Versus Heart Failure dysfunction.56,57 A defining characteristic of the neurohormonal
response to cardiac injury or heart failure is the predominance of
Under normal conditions, tightly counterbalanced neurohormo- vasoconstrictor over vasodilator systems. This loss of counter-
nal systems provide dynamic regulation of the circulation and of poise leads to attenuation of the beneficial effects of vasodilator
volume status.45 These finely tuned systems respond with various systems and contributes to or mediates many of the major adverse
time frames to perturbations in body posture and volume status— pathophysiological changes in heart failure, including progressive
for example, to maintain optimal perfusion of vital organs. On the renal dysfunction and LV remodeling.58–64
one hand, arginine vasopressin (AVP), the SNS, and the RAS
respond rapidly to stimuli such as falls in arterial pressure, reduced
delivery of chloride and sodium to the macular densa, and altered Neurohormones and the Transition from
plasma osmolality to maintain homeostasis by increasing vascular Hypertrophy to Heart Failure
tone and inducing renal retention of sodium and water.45 In con- Adverse cardiac remodeling characterized by myocyte hypertro-
trast, increased cardiac or vascular wall stress stimulates secretion phy and interstitial or perimysial fibrosis are hallmarks of heart
of natriuretic peptides, AM, urocortin, and other endothelium- failure with preserved ejection fraction (EF).65–67 While hemody-
derived peptides that produce vasodilatation and promote diure- namic loading such as in hypertension or valvular disease is a
sis.17,20,46 Within this complex counterpoised system, there are critical stimulus for adverse remodeling, neurohormonal factors
multiple levels of feedback and control. Vasoconstrictor systems appear to be key mediators of cardiac and vascular remodeling
can respond rapidly through near instantaneous changes in sym- processes that lead to heart failure.68–70 Increased myocardial
pathetic outflow or rather more gradually through the renin- levels of A-II, ET, and aldosterone have been demonstrated in
angiotensin pathway and aldosterone.47 Equally, release of stored models of hypertensive heart disease.55,71 Each has been linked to
atrial natriuretic peptide (ANP) from granules in the atria allows the development of fibrosis, cardiomyocyte hypertrophy, ven-
rapid vasodilator and natriuretic responses,48 whereas more tricular remodeling, and progression to the heart failure pheno-
gradual effects occur through changes in constitutive BNP syn- type.55,69,72–74 Increased levels of these and other hormones,
thesis.49 Multiple feedback interactions between vasodilator and including NE, can be directly toxic to the myocardium.75 Experi-
vasoconstrictor systems at several levels modulate the overall mentally, blockade of these hormones attenuates the development
balance. For example, A-II attenuates the natriuretic effect of of hypertrophy and fibrosis while delaying the onset of heart
BNP while simultaneously contributing to activation of ANP failure.76–78 In contrast, other hormones, such as AM and the
and BNP synthesis through increased wall stress in cardiac myo- cardiac natriuretic peptides, are also activated in hypertension and
cytes.50 In contrast, the natriuretic peptides inhibit renin release heart failure but appear to attenuate adverse remodeling.79–81
and the aldosterone-stimulating actions of A-II.51,52
In established heart failure, the normal balance of neurohor-
monal regulation is disturbed (Fig. 27-1). Marked activation of Neurohormonal Factors Contributing to
both vasodilator and vasoconstrictor systems is seen.47 A key Heart Failure Pathophysiology
mechanism in this activation appears to be perceived end-organ
hypoperfusion and a reduced ability of the heart to maintain Sympathetic Nervous System
adequate arterial filling and cardiac output.8,45,53 Such activation The SNS is a crucial regulator of arterial pressure and vital organ
can be detected as an increase in circulating plasma neurohor- perfusion during the myriad of daily activities such as exercise,
mone levels, but it occurs first at the tissue level through upregu- eating, and changing body posture.47 In heart failure, the SNS is
 Chapter 27 • Role of Neurohormones 347

activated at an early stage82 in response to reduced carotid and systemic and renal arterial perfusion pressure (renal baroreceptor
aortic baroreceptor sensitivity and altered arterial compliance.83 mechanism), and reduced delivery of chloride and sodium to the
Changes in SNS activity in heart failure produce a dramatic distal renal tubule (macula densa mechanism).47 Vasopressin,
reduction in regional blood flow to the skin, gut, and kidney while prostaglandins, nitric oxide levels, the natriuretic peptides, AM,
maintaining vital flow to coronary, cerebral, and skeletal muscle and A-II—by negative feedback—all modulate renin secretion.47
circulations.47 The SNS also contributes to the pathophysiology Circulating renin acts on angiotensinogen to produce angiotensin
of heart failure through its stimulation of renin release.84 Increased I, which is converted to A-II by ACE. A-II generated through
sympathetic activation in heart failure can be documented by non-ACE pathways, including tissue and serum proteases (chy-
elevated plasma or urinary catecholamines; by increased NE spill- mases), may contribute to increased tissue and circulating A-II
over from the heart, kidney, brain, and skeletal muscle; or by and return of plasma aldosterone to baseline, pre-ACE inhibitor
increased common peroneal nerve sympathetic nerve traffic from treatment levels.99
microneurographic recordings. However it is documented, this The major pathophysiological actions of A-II are mediated via
activation correlates with the severity of LV dysfunction and pre- A-II type 1 receptors (AT1R).99 A potent vasoconstrictor, A-II
dicts survival.2,82,85 While increased SNS activity in established also stimulates aldosterone secretion and AVP release and thirst,
systolic heart failure acts to maintain blood flow to vital organs, augments SNS activity, and antagonizes the actions of the natri-
long-term and intense overactivation can have harmful effects uretic peptides.47 A-II has critical effects on renal function and,
through direct toxicity to myocardium, an adverse increase in LV experimentally, stimulates hypertrophy of vascular smooth muscle
afterloading (as a consequence of peripheral vasoconstriction), cells (VSMCs) and cardiomyocytes, thereby contributing to vas-
and LV hypertrophy (LVH) and subsequent dilatation.75 cular as well as cardiac remodeling.99 The pivotal role of the RAS
The pathophysiological importance of SNS activation and the in systolic heart failure and the beneficial effect of either ACE
benefit of β-adrenergic receptor blockade in systolic heart failure inhibition or AT1R blockade is well established.100–102
is clearly established.14,15,86 SNS activation is generally considered A large body of basic science and clinical research implicates
to be also important in primary (essential) hypertension87–90 and the RAS in the pathophysiology of heart failure with normal
reflects increased sympathetic neuronal firing and decreased NE systolic function.69,72–74,103,104 In animal models and cell culture
uptake.88 SNS activation is further augmented in hypertensive studies, A-II has been shown to stimulate stretch-induced cardio-
patients with heart failure, possibly through impaired barorecep- myocyte hypertrophy105 and promote fibrosis through increased
tor function.91 There are, however, limited data regarding the collagen deposition and impaired metalloproteinase function. A-
degree of SNS activation in heart failure with preserved LVEF. II also augments diastolic wall stress during volume overload,
Nevertheless, plasma NE levels do appear to rise in diastolic heart leading to increased expression of fetal genes associated with
failure, but not to the extent seen in systolic heart failure.39,40 In remodeling.50 Furthermore, A-II stimulates increases in intra-
animal models, the SNS appears to have a significant role in the cellular calcium levels, which may contribute to abnormal
development of LVH, LV remodeling, and heart failure due to diastolic function and wall stress. A-II also increases activity of
pressure overload. Dopamine beta-hydroxylase knockout mice do nicotinamide adenine dinucleotide phosphate oxidase (NADPH),
not develop LVH during aortic banding, suggesting an important causing superoxide production that may trigger vascular nitric
requirement for the SNS in activation of signaling pathways and oxide synthase uncoupling, leading to impaired nitric oxide signal-
the development of hypertrophy and heart failure, at least in this ing, endothelial dysfunction, and vascular remodeling.106,107
model.92 Evidence from animal models points to a contributory role for
Modulation of sympathetic activity may be one important A-II in hypertensive heart failure. Dahl salt-sensitive rats fed a
mechanism of effective antihypertensive therapy and prevention high salt diet developed hypertension and subsequent hyperten-
of heart failure. Therapy with angiotensin-converting-enzyme sive cardiomyopathy and heart failure by age 19 weeks.72 In this
(ACE) inhibitors and angiotensin receptor blockers, both of model, expression of A-II mRNA increases more than fourfold
which reverse LVH and reduce heart failure events in high-risk at the onset of heart failure. Administration of low-dose AT1R
or hypertensive subjects, also suppresses cardiac efferent sympa- blocker at subvasodepressor levels prevents the onset of heart
thetic activity.93.94 The role of β-adrenergic receptor blockade as failure in this model, suggesting an important effect of A-II that
first-line therapy for hypertension has, however, been questioned is independent of arterial pressure.72 In the same model, AT1R
recently.95 First-line treatment with the alpha-adrenergic blocker blockade expression was upregulated despite increased A-II
doxazosin was reportedly associated with increased heart failure expression, suggesting abnormal receptor/agonist balance.108
events compared with treatment with chlorthalidone, lisinopril, Further evidence for A-II causing hypertrophy and subsequent
or amlodipine,96 although the accuracy of the diagnosis of heart heart failure comes from a transgenic mouse model of localized
failure has been questioned. Whereas the therapeutic efficacy of excess angiotensinogen production.74,103 In this model, excess
selected β-adrenergic receptor blockers in patients with all grades localized cardiomyocyte A-II levels are associated with myocyte
of systolic heart failure is not in question, the place of these drugs and ventricular hypertrophy even in the absence of increased arte-
in the treatment of established diastolic heart failure remains rial pressure. Hypertrophy is reversed with effective blockade of
unclear. Treatment with carvedilol has been shown to have benefi- A-II production by ACE inhibition or by AT1R blockade at
cial effects on LV diastolic function in the setting of heart failure hemodynamically neutral doses.74,103
with preserved EF,97,98 but the effect on clinical outcomes is also Studies of hypertension in humans indicate a pivotal role for
uncertain. the RAS. In particular, treatment of hypertension with ACE
inhibitors or AT1R blockers is associated with greater reductions
in LVH than are seen with beta blockers and calcium channel
Renin-Angiotensin System blockers, achieving similar blood pressure lowering.109
Secretion of renin from renal juxtaglomerular cells increases in In LVH secondary to aortic stenosis, intracoronary adminis-
response to many stimuli, including increased SNS activity, low tration of the ACE inhibitor enalaprilat, at a level that did not
348 Chapter 27 • Role of Neurohormones

alter measured ACE activity or plasma levels of renin and ANP, Arginine Vasopressin
produced decreases in LV end diastolic pressure accompanied by
improvements in diastolic distensibility and isovolumic relax- AVP secretion is mediated by multiple stimuli, including high
ation, suggesting that the actions of intracardiac A-II contribute plasma osmolality, low intracardiac and arterial pressure, circulat-
to abnormal diastolic wall stress and filling patterns in LVH.110 ing A-II, ANP, and adrenergic and other neurohormonal factors.45
Treatment with AT1R blockade or ACE inhibition has been AVP increases water uptake in the collecting ducts via vasopres-
shown to reduce fibrosis and indices of cardiac stiffness and dia- sin (V)2 receptors and produces vasoconstriction and impaired
stolic dysfunction in subjects with hypertension.111–113 Impor- cardiac contractility via V1 receptors.129 Elevated plasma AVP
tantly, ACE inhibition or AT1R blockade in high-risk subjects or levels are often seen in heart failure even when cardiac filling pres-
after myocardial infarction has been shown to reduce cardiovas- sures are high, suggesting that carotid baroreceptor activation may
cular events, including heart failure.114,115 The largest randomized outweigh inhibitory cardiac stretch reflexes.45 Experimentally,
treatment study in heart failure with preserved systolic function AVP receptor antagonists partially correct hyponatremia in this
demonstrated that AT1R blockade with candesartan reduced setting, suggesting that AVP along with the RAS and other
heart failure hospitalization.24 systems play a mechanistic role in the hyponatremia of heart
failure.47
AVP levels are often elevated in asymptomatic LV dysfunc-
Aldosterone tion.57 In addition, levels are elevated in heart failure when LVEF
Aldosterone secretion from the zona glomerulosa of the adrenal is preserved, suggesting an important pathophysiological role in
cortex is stimulated by a range of secretagogues, of which A-II is this context.39 AVP has recently become a therapeutic target in
the most potent, although potassium and adrenocorticotropic heart failure.130 V2 blockade increases free water excretion without
hormone (ACTH) (which augment aldosterone production) and altering renal hemodynamics or function131 and appeared benefi-
the cardiac natriuretic peptides (which are inhibitory) may be cial in initial studies: Larger morbidity and mortality studies are
important in heart failure.116 ACE inhibitors may initially reduce under way.25,26 Given the elevation of AVP levels in heart failure
aldosterone formation, but levels often rise later,117 possibly with preserved LVEF, V2 blockade could potentially be a target
reflecting incomplete ACE inhibition, non-ACE-generated A-II, for therapy in this context, but this possibility remains to be tested
and the action of other aldosterone secretagogues.118 in this setting.
Aldosterone has an important role in established systolic heart
failure.116 Early studies in patients with heart failure demonstrated
that aldosterone levels were often (though not invariably) ele- Endothelin-1
vated; but perhaps more importantly, the kidney failed to “escape” ET-1 is a potent vasoconstrictor peptide secreted mainly from
from the antinatriuretic actions of aldosterone.119 Furthermore, vascular endothelial cells in response to falls in vascular shear
the kidney in heart failure is more sensitive than normal to the stress and stimulation by neurohormones (NE, A-II, and AVP),
sodium-retaining action of aldosterone.119,120 There is evidence for tissue growth factor–β, and cytokines (such as tumor necrosis
an equally important role for aldosterone in mediating the cardiac factor [TNF]–α).18,132 Nitric oxide, the natriuretic peptides, and
and vascular remodeling that occurs as hypertension progresses prostacyclin inhibit ET-1 synthesis. ET-1 is synthesized also in
to heart failure.73,121 Local synthesis of aldosterone and expression cardiac myocytes, VSMCs, and renal tubular and glomerular
of mineralocorticoid receptors (MCRs) have been demonstrated mesangial cells.133
within the cardiac interstitium and cardiomyocytes, although Pre-pro-ET is cleaved to form “big endothelin” (Big ET), which
there is dispute regarding the capability of the heart to secrete in turn is converted to vasoactive ET-1 by endothelin-converting
aldosterone.122 Whether of adrenal origin or secreted within the enzyme.133 ET-1 acts via ET-A and ET-B receptors.134,135 Binding
heart, aldosterone appears to increase collagen deposition and with ET-A increases mobilization of intracellular calcium to
fibrosis and cause hypertrophy of cardiomyocytes.121 Recent produce vasoconstriction and positive inotropy. ET-A receptors
cohort studies demonstrate correlations between plasma aldoste- also mediate the hypertrophic action of ET-1 in VSMCs, cardio-
rone levels and the degree of concentric LVH,123,124 particularly myocytes, and glomerular mesangial cells via protein kinase C and
in women.124 The relationship of aldosterone to LVH may be mitogen-activated protein kinase.133
independent of hemodynamic loading, indicating specific effects Plasma ET-1 levels are higher in venous than arterial blood,
on cardiomyocyte hypertrophy and interstitial fibrosis.73 Aldoste- reflecting vascular secretion.133 Under normal conditions, ET-1
rone may also impair arterial compliance, an index of vascular contributes to basal vascular tone and cardiac function through
remodeling in hypertensive heart failure.125,126 paracrine and autocrine actions. In heart failure, plasma ET levels
Specific aldosterone blockade appears to reduce collagen for- rise in proportion to the severity of cardiac dysfunction136–139 and
mation and fibrosis.76,78,127 More recently, aldosterone blockade are powerful independent predictors of outcome.140,141 Myocar-
was shown to improve myocardial function in hypertensive dial ET-1 levels and ET-A receptor density also increase in heart
patients with heart failure symptoms and echocardiographic evi- failure,55,142,143 in which ET-1 initially increases cardiac contractil-
dence of LVH with diastolic dysfunction.128 Compared with ity at the cost of impaired myocardial energy balance.133 Under
placebo, 6 months of treatment with spironolactone resulted in experimental conditions, ET-1 induces vasoconstriction, hyper-
significant improvements in longitudinal systolic LV strain and trophy of cardiac myocytes, and cellular injury through direct
strain rate, a decrease in left atrial (LA) area, and improvements toxic effects.133,142 Chronic activation of tissue and plasma ET-1
in conventional Doppler estimates of LV stiffness and end dia- in experimental models is associated with cardiac and vascular
stolic pressure. There was also a significant improvement in arte- remodeling and a decline in LV function.136 In contrast, myocar-
rial compliance with spironolactone. These effects support the dial ET-1 expression falls with unloading of the left ventricle.144
hypothesis that aldosterone contributes to adverse myocardial A number of studies implicate a synergistic interaction of ET-1
and vascular remodeling in hypertensive heart disease. with A-II in the development of LVH and diastolic heart
 Chapter 27 • Role of Neurohormones 349

failure.55,71,72,145,146 Myocardial expression of A-II occurs prior to tensive rat hearts attenuated the progression to heart failure, indi-
ET-1 in models of hypertensive heart failure and appears to stim- cating a potential protective role.161
ulate myocardial ET-1 expression.55,72,145 ET-A receptor blockade
attenuates the development of LVH and heart failure in hyper-
tension models71,146 but is associated with augmented RAS activ- Adrenomedullin
ity.147 Unsurprisingly then, combined ET receptor blockade and AM is a 52–amino-acid peptide from the calcitonin gene related
ACE inhibition appears more effective than either agent alone at peptide (CGRP) family that acts via calcitonin receptorlike recep-
reversing LVH in heart failure models.145 tors (CRLRs) modified by receptor activator modifying proteins
While a short-term ET-A or a combined ET-A/ET-B recep- (RAMPs) 2 and 3, with cAMP as second messenger.17,79,162,163
tor blockade in systolic heart failure demonstrated beneficial Secreted mainly from vascular endothelial and smooth muscle
effects on endothelial function and hemodynamics,148–150 results cells, mRNA and peptide immunoreactivity for AM and its
of mortality and morbidity studies with dual receptor blockade receptors have been demonstrated in cardiac myocytes and fibro-
have been disappointing.151 The relative merit of selective ET-A blasts with increased expression in models of cardiac hypertrophy
blockade and whether earlier blockade of ET in hypertension can and heart failure.79 Recent data suggest that AM may have protec-
prevent LVH and diastolic heart failure is the focus of current tive actions during development of hypertensive heart failure.
research. Exogenous AM appears to reduce fibrosis in vivo and in cultured
cardiac fibroblasts.17 AM also appears to specifically inhibit A-
II–stimulated hypertrophic responses and upregulation of ANP
Tissue Necrosis Factor–Alpha and BNP in cardiac myocytes.164 During development of hyper-
TNF-α is a 76–amino-acid peptide secreted in response to a trophy in the salt-sensitive hypertensive rat model, myocardial
range of stimuli.152 TNF-α circulates in the blood (and is also expression and peptide levels of AM increased early, congruent
present as a transmembrane form) and acts via specific receptors with natriuretic peptide levels and before RAS activation
to induce pleomorphic effects in many cells. TNF-α promotes the occurred.79 Chronic administration of low-dose AM in this model
inflammatory response, stimulates growth factors, and is directly significantly lowered LV diastolic pressure, increased cardiac
cytotoxic to endothelial cells. Plasma TNF-α levels are elevated output, and lowered end systolic elastance. These effects were
and may have a pathophysiological role in malignancy, septic accompanied by a significant attenuation of RAS activation and
shock, rheumatoid arthritis, and transplant rejection.152 prolongation of the time to onset of heart failure or death.163 In
TNF-α appears to have a role in the pathophysiology of end- human subjects, plasma levels of AM increase in relation to the
stage heart failure, where plasma levels are elevated and correlate severity of heart failure.162,165 Short-term infusion in human
with symptomatic status.152 It has a direct effect on cardiac muscle, hypertensive or heart failure subjects to achieve AM levels within
including negative inotropism (through inhibition of calcium the pathophysiological range significantly lowered blood pressure
regulation in the cytoplasmic reticulum and inactivation of β- and increased cardiac output and diuresis, while attenuating aldo-
adrenergic receptors), activation of matrix metalloproteases, and sterone secretion.30,166 These findings suggest that AM may have
promotion of cardiomyocyte hypertrophy.152 Overexpression of an important protective role in attenuating the progression to
TNF-α produces a dilated cardiomyopathy phenotype with heart hypertrophy and heart failure. Whether augmentation of endog-
failure and premature death.152 TNF-α may mediate these effects enous levels or exogenous treatment could be used therapeutically
through expression of fetal gene programs in cardiac myocytes, has not been evaluated.
activation of pro-apoptotic pathways, and stimulation of other
cytokines. Despite promising indications that expression of the
cardiomyopathic phenotype could be attenuated by anticytokine Urocortin
strategies, subsequent studies in advanced heart failure have not The urocortin (UCN) peptides 1, 2, and 3 belong to the
demonstrated a clinical benefit from TNF-α blockade.153–155 corticotrophin-releasing factor (CRF) family that acts via CRF
receptor subtypes with cAMP as second messenger.167,168 These
peptides have multiple actions, including stress and inflammatory
Cardiotrophin-1 responses. Plasma levels are increased in human heart failure but
Cardiotrophin (CT)-1 is a 201–amino-acid peptide from the inter- have not been carefully examined in hypertension. Infusion
leukin (IL)-6 family of cytokines. It appears to have a key role in studies in animal models and human subjects demonstrate that
mediating myocyte hypertrophy.156 Absence of CT-1 leads to hypo- UCN-1 and UCN-2 have differential cardiovascular actions,
plastic development of the heart, whereas increased CT-1 is associ- with the latter causing more profound lowering of blood pressure
ated with myocyte hypertrophy that can lead to eccentric LVH and and increased cardiac output associated with attenuation of RAS
chamber dilatation.156 CT-1 expression is induced by mechanical activation and maintenance of renal function.20,29,169 The role of
stretch and is augmented by sympathetic stimulation.157 Increased UCN-1 and -2 in the development of cardiac hypertrophy and
expression is also seen in hypoxia, indicating a potential protective progression to heart failure has not been clearly elucidated.20,170
and reparative role in myocardial ischemia.158 CT-1 expression
increases in experimental heart failure and may precede BNP acti-
vation.21,22 Circulating CT-1 levels appear to rise in human heart Cardiac Natriuretic Peptides
failure in relation to the severity of LV dysfunction.159 Increased The cardiac natriuretic peptides are a group of related hormones
myocardial CT-1 expression is associated with downregulation of with structural homology and similar bioactivity.81,171 These pep-
its major receptor, glycoprotein 130,160 but whether or not this tides share a highly conserved ring structure that is responsible
contributes to impaired contractility is unclear.156 The role of CT-1 for bioactivity (Fig. 27-2).172 Each is secreted in a 1 : 1 ratio with
in diastolic heart failure is less clear. However in experimental the amino-terminal portion of its pro-hormone.49 Normally
models, transplantation of CT-1–expressing myoblasts into hyper- secreted in small amounts—giving picomolar levels in the
350 Chapter 27 • Role of Neurohormones

ANP BNP CNP

H2N Ser
Pro
Lys
H2N Ser Met
Leu Val H2N Gly
Arg Gln Leu
Arg Gly Arg Met Gly Arg Lys Met Ser Leu Lys Leu
Gly Asp Gly Asp Gly Asp
Ser Ser Lys
Phe Arg Phe Arg Phe Arg
Ser Gly Gly
Cys Ile Cys Ile Cys Ile
Cys Gly Cys Ser HOOC Cys Gly
Asn Lys
Gly Ala Gly Ser Gly Ser
Ser Val
Leu Gln Leu Ser Leu Met
Phe Gly Ser Leu Gly Ser Gly Ser
Arg Arg
HOOC Tyr Arg
HOOC His

Figure 27-2 The natriuretic peptide family: atrial natriuretic peptide (ANP); B-type, or brain, natriuretic peptide (BNP); and C-type natriuretic peptide (CNP)
share the same ring structure, which forms the basis for many of their shared physiological actions. Dark (filled) circles indicate amino acids common to
all three human hormones. (Modified from Ruskoaho R: Endocrine Reviews 2003;24:341–356.)

circulation—synthesis increases with pressure and volume over- preload and direct arterial vasodilatation.81 Long-term (4–5 day)
load as fetal gene expression is reactivated.49 infusions of low-dose ANP induce sustained falls in arterial pres-
The ANP and BNP peptides are synthesized primarily by sure, peripheral vascular resistance, plasma volume, and central
cardiac myocytes in response to mechanical stretch.16,48 Synthesis filling pressure, without activating the RAS, aldosterone, or
is regulated by multiple factors, including activity of other vasoac- SNS.179 Similar effects have been seen during BNP infusion,
tive hormones, such as A-II. Their major actions are mediated although fewer studies have been performed.180
through natriuretic peptide receptor (NPR)–A, which is wide- The cardiac peptides produce natriuresis and diuresis via renal
spread, including in the vasculature and renal tubules.173 These glomerular and tubular actions.52 The natriuretic action of ANP
peptides produce vasodilatation and natriuresis and also suppress and BNP is highly dependent on renal perfusion pressure.179
thirst and inhibit RAS and aldosterone secretion, fibrosis, and ANP increases glomerular filtration rate by simultaneously dilat-
proliferative responses to cardiac or vascular injury.46 ANP and ing glomerular afferent arterioles, constricting efferent arterioles,
BNP are actively cleared by competitive uptake at NPR-C recep- and relaxing glomerular mesangial cells.181,182 It also blocks sodium
tors or by cleavage of the ring structure by neutral endopeptidase, reabsorption in the distal collecting ducts, antagonizes AVP-
which is found in high density within the renal tubules.174 Plasma mediated water uptake in collecting ducts, and inhibits A-II–
levels of atrial and B-type peptides are higher in women, increase mediated sodium and water uptake in proximal tubules.52 Admin-
with age and renal dysfunction, and fall with increasing body mass istration of a competitive antagonist for the NPR-A receptor
index (BMI).175 In contrast, C-type natriuretic peptide (CNP) is blocks the natriuretic action of the natriuretic peptides in normal
secreted primarily from vascular endothelial cells and acts pre- and heart-failed animals.183
dominantly as a vasodilator.176 Its metabolism and clearance are Under most circumstances, ANP and BNP inhibit the RAS,
less well characterized.23 aldosterone, and SNS. Experimental administration of the NPR
Although circulating levels of all the natriuretic peptides show blocker HS142 produces an elevation in plasma levels of renin
relationships with indices of systolic and diastolic LV function activity, aldosterone, and catecholamines.179 Conversely, low-dose
and to LVH, the strongest correlations are seen in general for infusion of ANP to produce physiological or mildly elevated
BNP.177 plasma levels results in suppression of aldosterone secretion and
reduced renin and SNS activity.179 ANP (and BNP) inhibits
Atrial Natriuretic Peptide (ANP/NT-proANP)
renin release from the juxtaglomerular apparatus and reduces
This peptide is secreted mainly from the cardiac atria and to a
peripheral sympathetic tone through effects on baroreceptors,
lesser extent from the ventricles. Increased wall stretch stimulates
suppression of catecholamine release from autonomic nerve
its release from storage granules while also augmenting its tran-
endings, and inhibition of central sympathetic outflow.179
scription and synthesis.178 ANP contributes to control of basal
vascular tone and blood pressure. In ANP gene knockout mice, C-type Natriuretic Peptide (CNP/NT-CNP)
absence of ANP was associated with mildly elevated basal blood Produced mainly from vascular endothelial cells,176 CNP is
pressure compared with wild-type littermates.171 NPR-A recep- synthesized as a precursor and cleaved into a biologically active
tor knockout mice also developed hypertension by a mechanism carboxy-terminal peptide, CNP, and an apparently inactive
independent of salt intake.171 amino-terminal peptide, NT-proCNP. In normal humans, circu-
In healthy human volunteers, low-dose ANP and BNP infu- lating levels of CNP are very low and at the limits of detection
sions that produce plasma levels within the normal range induced measurement by immunoassays. The greater size and presumed
vasodilatation, natriuresis, and inhibition of renin and aldoste- longer plasma half-life of NT-proCNP may allow more accurate
rone.179 Falls in blood pressure reflect a reduction in cardiac measurement and a more reliable indication of CNP production.
 Chapter 27 • Role of Neurohormones 351

Contradictory reports have suggested the presence or absence of indices of LV filling pressure, LV stiffness,192 and measures of
elevated plasma CNP concentrations in congestive heart failure.184 LA size.193
In one large cohort, NT-proCNP levels were clearly shown to be Wide interindividual variation in BNP and NT-proBNP levels
elevated in heart failure.23 Levels of NT-proCNP are indepen- in stable symptomatic heart failure reflects many factors.187,194,195
dently related to gender, age, and LV systolic function. Levels rise In addition to age and gender, key determinants include renal
with age, are higher in men than women, and are inversely related dysfunction and atrial fibrillation, both of which cause higher
to creatinine clearance. Plasma NT-proCNP also appears to levels.175,195–199 Higher levels in renal dysfunction appear to reflect
identify heart failure with modest incremental diagnostic value reduced clearance, as the transcardiac gradient, reflecting cardiac
over NT-proBNP and independent of age, gender, and renal secretion, appears unaltered in this setting.195 Nevertheless,
function.23 Although CNP is reportedly a potent venodilator,171 increased cardiac production is probable in many patients with
it has little effect on arterial pressure when infused intravenously end-stage renal failure, since heart failure, LVH, and coronary
into healthy volunteers.176 Its actions in heart failure and hyper- artery disease are common and leading causes of death in this
tension are not yet clearly defined. setting. Body mass is an important determinant of BNP levels,
possibly through increased NPR-C receptors in adipose tissue.
B-Type Natriuretic Peptides NT-proBNP levels are less affected by body mass, possibly owing
BNPs/NT-proBNPs are synthesized and secreted mainly to a different clearance mechanism.200 RV systolic function and
from LV cardiomyocytes. The primary stimulus is mechanical mitral regurgitation are key determinants in more advanced heart
stretch due to increased wall stress. Diastolic wall stress appears failure, reflecting LA and RV production. Most of the inter-
to be the most important stimulus (Fig. 27-3),185 which in individual variation in peptide levels is explained by LV systolic
part explains higher levels in systolic dysfunction where end and diastolic functions, RV dysfunction, renal function, gender,
diastolic volumes are larger.16,54,185,186 Significant atrial and right age, and mitral regurgitation.187 Hereditary factors or molecular
ventricular (RV) contributions to total BNP/NT-proBNP heterogeneity may be responsible for much of the residual varia-
secretion are seen in advanced heart failure.187,188 Cleavage of the tion in BNP levels.201,202 BNP levels therefore act as a global
precursor peptide (proBNP, amino acids 1–108) produces the marker of cardiac as well as end-organ dysfunction rather than as
32–amino-acid BNP (77–108) and its corresponding amino- an index of a single cardiac index, such as LA pressure.203 Levels
terminal component, NT-proBNP (1–76), which are secreted in should be understood within the context of these multiple deter-
1 : 1 ratio.16,189 Plasma levels of these peptides correlate strongly mining factors.
with each other.34,190 BNP is bioactive and has a shorter half-life In severe heart failure, BNP levels and gene expression are
due to active clearance, hence levels are lower than for the more strongly related to changes in multiple genes that play a part in
stable NT-proBNP by a factor of 5–10-fold.34 Levels of both LV remodeling, such as matrix metalloproteinases.204 Mehra et al.
peptides increase in parallel with LV pressure or volume looked at gene expression in myocardium from donor hearts at
loading16,191 and reflect the severity of LV dysfunction, correlating the time of transplantation and demonstrated that upregulation
inversely with LVEF and positively with increasing LV mass, of BNP was associated with upregulation of more than 25 specific

2200 2200
2000 2000
r 2 = 0.325, P < 0.001 1800 r 2 = 0.328, P < 0.001
1800
1600 1600
BNP (pg/ml)

1400
BNP (pg/ml)

1400
1200 1200
1000 1000
800 800
600 600
400 400
200 200
0 0
–200 –200
0 10 20 30 40 50 60 70 80 0 5 10 15 20 25 30 35 40
A EF (%) B EDP (mm/Hg)
Figure 27-3 Correlation between B-
type natriuretic peptide (BNP) and left 2200 2200
r 2 = 0.277, P < 0.001 2000 r 2 = 0.887, P < 0.001
ventricular functional parameters in 2000
160 patients with systolic or diastolic 1800 1800
heart failure. A, Left ventricular ejec- 1600 1600
BNP (pg/ml)
BNP (pg/ml)

1400 1400
tion fraction (EF) (%). B, End diastolic 1200 1200
pressure (EDP) (mmHg). C, End systolic 1000 1000
wall stress (SWS) (kdynes/cm2). D, End 800 800
diastolic wall stress (EDWS) (kdynes/ 600 600
cm2). Plasma BNP levels are most 400 400
closely related to EDWS. (Modified from 200 200
Iwanaga et al: B-type natriuretic peptide 0 0
strongly reflects diastolic wall stress in –200 –200
patients with chronic heart failure: Com- 0 100 200 300 400 500 600 0 20 40 60 80 100 120 140 160
parison between systolic and diastolic
heart failure. JACC 2006;47:742–748.) C SWS (kydnes/cm2) D EDWS (kdynes/cm2)
352 Chapter 27 • Role of Neurohormones

genes associated with cellular remodeling, vascular injury and Prostaglandins

repair, and alloimmune inflammatory interactions. Additional
genes involved in stem cell mobilization pathways and apoptosis Hormones in the prostaglandin family are derived from arachi-
were also identified. These findings suggest that BNP may be a donic acid and are synthesized throughout the body.220 Prosta-
marker of active remodeling.204 glandin I2 and E2 are potent vasodilators.220 Their levels increase
A variety of immunoassays are available for the measurement in heart failure in plasma and at tissue level, particularly in the
of BNP and NT-proBNP.34,205,206 Each has different assay char- kidneys.45,47,220 The prostaglandins modulate the secretion and
acteristics with specific detection limits and analytical coefficients effects of ANP, renin, and A-II, and prostaglandin release is in
of variation. There are significant correlations between different turn increased by A-II, NE, and AVP.45,47,49 Prostaglandins play
assay measurements taken from the same samples.34 However, an important role in renal homeostasis during heart failure.47,53,220
assays with lower analytical variation are more likely to detect The adverse renal glomerular and tubular effects of nonsteroidal
clinically important changes in serial samples.205,207 There has anti-inflammatory drugs in heart failure reflect their inhibition of
been recent interest in the biological variation in serial samples prostaglandins.47,220
from clinically stable patients. Coefficients of biological variability
in circulating levels of BNP or NT-proBNP vary between 30% Pattern of Neurohormonal Activation in
and 55%.208–210 In healthy subjects in whom peptide levels are very Heart Failure with Normal Left Ventricular
low, a doubling in levels—for example, from 8 to 16 pg/ml—
would be necessary for a change to confidently exceed usual bio-
Ejection Fraction
logical variation.208–210 In unstable heart failure patients, a change The pattern of neurohormonal activation in systolic heart failure
of 30% is likely to exceed background variation. The clinical has been well characterized.2,3 In contrast there are fewer data in
importance of the usual variation seen in peptide levels requires the context of heart failure when LVEF is preserved.221 While the
some clarification. These changes almost certainly reflect subclini- clinical presentation may be similar, the demographic features of
cal changes in hemodynamic indices,209 dynamic myocardial isch- heart failure with preserved EF differ from those of systolic heart
emia,211 and the complex neurohormonal milieu that regulates failure.41 Patients with preserved EF are generally older, more
BNP secretion.208–210 Serial BNP or NT-proBNP levels have likely to be female, more likely to have antecedent hypertension
greater prognostic value than a single value, suggesting that there and diabetes, and less likely to have had prior myocardial infarc-
may be a role for repeated measurements to identify response to tion than counterparts with systolic heart failure.41 There may be
therapy and to stratify risk.211–215 differences in ethnic or racial profiles as well. Each of these dif-
Activation of the cardiac natriuretic peptide system is a feature ferences is likely to affect the neurohormonal profile seen in heart
of hypertension. Plasma levels increase in relation to hemody- failure with preserved EF.221
namic load and to the degree of LVH.177 In animal models such Intuitively, it seems likely that there may be a lesser degree of
as the spontaneously hypertensive rat, BNP gene expression has hemodynamic impairment in the context of heart failure with
been demonstrated before the development of LVH. In human preserved EF, particularly with regard to arterial underfilling, a
hypertensive subjects, plasma BNP levels are elevated compared key stimulus for neurohormonal activation.45 Hence it seems
with age-matched controls and reflect LV wall thickness, the likely that the degree of neurohormonal activity detected in
severity of LVH, and LA dilatation. Levels of BNP are higher plasma may be less than that seen in systolic heart failure. In one
again in subjects with symptomatic heart failure due to diastolic sense, the differentiation of systolic from diastolic heart failure on
dysfunction when compared with matched controls with hyper- the basis of arbitrary cutpoints in EF could be regarded as artifi-
tension and LVH.216 cial and an oversimplification of the underlying pathophysiology.
It seems unlikely that BNP levels can be used to accurately This is particularly so as the degree of neurohormonal activation
determine invasively measured LV pressures, particularly in the reflects indices of cardiac function such as LVEF, wall stress, and
setting of a normal LVEF.217 While cross-sectional observational end diastolic pressure in a relatively continuous manner.
studies demonstrate statistically significant positive correlations Data from the Vasodilator in Heart Failure Trials (V-HeFT)
for BNP with LV end diastolic pressure and pre-atrial contrac- study indicate that lesser degrees of systolic impairment are
tion (pre-A) pressure, the associations are relatively weak.217 In associated with less neurohormonal activation. The V-HeFT
patients with more advanced heart failure during hemodynami- study group assessed patients with milder versus more severe
cally guided treatment with pulmonary artery catheter monitor- (LVEF <35%) systolic dysfunction. Patients with a higher
ing of LV filling pressures, there are concordant changes in LVEF (>35%) had less activation of NE and fewer adverse clinical
simultaneously measured BNP levels and pulmonary capillary outcomes.222
wedge pressures, but the changes do not correlate strongly.218,219 A number of studies have attempted to define the neurohor-
Maximal changes in BNP levels lag hemodynamic changes by up monal profile of heart failure with preserved systolic function.39,40
to 24 hours, presumably reflecting relatively sluggish changes in Cohort sizes are relatively small, but the study groups were well
constitutive synthesis and secretion of these peptides. Patients in characterized and afford some insight. In general, these studies
whom BNP levels do not fall, despite an improvement in LA demonstrate that there is neurohormonal activation in heart
pressure estimates, are, however, at highest risk for adverse failure where LV ejection is preserved but that this activation is
events.218,219 Data from patients with implantable hemodynamic mild and significantly less than that seen in systolic heart failure.221
monitoring devices indicate that while absolute levels of BNP or A group of patients from the Studies of Left Ventricular Dysfunc-
NT-proBNP reflect multiple factors specific to that individual tion (SOLVD) registry with radiological pulmonary congestion
patient, changes in BNP from baseline for that patient are highly and either preserved LVEF (>45%, n = 41) or systolic impairment
correlated with changes in estimated LV filling pressures.209 (LVEF <45%, n = 89) were compared with matched controls.39
Whether this is true in the setting of a normal EF is still the Plasma levels of NE, vasopressin, ANP, and renin activity were
subject of ongoing study. significantly elevated in systolic heart failure subjects compared
 Chapter 27 • Role of Neurohormones 353

with controls and, with the exception of vasopressin, were higher plasma NE, ANP, and BNP levels were significantly higher than
than in heart failure patients with a normal EF. These differences controls in both diastolic and systolic heart failure groups.40
remained significant when adjusted for clinical and treatment Whereas NE levels were similar in the two heart failure groups,
variables. Subjects with preserved EF had small but significant both ANP and BNP were significantly higher in patients with
increases in plasma renin activity and vasopressin levels compared systolic versus diastolic heart failure.40
with controls (Fig. 27-4). The impact of drug treatment, including In a prospective study of 556 patients presenting with heart
diuretics and ACE inhibitors, may have contributed to differences failure in the Olmsted County community, Bursi et al. found that
in hormones between the groups. plasma BNP levels (median, 257; interquartile range [IQR],
In a second, more recent study, Kitzman et al. studied 147 115–211 pg/ml) were significantly higher than those of asymp-
clinically stable subjects aged at least 60 years.40 Fifty-nine sub- tomatic subjects in the same community (17–58 pg/ml).175,223
jects had stable heart failure with an LVEF of at least 50% and BNP levels in the 248 subjects with an LVEF below 50% (388
no evidence of valvular disease, ischemic heart disease, or pulmo- [164–251] pg/l) were significantly higher than levels in the 308
nary disease. A further 60 subjects had systolic heart failure with subjects with preserved EF (183 [88–351] pg/ml; p < 0.001).
LVEF under 35%. These two groups were compared with 28 BNP levels also increased significantly with more severe diastolic
age-matched control subjects.40 All subjects underwent compre- dysfunction in the group of patients with reduced systolic func-
hensive echocardiography, symptom-limited exercise testing, and tion and in the group with preserved systolic function. BNP levels
blood sampling for neurohormones. Compared with both control were independently associated with age, LVEF, and severity of
and systolic heart failure groups, the diastolic heart failure group diastolic dysfunction. These findings indicate that both systolic
differed significantly, with more women, greater mean BMI, a and diastolic dysfunctions are important determinants of BNP
higher frequency of hypertension, higher recorded blood pres- levels.
sures, and less frequent treatment with diuretics, ACE inhibitors, The pattern of neurohormonal activation in acute heart failure
nitrates, and beta blockers. There were also trends to more fre- with preserved systolic function is less clear. In one small study,
quent diabetes history and greater use of calcium channel block- 14 of 30 patients presenting with acute heart failure had an LVEF
ers. Diastolic heart failure subjects had similar LV volumes and greater than 50%.224 Plasma NE and BNP levels were measured
EFs to controls, but greater LV mass. Systolic heart failure sub- within 48 hours of presentation and at follow-up. NE levels were
jects had substantially larger LV volumes, lower EFs, and greater significantly elevated in both diastolic and systolic heart failure
LV mass than both diastolic heart failure and control subjects. groups to a similar degree both at admission with acute heart
Diastolic indices were similar in all heart failure subjects. LA size failure and at follow-up. In contrast, BNP levels were elevated
was not reported. Exercise performance was impaired to a similar above normal controls in the diastolic heart failure group but on
degree in both systolic and diastolic heart failure groups. Mean average were less than half the level seen in systolic heart failure.224

PLASMA NOREPINEPHRINE PLASMA RENIN ACTIVITY

600 P < 0.002 5

Median PRA (ng/ml/hr)

500
Median PNE (ng/ml)

4
P < 0.02
400
3
300 P < 0.02
2
200

100 1

0 0
(246–446) (282–449) (350–698) (0.3–0.8) (0.4–2.1) (0.5–8.7)

VASOPRESSIN ATRIAL NATRIURETIC PEPTIDE

P < 0.0007
5 5
Median ANP (pg/ml)
Median AVP (pg/ml)

4 4
P < 0.005
3 3

Figure 27-4 Neurohormonal activation in 2 2

patients with heart failure and preserved (green
bars) and reduced (purple bars) left ventricular sys- 1 1
tolic function in the Studies of Left Ventricular
Dysfunction (SOLVD) registry. Healthy controls are
0 0
shown by the blue bars. CHF, congestive heart
failure; EF, ejection fraction. (Modified from Hogg (1.4–2.4) (1.7–3.1) (1.9–3.5) (31–64) (32–116) (54–225)
et al: Neurohumoral pathways in heart failure with N = 56 n = 41 n = 89 N = 56 n = 41 n = 89
preserved systolic function. Prog Cardiovasc Dis Control CHF with CHF with Control CHF with CHF with
2005;47:357–366.) EF > 45% EF < 45% EF > 45% EF < 45%
354 Chapter 27 • Role of Neurohormones

These findings suggest a similar level of compensatory sympa- and nonrestrictive filling (38 ± 7) or preserved systolic function
thetic activation whether heart failure is due to systolic or primar- (34 ± 6).
ily diastolic abnormality. Higher BNP levels in systolic heart
failure most likely reflect the effect of LV geometry on wall stress,
the primary stimulus for BNP secretion.185 Iwanaga et al. assessed CLINICAL RELEVANCE
62 subjects with diastolic heart failure and 98 with systolic heart
failure and found a strong correlation in both groups between Neurohormones as Treatment Targets for
plasma BNP levels and end diastolic wall stress, both of which Hypertension and Diastolic Heart Failure
were higher in the systolic heart failure group, reflecting in part Neurohormonal systems are the target for a number of the effec-
larger LV volumes (Fig. 27-5).185 tive antihypertensive therapies.14,15,227 Treatment of hypertension
The relative levels of BNP in acute heart failure with reduced with ACE inhibitors, AT1R antagonists, or aldosterone receptor
versus preserved EF have been confirmed in larger studies. In the blockade is associated with regression of LVH and improved
Breathing Not Properly (“BNP”) multinational study, of 1582 diastolic function.104,228,229 More importantly, these agents reduce
patients presenting with acute dyspnea, a subgroup of 452 patients the incidence of new heart failure.228,230–232 Furthermore, in com-
with confirmed heart failure subsequently underwent echocar- bination with β-adrenergic receptor blockers, they are the corner-
diography within 30 days of admission.225 One hundred and sixty stone therapy for systolic heart failure,13–15,101,116,233 but only AT1R
five of these (35%) had preserved LV systolic function with LVEF antagonists have been tested in a large randomized study in the
greater than 45%. Within this group, median BNP levels of context of heart failure with preserved systolic function.24 Smaller
413 pg/ml at presentation were higher than for non–heart failure studies suggest beneficial effects on diastolic function and neuro-
patients (34 pg/ml) but significantly lower than for the 283 sub- hormonal activation from aldosterone, β-adrenergic receptors,
jects with systolic heart failure (821 pg/ml). There were, however, and ACE inhibitors. However, adequate mortality studies have
significant differences in demographic and clinical factors between not been performed in the setting of heart failure with preserved
the two heart failure groups, rendering interpretation difficult. systolic function.97,128,234–237
BNP levels for the systolic heart failure group may have been
underestimated due to an upper limit of only 1300 pg/ml for the
assay.225,226 No other neurohormones were reported from this Natriuretic Peptides and Screening for
series.
Plasma AM levels were assessed by Yu et al. in a study of
Cardiac Dysfunction
77 patients with heart failure and either normal or impaired Because plasma BNP and NT-proBNP levels reflect LV structural
LVEF.162 AM levels were higher in subjects with heart failure and functional abnormalities, potentially they could be used to
(47.5 ± 6.5 pmol/L) than those without (6.9 ± 1.2; p < 0.01). screen for cardiac dysfunction. This approach could identify
There was a gradient in AM levels, which were significantly higher subclinical abnormalities or facilitate more appropriate referral
in those with both systolic heart failure and a restrictive filling for echocardiography. Several studies have demonstrated
pattern (92 ± 21) than in those with either systolic impairment potential utility for screening with BNP or NT-proBNP

1000
900 30
800 25
700
BNP (pg/ml)

ENP (mmHg)

P <0.001 P = n.s.
600 20
500 15
400
300 10
200 5
100
0 0
Figure 27-5 Differences in B-type natriuretic
SHF DHF SHF DHF
peptide (BNP) and left ventricular (LV) functional
parameters between subjects with systolic heart
failure (SHF) (n = 98) and diastolic heart failure
(DHF) (n = 62). The box defines the interquartile
450 range with the median indicated by the crossbar.
100 The error bars indicate the 10th and 90th percen-
400 90
EDWS (kydnes/cm2)
SWS (kdynes/cm2)

tiles. LVEDP is similar in subjects with heart failure

350 80 due to either cause, but SWS, EDWS, and plasma
P <0.001 70 P <0.001
300 levels of BNP are all higher in SHF. EDP, end dia-
250 60 stolic pressure (mmHg); EDVI, end diastolic
200 50 volume index (ml/m2); EDWS, end diastolic wall
150 40 stress (kdynes/cm2); SWS, end systolic wall stress
30 (kdynes/cm2). (Modified from Iwanaga et al: B-type
100
20 natriuretic peptide strongly reflects diastolic wall
50 10 stress in patients with chronic heart failure: Com-
0 0
parison between systolic and diastolic heart failure.
SHF DHF SHF DHF JACC 2006;47:742–748.)
 Chapter 27 • Role of Neurohormones 355

(Table 27-1).238–243 Accuracy of these peptides for detecting cardiac isolated diastolic abnormality, BNP levels were higher in those
dysfunction appears to depend on the clinical context, the abnor- with restrictive filling patterns than those with impaired relax-
mality in question, and its prevalence within that population.241 ation. Highest levels were seen with systolic impairment and
In patients referred for echocardiography, several studies with restrictive diastolic filling. Because of overlap between groups,
moderate-sized cohorts have demonstrated that BNP has excel- BNP levels did not differentiate systolic from primary diastolic
lent sensitivity and specificity for detecting systolic (LVEF dysfunction with preserved EF.244
<40%–50%) or diastolic dysfunction. Greater negative predictive, Lubien et al. assessed the utility of BNP in detecting diastolic
or “rule out,” values are seen when prevalence is lower, while speci- dysfunction in the setting of normal systolic function (LVEF
ficity and positive predictive values are higher with higher preva- >50%; LV internal diastolic diameter <5.5 cm) in 294 patients
lence.242,243 Krishnaswamy et al. studied 400 patients referred for referred for echocardiography.242 Clinical heart failure was present
echocardiography and demonstrated excellent detection of any in 5% of the cohort. Diastolic function was defined as normal,
ventricular dysfunction by BNP, with a level of at least 75 pg/ml impaired relaxation, pseudonormal, or restrictive based on trans-
having an accuracy of 90% for detecting either systolic (LVEF mitral filling patterns without reference to tissue Doppler or other
<50%, n = 225) or diastolic dysfunction (impaired relaxation diastolic indices. BNP levels (Biosite® assay) increased with
or worse on transmitral filling; n = 98).244 Among patients with greater severity of diastolic dysfunction and were higher still if

TABLE 27-1
SENSITIVITY AND SPECIFICITY OF BNP AND NT-PROBNP LEVELS IN SCREENING FOR LEFT VENTRICULAR
DYSFUNCTION. Adapted with Permission From Rodeheffer, JACC 2004; 44: 740–9 [240].
B-TYPE NATRIURETIC PEPTIDE AS A MEASURE OF VENTRICULAR FUNCTION IN SUBJECTS REFERRED FOR ECHOCARDIOGRAPHY

Study Cohort Type End Point Prevalence AUC SENS* SPEC* PPV* NPV*

Yamamoto et al177 Echocardiography EF < 45% 11% 0.79 79% 64% 21% 96%
referrals; n = 466
Maisel et al243 Echocardiography EF < 50% or 47% 0.96 86% 98% 98% 89%
referrals; n = 200 diastolic
dysfunction
Lubien et al242 Echocardiography Diastolic 40% 0.92 74% 98% 96% 85%
referrals; n = 294 dysfunction

B-TYPE NATRIURETIC PEPTIDE FOR SCREENING COMMUNITY AND CLINIC POPULATIONS

Study Cohort Type End Point Prevalence AUC SENS* SPEC* PPV* NPV*

Vasan et al246 Community volunteers, EF ≤ 50% 5.6% M 0.72; W 0.56 42% 90% 30% 94%
n = 3,177; age 55 ± EF ≤ 40% 2.2% M 0.79; W 0.85 55% 89% 18% 98%
10 yrs
LV mass ↑ 4.8% M 0.72; W 0.57 41% 90% 32% 93%
Redfield et al245 Community EF ≤ 50% 6.0% M 0.69; W 0.70 64% 68% NA NA
population based, EF ≤ 40% 1.1% M 0.90; W 0.92 90% 76% 4% 99%
n = 1,997; age
Moderate-severe 6.9% M 0.79; W 0.77 75% 69% 15% 97%
62 ± 11 yrs
DD %
Costello- Community
Boerrigter200 population based,
n = 1,869;
Age < 65 yrs EF < 40 1% M 0.97; W 0.97 90.9% 90.9% NA NA
Age > 65 yrs EF < 40 3.5% M 0.93; W 0.91 88.5% 88.4% NA NA
McDonagh et al56 Community EF ≤ 30% 3.2% 0.88 76% 87% 16% 98%
population based;
n = 1,252; age
51 ± 14 yrs
Nakamura et al238 Community “Heart disease” 3.6% 0.97 90% 96% 44% 99%
volunteers, (atrial fibrillation-
n = 1,098; age flutter, MI,
56 yrs valvular or
hypertensive,
cardiomyopathy,
ASD, cor
pulmonale)
Niinuma et al240 Health screening “Heart disease” 2.7% 0.94 85% 92% NA NA
clinic; n = 481

*Calculated at the B-type natriuretic peptide discriminatory value that provides best overall test accuracy; i.e., provides the highest combination of sensitivity and specificity.
ASD, atrial septal defect; DD, diastolic dysfunction; LV, left ventricular; M, men; MI, myocardial infarction; NA, not available; W, women; AUC, area under the receiver operating curve;
EF, ejection fraction; NPV, negative predictive value; PPV, positive value; SENS, sensitivity; SPEC, specificity.
356 Chapter 27 • Role of Neurohormones

500 800
No clinical P = 0.003
700 CHF
400 Clinical CHF Figure 27-6 A, Mean ± SEM for normal
600 values of brain natriuretic peptide (BNP)
versus impaired relaxation, pseudonor-
300 500 mal, and restrictive-like filling patterns.
Each abnormal group was different from
400
the normal group (p <0.001). B, Compari-
200 son of three diastolic filling patterns
300
subdivided by whether patients had
200 symptoms. Values are mean ± SEM. Sub-
100 groups of diastolic dysfunction patients
100 with clinical congestive heart failure (CHF)
overall had higher BNP levels than those
0 0 without symptoms. (Modified from Lubien
Normal Impaired Pseudo- Restrictive- Impaired Pseudo- Restrictive- et al: Utility of B-natriuretic peptide in
relaxation normal like relaxation normal like detecting diastolic dysfunction: Compari-
son with Doppler velocity recordings. Circu-
A B lation 2002;105:595–601.)

clinical heart failure was present (Fig. 27-6). A BNP level of sitivity and specificity of between 90% and 100% could be achieved
65 pg/ml had a sensitivity of 85%, a specificity of 83%, and an for NT-proBNP in detecting an LVEF less than 40%. Use of age-
overall accuracy of 84% for detecting any diastolic abnormality and gender-adjusted cutpoints for NT-proBNP reduced the
when systolic function was normal. Accuracy was higher when number of confirmatory echocardiograms required to at most
only restrictive filling was considered, with an area under the 9.5% of the population and reduced “missed cases” to no more than
receiver operating characteristic (ROC) curve of 0.98. BNP levels 12.5% of the population.200 Both NT-proBNP and BNP were less
also differentiated the presence of an LA abnormality and robust when screening for diastolic dysfunction, either alone or in
increased LV mass.242 combination with systolic dysfunction. These findings suggest that
Findings from these studies suggest that BNP levels reflect the NT-proBNP may be a useful screening test for systolic dysfunc-
severity of diastolic dysfunction and may accurately predict tion—especially if appropriate age and gender cutpoints are
abnormal diastolic function, particularly restrictive filling, in the applied—but not for diastolic dysfunction. Lack of specificity in
majority of patients referred for echocardiography. In particular, this context is likely to reflect increased peptide levels due to other
low levels appear to rule out significant diastolic or systolic cardiac abnormalities, such as RV dysfunction, valvular disease,
abnormality. and concomitant conditions, like azotemia, atrial fibrillation, and
In community settings, up to half of all cases with LV dysfunc- thyroid disease.249,250 A major potential confounder could also be
tion may be clinically undetected.56 A reliable and inexpensive inducible myocardial ischemia, which has been shown to increase
screening test for asymptomatic LV dysfunction could potentially BNP and NT-proBNP levels.251,252
improve detection in the community. Several large studies have
assessed screening of the general population with BNP or NT-
proBNP to detect systolic dysfunction (LVEF <50%), increased Diagnosis of Acute Heart Failure
LV mass, or diastolic dysfunction graded primarily on the basis of The accurate diagnosis of acute heart failure can be a difficult
transmitral filling as at least moderate (pseudonormal) or severe challenge. The diagnosis may be incorrect in up to half of cases
(restrictive).7,245–247 The prevalence of these abnormalities in each in primary care and more frequently in the setting of preserved
study was low (≤6%). The consistent finding was a high negative LVEF.253,254
predictive value (93%–99%) for low BNP levels, but lower overall BNP and NT-proBNP are now validated as diagnostic markers
specificity and accuracy.245,248 The Framingham study group found for acute heart failure based on consistent findings from multiple
that BNP did not significantly improve detection of LV systolic observational studies performed in different countries and using
dysfunction or LVH over standard clinical and electrocardio- multiple assays.32,33,35,255 Plasma levels of BNP and NT-proBNP
graphic parameters.248 In the study from Olmsted County, differ- are elevated in acute heart failure. Distinct cutpoints with high
ences in BNP and NT-proBNP test performance were noted for negative predictive value can be defined that rule out acute heart
men and women. Although very low levels of BNP excluded failure. Levels of 100 pg/ml for BNP and 400 pg/ml for NT-
significant LV dysfunction, unadjusted levels appeared subopti- proBNP have become established as rule-out values.32,33,35,255 In
mal for routine use in screening the general population, with con- contrast, because of the effect of age, gender, and other factors on
firmatory echo still required in up to 40% of the study population peptide levels, a single level with high positive predictive value for
and up to 60% of cases missed when a single unadjusted BNP confirming heart failure is difficult to define. A greater under-
value was used.241 The same group subsequently tested NT- standing of the factors influencing BNP and NT-proBNP levels
proBNP, compared it with BNP in 1869 community subjects, and has led to a more sophisticated approach to choosing cutpoint
found that NT-proBNP was at least as effective as BNP (mea- levels for accurate heart failure diagnosis, depending on age,
sured by the Biosite assay) in detecting an LVEF of less than 40%, gender, renal function, and other factors.35,256 In general, very high
and in older men it was superior to BNP.200 Because the dominant levels, such as greater than 1600 pg/ml for NT-proBNP, have
effect on BNP and NT-proBNP levels was from age and gender, high positive predictive value for a diagnosis of acute heart failure.
use of cutpoints that adjusted for these variables provided more Values between the rule-out and rule-in cutpoints could indicate
accurate detection of LV systolic or diastolic dysfunction.200 Sen- heart failure, but diagnoses such as atrial fibrillation, pulmonary
 Chapter 27 • Role of Neurohormones 357

embolism, and even LV dysfunction without acute decompensa- Prediction of Heart Failure Events after
tion could also explain these levels. Myocardial Infarction
The studies that validated BNP and NT-proBNP for diagno-
sis were performed in mixed populations in whom acute heart Heart failure is an important complication of acute coronary syn-
failure occurred in the context of either normal or impaired LVEF. dromes (ACSs), including MI. Multiple studies have demon-
The “BNP” study investigators assessed the utility of BNP in strated that neurohormonal activation occurs after an ACS or
differentiating acute heart failure associated with normal or MI.190,267–272 This activation reflects the severity of myocardial
impaired LVEF in a cohort of 452 patients who subsequently damage and hemodynamic compromise. Increased RAS, aldoste-
underwent echocardiography within 30 days of admission.257 rone, and SNS activation contribute to progressive cardiac remod-
BNP levels were higher in all patients with heart failure than for eling and adverse clinical outcomes. Blockade of these systems
non–heart failure subjects. BNP levels were also significantly attenuates LV remodeling and reduces mortality and heart failure
higher in subjects with systolic heart failure than those with heart events in subjects with systolic impairment after MI.228,273–276
failure but preserved EF.257 Despite this, BNP levels did not Recently, the role of neurohormones as markers of prognosis
accurately differentiate between heart failure with preserved or after ACS or MI has been highlighted.190,267–271 BNP and NT-
impaired EF. A combination of higher BNP levels, lower oxygen proBNP levels are equally powerful independent predictors of
saturation, previous history of myocardial infarction (MI) and mortality and heart failure events after an ACS.190,267–270 Predic-
higher heart rate suggested systolic heart failure. While BNP or tion of mortality and heart failure events is both incremental and
NT-proBNP can therefore be used to accurately diagnose acute complementary to risk stratification by LVEF.267 The highest
heart failure, the etiology of heart failure needs to be characterized mortality or heart failure rates are seen in subjects with LV sys-
with additional tests such as echocardiography. tolic impairment (LVEF <40%) and higher NT-proBNP levels
More importantly, two recent randomized studies have dem- (>1200 pg/ml). Subjects without systolic impairment or NT-
onstrated that routine use of BNP improves the accuracy of proBNP elevation were at very low risk for heart failure (1%) or
diagnosis and initial management of heart failure while also death (5%) over 3 years of follow-up. Either isolated systolic
proving to be cost effective.254,258 Both studies included unselected impairment or NT-proBNP elevation carries an intermediate
patients with acute dyspnea that was due to heart failure in risk (Fig. 27-7). The increased risk in subjects in the latter group
50% of cases. Heart failure could be due to impaired or preserved with preserved systolic function but elevated NT-proBNP may
EF. In the first study, 305 patients who presented with unex- be multifactorial, relating perhaps to age, abnormalities of LV
plained dyspnea in primary care were randomized to routine mass and diastolic function, inducible ischemia, or greater renal
care with or without access to NT-proBNP levels.254 In the impairment.252,267,277,278
group for whom physicians had NT-proBNP levels available,
accuracy of diagnosis improved from 50% to 70% (p < 0.01 com- Monitoring Heart Failure and Optimizing Therapy
pared with control).254 In the second study, a similar design was
employed in the emergency department, where subjects present- The best method for monitoring and optimizing the treatment of
ing with acute dyspnea were randomized to treatment groups heart failure remains unclear.279 This is particularly true in the
with or without NT-proBNP levels. Subjects in the NT-proBNP setting of a preserved LVEF, where there is a limited evidence base
group were less likely to be admitted to the hospital or the inten- for effective medications and where some therapeutic windows,
sive care unit and had shorter hospital stays and lower overall cost like for diuretics, are narrow. Recent attention has focused on
of care. No differences were seen in 30-day mortality or readmis- whether neurohormonal markers that reflect symptomatic status
sion rates.258 and the severity of cardiac dysfunction can also be used to monitor
heart failure status and guide optimal drug dosing. The most
likely candidates for monitoring and guiding therapy are the
Assessment of Prognosis BNPs. Recent studies in patients with systolic heart failure suggest
It was a seminal finding that neurohormonal activation in heart a potential benefit for drug treatment guided by BNP or NT-
failure was associated with an adverse prognosis, particularly for proBNP levels.38,280 Given that natriuretic peptide levels fall with
NE, the RAS, aldosterone, AM, and AVP.2,3,47 A large number of effective loop diuretics, ACE inhibitors, AT1R blockers, aldoste-
studies have since demonstrated the consistent finding that BNP rone receptor antagonists, and, after an initial rise, beta blockers
or NT-proBNP levels are among the most powerful prognostic in subjects with preserved systolic function,97,128,236,281 it is possible
markers in heart failure, independent of LVEF, symptomatic that treatment guided by BNP or NT-proBNP may be effective
class, age, and other key determinants of survival.259–264 Levels of in this setting. This hypothesis is currently being tested in several
these peptides predict mortality, risk of hospitalization, and heart studies that include patients with heart failure and preserved
failure decompensation across all stages of heart failure, from EF.36,37
asymptomatic subjects without heart failure to advanced stage D
heart.86,264–266 Recently, additional studies have demonstrated that
Exogenous Administration of B-Type
serial measurement of BNP or NT-proBNP provides indepen-
dent prognostic information that is incremental to single baseline Natriuretic Peptide
values.212–215 Because of their widespread use in the diagnosis of Infusion of BNP has beneficial effects in systolic heart failure,
heart failure, BNP and NT-proBNP are the best candidates for producing vasodilatation, reduced filling pressures, and increased
routine clinical use as prognostic markers. Other neurohormones, diuresis.31,282,283 This has led to its use as a therapy for decompen-
such as ET-1, are also powerful predictors of prognosis, some- sated heart failure, although concerns have been expressed regard-
times incremental to BNP; but as for the RAS, AM, and NE, ing possible adverse effects of BNP infusion on renal function.
their routine use in clinical management is not currently The majority of studies have assessed BNP infusion in the setting
recommended.140 of impaired LV systolic dysfunction.282,283 Whether BNP infusion
358 Chapter 27 • Role of Neurohormones

100 myocardial wall stress is not elevated. The value of BNP when
pericardial and myocardial dysfunctions are both present is
Event free survival %
90 ns † unclear, but levels may not be as discriminating in this context.
80
†
† Cardiac Amyloid
70 †
In one large consecutive series of patients with light chain amy-
60 loidosis, NT-proBNP levels were highly sensitive and specific in
Death detecting cardiac involvement.286 Levels were much higher in
50 subjects with cardiac involvement (508 pmol/L) than in those
0 400 800 1200 1600 without (22 pmol/L) and were strongly related to the severity of
Days diastolic abnormality. NT-proBNP levels were the strongest pre-
dictor of clinical outcome, and serial levels were more sensitive
Group Events %
1 296 248 198 138 53 (14) 5 than conventional echocardiographic indices at detecting a clinical
2 193 154 125 70 34 (27) 14 improvement or worsening during follow-up. These findings
3 36 31 26 18 6 (2) 6 suggest that NT-proBNP may be a useful marker for detection
4 141 103 73 46 22 (52) 37 and monitoring of cardiac amyloid.
100
Chronic Renal Failure
Event free survival %

† †

90
Plasma BNP and NT-proBNP levels are elevated in chronic renal
ns
failure in relation to the severity of renal dysfunction.287–289
†
† Peptide levels also reflect the presence of LVH, underlying coro-
ns nary artery disease, and heart failure but lack specificity as markers
80
of systolic versus diastolic dysfunction.287–289 In subjects with
renal dysfunction, these peptides retain their value as diagnostic
Heart failure admission and prognostic markers for heart failure and risk of all-cause and
70
0 400 800 1200 1600 cardiovascular mortality,290 but discriminating cutpoints are
higher.197,291 For example, in the “BNP” study, optimal values for
Days
diagnosing acute heart failure based on ROC curves were 70, 104,
Group Events % 201, and 225 pg/ml for patients with estimated glomerular filtra-
1 296 245 196 137 53 (3) 1 tion rates of greater than 90, 60–89, 30–59, and less than 30 ml/
2 193 144 116 63 29 (15) 8
3 36 30 23 15 3 (4) 11
min/1.73 m2, respectively.197 Levels of BNP and NT-proBNP
4 141 87 58 34 13 (26) 18 reflect volume status, and hence these peptides have been pro-
posed as a guide to hemodialysis; however, their role in this regard
Figure 27-7 Event-free survival in 666 patients with acute myocardial
infarction for death (top) or admission with heart failure (bottom) according is untested.292
to combinations of plasma N-terminal brain natriuretic peptide (N-BNP)
above or below median levels and left ventricular ejection fraction (LVEF)
<40% or ≥40%. Group 1 (yellow line), N-BNP less than median; LVEF ≥40%. Valvular Heart Disease
Group 2 (blue line), N-BNP greater than median; LVEF ≥40%. Group 3 (green
line), N-BNP less than median; LVEF ≥40%. Group 4 (red line), N-BNP greater
Levels of BNP and NT-proBNP reflect severity of LVH and
than median; LVEF <40%. *p < 0.05; **p < 0.01; †p < 0.001. (Modified from diastolic wall stress in aortic stenosis.293,294 Levels of both peptides
Richards AM et al: B-type natriuretic petides and ejection fraction for prognosis are strongly related to symptom onset with aortic stenosis and
after myocardial infarction. Circulation 2003;107:2786–2792.) increase according to New York Heart Association class.250
Plasma BNP levels also correlate with symptom severity in
patients, even when LV systolic function is normal.295
is effective in the setting of preserved EF is less clear; however, Serial monitoring could potentially identify subjects with val-
beneficial hemodynamic and neurohormonal actions of BNP vular disease progressing to a more symptomatic stage and could
have been demonstrated in this setting.284 therefore guide timing of surgical intervention.

Differentiation of Constrictive Pericarditis from Hypertrophic Cardiomyopathy

Restrictive Cardiomyopathy Levels of the natriuretic peptides are elevated in subjects with
Constrictive pericarditis and restrictive cardiomyopathy can be hypertrophic cardiomyopathy (HCM) in relation to the severity
difficult to differentiate either clinically or with imaging. One of LVH.296–298 Levels are higher in patients with more advanced
recent small study demonstrated that BNP levels could accurately heart failure symptoms and greater abnormalities of diastolic
differentiate pericardial constriction from restrictive cardio- function.296,297,299 The transcardiac gradient in BNP levels also
myopathy.285 In this study, BNP levels were higher in restrictive correlates with the degree of LV outflow obstruction.300 BNP
cardiomyopathy compared with the constriction group (828 ± levels may also reflect subclinical myocardial ischemia in
172 pg/ml vs. 128 ± 53 pg/ml), reflecting increased myocardial HCM.301
diastolic wall stress. In contrast, lower levels in pericardial con- Plasma NT-proANP levels are elevated in children with genes
striction reflect the underlying pathophysiology, with abnormal associated with HCM before significant phenotypic changes
diastolic filling resulting from pericardial constraint, while or hypertrophy develops, suggesting that there may be a role
 Chapter 27 • Role of Neurohormones 359

for screening of potential carriers with natriuretic peptide “adverse” and enhancing “protective” neurohormonal systems in
levels.302 these patients.

Hypertensive Subjects
FUTURE RESEARCH
A series of studies indicate that BNP and NT-proBNP levels
identify LVH, significant diastolic dysfunction, and heart failure A greater understanding is needed of the pattern and severity of
in hypertensive subjects.177,216,303,304 Peptide levels correlate with neurohormonal activation in heart failure where systolic function
the severity of LVH and with indices of diastolic dysfunction177,303 is preserved. This can be obtained only from larger observational
and are also higher in hypertensive patients with LVH and dia- studies with accurate characterization of cardiac function. Further
stolic heart failure than in matched subjects with a similar degree studies are needed that carefully document the pattern of neuro-
of LVH and diastolic dysfunction but no heart failure.216 BNP hormonal activation in relation to clinical, hemodynamic, and
levels also may identify hypertensive subjects with LV systolic echocardiographic indices in patients with heart failure and
dysfunction.304 In community screening, higher BNP levels are preserved LVEF. In addition to defining the pattern of plasma
associated with a higher risk of subsequently developing hormone levels, there is a need for greater characterization of the
hypertension.305 pattern of gene expression and neurohormonal synthesis in myo-
These findings suggest that BNP levels could potentially help cardium and other tissue beds across the spectrum from asymp-
identify risk of hypertension and subsequent onset of heart failure tomatic stage A to symptomatic stages B to D heart failure.265 A
or development of LV systolic dysfunction in hypertensive greater understanding of patterns of plasma and tissue neurohor-
patients. monal activation and of the major stimuli and regulators of this
activation can lead to new therapeutic interventions that attenuate
or prevent the progression to heart failure.
SUMMARY Further studies are needed to clarify the role that neurohormones
may have as biomarkers in identifying subjects at risk for progressing
Neurohormonal factors play an important role in volume, blood to heart failure. Early identification of high-risk individuals can lead
pressure, and electrolyte homeostasis under physiological circum- to earlier intervention and prevention of heart failure. The use of
stances and in the pathophysiology of “essential” hypertension and neurohormones such as BNP and NT-proBNP to guide the optimal
heart failure with preserved LV systolic function. These neuro- drug treatment of heart failure is currently being tested. In at least
hormonal factors contribute to many of the adverse cardiac two studies, patients with heart failure and preserved systolic func-
remodeling processes that are pivotal in the transition from tion are included in the sample populations.36,37
hypertension to heart failure. For example, the SNS, the RAS, Recently published European guidelines on diastolic heart
aldosterone, and ET stimulate cardiomyocyte hypertrophy and failure suggest that cardiac natriuretic peptides are recommended
interstitial fibrosis while also creating adverse effects on blood for exclusion of diastolic heart failure because of their high nega-
vessels and some aspects of renal function. The counterbalancing tive predictive value and are not recommended for diagnosis.
effects of the natriuretic peptides, AM, and other vasodilating However, when they are used for diagnosis of diastolic heart
compounds attenuate the actions of the vasoconstrictor, growth- failure (NT-proBNP > 220 pg/ml, Roche Diagnostics or BNP
promoting, sodium-retaining systems and also inhibit adverse > 220 pg/ml, Triage Biosite), there must be additional noninva-
cardiac remodeling. Circulating levels of some neurohormones, sive studies showing diastolic dysfunction including tissue
including renin, the natriuretic peptides, NE, and vasopressin, are Doppler imaging, echo blood flow Doppler parameters, left ven-
increased in heart failure with preserved systolic function, but not tricular volume mass index, or presence of atrial fibrillation (see
to the same extent as is seen in systolic heart failure. Whether or Chapter 6).306
not this observation has therapeutic implications remains to be Neurohormonal systems are currently the targets of new thera-
seen. pies being evaluated for the treatment of severe hypertension and
Blockade of neurohormonal systems that contribute to the of systolic heart failure. ET receptor blockade may be of value in
pathophysiology of hypertension and heart failure is now a key the treatment of severe hypertension. V2 receptor antagonism
pharmacotherapeutic strategy. In particular, the ACE inhibitors, and adenosine receptor blockade are currently being tested for the
angiotensin receptor blockers, and beta blockers all reduce or treatment of systolic heart failure. Whether these agents are effec-
attenuate LVH and reduce morbidity and mortality. Whereas use tive in treating acute heart failure in patients with preserved
of these drugs in heart failure due to LV systolic dysfunction is LVEF is uncertain.
soundly based, their effects on morbidity and mortality in patients
with preserved systolic function remain to be defined. Likewise,
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 WILLIAM H. GAASCH, MD
EDMUND A. BERMUDEZ, MD
CATALIN F. BAICU, PhD
28
Global and Regional
Systolic Function of
the Left Ventricle in
Diastolic Heart Failure
INTRODUCTION PATHOPHYSIOLOGY
PATHOPHYSIOLOGY
Cardiac Structure and Diastolic Function The term diastolic dysfunction refers to an abnormality of LV dia-
Contractile Behavior stolic distensibility, filling, or relaxation—regardless of whether
Response to Exercise the EF is normal or abnormal and whether the patient is asymp-
tomatic or symptomatic with clinical evidence of heart failure. In
FUTURE RESEARCH the absence of symptoms, those with a normal EF and diastolic
dysfunction are said to have preclinical heart disease or asymp-
tomatic diastolic dysfunction.10,11 Patients with the signs and
symptoms of heart failure, a normal LVEF, and LV diastolic dys-
function are said to have diastolic heart failure.2 If nonmyocardial
causes of heart failure (e.g., mitral stenosis) are excluded, such
INTRODUCTION patients meet published criteria for diastolic heart failure.12 Thus,
diastolic heart failure refers to a syndrome of heart failure that is
In diastolic heart failure, the left ventricular ejection fraction not caused by reduced systolic function, but rather is closely
(LVEF) is normal and the dominant functional abnormality related to chronic structural remodeling and abnormalities in the
resides in diastole. Thus, there is increased passive stiffness with diastolic properties of the left ventricle. These definitions of
impaired relaxation of the ventricle, which results in a disturbed asymptomatic diastolic dysfunction and diastolic heart failure
pattern of left ventricular (LV) filling and elevated end diastolic parallel those used in asymptomatic and symptomatic patients
pressure.1,2 Global systolic performance, function, and contractil- with LV systolic dysfunction and facilitate the use of a patho-
ity remain normal.3,4 However, several reports indicate that physiologic, diagnostic, and therapeutic framework that includes
abnormalities in regional shortening are present in patients with all patients with LV dysfunction.11
diastolic heart failure.5–9 These findings have been interpreted as
evidence supporting the notion that heart failure is somehow
caused by these regional abnormalities in shortening.5 The signifi- Cardiac Structure and Diastolic Function
cance of these observations, particularly their relation to the syn- The anatomic features of hearts from patients with diastolic heart
drome of heart failure, remains uncertain. Accordingly, in this failure differ substantially from those with systolic heart failure
chapter we will review the published data on LV global and (Table 28-1) (see Chapter 2). Patients with diastolic heart failure
regional systolic function in diastolic heart failure and will attempt generally exhibit a concentric pattern of LV remodeling and a
to reconcile what appear to be disparate conclusions about LV hypertrophic process that is characterized by a normal or near-
systolic function in patients with this condition. normal end diastolic volume and increased wall thickness with a
367
368 Chapter 28 • Global and Regional Systolic Function of the Left Ventricle in Diastolic Heart Failure

TABLE 28-1 arterial tone can cause a substantial increase in left atrial (LA)
and pulmonary venous pressures (i.e., diastolic heart failure).
CHARACTERISTICS OF DIASTOLIC VS. SYSTOLIC
HEART FAILURE (HF)
Contractile Behavior
DIASTOLIC HF SYSTOLIC HF
A comprehensive description of the systolic or contractile behav-
Clinical Features ior of the left ventricle requires measurement of LV performance,
Symptoms (e.g., dyspnea) Yes Yes function, and contractility, as well as a consideration of ventricular
Congestive state (e.g., Yes Yes remodeling and loading conditions and a distinction between
edema) global and regional properties.
Exercise tolerance Decreased Decreased
Neurohormonal Yes Yes
activation (e.g., BNP)
Global Contractile Behavior
LV Structure and Geometry
LV mass and geometry Concentric LVH Eccentric LVH The functional capacity of the whole ventricle is most appropri-
Relative wall thickness Increased Decreased ately described by a composite of parameters reflecting LV per-
End diastolic volume Normal Increased formance, function, and contractility. Such parameters are
Cardiomyocytes Increased Increased length
diameter
determined using a combination of cardiac catheterization and
Extracellular matrix Increased Decreased collagen imaging techniques.1,3
collagen
Performance
The pumping ability or performance of the left ventricle is best
BNP, brain natriuretic peptide; LV, left ventricular; LVH, left ventricular hypertrophy.
described by the stroke work, which credits the ventricle for pres-
sure and volume work in a single integrated index. This index of
performance is determined as the product of developed pressure
TABLE 28-2 and total stroke volume. Thus it becomes obvious that it may be
LEFT VENTRICULAR (LV) VOLUME, MASS, GEOMETRY, increased in hypertensive patients or decreased in patients with a
AND SYSTOLIC LOAD IN NORMAL CONTROL small LV chamber and a low stroke volume. However, stroke work
SUBJECTS AND PATIENTS WITH DIASTOLIC HEART is normal in the vast majority of patients with diastolic heart
FAILURE (DHF) failure (Fig. 28-1 and Table 28-3).3 It should be recognized that
this performance index reflects a pumping property of the whole
NORMAL DHF p ventricle, not that of a unit of myocardium. Indeed, if the value
for stroke work is expressed relative to LV mass, work may be
LV end diastolic volume (ml) 115 ± 9 103 ± 22 <0.001
LV end systolic volume (ml) 45 ± 12 45 ± 11 NS subnormal. Thus, myocardial performance (work per gram of
LV mass (g) 164 ± 35 251 ± 101 <0.001 myocardium) may be abnormal in patients with LV hypertrophy
Relative wall thickness 0.38 ± 0.06 0.53 ± 0.11 <0.001 (LVH), but the pump performance (stroke work) of the whole
Systolic blood pressure 128 ± 8 160 ± 40 <0.001 ventricle remains normal.
(mmHg)
LV systolic wall stress (g/cm2) 201 ± 32 187 ± 44 NS Function
A classic ventricular function curve can be constructed by plot-
Data are mean ± SD. From Baicu CF et al: Left ventricular systolic performance, ting coordinates of LV performance (stroke work) against preload
function, and contractility in patients with diastolic heart failure. Circulation
2005;111:2306–2312.
(end diastolic volume). When LV contractility is increased, this
stroke work versus preload relation is shifted upward; when con-
tractility is decreased, the relation is shifted downward. Such
high ratio of mass-to-volume and a high ratio of wall thickness- Frank-Starling ventricular function curves credit the ventricle for
to-chamber radius (Table 28-2). At the microscopic level, the pressure development and shortening, and the analysis incor-
cardiomyocyte exhibits an increased diameter, and there is an porates ventricular preload. This method provides a preload-
increase in the amount of collagen surrounding the myocytes. recruitable stroke work relation, which remains normal in patients
These anatomic or structural features tend to parallel abnormali- with diastolic heart failure (see Fig. 28-1 and Table 28-3).
ties in diastolic function.3,4 The term ventricular function has been redefined and expanded
The passive elastic properties of the ventricle and the process to include a variety of shortening parameters, the most common
of active relaxation determine the LV diastolic pressure-volume of which is LVEF. This dimensionless parameter reflects
(P-V) relation and diastolic function.1 Abnormal passive elastic volume strain (change in volume divided by initial volume). It is
properties are caused largely by increased myocardial mass and by definition normalized and does not require consideration of
alterations in the extramyocardial collagen network, but changes absolute volume or body size. Decades ago, the prognostic value
in intramyocardial components (e.g., titin) also contribute to an of the EF was confirmed in patients with coronary and valvular
increase in passive stiffness.13,14 The effects of abnormally pro- heart disease.15 Since then, it has been applied in virtually all
longed or delayed myocardial relaxation can be superimposed on forms of heart disease, and with rare exception, if the EF is
the passive diastolic P-V curve and cause a further increase in normal—all other indices of LV global performance, function,
diastolic pressure relative to volume. Those changes in passive and contractility remain in the normal range. It should be recog-
stiffness, relaxation, or both produce an upward displacement of nized, however, that the EF, like all other shortening parameters,
the diastolic P-V relation, and as a result, chamber compliance is is influenced by acute or short-term alterations in LV preload,
reduced, the time course of filling is altered, and LV diastolic afterload, and contractility, as well as by chronic remodeling and
pressure is elevated. Under these circumstances a relatively small hypertrophy, both of which contribute to long-term changes in
increase in central blood volume or an increase in venous and load and contractility. Despite these limitations, EF remains the
 Chapter 28 • Global and Regional Systolic Function of the Left Ventricle in Diastolic Heart Failure 369

Peak (+)dP/dt (mmHg/sec)

12 p = 0.26 80 p = 0.29 2400
150 p = 0.54

stroke work (gram/cm2)

Stroke work (Kg.cm) p = 0.13

Ejection fraction (%)

10

Preload recruitable
120 60 1800
8
90
6 40 1200
4 60
20 600
2 30
0 0 0 0
Normal Diastolic Normal Diastolic Normal Diastolic Normal Diastolic
heart heart heart heart
failure failure failure failure
Figure 28-1 Left ventricular stroke work and preload-recruitable stroke Figure 28-2 Left ventricular ejection fraction and peak positive (+)dP/dt
work in diastolic heart failure. Stroke work (left) is not significantly different in diastolic heart failure. The ejection fraction, by definition, exceeds 50%
from normal. Preload-recruitable stroke work (right) is not significantly dif- and is not significantly different from normal. Peak (+)dP/dt (right) is not
ferent from normal. Thus, ventricular performance and function are normal significantly different from normal in diastolic heart failure; this indicates
in diastolic heart failure. Data are mean ± SE. normal ventricular contractility. Data are mean ± SE.

TABLE 28-3
LEFT VENTRICULAR (LV) SYSTOLIC PERFORMANCE,
FUNCTION, AND CONTRACTILITY IN NORMAL Unfortunately none of these indices is truly independent of
CONTROL SUBJECTS AND PATIENTS WITH loading conditions or ventricular remodeling. For example,
DIASTOLIC HEART FAILURE (DHF) (+)dP/dt may be altered by an acute change in preload, whereas
end systolic elastance (Ees) may be affected by chronic changes in
NORMAL DHF p
LV mass/volume ratio (m/v).16,17
LV Systolic Performance When studied in a chronic steady state, patients with diastolic
SW (kg-cm) 8.8 ± 2.5 8.4 ± 2.3 NS heart failure exhibit normal values for peak (+)dP/dt, normal
LV Systolic Function values for systolic elastance, and normal stress-shortening rela-
SW/EDV (g/cm2) 74 ± 10 81 ± 14 <0.01 tions (Figs. 28-2, 28-3, and 28-4, and see Table 28-3). These data
PRSW (g/cm2) 109 ± 18 99 ± 22 NS indicate that ventricular contractility is normal in patients with
Fractional shortening (%) 33 ± 5 27 ± 4 NS diastolic heart failure.
Ejection fraction (%) 0.61 ± 0.07 0.58 ± 0.06 NS
Vcf (circumferences/sec) 1.8 ± 0.2 1.8 ± 0.2 NS
PEP/LVET 0.37 ± 0.19 0.35 ± 0.13 NS Summary
LV Contractility Indices of LV systolic performance, function, and contractility
Peak (+)dP/dt (mmHg/s) 1664 ± 305 1596 ± 362 NS are normal in patients with diastolic heart failure. These normal
ESP/ESV (mmHg/ml) 2.1 ± 0.8 2.6 ± 1.1 <0.05 indices can be taken as evidence that the pumping ability of the
Ees (mmHg/ml) 1.6 ± 0.5 2.4 ± 0.9 <0.001
Ees′ (mmHg/g) 1.2 ± 0.4 1.1 ± 0.6 NS whole ventricle (global systolic behavior) is normal. This conclu-
sion does not exclude the possibility that abnormalities in regional
Data are mean ± SD. SW, stroke work, EDV, end diastolic volume, PRSW, preload
function may exist in some patients.
recruitable stroke work, Vcf, circumferential fiber shortening velocity, PEP, pre-ejection
period, LVET, left ventricular ejection time, ESP, end systolic pressure, ESV, end systolic
volume, Ees, elastance at end systole, Ees′, normalized elastance.
From Baicu CF et al: Left ventricular systolic performance, function, and contractility in
patients with diastolic heart failure. Circulation 2005;111:2306–2312.
Regional Contractile Behavior
Measurements of the extent and velocity of regional myocardial
most widely applied and clinically useful index of LV systolic length transients (both shortening and lengthening) can be made
function. By definition, EF is normal (or near normal) in diastolic using a variety of techniques, including echocardiography and
heart failure. Likewise, circumferential shortening measured at tissue Doppler imaging (TDI). For example, M-mode echocar-
the endocardial surface, expressed as a fractional change (%), is diography can be used to describe mitral annular motion or dis-
normal, as is the relation between fractional shortening (FS) and placement and to assess long-axis shortening. Echocardiography
systolic wall stress. can also be used to define circumferential shortening at the LV
endocardial surface or at the midwall. TDI technology has made
Contractility
it possible to assess length transients in multiple areas of interest
The inotropic or contractile state of the whole ventricle is
along the long axis of the ventricle. To be interpreted appropri-
referred to as ventricular contractility. The concept of LV contrac-
ately, the measurements must be normalized to produce regional
tility is analogous to that of myocardial contractility, which is a
strain and strain rate; these parameters are dimensionless and are
property of the myocardium that is independent of loading condi-
expressed as percent change and inverse seconds, respectively.
tions. Indices of ventricular contractility have conventionally been
Figure 28-5 illustrates the directions of LV longitudinal, circum-
classified as:
ferential, and radial strain (ε). Systolic strain or shortening may
1. Isovolumic phase indices (e.g., (+)dP/dt) be expressed as the ratio of:
2. Ejection phase indices (e.g., relation of systolic wall stress
to ejection fraction) (end diastolic length − end systolic length)/
3. End systolic indices (e.g., end systolic elastance) end diastolic length
370 Chapter 28 • Global and Regional Systolic Function of the Left Ventricle in Diastolic Heart Failure

50 εl

Midwall fractional shortening (%)

Normal
Normal +/ – 95%
40 Diastolic heart failure εl : Longitudinal strain
εr
30
εr : Radial strain

20 εc
εc : Circumferential strain
10

0
0 75 150 225 300

Figure 28-5 Diagram indicating the direction of different myocardial

Endocardial fractional shortening (%)

50 Normal strain vectors.

Normal +/– 95%
40 Diastolic heart failure

even some individuals with LV concentric remodeling in the

30 absence of hypertension.18–20 These regional shortening
abnormalities reflect regional myocardial function and may have
20 prognostic value, but there is little relation between midwall
shortening and the signs or symptoms of heart failure.
10 Longitudinal Shortening
The published data on regional (long-axis) function in diastolic
0
heart failure are limited, but there is general agreement that
0 75 150 225 300
abnormal extent and velocity of shortening are abnormal in a
minority of patients with diastolic heart failure.4 For example, Yip
Mean systolic stress (gram/cm2) et al.5 and Petrie et al.7 found systolic mitral annular displacement
Figure 28-3 Left ventricular stress-shortening relations in diastolic heart to be abnormal in one third to one half of their patients. Yu et al.6
failure. At the endocardial surface in the circumferential plane, all stress- and Nikitin et al.8 found reduced velocity along the long axis
shortening coordinates lie in the normal range (top). By contrast, approxi-
mately one third of the midwall stress-shortening coordinates lie below
in less than half of their patients. Critical review of these data
the range of normal (bottom). Thus, ventricular contractility remains normal suggests that the heart failure seen in their patients with a
in the presence of depressed regional (i.e., midwall) stress-shortening normal EF was not related to the abnormalities in long-axis
relations. shortening.4
Summary
4 1.6 p = 0.56
Based on the published data from patients with diastolic heart
End systolic elastance
End systolic elastance

p < 0.001 failure (and some with asymptomatic LVH and diastolic dysfunc-
3 1.2 tion), it appears that approximately one third to one half of the
(mmHg/ml)

(mmHg/g)

patients exhibit some abnormality of regional systolic function,

2 0.8 but it has not been shown that such abnormalities are responsible
for the clinical syndrome of heart failure. This area of clinical
1 0.4 investigation requires additional studies using appropriate strain
and strain rate calculations and modern imaging techniques.
0 0
Normal Diastolic Normal Diastolic
heart heart
Response to Exercise
failure failure The presence of normal LV performance, function, and contractil-
Figure 28-4 Left ventricular end systolic elastance in diastolic heart failure. ity in a stable resting or basal state does not necessarily mean that
End systolic elastance is higher than normal in diastolic heart failure (left). the LV response to exercise is normal. Indeed, there is evidence
When normalized for the mass/volume ratio, which corrects for the effects
of chronic ventricular remodeling, the elastance value is not significantly
that increased diastolic stiffness of the ventricle has at least two
different from normal (right). Data are mean ± SE. limiting effects on the LV response to exercise. First, increased LV
stiffness limits utilization of the Frank-Starling mechanism and
thereby reduces the ability to augment stroke volume.21 Thus, LV
Circumferential Shortening diastolic dysfunction is responsible for an abnormality in systolic
Stress-shortening relations at the midwall of the left ventricle performance (during exercise). Second, increased LV stiffness is
are abnormal in approximately one third of patients with diastolic responsible for the dramatic increase in LV diastolic and pulmo-
heart failure and normal shortening at the endocardial surface nary venous pressure that occurs as venous return increases
(see Fig. 28-3). A similar finding has been described in patients during exercise.22 While other factors likely contribute to the
with hypertensive heart disease, patients with aortic stenosis, and impaired exercise tolerance that is seen in patients with diastolic
 Chapter 28 • Global and Regional Systolic Function of the Left Ventricle in Diastolic Heart Failure 371

dysfunction, with or without heart failure, these studies indicate 8. Nikitin NP, Witte KK, Clark AL, Cleland JCF: Color tissue Doppler-
that a primary causative mechanism resides in diastole. derived long-axis left ventricular function in heart failure with preserved
global systolic function. Am J Cardiol 2002;90:1174–1177.
9. Bruch C, Herrmann B, Schmermund A, et al: Impact of disease activity on
left ventricular performance in patients with acromegaly. Am Heart J
FUTURE RESEARCH 2002;144:538–543.
10. Redfield MM, Jacobsen SJ, Burnett JC, et al: Burden of systolic and diastolic
ventricular dysfunction in the community. JAMA 2003;289:194–202.
The diagnosis of heart failure is made clinically, requiring the 11. Gaasch WH: Diagnosis and treatment of heart failure based on left
presence of signs and symptoms (e.g., dyspnea, edema). Heart ventricular systolic or diastolic dysfunction. J Am Med Assoc 1994;271:
failure syndrome can be caused by LV systolic dysfunction, 1276–1280.
diastolic dysfunction, or both. In systolic heart failure, the 12. Yturralde FR, Gaasch WH: Diagnostic criteria for diastolic heart failure.
Progress in CV disease. Prog Cardiovacs Dis 2005;47:314–319.
dominant abnormalities reside in systole. In diastolic heart failure, 13. LeWinter MM: Titin isoforms in heart failure. Circulation 2004;110;
the dominant functional abnormalities reside in diastole; LV 109–111.
global systolic performance, function, and contractility remain 14. Katz AM, Zile MR: New molecular mechanism in diastolic heart failure.
normal. Abnormal regional systolic function is present in one Circulation 2006;113:1922–1925.
15. Cohn PF, Gorlin R, Cohn LH, Collins JJ: Left ventricular ejection fraction
third to one half of all patients with diastolic heart failure, but as a prognostic guide in surgical treatment of coronary and valvular heart
more research is needed to determine whether such regional dys- disease. Am J Card 1974;34:136–140.
function contributes significantly to the clinical syndrome of heart 16. Kawaguchi M, Hay I, Fetics B, Kass DA: Combined ventricular systolic and
failure. arterial stiffening in patients with heart failure and preserved ejection frac-
tion: Implications for systolic and diastolic reserve limitations. Circulation
2003;107:656–658.
17. Pak PH, Maughan WL, Baughman KL, et al: Mechanism of acute mechani-
REFERENCES cal benefit from VDD pacing in hypertrophied heart: Similarity of responses
1. Zile MR, Baicu CF, Gaasch WH: Diastolic heart failure: Abnormalities in in hypertrophic cardiomyopathy and hypertensive heart disease. Circulation
active relaxation and passive stiffness of the left ventricle. N Eng J Med 1998;98:242–248.
2004;350:1953–1959. 18. Aurigemma GP, Silver KH, Priest MA, Gaasch WH: Geometric changes
2. Aurigemma GP, Gaasch WH: Diastolic heart failure. N Engl J Med allow for normal ejection fraction despite depressed myocardial shortening
2004;351:1097–1105. in hypertensive left ventricular hypertrophy. J Coll Cardiol 1995;26:
3. Baicu CF, Zile MR, Aurigemma GP, Gaasch WH: Left ventricular systolic 195–202.
performance, function, and contractility in patients with diastolic heart 19. Aurigemma GP, Silver KH, McLaughlin M, et al: Impact of chamber geom-
failure. Circulation 2005;111:2306–2312. etry and gender on left ventricular systolic function in patients >60 years of
4. Aurigemma GP, Zile MR, Gaasch WH: Contractile behavior of the left age with aortic stenosis. Am J Cardiol 1994;74:794–798.
ventricle in diastolic heart failure: With emphasis on regional systolic func- 20. Aurigemma GP, Gaasch WH, McLaughlin M, et al: Reduced left ventricular
tion. Circulation 2006;113:296–304. systolic pump performance and depressed myocardial contractile function
5. Yip G, Wang M, Zhang Y, et al: Left ventricular long axis function in dia- in patients >65 years of age with normal ejection fraction and a high relative
stolic heart failure is reduced in both diastole and systole: Time for a redefi- wall thickness. Am J Cardiol 1995;76:702–705.
nition. Heart 2002;87:121–125. 21. Cuocolo A, Sax FL, Brush JE, et al: Left ventricular hypertrophy and
6. Yu C, Lin H, Yang H, et al: Progression of systolic abnormalities in patients impaired diastolic filling in essential hypertension: Diastolic mechanisms for
with “isolated” diastolic heart failure and diastolic dysfunction. Circulation systolic dysfunction during exercise. Circulation 1990;81:978–986.
2002;105:1195–1201. 22. Kitzman DW, Higginbotham BM, Bobb FR, et al: Exercise intolerance in
7. Petrie MC, Caruana L, Berry C, McMurray JJV: Diastolic heart failure or patients with heart failure and preserved left ventricular systolic function:
heart failure caused by subtle left ventricular systolic dysfunction. Heart Failure of the Frank-Starling mechanism. J Am Coll Cardiol 1991;17:
2002;87:29–31. 1065–1072.
 SANJAY KUMAR, MD
RICHARD A. GRIMM, DO
29
Pacing and Diastolic
Heart Failure
INTRODUCTION Optimization of Interventricular Interval and
Diastolic Function
PATHOPHYSIOLOGY
Adverse Effects of Pacing
Basics of Pacing and Cardiac
Resynchronization Therapy FUTURE RESEARCH
Diastolic Dysfunction Right Ventricular Outflow Tract Pacing
Atrial-Based Managed Ventricular Pacing
CLINICAL RELEVANCE
Mode in Dual-Chamber Implantable
Overall Effects of Pacing on Cardiac
Cardioverter-Defibrillators
Function
The Best Modality of Cardiac
Pacing and Diastolic Function
Resynchronization Therapy
Effect of Cardiac Resynchronization Therapy
Direct His Bundle Pacing
on Diastolic Function
Role of Cardiac Resynchronization Therapy
Optimization of Atrioventricular Delay and
for Diastolic Heart Failure
Diastolic Function

INTRODUCTION for the clinical manifestation of heart failure in these patients.

Persson et al. studied 312 patients (mean age, 66; EF, 50%;
According to the American Heart Association, nearly 5 million female, 34%) over a median 569 days. Patients with normal
Americans are living with heart failure, and approximately 550,000 diastolic function and mild diastolic dysfunction (abnormal
new cases are diagnosed each year. Diastolic heart failure (DHF) relaxation) had a good prognosis, whereas moderate and severe
contributes to approximately 40% to 50% of congestive heart diastolic dysfunctions (restrictive physiology) were associated
failure (CHF) patients admitted to hospitals. DHF is character- with increased cardiovascular morbidity and mortality. Moderate
ized by clinical signs and symptoms of heart failure, normal ejec- and severe diastolic dysfunctions were the only predictors
tion fraction (EF), and evidence of abnormal left ventricular (LV) for cardiovascular death or heart failure hospitalization
relaxation, filling, diastolic distensibility, or diastolic stiffness.1,2 (p < 0.003).5 Apart from prognosis, the ventricular myocardium
Zile et al. studied 63 patients with DHF with cardiac catheter- of DHF differs from that of SHF. DHF is associated with
ization and echocardiography. Almost all had one or more abnor- myocyte hypertrophy, higher myofibrillar density, elevated
mal indices of diastolic function.3 A recent population study myocyte relative thickness, and increased myofilamentary Ca2+
showed that by comparison with systolic heart failure (SHF), sensitivity.6
DHF is more likely distinguished by older age, female sex, and a Since the beginning of pacing therapy in 1958, tremendous
history of hypertension, as well as atrial fibrillation. Although the improvement in technology has produced more sophisticated,
adjusted 1-year mortality rate was higher for systolic than dia- efficient, and compact pacemakers. The pacing sites, pacing modes,
stolic dysfunction, the heart failure readmission rate was similar and baseline heart function influence diastolic heart function, and
at 30 days (4.5% vs. 4.7% p = 0.66) and 1 year (13.5% vs. 16.1% various authors have reported the effects of pacing on one or more
p = 0.09).4 diastolic function parameters. This chapter will discuss and
More than 40% of heart failure patients have preserved systolic explore this evolving understanding of the effects of pacing
function, suggesting that diastolic dysfunction may be responsible therapy on diastolic function and DHF.
373
374 Chapter 29 • Pacing and Diastolic Heart Failure

PATHOPHYSIOLOGY stroke volume is related to end diastolic volume. The greater the
initial LV volume, the greater the peak pressure reached and the
Basics of Pacing and Cardiac faster the rate of relaxation (lusitropic effect).8
Resynchronization Therapy There are two major disease processes of diastole that affect
Pacemakers generate an electrical charge through electrodes that filling or distensibility: abnormal relaxation and increase in myo-
produce action potentials in myocardial cells. These action poten- cardial stiffness. Abnormal relaxation is usually affected early in
tials, if above threshold, stimulate surrounding myocardium the disease process and can be measured by cardiac catheteriza-
(capture), and a wave of electrical discharge (depolarization) tion or echocardiographic techniques. An increase in myocardial
moves away from the electrode to energize cardiac chambers. stiffness represents advanced diastolic dysfunction and is usually
Electromechanical coupling follows in the direction of depolariza- associated with an increase in LV end diastolic pressure. LV stiff-
tion. A unichamber lead is usually in the right ventricular apex ness refers to a change in diastolic LV pressure relative to diastolic
(RVA), from which a wave of depolarization travels posteriorly LV volume (dp/dv) and equals the slope of the diastolic pressure-
and toward the cardiac base. Although it affects ventricular con- volume relation (P-VR). It is also inversely proportional to
traction, this can be at the cost of ventricular dyssynergy. deceleration time (DT). Thus, a rapid DT indicates elevated LV
Dual-chamber pacemakers have an additional lead in the right early diastolic chamber stiffness.9
atrium. Depending on the mode, the atrial lead will sense intrinsic Echocardiography has emerged as a simple and reliable non-
atrial depolarization and be inhibited as well as activate the ven- invasive method of evaluating systolic and diastolic function.
tricular lead at a preset time interval (atrioventricular [AV] delay) Detailed description of the role of echocardiography in the clas-
if no intrinsic ventricular depolarization is sensed. This allows for sification of diastolic dysfunction is discussed in Chapters 6 and
AV synchrony and improved diastolic filling of the left ventricle. 10–12.
AV synchrony is achieved by single-chamber atrial rate-
responsive (AAIR) or dual-chamber rate-responsive (DDDR)
programming. CLINICAL RELEVANCE
Cardiac resynchronization therapy (CRT) requires placement
of two ventricular leads: one positioned at the RVA (or RV outflow Diastolic dysfunction is a feature representing abnormal diastole;
tract [RVOT]) and the other in the posterolateral ventricular wall however, DHF as an entity needs only one or more features of
(via the coronary sinus). CRT has been advocated for patients diastolic dysfunction. The currently accepted definition of DHF
with New York Heart Association (NYHA) stage III/IV heart requires signs and symptoms of heart failure and normal EF
failure, left ventricular (LV) dysfunction (EF ≤35%) refractory to (≥50%). Historically, EF has been regarded as a vital component
optimal drug therapy, and prolonged QRS interval (>120 ms). of normal systolic function, but other markers (e.g., ventricular
CRT has resulted in improvement in quality of life, 6-minute hall systolic synchrony, LV end systolic volume [LVESV], dp/dt) are
walk, EF, and reversal of LV remodeling and mortality.7 also important. Interestingly, DHF has been shown to have many
The principal mechanism underlying CRT is that LV dysfunc- features typically regarded as markers of systolic dysfunction.
tion is often associated with QRS prolongation. Such conduction Recent studies have dispelled the commonly held belief that
delay can cause dyssynchronous contraction of the ventricle, patients with DHF have only abnormalities of relaxation. Syn-
resulting in inefficient function. Delay of different myocardial chronicity studies, especially based on tissue Doppler imaging
segments of the ventricular wall can be seen on standard two- (TDI), have shown that systolic asynchrony is a relatively common
dimensional echocardiographic imaging, but more sophisticated finding (33%–39%) in DHF.10,11 Yu et al. reported the prevalence
Doppler modalities have proven useful and predictive of a favor- of isolated diastolic asynchrony in 22%, isolated systolic asyn-
able response to CRT when measured prior to a planned implant. chrony in 25%, and coexisting diastolic and systolic asynchrony
More specifically, tissue velocity imaging has proven useful, as in 14% of patients with DHF. The corresponding prevalence in
longitudinal velocity timing can be sampled and compared the SHF group was 17%, 31%, and 26%, respectively (Figs. 29-1
between opposing basal segments of the left ventricle, resulting in and 29-2).11
a measure of intraventricular dyssynchrony. This provides a more Biventricular (biV) pacing produces improvement in LV func-
precise parameter for identifying dyssynchronous contraction tion and symptomatic status by reducing systolic dyssynchrony in
than QRS morphology or duration. patients with SHF.12 Patients with CRT have consistently shown
an improvement in many echocardiographic systolic as well as
diastolic parameters. Though studies are brimming with reports
of improvement in systolic parameters (e.g., EF, LVESV, time to
Diastolic Dysfunction
peak systolic myocardial velocities) in CRT patients, a similar
Diastolic dysfunction is associated with functional abnormalities demonstration for diastolic parameters has been less consistent.
of diastolic relaxation, filling, or distensibility, while DHF is asso- A recent wave of articles has explored the subtle but significant
ciated with signs and symptoms of heart failure, normal EF, and role of diastolic function in heart failure.13–15 This chapter attempts
abnormalities of one or more parameters of diastolic function.3 to uncover current evidence for the role and interaction of pacing,
It is important to understand that physiologically, diastole is particularly CRT, in influencing diastolic dysfunction and DHF.
considered to begin from the period of reduced ventricular ejec-
tion, encompassing isovolumic relaxation and filling phases of
ventricles. It begins when calcium ions are taken up into the sar- Overall Effects of Pacing on Cardiac Function
coplasmic reticulum so that myocyte relaxation dominates over Pacing has multiple effects on ventricular function depending on
contraction, and LV pressure starts to fall. Performance of the pacing site, pacing configuration, and disease status. The effect
ventricle as a pump is highly dependent on diastolic filling of the may be positive, as seen with atrial pacing in patients with sinus
ventricle (preload). Frank-Starling’s law of the heart dictates that node dysfunction, where it results in an increase in heart rate and
 Chapter 29 • Pacing and Diastolic Heart Failure 375

Figure 29-1 Mechanical asynchrony in diastolic heart failure (DHF) Figure 29-2 Mechanical asynchrony in diastolic heart failure (DHF)
observed by tissue Doppler imaging. An example of a patient with DHF observed by tissue Doppler imaging. Another patient with DHF (ejection
(ejection fraction, 62%) who had evidence of diastolic asynchrony, as illus- fraction, 55%) had evidence of systolic asynchrony, as illustrated by the
trated by the scattered time to peak early diastolic velocity (arrowheads). scattered time to peak systolic velocity (arrow). This patient had no evi-
The systolic asynchrony is relatively mild (arrow). (From Yu et al: Diastolic dence of diastolic asynchrony (arrowhead). (From Yu et al: Diastolic and
and systolic asynchrony in patients with diastolic heart failure: A common but systolic asynchrony in patients with diastolic heart failure: A common but
ignored condition. J Am Coll Cardiol 2007;49:97–105.) ignored condition. J Am Coll Cardiol 2007;49:97–105.)

TABLE 29-1
EFFECT OF PACING ON DIASTOLIC PARAMETERS
ATRIAL PACING RIGHT VENTRICULAR PACING BIVENTRICULAR PACING LEFT VENTRICULAR PACING

Increase in LVEDP66 Minimal change in LVESV7 Decreased LVEDV and LVESV69,71,20 Decreased LVEDV18,45
No significant change in LVEDD and No change in LVEDV and LVESV69 Increased diastolic filling time7,16 Decreased LVEDP17,18
LVESD67 Increased LVEDP Decreased E-wave velocity69 Decreased LVESV21
Decrease in E-wave TVI and increase Increased myocardial stiffness70 Decrease in E/A ratio7,23
in pulmonary venous flow in Decreased E-wave velocity69 Decrease in E/Vp ratio
CAD68 Increase in pulmonary S/D flow ratio
Decrease in pulmonary vein atrial
reversal velocity
Increase in DT23
Decrease in LV (−)dp/dt72 Decreased LV (−)dp/dt17 Lower Tau but higher LV (−)dp/dt Decreased LV (−)dp/dt17
Increase in Tau72 Increased Tau70 compared with RVA pacing16 No significant change in
No significant change in peak LV Decreased LV (−)dp/dt17 LV(−)dp/dt18
(−)dp/dt between RVOT and
RVA pacing56

cardiac output. However, the effect may be negative, as seen with Myocardial relaxation is influenced by chamber load and
right ventricular (RV) apical pacing in patients with bradycardic homogeneity of activation. Auricchio et al. studied 27 CHF
indications and normal baseline LV function, which is thereby patients with conduction disorders. RV, LV, and biV pacing were
impaired. A detailed overview of the effects of pacing on diastolic compared. BiV and LV pacing increased LV (+)dp/dt and aortic
cardiac function (as it pertains to diastolic physiology) is given in pulse pressure more than did RV pacing. LV diastolic perfor-
Tables 29-1 and 29-2. mances also changed in all pacing configurations, but the changes
were small and inconsistent (LV end diastolic pressure [LVEDP]
decreased and absolute value of LV (−)dp/dt also decreased, indi-
Pacing and Diastolic Function cating slower relaxation). The important variables predicting
Hay et al.16 studied short-term effects of RV pacing (RVA and outcome were pacing site, appropriate AV delay, and prolonged
RVOT), LV free wall pacing, and biV pacing in patients with QRS width.17
heart failure (EF 14%–30%). Systolic function improved in all Simantirakis et al. studied 12 patients with AV node ablation
modes, but more so in the biV group. However, only the biV (due to atrial fibrillation) but with normal LV systolic function.
group showed improved diastolic function (isovolumic relaxation LV-based pacing (LV free wall or biV) was compared with RV
and diastolic filling times). The authors suggested that single-site apical pacing. LV-based pacing improved indices of LV systolic
LV pacing, in contrast to biV pacing, might induce some intra- function more than did RV pacing. Indices of LV diastolic filling
ventricular dyssynchrony that could impact relaxation. (EDP, EDV) were better during LV-based pacing, whereas LV
376 Chapter 29 • Pacing and Diastolic Heart Failure

TABLE 29-2
EFFECTS OF PACING SITE ON CARDIOVASCULAR SYSTEM
DYSSNCHRONOUS PACING, RVA PACING SYNCHRONOUS PACING, BIV PACING

Cellular Level Increased tissue norepinephrine level42 Increased septal glucose uptake24
Asymmetric hypertrophy58 Decreased interstitial remodeling, TNF-α expression, and
Increased stress kinase phosphorylation73 apoptosis76
Shift in titin isoform74
Reduced Ca++-ATPase, phospholamban, and connexin43,75
Tissue Level Mismatch of tissue perfusion42 Correction of LV contractile dysfunction
Reduction in LV shortening fraction54 Reverse remodeling7
Chronic LV remodeling58 Increased myocardial efficiency of O2 use78,79
Depressed fiber-sheet extension and wall thickening by Effect on myocardial perfusion (increase80,81; no change79)
epicardial pacing77
Prolonged QRS duration62
Organ Level Increased LAE and LAP37,38 Increased SBP, SV, dp/dtmax, and EF but decreased EDV, ESV, Tei
Rightward shift of LV ES PVR index, and MR7
Decreased SV and EDV42 Increased diastolic filling16,24
Upward and left shift of LV end diastolic P-VR70 Shortening of IVMD
Reduced cardiac output34,57,62 Increased DT and E-A separation24
Increased atrial fibrillation82,83 Increased EF and IVRT16
Body Level Increased risk of heart failure and death34,52,82 Improved NYHA class, quality of life, and 6 min walk7
Increased incidence of thromboembolism40 Reduced heart failure, hospitalization, and mortality84,85

diastolic function indices such as (−)dp/dtmax, Tau [τ], and In the Multicenter Insync Randomized Clinical Evaluation
passive diastolic chamber stiffness did not change significantly.18 (MIRACLE) study, 323 patients were randomized into two
This reflects a more complex influence of preactivation and atrial groups: control (n = 151) and CRT (n = 172). Echocardiographic
contraction on chamber load present during sinus rhythm. parameters were measured at baseline, then 3 and 6 months after
intervention. Significant reduction in LVEDV and LVESV
occurred at 3 months in the CRT group compared with the
Effect of Cardiac Resynchronization Therapy on control group. The reduction in LVEDV and LVESV continued
Diastolic Function between 3 and 6 months. There were significant increases in EF
CRT has been shown to improve NYHA functional class, quality of 2.6% at 3 months and 3.6% at 6 months in the CRT group.
of life indicators, and EF. It is also associated with improved LV There was also a significant increase in deceleration slope and
geometry (reduction in LV end diastolic and systolic diameter as deceleration time of the E wave (during rapid filling) at 3 and 6
well as volume) and reduction in mitral regurgitation. Patients months in the CRT group. The maximum E-wave velocity and
who respond to CRT are often those with positive structural and myocardial performance index decreased significantly at follow-
functional LV remodeling.7,19 up, consistent with improved ventricular function. There was no
The mechanisms of benefit of CRT are several, including significant change in peak A-wave velocity, E/A wave velocity
synchronization of systolic function as well as enhancement of ratio, and isovolumic relaxation time (IVRT) in the CRT or the
diastolic function.17,20–22 The literature is replete with studies sup- control group.7
porting the beneficial effects of CRT on systolic function but is Of note, optimization of the AV delay and synchronous biV
less prolific with respect to diastolic function.13,14,16–18 Table 29-3 pacing resulted in prolongation of the duration of LV filling (dia-
provides a list of effects of CRT on diastolic parameters. stolic filling time), separation of the rapid filling phase from atrial
CRT does appear to have a beneficial effect on diastolic proper- systolic contraction, concomitant shortening of interventricular
ties of the failing heart. CRT enhances diastolic filling patterns in mechanical delay (IVMD), and simultaneous ventricular depo-
patients with systolic dysfunction. In a recent study, 23 patients larization that coordinated contraction and relaxation. There was
were evaluated at 1 week prior as well as 1 and 6 months after also a significant improvement in the diastolic deceleration slope
implantation. Significant clinical improvement was noted in all and deceleration time of the rapid ventricular filling wave velocity
patients. Compared with baseline, the ratio of early to late peak (E wave), leading to better diastolic filling.7,24
velocities (E/A) decreased significantly (1.5 to 0.8) at 6 months. In CRT patients, there was a significant improvement in the
The pulmonary systolic flow to diastolic flow ratio (PVs/PVd) myocardial performance index (Tei index) at 3 months that con-
increased from 0.9 to 1.3 at 6 months, and the ratio of early peak tinued between 6 and 12 months compared with the control
velocity to LV flow propagation velocity (E/Vp) decreased from group. The Tei index is a parameter representing both systolic and
2.7 to 2 at 1 month, then to 1.9 at 6 months. Patients who dem- diastolic performance and is the summation of isovolumic con-
onstrated improvement in EF of more than 25% were designated traction time and IVRT divided by the ejection time. CRT failed,
responders (N = 17, 74%). In these patients, the E wave and pul- however, to show significant remodeling in patients with SHF
monary venous (PV) atrial reversal velocity decreased, E-wave and restrictive LV diastolic filling (characterized by a short decel-
deceleration time increased, and the E/Vp ratio improved signifi- eration time and peak E-wave velocity >1 m/sec).7,24
cantly (all diastolic parameters), whereas in the nonresponder Reduction in ventricular systolic dyssynchrony is one of the
population, changes in LV diastolic parameters remained major mechanisms by which CRT provides benefit.12,25 Various
insignificant.23 methods of measuring synchrony are being investigated. TDI has
 Chapter 29 • Pacing and Diastolic Heart Failure 377

TABLE 29-3 provided an easy-to-use tool to quantify dyssynchrony both in

systole and in diastole. Echocardiographic studies have concen-
EFFECTS OF CRT ON DIASTOLIC DYSFUNCTION trated on the basal and middle segments of the heart, ignoring the
PARAMETERS apex, because of limitations of TDI when applied to the apical
segments. Dyssynchronous contraction and relaxation have been
DIASTOLIC
DYSFUNCTION INFLUENCE measured as standard deviations of the time to peak segmental
PARAMETERS MARKERS OF CRT REFERENCES myocardial velocity of 12 myocardial segments, the maximum
time difference between opposing myocardial segments, or the
Velocities Mitral E velocity Yes 13,14,7 average of peak myocardial velocities of myocardial segments.
Mitral A velocity No
Flow No Waggoner et al. studied diastolic function in patients with
propagation severe SHF after CRT. Diastolic LV filling indices (mitral E/A,
velocity E/Em, E/filling pressure [FP] ratios), as well as diastolic syn-
Mean Em Yes chrony (Q-Em velocity difference) changed favorably at 4 months,
velocity
(Global Em)
especially in the non-ischemic cardiomyopathy group. The cohort
Mean Am No with ischemic cardiomyopathy had significant improvement in
velocity only Em global velocity (a measure of diastolic asynchrony) at 4
Time Deceleration Yes 13,7 months. Diastolic filling indices were also predictive of long-term
time event rates (heart failure hospitalization).13 In another study, by
Diastolic filling Yes 13,14,7
time Yu et al., in which patients were divided between responders
Isovolumic Yes 13,14 (45%) and nonresponders (55%) based on LV reverse remodeling
relaxation (reduction of LVESV ≥15%) after CRT, responders had signifi-
time cant reduction in E/Em ratio (a marker of LV FP; 30 to 22, p <
Tau, time Yes 16
constant of
0.05). Responders also had significant prolongation in LV filling
relaxation time (381 to 441 msec, p < 0.05). Patients with baseline abnormal
Negative dp/dt Yes 17 relaxation patterns had greater reduction of LV volumes than
Q-Em time Yes 13,14 those exhibiting a pseudonormal pattern (29% vs. 11%, p < 0.05).
difference Another interesting finding was that nonresponders differed sig-
(SD in Te)
Te-difference No nificantly from responders with respect to baseline E/A ratio,
between 2 IVRT, mean Em, and mean Am (Table 29-4). However, in this
wall segments uncontrolled trial, systolic (but not diastolic) dyssynchrony was a
Interventricular Yes 7 predictor of favorable reduction in LVESV.14 As yet, there is no
mechanincal
delay
indisputable evidence that CRT improves either systolic or dia-
Ratios Mitral E/A ratio Yes 13,23 stolic function in DHF. It is hoped that recognition of diastolic
Mitral E/Em ratio Yes 13 dyssynchrony and subsequent intervention may improve outcome
Mitral E/Vp ratio Yes 13,23 in patients with heart failure.
PVs/Pvd ratio Yes 23
Deceleration Yes 7
slope Optimization of Atrioventricular Delay and
Myocardial Yes 7,14
performance Diastolic Function
index An optimal and appropriate AV delay should result in optimum
Volume LVEDV Yes 7
LVESV Yes 7,13,14 filling of the left ventricle without interruption of the A wave,
thereby allowing complete diastolic filling. A short AV delay may

TABLE 29-4
DIFFERENCE BETWEEN RESPONDERS AND NONRESPONDERS TO CRT WITH RESPECT TO BASELINE DIASTOLIC
AND SYSTOLIC PARAMETERS
PARAMETERS BASELINE PARAMETERS RESPONDERS (N = 42) NONRESPONDERS (N = 34) p VALUE

Diastolic Parameters E/A ratio 0.89 ± 0.72 1.29 ± 0.56 <0.05

Isovolumic relaxation time (msec) 131 ± 33 106 ± 37 <0.05
Mean Em (cm/sec) 3.17 ± 1.72 4.33 ± 1.88 ≤0.005
Mean Am (cm/sec) 4.48 ± 1.54 3.62 ± 1.38 ≤0.005
Systolic Parameters SD in Ts, 12 segments (msec) 44.9 ± 9.5 26 ± 11 <0.001
Septal-to-lateral delay in Ts (msec) 60.9 ± 35.9 23 ± 30 <0.001

From Yu CM et al: Are left ventricular diastolic function and diastolic asynchrony important determinants of response to cardiac resynchronization therapy? Am J Cardiol
2006;98:1083–1087.
378 Chapter 29 • Pacing and Diastolic Heart Failure

enable ventricular contraction before complete emptying of the lengthened in 10 msec steps until there is no truncation. This
left atrium has occurred. Approximately one third of CRT generates an optimized AV delay when ventricular contraction
patients either do not improve or may in fact worsen following occurs just at the end of the atrial contribution.
implantation of a biV pacing device. Optimization of AV timing Kedia et al. studied the effects of AV optimization in a cohort
is not only critical to achieve optimal resynchronization therapy, of CRT patients. These patients had an AV optimization per-
and in turn LV function, but it may enable some of these non- formed within 30 days post-implantation and were followed up
responders to improve functionally and hemodynamically.17,26 for 23 months. At baseline, approximately 50% of the patients
Diastolic, rather than systolic, function has been the target and had stage 1 (abnormal relaxation) diastolic filling. Nearly 10% had
parameter of choice to optimize hemodynamics in many labs that improvement in diastolic stage (e.g., stage III to II, stage II to I).
routinely conduct AV optimization examinations. This is, in part, Approximately 40% had a final AV delay setting greater than
because of the relative ease by which diastolic function can be 140 msec. AV block, atrial enlargement, and a paced rhythm were
interrogated noninvasively with Doppler echocardiography. Rokey significantly associated with a final AV delay setting of greater
et al. studied patients with programmable AV sequential pace- than 140 msec. Regardless of whether the AV delay was set at
makers with pulse Doppler interrogation of the mitral inflow. less than or greater than 140 msec, the mortality rate was similar
Doppler velocities were recorded for three settings of AV delay: between groups. The authors suggested that interrogation of the
75, 150, and 250 msec. They found an inverse relation between mitral inflow for diastolic function staging be performed in all
the effectiveness of atrial contraction and early diastolic filling (E patients following implant of a CRT device and that AV optimi-
wave). It was postulated that at a short AV delay, atrial contrac- zation be attempted primarily in patients with stage II or III dia-
tion is aborted and the left atrium remains with a larger residual stolic dysfunction (Fig. 29-3).26 Moreover, patients who initially
volume at end diastole. During systole, LA volume and pressure
increase further, resulting in a higher AV pressure gradient after
mitral opening and thus an increase in peak inflow rate. The
opposite occurs with enhanced atrial emptying and an improved
atrial filling fraction brought about by optimizing the AV
delay.27
Dual-chamber pacing in patients with hypertrophic cardiomy-
opathy revealed that there was a decrease in cardiac output and
peak dp/dt as well as an increase in mean LA pressure and time
constant of isovolumic relaxation (τ) in patients when paced with
a short AV delay (<60 msec). During pacing at optimal AV delay
(the longest AV interval with pre-excitation), there was a similar A
trend, with deterioration in both systolic and diastolic function
variables, but of less magnitude than those during pacing at the
shortest AV interval.28
The effects of AV delay optimization for patients with AV
conduction disease requiring dual-chamber pacing are well
described, but the influence on patients with heart failure who
frequently have normal AV conduction is just becoming apparent.
It has been shown that patients with CHF have higher LV (+)dp/
dt and aortic pulse pressure at patient-specific optimal AV delays.
Response seems to differ for patients with wide QRS compared
with narrow QRS. Aurrichio et al. studied pacing in CHF and B
suggested that the maximum acute benefit of CRT could be
achieved by patient-specific AV delays.17
AV synchrony is frequently targeted in CRT patients as a
means for optimization. Studies have shown that optimization of
AV delay results in improved NYHA functional class as well as
greater cardiac output.29 An optimum AV delay is programmed
when the end of the Doppler A wave (corresponding to LA con-
traction) occurs just before the onset of aortic systolic Doppler
flow. Ritter et al. and others have reported simple and practical
AV delay optimization algorithms. Ritter’s method includes C
setting the AV delay to an inappropriately short then long AV
interval and measuring a surrogate of the atrial electrical mechani- Figure 29-3 This patient with an ischemic cardiomyopathy presented to
the echocardiography laboratory with a baseline, out-of-the-box atrioven-
cal delay (QA interval) at each setting. This is accomplished by tricular (AV) delay setting of 110 msec, following implantation of a biven-
measuring the interval between the onset of the Q wave and the tricular pacemaker. A, Mitral inflow interrogation revealed a large E wave
termination of the mitral A wave.30 and a very low amplitude A wave consistent with stage III diastolic dysfunc-
The iterative technique to AV delay optimization also requires tion. B, Prolongation of the AV delay to 280 msec demonstrates signifi-
recognition of A-wave truncation. Mitral inflow is recorded at cantly improved diastolic function (A-wave amplitude = 60 cm/sec);
however, the A wave terminates prior to the onset of ventricular depolar-
programmed long sensed AV delay, such as 150 msec, then AV ization (prior to the QRS onset). C, Empiric adjustment of the AV delay
delay is decreased by intervals of 10–20 msec until the A-wave setting back to 230 msec now reveals a satisfactory (physiologic) relation-
begins to truncate. Once A-wave truncation is seen, AV delay is ship of the A-wave and the QRS onset, optimizing diastolic filling.
 Chapter 29 • Pacing and Diastolic Heart Failure 379

present with stage I diastolic filling should be maintained at their 23%, p < 0.01) and increasing EF (from 22% to 29%, p < 0.01).
present AV delay settings (Fig. 29-4). A recommended strategy However, optimum sequential CRT (preactivation of the left ven-
for managing patients who have recently undergone CRT is illus- tricle in 9 patients and of the right ventricle in 11) caused a further
trated in Figure 29-5. reduction in the extent of DLC from 33% to 23% (p < 0.01) and
an increase in EF from 29% to 33% (p < 0.01). Without any
further optimization of AV delay, the diastolic filling time
Optimization of Interventricular Interval and
increased from 430 ± 88 msec during simultaneous CRT to 460
Diastolic Function ± 80 msec (p < 0.05) during optimum sequential CRT.33
Current generations of CRT devices also allow for optimization
of ventricle-to-ventricle (VV) timing. In patients with heart
failure and LV dyssynchrony, proper timing of the interventricu-
Adverse Effects of Pacing
lar pacing interval (VV interval) may further optimize LV func- Recently, there has been a surge in the discussion on the
tion. Although the proper timing of the VV interval is clearly adverse effects of pacing, which depend on the pacing mode,
beneficial in select patients, a definitive benefit of this feature has
not yet been proven. Van Gelder et al. studied LV dp/dt in
patients with severe LV dysfunction. They were able to elicit Mitral inflow pattern following CRT procedure
additional increase in dp/dt after optimizing the VV interval
(3%–8%). Maximum dp/dt was achieved with pacing “LV first” Stage I Stage II or III
in 44 patients; “simultaneous right and LV” pacing in 6 patients;
and “RV pacing first” in 3 patients. Such benefit has been attrib-
uted to improved LV synchrony, resulting in a change in preload Mitral E-A reversal,
and reduction in mitral regurgitation.31 QA interval > 40 msec,
AV optimization
(Ritter or iterative)
Specific measurements for ventricular dyssynchrony corre- pulmonary vein S>D
late with hemodynamic changes in patients with biV pacing.
Bordachar et al. demonstrated that individually optimized sequen-
tial biV pacing compared with simultaneous biV pacing increases
Maintain baseline Target Stage I
cardiac output and decreases mitral regurgitation in patients with AV delay setting diastolic filling
heart failure.32 The definition of an optimum VV delay has not
been characterized. However, it has been suggested to be an inter- Figure 29-5 Recommended approach for optimizing atrioventricular (AV)
ventricular delay that reduces LV dyssynchrony and/or maxi- delay utilizing mitral inflow assessment of diastolic function in patients
mizes LV systolic function. Sogaard et al. evaluated the impact of undergoing cardiac resynchronization therapy (CRT). In patients exhibiting
an E/A reversal pattern (stage I diastolic dysfunction), no adjustment in AV
sequential CRT with individualized interventricular delay pro- delay is necessary, whereas in those manifesting stage II or III diastolic
gramming. Simultaneous CRT was better than “no CRT” in dysfunction, an attempt is made to achieve stage I diastolic dysfunction
reducing delayed longitudinal contraction (DLC) (from 48% to by adjusting the AV delay.

Baseline
AV delay
120 msec

Mitral flow
40 msec

Figure 29-4 This 65-year-old female with a dilated cardio-

myopathy systolic/pulmonary cardiac resynchronization
therapy 24 hours earlier presented to the echocardiography
laboratory for an atrioventricular (AV) delay optimization. B
The AV delay was empirically set at 120 msec at the time of
the implant. A, Mitral inflow upon presentation to echo lab. Final
B, Interrogation of mitral inflow revealed stage I diastolic AV delay
dysfunction (E/A reversal), satisfactory E- and A-wave sepa- 120 msec
ration, termination of the A wave >40 msec after the onset
of ventricular depolarization (QRS onset), and normal pul-
monary vein systolic/diastolic (S/D) ratio, suggesting low/
normal atrial filling pressures. C, Based on these satisfactory
hemodynamic findings, the AV delay was maintained at
120 msec. C
380 Chapter 29 • Pacing and Diastolic Heart Failure

dyssynchrony, duration of pacing, and underlying cardiac compared with 0.6%–3.0% in the VVI group. The authors attrib-
disease. uted the increased incidence of adverse effects to a higher fre-
quency of ventricular pacing.52 In MOST, patients with sinus
node dysfunction were divided into a rate-responsive VVI
Pacing Mode (VVIR) and a DDDR group. Cumulative percent ventricular
Rosenqvist et al. compared two pacing modes (single-lead ven- pacing (Cum%VP) was obtained from stored pacemaker data.
tricular [VVI] vs. single-lead atrial [AAI]) in sinus node disease The VVIR group with Cum%VP greater than 80, as well as the
and showed that the incidence of CHF and high-degree AV block combined group (the VVIR group with Cum%VP ≤80 plus the
was higher in the VVI group than in the AAI group.34 The Pace- DDDR group with Cum%VP >40), had a higher incidence of
maker Selection in Elderly (PASE) trial revealed that patients heart failure hospitalization compared with the DDDR group
with sinus node dysfunction (no AV block) had a poorer quality with no greater than 40 Cum%VP.51
of life and cardiovascular functional status with ventricular pacing
than with dual-chamber pacing. Although there was an improved Underlying Cardiac Status
quality of life with dual-chamber pacing compared with ventricu-
lar pacing, superiority of preventing stroke or death was not seen Importantly, the underlying cardiac condition also affects the inci-
in these larger trials.35,36 dence of adverse effects. In MOST, the authors noted that risk of
heart failure hospitalization was 42 times higher in patients with
high-risk substrates (low EF, history of myocardial infarction,
Dyssynchrony CHF, and spontaneous prolonged QRS duration).51 In pediatric
patients, chronic RV pacing reduced LV shortening fraction only
Ventricular dyssynchrony is associated with pacing modes as well in those with structural heart disease.54 A recent trial, however,
as cardiac disease. Two areas of dyssynchrony are AV dyssyn- reported a reduction in LV function in patients with complete
chrony and ventricular dyssynchrony. AV dyssynchrony occurs heart block irrespective of their baseline LV function. A clinically
when the atria do not contract synchronously with the ventricle. significant decrease in LVEF was noted in 29% of all patients and
It can result in incomplete filling of the ventricles and is associated 33% of those with normal baseline LVEF.55
with LA enlargement, elevated LA pressure, and dizziness (pace-
maker syndrome).37,38 Ventricular pacing without atrial pacing
(lack of AV synchrony) is associated with a higher incidence of Pacing Site Location
AV block, atrial fibrillation, CHF, and mortality.34,39,40 Generally, pacing is believed to enhance pump function by increas-
Ventricular dyssynchrony has been studied widely with respect ing systolic contraction and improving diastolic filling; however,
to LV activation from the RVA. RVA pacing leads to abnormal the performance is based on the clinical indication, clinical sub-
activation of the ventricle, QRS prolongation, and dyssynchro- strate, pacing mode, and pacing site. The search for the optimal
nous contraction. Studies have revealed that ventricular pacing pacing site is ongoing and potentially patient specific. Bucking-
depresses LV pumping function, causes mismatching of perfu- ham et al. compared the effects of pacing at the RVOT to RVA
sion, and elevates tissue norepinephrine levels.41,42 RV apical in patients with low EF (<40%). EF, peak dp/dt, peak (−)dp/dt,
pacing produces an LV activation sequence resembling left bundle and τ were measured. There was a subtle improvement in diastolic
branch block.43 This alteration in mechanical activation may cause and systolic function with pacing in the RVOT compared with
impaired hemodynamic performance.44 Prolonged QRS duration traditional RVA pacing.56
(≥190 msec) is associated with an increase in morbidity of CHF.45 Pacing of the left ventricle at the site of greatest delay is also
RVA pacing is also associated with increased LA pressure and associated with increased stroke work and lower ESV in patients
giant PV flow reversal.46 RV apical pacing can cause chronic with dilated cardiomyopathy. RV pacing in such patients pro-
changes in regional myocardial perfusion, cellular structure, duces minimal changes in the pressure-volume analysis.20 Prinzen
and ventricular geometry that may impair ventricular perfor- et al. noted that dyssynchronous activation of the ventricles in
mance.47–50 The adverse effects of ventricular dyssynchrony and canine models reduced LV pump function. Pacing at the RVA
AV dyssynchrony may explain the association of RVA pacing (conventional pacing site) reduced LV function more than pacing
with increased risk of heart failure hospitalization in clinical at a high ventricular septum or at LV sites.57
trials.51 The Dual Chamber and VVI Implantable Defibrillator RVOT pacing intuitively enables more natural electrical activa-
(DAVID) trial found an increase in the composite endpoint of tion. Pacing at three different sites (RVOT, LV apex, and right
death and first heart failure hospitalization in the DDDR-70 atrium) in dogs was also studied in detail by Prinzen et al. Maps
group, who had more RV pacing than the VVI-40 group.52 Moss of the sequence of electrical activation, fiber strain, and blood flow
et al. also noted a higher incidence of heart failure in patients in epicardial layers were obtained. Gradients of epicardial electri-
receiving a defibrillator compared with the group on medical cal activation time, fiber strain, and blood flow pointed in the
therapy for ventricular arrhythmias.53 same direction during RVOT pacing, but in opposite directions
compared with LV apical pacing. The result indicated that electri-
cal activation is an important determinant for the distribution of
Duration of Pacing fiber strain and blood flow in the LV wall.58 The impact of RVOT,
The actual amount and duration of RVA pacing are also associ- LV, and biV pacing on LV function was studied in humans by
ated with adverse effects, as demonstrated in the DAVID trial as Lieberman et al. LV pressure-volume data were recorded for 13
well as the Mode Selection Trial (MOST). In the DAVID trial, patients (average age, 65; 10 with CHF and 4 without; mean
the VVI group had a backup pacing rate of 40/minute, but the QRS, 89 ms). Results showed that single-site LV pacing was
DDDR group had a rate-responsive pacing at 70/minute. The similar to biV pacing. LV and biV pacing were superior to all RV
DDDR group paced the ventricle approximately 55% of the time sites for the most variables (EF, stroke volume, (+)dp/dt). The
 Chapter 29 • Pacing and Diastolic Heart Failure 381

optimal RV lead location varied among patients depending on tion. RV bifocal pacing provided a modest but favorable effect.
underlying etiology.59 LV lateral, biV, and trisite pacing showed better performance in
systolic phase. Trisite pacing demonstrated an additional effect on
diastolic function (increase in LV (−)dp/dt).64
Modes of Pacing
Evidence favors maintaining AV synchrony for better clinical out- Direct His Bundle Pacing
comes. Patients with sick-sinus syndrome without AV block do
well with AAIR pacing; however, if a patient has significant AV Direct His bundle (DHB) pacing has been considered to prevent
block, a ventricular lead is needed. Whether all patients should ventricular dyssynchrony that results from RVA pacing. Perma-
have a dual-chamber pacemaker has been debated on two fronts: nent DHB pacing was tested in 20 patients. Mechanical dyssyn-
cost of the device and the recent suggestion of increased adverse chrony was measured in terms of interventricular mechanical
events. delay (IMD), and septal to left posterior wall motion delay
Pacing modes that do not restore AV synchrony are associated (SPWD) was measured. There was significant reduction in the
with regurgitation of the mitral and tricuspid valves, incidence of index of dyssynchrony in DHB versus RVA pacing.65
atrial fibrillation, and thromboembolism.37,60 For systolic heart
failure, the Device Evaluation of Contak Renewal 2 and Easytrak Role of Cardiac Resynchronization Therapy for
2 (DECREASE-HF) trial compared simultaneous biV (SimBiv),
sequential biV (SeqBiv), and LV pacing in 306 patients (NYHA
Diastolic Heart Failure
III or IV; mean EF ≤35%; QRS ≥150 msec). After 6 months, the Whether CRT could be used as therapy for DHF is unclear
SimBiv group had the greatest reduction in LVEDV and LVESV. today, but recent articles have provided interesting data on DHF.
All groups exhibited a reduction in LV volumes as well as improve- Investigators have argued that the exact pathophysiologic mecha-
ment in systolic performances.61 nism of symptoms in DHF patients is still unclear. It seems that
a mixture of systolic and diastolic abnormalities varying in patients
depending on etiology and comorbidities may be responsible.15
FUTURE RESEARCH CRT has established its role for patients with systolic dysfunction
and seems linked to diastolic parameters. One may speculate that
Right Ventricular Outflow Tract Pacing advanced pacing techniques would find a role in treatment of
Major drawbacks of RVA pacing are asynchrony and the abnor- DHF.
mal sequence of activation of the left ventricle. Adverse effects like An understanding of the positive and negative effects of pacing
reduced pump function, heart failure, and death have been attrib- is imperative in order to appropriately apply pacing modalities
uted to these mechanisms. It is surmised that RVOT pacing and appropriate configurations when treating patients with both
would preserve normal activation sequence and may provide SHF and DHF. Although in many instances a predictable result
benefit. Skadsberg compared RVA with RVOT pacing in swine can be anticipated when applying pacing therapy to a given condi-
and found that RVOT pacing provided intrinsic like activation tion, it is important to recognize that interrogation of ventricular
and preserved LV systolic and diastolic functions.62 function (systolic and diastolic) is necessary to confirm the antici-
pated result.

Atrial-Based Managed Ventricular Pacing

Mode in Dual-Chamber Implantable ABBREVIATIONS
Cardioverter-Defibrillators
A wave: late left ventricular filling velocity wave Doppler tracing
Due to ventricular dyssynchronization caused by RV pacing and secondary to atrial contraction
increased risk of CHF, atrial fibrillation, and death, investigators AAI: pacing configuration where atrium is paced, atrium is
are trying to devise a mode that reduces Cum%VP compared sensed, and on sensing, atrium gets inhibited
with DDDR. Managed ventricular pacing (MVP) would provide Am: peak myocardial velocity at late diastole, measured to assess
AAIR pacing with ventricular monitoring and backup DDDR diastolic function
during AV block. An early report shows an absolute and relative A rev: atrial reversal wave velocity detected by Doppler at right
reduction in Cum%VP during MPV (from 99% to 85%).63 upper pulmonary vein
AV: atrioventricular
AVD: atrioventricular delay
The Best Modality of Cardiac
BiV: biventricular (involving both right and left ventricle)
Resynchronization Therapy CAD: coronary artery disease
Investigation for the best modality of CRT is ongoing. All the CHF: congestive heart failure
modalities compared in the DECREASE-HF trial (SimBiv, CRT: cardiac resynchronization therapy
SeqBiv, and LV pacing) were effective in reducing LV volumes DCM: dilated cardiomyopathy
during follow-up, but the SimBiv pacing group had the greatest DDD: pacing configuration where both atrium and ventricle can
improvement.61 be paced, both can sense, and on sensing, the atrium gets inhib-
In CRT, improving LV dp/dt has been a major target. Multisite ited and paces ventricle at preset AV delay (if no intrinsic
pacing including RV bifocal (RVA + RVOT), biV 1 (RVA + LV ventricular depolarization noted); on sensing, ventricular leads
lateral), biV 2 (RVOT + LV lateral), and trisite pacing (RVA + get inhibited.
RVOT + LV lateral) has been compared. RVA stimulation DDDR: R refers to rate responsiveness of pacer to physiological
impaired LV function, whereas RVOT pacing preserved LV func- demand. A feature of newer pacemakers
382 Chapter 29 • Pacing and Diastolic Heart Failure

DHF: diastolic heart failure, a measure of systolic dyssynchrony ventricular relaxation. The normal range is 37–
DLC: delayed longitudinal contraction 67 msec.
dp/dt: pressure derivative of left ventricle showing ability to build Tei index: summation of isovolumic contraction time and isovolu-
pressure per unit change in time mic relaxation time divided by ejection time; a measure of sys-
dp/dv: change in pressure per unit change in volume (stiffness) tolic as well as diastolic function
DT: deceleration time Te: time to peak myocardial early diastolic velocity with reference
dv/dp: change in volume per unit change in pressure to QRS
(compliance) Te-diff: maximal difference in myocardial time to peak early dia-
−dp/dt: LV pressure-derivative minimum. Negative pressure stolic velocity between two left ventricular segments
derivative of left ventricle showing fall in pressure per unit Ts: time to peak myocardial systolic velocity during the ejection
change in time, an indicator of relaxation phase with reference to QRS
dp/dtmax: maximum rate of rise of ventricular pressure; is highly Ts-diff: maximal difference in myocardial time to peak systolic
sensitive to acute changes in contractility. It is more useful in velocity between two left ventricular segments
assessing directional changes in contractility during acute TVI: time-velocity integral; measured by outline of spectral
intervention when used in combination with a measure of left Doppler tracing. It represents the distance traveled by the
ventricular preload. column of blood in one beat.
dp/dtmin: peak rate of ventricular pressure fall during isovolu- Vp: left ventricular flow propagation velocity recorded at mitral
metric pressure decline. It is influenced by the pressure at the valve level in diastole
time of aortic valve closure and is not a good measure of the VV: interventricular (between right and left ventricle)
rate of isovolumetric relaxation. VVI: pacing configuration where ventricle is paced, ventricle is
E-wave: early left ventricular filling velocity wave, an early part of sensed, and gets inhibited after sensing an intrinsic depolariza-
diastolic phase detected as Doppler wave by echo tion (In VVIR, R stands for rate responsiveness.)
E/A ratio: peak velocity of E wave divided by peak velocity of
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36. Kerr CR, Connolly SJ, Abdollah H, et al: Canadian Trial of Physiological performance with cardiac resynchronization therapy: A comparison
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63. Sweeney MO: Multicenter, prospective, randomized trial of a new atrial- 75. Spragg DD, Leclercq C, Loghmani M, et al: Regional alterations in protein
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2006:23A, 969–138. ventricular epicardial pacing site. Am J Physiol Heart Circ Physiol 2004;286:
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Eur Heart J 1994;15:1096–1105. 81. Knaapen P, van Campen LM, de Cock CC, et al: Effects of cardiac
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Am Heart J. 2003;145:E18. ventricular pacing on heart failure and atrial fibrillation among patients
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71. Lamp B, Faber L, Heintze J, et al: Long-term outcome of cardiac resynchro- 83. Nielsen JC, Andersen HR, Thomsen PE, et al: Heart failure and echocar-
nization therapy. Circulation 2004;110(Suppl III):480, 2263. Abstract. diographic changes during long-term follow-up of patients with sick sinus
72. Bedotto JB, Grayburn PA, Black WH, et al: Alterations in left ventricular syndrome randomized to single-chamber atrial or ventricular pacing.
relaxation during atrioventricular pacing in humans. J Am Coll Cardiol Circulation 1998;97:987–995.
1990;15:658–664. 84. Bristow MR, Saxon LA, Boehmer J, et al: Cardiac-resynchronization
73. Schulz R, Aker S, Belosjorow S, et al: Stress kinase phosphorylation is therapy with or without an implantable defibrillator in advanced chronic
increased in pacing-induced heart failure in rabbits. Am J Physiol Heart Circ heart failure. N Engl J Med 2004;350:2140–2150.
Physiol 2003;285:H2084–2090. 85. Cleland JG, Daubert JC, Erdmann E, et al: The effect of cardiac resynchro-
74. Bell SP, Nyland L, Tischler MD, et al: Alterations in the determinants of nization on morbidity and mortality in heart failure. N Engl J Med
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 ANAND PRASAD, MD
BENJAMIN D. LEVINE, MD
30
Aging and Diastolic
Heart Failure
INTRODUCTION Etiology of Diastolic Dysfunction and
Diastolic Heart Failure in the Senior
PATHOPHYSIOLOGY
Population
Clinical Presentation of Diastolic
Heart Failure in the Senior CLINICAL RELEVANCE
Population Challenges in Designing Trials and
Diagnosis of Diastolic Heart Failure in the Treatments for Diastolic Heart Failure
Senior Population Novel Therapies on the Horizon
Prognosis of Diastolic Heart Failure in the
FUTURE RESEARCH
Senior Population
APPENDIX

INTRODUCTION fraction (EF), or so-called diastolic heart failure (DHF).4–6 This

chapter will address the effect of DHF in the senior population,
The number of seniors in the United States and throughout the explore the specific age-associated pathophysiological changes of
developed world is rising. As of 2003, roughly 36 million, or 12%, the heart that may provide the substrate for the development of
of the U.S. population were older than 65 years of age. Improve- DHF, and finally examine the challenges involved in devising new
ments in nutrition, disease prevention, and treatment have all therapies for this disorder.
contributed to this rise, with life expectancy at birth increasing
from 47.3 years in 1900 to 76.9 years in 2000.1 Despite declining
death rates from cardiovascular disease, more seniors now are PATHOPHYSIOLOGY
living with chronic heart conditions, including hypertension
Clinical Presentation of Diastolic Heart Failure in
(HTN), coronary artery disease (CAD), and congestive heart
failure (CHF). In fact, the primary index diagnosis for the major- the Senior Population
ity of hospitalizations of seniors in the United States is now CHF. The clinical profile of senior heart failure patients is markedly
The morbidity, mortality, and financial costs of this disease are different than that of younger patients. In 1995, Vasan et al. con-
substantial in this population, with approximately 43,600 deaths cluded, based on a cumulative analysis of available studies of CHF
(94% of total deaths from CHF) and 700,000-plus hospitaliza- and normal left ventricular (LV) systolic function, that the preva-
tions costing more than $20 billion per year in the United States.2,3 lence of normal function in CHF patients under 65 years of age
This epidemic is likely to worsen in the near future, as the “baby was significantly lower than that in those older than 65.7 More
boom” generation enters its seventh decade (Fig. 30-1). By 2050, recent data support this claim. Based on population and hospital-
the senior population is expected to top 86 million individuals, ization registry data, such as the Olmsted County experience, the
highlighting the importance of this issue.1 Enhanced Feedback for Effective Cardiac Treatment (EFFECT)
To effectively manage this rising burden of CHF in the senior dataset from Ontario, Canada, and the Acute Decompensated
population, a better understanding of the specific cardiovascular Heart Failure National Registry (ADHERE), DHF is predomi-
changes that occur with senescence is necessary. Unlike younger nantly a disease of the elderly, and its prevalence is on the rise
CHF patients, who often present with depressed ventricular (Fig. 30-2).8–10 Data from these and several other studies have
function and chamber dilatation due to ischemic heart disease, as demonstrated that the prototypical patient presenting with this
many as half of the senior CHF population has no evidence of disorder is in the seventh or eighth decade of life, female, obese,
depressed ventricular function and actually has a normal ejection hypertensive, more often diabetic, and often afflicted with atrial
385
386 Chapter 30 • Aging and Diastolic Heart Failure

100 772,000 TABLE 30-1

Projected new CHF cases in 2040
Population of seniors (millions)

77.2 VALUES USED TO DEFINE “NORMAL” LEFT

80
348,000 VENTRICULAR EJECTION FRACTION (EF)8–14
New CHF cases in 2000
EF % USED AS “NORMAL”
60 53.7 STUDY OR “PRESERVED”

Olmsted County study ≥50

40 34.8 ADHERE ≥40
25.5 Ancillary DIG study ≥45
16.6 CHARM-Preserved study ≥40
20 MISCHF registry ≥50
20.5
16.5 PEP-CHF ≥45
11.3 12.7
9.2 Yale–New Haven Experience ≥40
0
1940 1960 1980 2000 2020 2040 2060 ADHERE, Acute Decompensated HEart Failure National REgistry; DIG, Digitalis
Time (years, projected into the future) Investigation Group; CHARM, Candesartan in Heart Failure: Assessment of Reduction in
Mortality and Morbidity; MISCHF, Management to Improve Survival in Congestive Heart
Failure; PEP-CHF, Perindopril in Elderly People with Chronic Heart Failure.
Persons (millions)
% of population

Figure 30-1 Incidence of congestive heart failure (CHF) in persons aged symptoms of CHF coupled with a preserved or relatively pre-
at least 65 years. The population of seniors is expected to rise over the next served EF.”15 In contrast, the 2005 guidelines from the American
40 years in the United States, as is the number of patients with new-onset Heart Association/American College of Cardiology for the diag-
CHF. (Modified from Owan TE, Redfield MM: Epidemiology of diastolic heart nosis and management of chronic heart failure suggest that the
failure. Prog Cardiovasc Dis 2005;47:320–332.)
addition of measures of LV relaxation and LV volume are needed
for a definitive diagnosis.16 Unfortunately, the inclusion criteria
70 r = 0.92, P <0.001 for a diagnosis of DHF and the terms “preserved” and “normal”
are open to interpretation, and this uncertainty has led to signifi-
60 cant debate and inconsistency among studies.17–19
Patients with preserved
ejection fraction (%)

The vague definition of DHF is a source of much controversy

50 in its trials. The EF used in the clinical studies, registry analyses,
and population surveys has varied (Table 30-1). For example, in
40 the dataset from the Candesartan in Heart Failure: Assessment
of Reduction in Mortality and Morbidity (CHARM) trial, of the
30 3023 patients with “preserved” systolic function randomized, 35%
(1072 patients) had EFs of 41%–49%. These EF determinations
20 are not absolute numbers and carry with them a margin of error.
0 The EF measurement has a high degree of variability, depending
1986 1990 1994 1998 2002 on the specific technique used, and is subject to both intra- and
Figure 30-2 Based on a community sample of 4596 consecutive patients interobserver variability.20,21 Using noncontrast echocardiography,
admitted with congestive heart failure (CHF) from Olmsted County, Min- for example, the variation for individual patients can be as high as
nesota, the prevalence of CHF with a preserved ejection fraction has 10% (EF units) compared with measurements on magnetic reso-
increased over a 15-year period. (Modified from Owan TE et al: Trends in nance imaging (MRI), and the intra- and interobserver variabili-
prevalence and outcome of heart failure with preserved ejection fraction.
NEJM 2006;355:251–259.)
ties can reach as high as 10%–15% (EF units).21 Therefore, an EF
at the lower limits of what is considered normal in a clinical trial,
such as 41% in the CHARM trial, could actually be significantly
fibrillation.11–14 These comorbid conditions are not simply inno- lower and introduce error into the dataset.
cent bystanders but, as will be described in this chapter, may This issue may be of particular importance in women.
actively contribute to the pathophysiology of DHF. The Dallas Heart Study examination of MRI-derived EF in a
probability-based sample of Dallas County residents aged 30 to
65 years (1435 women and 1183 men) found that women tended
Diagnosis of Diastolic Heart Failure in
to have higher EFs than men (Fig. 30-3).22 These findings per-
the Senior Population sisted even when body size was taken into consideration. The
The diagnostic criteria for DHF have been reviewed elsewhere in authors concluded that a low EF (below the 2.5th percentile of
this book and are no different in the senior population (see the population sampled) was defined as below 61% in women and
Chapter 6). It should be emphasized, however, that it is difficult, below 55% in men. These data suggest that an EF of 50% in
if not impossible, to make a diagnosis of DHF, as opposed to women may not be normal, and an EF of 40% is certainly
systolic heart failure (SHF), by history or clinical presentation abnormal.
alone. Patients with DHF may have higher blood pressure and While the designation of a particular EF as “normal” is some-
more often have atrial fibrillation at the time of presentation, but what arbitrary, the use of a higher EF as the cutoff for differentiat-
these are by no means universal findings.7–9 The most recent ing systole versus diastole may be more helpful in limiting
Heart Failure Society 2006 guidelines recommend that a diagno- inclusion of patients with SHF into clinical trials. This ambiguity
sis of DHF “can be made by the combination of clinical signs and surrounding EF also raises the point that the actual incidence of
 Chapter 30 • Aging and Diastolic Heart Failure 387

35 p <0.001

Percent of participants (%)

Men
30 Women
25
20
15
Figure 30-3 Women have higher ejection frac- 10
tions (EFs) than men. Histograms of EF from the 5
Dallas Heart Study. (Modified from Chung AK et al:
Women have higher left ventricular ejection frac- 0
tions than men independent of differences in left <40 45 50 55 60 65 70 75 80 85 90 >95
ventricular volume: The Dallas Heart Study. Circula-
tion 2006;113:1597–1604.) Left ventricular ejection fraction (%)

200
LBNP Baseline Saline infusion

180

Sedentary
160 Fit
IVRT (msec)
Young
140

Figure 30-4 Effect of aging and lifelong fitness on Doppler vari-

ables. Isovolumetric relaxation time (IVRT) derived from Doppler 120
echocardiography in young subjects, sedentary seniors, and
master athlete seniors. Normal healthy aging results in a prolon-
gation of IVRT across all loading conditions: baseline, lower 100
body negative pressure (LBNP), and saline loading (p < 0.001),
while lifelong endurance training has no effect on relaxation
(p = 0.546). PCWP, pulmonary capillary wedge pressure. 80
(Modified from Prasad A et al: The effects of aging and physical 0 2 4 6 8 10 12 14 16 18 20 22
activity on Doppler measures of diastolic function. Am J Cardiol
2007;99:1629–1636.) PCWP (mmHg)

DHF in the community may not be as high as the rates that have the argument that the terms diastolic dysfunction and abnormal
been previously reported. Since the prototypical patient with filling pattern are inexact when used in this context and should
DHF is more often female, the growing epidemic of DHF in perhaps be revised. The diastolic Doppler patterns seen in the
women may reflect inclusion of patients with occult or misclassi- senior population are best described as normal for age, much like
fied systolic dysfunction. The use of more rigid EF criteria in gray hair or wrinkling of the skin (see Appendix).
population studies may also help clarify this issue as well.
In addition to controversies regarding EF, there has been dis- Prognosis of Diastolic Heart Failure in
cussion in the literature as to whether Doppler velocity patterns
are sufficient to diagnose DHF, or for that matter whether such the Senior Population
measurements are even needed at all.18,19 DHF, like all forms of While slightly better than that of SHF, the short-term prognosis
CHF, is a clinical diagnosis that should be supported by an objec- of patients with DHF is not benign. The mortality rate during
tive assessment of LV systolic function. The use of Doppler echo- acute hospitalization was 2.8% in ADHERE (vs. 3.9% in the
cardiography in the senior population, in particular, raises some SHF group).9 Similar to patients with SHF, patients with DHF
important considerations. It is true that most, if not all, senior and concomitant hypotension, hyponatremia, advanced age (>73
patients with DHF will have alterations in Doppler measures of years), and elevated blood urea nitrogen (BUN) were at increased
diastolic function (diastolic dysfunction); however, these mea- odds for mortality based on multivariate analysis. Notably, eleva-
surements should not be assumed to be specific or pathogno- tion of resting heart rate (HR) (>78 bpm) was particularly det-
monic for DHF. Both completely healthy sedentary seniors and rimental to patients with preserved function, perhaps suggesting
highly trained senior master athletes manifest profound changes the importance of maintaining an adequate diastolic filling period
in their Doppler patterns compared with young controls, suggest- in this population.
ing that these alterations are a specific manifestation of normal The longer-term prognosis of patients with DHF versus SHF
aging (Figs. 30-4 and 30-5).23 The master athletes, who from a has been debated. These results have been conflicting, primarily
symptomatic and functional standpoint are at the extreme oppo- because of differences in study design and inclusion of community
site spectrum from DHF patients, have marked Doppler abnor- versus clinical-trial patient populations.8,10,25,26 Two recent studies
malities despite also having peak oxygen uptakes comparable to may help shed light on this issue. The long-term survival data
individuals 30 years younger.24 Given these data, one could make from the Olmsted County study are detailed in Figure 30-6A. In
388 Chapter 30 • Aging and Diastolic Heart Failure

E
E A 120
A
E 90

60
A
30

cm/sec
Young Sedentary senior Fit senior
A E/A = 2.8 B E/A = 0.6 C E/A = 1.1
Figure 30-5 Effects of aging and fitness on the E/A ratio. Transmitral Doppler velocity profiles taken at rest from A, a young subject, B, a sedentary senior,
and C, a master athlete senior. Normal healthy sedentary aging results in a decrease in the ratio of the peak early (E) to late (A) transmitral Doppler veloci-
ties (E/A ratio) (A vs. B). Lifelong endurance training does not completely prevent the decline in the E/A ratio (A vs. C). (Modified from Prasad A et al: The
effects of aging and physical activity on Doppler measures of diastolic function. Am J Cardiol 2007;99:1629–1636.)

this study, data from 4596 consecutive patients admitted with a the comorbid conditions that might be additive and result in heart
diagnosis of CHF were examined and segregated by EF. The failure.
mortality rate in DHF patients admitted with CHF was only Sedentary aging, even in the absence of comorbid conditions,
slightly lower than in patients with SHF (29% vs. 32% at one year results in marked changes of cardiovascular structure and func-
and 65% vs. 68% at 5 years).8 Interrogation of the EFFECT tion, including slowing of active myocardial relaxation and
dataset from Canada, which examined similar variables in 2802 decreased static LV chamber compliance. While a detailed exami-
patients with a discharge diagnosis of CHF, found no statistically nation of the hemodynamic determinants of diastolic function
significant difference in adjusted mortality rates at one year (see has been reviewed in Chapters 2, 5, and 7, we will examine the
Fig. 30-6B).10 These studies suggest that the late survival in the effects of aging on these processes in some detail.
two forms of CHF is not radically different from each other,
despite very different pathophysiological mechanisms.
Slowing of Myocardial Relaxation and
Impairment of Ventricular Suction
Etiology of Diastolic Dysfunction and Diastolic
There have been few invasive studies directly examining LV relax-
Heart Failure in the Senior Population ation of the aged human heart because of the obvious ethical
The cause or causes of DHF in seniors remain controversial. As concerns about cardiac catheterization in normal healthy subjects.
the name “diastolic heart failure” implies, the long-accepted but Furthermore, the few available studies have included only small
poorly understood explanation for the etiology of this disorder numbers of seniors, making it difficult to draw definite conclu-
has centered on impairments of lusitropic function in these sions. One of the first invasive studies to suggest a relationship
patients. Recent studies have now confirmed the presence of between age and slowing of active myocardial relaxation was done
abnormalities in active ventricular relaxation and static chamber by Hirota in 1980.29 He examined the time constant of LV pres-
stiffness, mostly in male patients with heart failure and a normal sure decline using micromanometer-tipped high-fidelity catheters
EF.27 However, our laboratory has demonstrated that even healthy in several groups of subjects with sufficient symptoms to warrant
sedentary aging results in marked abnormalities of these very referral for diagnostic cardiac catheterization. His subjects
same diastolic properties, suggesting that additional factors influ- included a group of 18 individuals (4 of whom were older than
ence the development of DHF in seniors.28 What then separates 60 years) whom he deemed “normal” because of an absence of LV
a patient with DHF from an otherwise healthy sedentary adult? dysfunction or CAD. In these subjects, he noted a weak but sig-
To answer this question, we will first examine the changes in nificant correlation between age and prolongation of the time
diastolic function that occur with normal aging and then discuss constant of LV relaxation (Fig. 30-7A). In contrast, Yamakado
 Chapter 30 • Aging and Diastolic Heart Failure 389

1.0 n = 18, r = 0.652

0.8
60
Survival Preserved ejection fraction
0.6

Age (years)
0.4 40

Reduced ejection fraction

0.2
P = 0.03 20
0.0
0 1 2 3 4 5
Year
10 20 30 40 50
No. at risk A Time constant T (nsec)
Reduced 2424 1637 1350 1049 813 604
ejection fraction 100 r = 0.001, nsec
90
Preserved 2166 1539 1270 1001 758 574
80
ejection fraction
70
A

Tb–1 (msec)
60
100
50
95 40
90 30
Survival (%)

Preserved ejection fraction

20
85
10
80
0
75 Reduced ejection fraction 10 20 30 40 50 60 70 80

70 Age (years)
0 80 r = 0.02, nsec
0 50 100 150 200 250 300 350 400
70
B Days
60
Figure 30-6 Slightly higher survival rates for patients with preserved
Tw–1 (msec)

versus reduced ejection fraction in the A, Olmsted County experience 50

(unadjusted hazard ratio = 0.96; 95% CI, 0.93–1.00; p = 0.03) and similar
adjusted mortality rates in B, the EFFECT dataset from Ontario, Canada 40
(hazard ratio = 1.13; 95% CI, 0.94–1.36; p = 0.18). (A, Modified from Owan TE
et al: Trends in prevalence and outcome of heart failure with preserved ejection 30
fraction. NEJM 2006;355:251–259. B, Modified from Bhatia RS et al: Outcome 20
of heart failure with preserved ejection fraction in a population-based study.
NEJM 2006;355:260–269.) 10
0
10 20 30 40 50 60 70 80
et al. examined LV relaxation using similar methods and found
no correlation with age and the time constants of relaxation (see B Age (years)
Fig. 30-7B).30 Unfortunately, of the 55 patients who met inclusion Figure 30-7 Relationship between age and left ventricular (LV) relaxation:
criteria for this study, only 9 were older than 65 years of age. invasive studies. A, Correlation between age and the time constant of
The most robust information examining the issue of aging and relaxation in normal subjects by Hirota (n = 18, r = 0.652). B, Example of
lack of correlation between age and time constants (Tb-1 and Tw-1) of LV
LV relaxation in humans comes from noninvasive data. Altera- relaxation. (A, Modified from Hirota Y: A clinical study of left ventricular relax-
tions in LV diastolic function with senescence were first hinted ation. Circulation 1980;62:756–763. B, Modified from Yamakado T et al: Effects
at by Harrison et al., who in 1964 used carotid pulse contour of aging on left ventricular relaxation in humans. Analysis of left ventricular
analysis and precordial “kinetocardiograms” (measuring chest isovolumic pressure decay. Circulation 1997;95:917–923.)
wall motion) to suggest a prolongation of isovolumetric relaxation
time in older compared with younger individuals.31 Subsequently,
M-mode echocardiograms were examined from the Baltimore of patients from diverse ethnic, geographic, and age distribu-
Longitudinal Study on Aging and demonstrated a reduction tions.33–52 One of the largest studies published to date, from the
in the rate of mitral valve closure (E-F slope) with increasing Cardiovascular Health Study examining more than 5000 men
age, also consistent with slowed relaxation.32 Since then, similar and women in a community-based population, confirmed that
observations have been made by many investigators, by assessing regardless of gender or the presence of specific cardiovascular
either peak filling rates by nuclear imaging or mitral inflow pat- diseases such as HTN or CAD, there is a progressive reduction
terns by Doppler echocardiography, involving many thousands in early filling velocity (E wave) and increase in late flow velocity
390 Chapter 30 • Aging and Diastolic Heart Failure

(A wave) with increasing age, consistent with the pattern of (Tau, τ) with normal aging.57 There are a variety of well-described
impaired relaxation.53 changes that occur within the aging cardiac myocyte, resulting in
With the introduction of newer Doppler techniques as dis- alterations of both the electrical and mechanical processes under-
cussed in Chapters 11 and 12, there have been additional insights lying contraction and relaxation. Some of these changes include
into the alterations of specific components of myocardial relax- altered myocyte Ca2+ handling, shifts in myosin heavy chain iso-
ation processes with aging. Early diastolic tissue Doppler veloci- forms, and reductions of β-receptor activity.58–60 There is a large
ties, which represent longitudinal myocardial motion during body of data, derived predominantly from rodent experiments, to
active relaxation, are slower with aging.23,54 In addition, color M- support the role of changes in Ca2+ handling as the central etiol-
mode–derived indices such as the propagation velocity of early ogy of this process.59,61–63 Since sequestration of Ca2+ occurs
mitral inflow (Vp) and the magnitude of early diastolic intraven- during the first third of diastole, it is not surprising that the
tricular pressure gradients (IVPGs) appear to be diminished by Doppler measures we have described, which examine early dia-
aging.23,55 The changes in these newer Doppler variables highlight stolic processes, would be altered with aging.
an important characteristic of the senescent heart, namely the loss Early diastole is very dependent on reuptake of Ca2+ from the
of vigorous diastolic suction. As discussed in a previous chapter cytosol back into the sarcoplasmic reticulum (Fig. 30-9) (see
of this book, diastolic suction is the result of restoring forces
created during contraction to below the equilibrium volume 4
during the prior ventricular systole (see Chapter 5). This stored Elderly sedentary
potential energy is released during the subsequent diastolic period, Young
actively drawing blood from the base of the heart to the apex. The 3
magnitude of this force can be estimated by examining the pres-

IVPG (mmHg)
sure differences within the LV chamber itself.55,56 These IVPGs
are markedly reduced during sedentary but healthy aging com- 2
pared with healthy young adults (Fig. 30-8).55 In theory, decreased
suction could impair filling of a stiff noncompliant heart during
conditions of rapid heart rate, orthostatic stress (as left atrial [LA] 1
pressure is acutely lowered), or a volume challenge when the left
ventricle must accommodate a large amount of blood in a rela-
tively short time. The potential clinical effect of this loss of suction 0
and its hemodynamic consequences in the aged population has 0 5 10 15 20
not yet been fully examined.
PCWP (mmHg)
Most of our knowledge of the mechanisms underlying the age-
associated changes in LV relaxation comes from animal- and cell- Figure 30-8 Early diastolic intraventricular pressure gradients (IVPGs) in
based experimental data. Concordant with human Doppler data, healthy sedentary seniors and young subjects. Normal aging results in a
decrease in diastolic suction. PCWP, pulmonary capillary wedge pressure.
invasive studies in rodents have demonstrated a reduction in the (Modified from Popovic ZB et al: Relationship among diastolic intraventricular
rate of LV pressure decline during early diastole (−dP/dT) and pressure gradients, relaxation, and preload: Impact of age and fitness. Am J
therefore prolongation of the time constant of early relaxation Physiol 2006;290:H1454–H1459.)

CELLULAR Ca FLUXES

3Na 2K Na

Na- Na-
Sarcolemma ATP CaX ATP HX

Ca 3Na H
RyR

Ca Ca
ICa SR
PLB

ATP Ca
TnC

Ca Ca
Ca
Myofil
2Na H
Ca Ca
Na- H
Na
CaX
T-Tubule

3Na Mito Figure 30-9 Diagram of Ca2+ regulation in the

cardiac myocyte. Ca2+ transport and require-
ments for activation of myofilament force.
Schematic diagram of cellular Ca2+ fluxes.
Ventricular myocyte (Modified from Bers DM: Calcium fluxes involved
in control of cardiac myocyte contraction. Circ
Res 2000;87:275–281.)
 Chapter 30 • Aging and Diastolic Heart Failure 391

Chapter 1). This is an energy-dependent process requiring the across five different levels of cardiac filling using invasive deter-
activity of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) mination of pulmonary capillary wedge pressure (PCWP) and
and the sarcolemmal Na+/Ca2+ exchanger. Regulation of concomitant measurement of LV end diastolic volume by echocar-
SERCA2a is modulated by the inhibitory subunit phospholam- diography (Fig. 30-11).24 These measurements were obtained in
ban. Phosphorylation of phospholamban removes inhibition of three groups of healthy subjects that consisted of young individu-
SERCA2a activity.59 Normal aging results in numerous changes als, sedentary seniors, and Masters athletes (competitive athletes
of this Ca2+-regulating system, including reduced SERCA2a over the age of 50 participating successfully in USA Masters sanc-
pumping rate, decreased SERCA2a-to-phospholamban ratio, and tioned events, such as track and field, swimming, and cycling).
reduced protein levels of the sarcolemmal Na+/Ca2+ exchanger, all Based on the data obtained from this study, normal sedentary aging
of which contribute to the slowing of early relaxation.59,60,64 results in a marked decrease of LV compliance.
Further supporting the role of altered Ca2+ reuptake in this regard When examining such data, it is important to consider the
is a series of experiments by Schmidt et al. that demonstrated contribution of deconditioning. LV compliance is sensitive to
restoration of Tau and −dP/dT to younger levels in senescent even relatively short periods of deconditioning. For example, as
hearts by adenoviral gene transfer of SERCA2a, suggesting that little as 2 weeks of strict bed-rest deconditioning leads to a shift
these Ca2+-handling mechanisms could also be potential targets of the end diastolic pressure-volume relationship to the left (Fig.
for therapeutic intervention in DHF (Fig. 30-10).61 30-12).67–69 Normal aging alone generally leads to reductions in
physical activity, in both humans and experimental animals. It is
therefore crucial to ascertain whether the loss of LV compliance
Decreased Left Ventricular Compliance and is specific to the aging process or is instead the result of lifelong
Physical Deconditioning deconditioning, which is known to increase LV stiffness. If the
When examining the diastolic process, not only LV relaxation but end diastolic pressure-volume curves for the Masters athletes in
also LV compliance must be considered. Animal studies have gen- Figure 30-11 are examined, it can be seen that the loss of LV
erally suggested that the heart may stiffen with age.65 Sophisticated compliance in the sedentary senior group is not specific for senes-
analysis of contractile performance and diastolic stiffness in older cence and is completely prevented by lifelong endurance exercise.
rats demonstrated prominent decreases in cardiac compliance as It should be pointed out that these data are in marked contrast
assessed from pressure-volume curves.66 Our laboratory has to the noninvasive data for these very same subjects, which dem-
recently studied the effect of aging and lifelong fitness on the end onstrate little if any effect of lifelong fitness on Doppler measures
diastolic pressure-volume relationship in normal healthy adults of relaxation (see Figs. 30-4 and 30-5).23 The discordance between
the training effect on LV compliance and relaxation is best
explained by the fundamental differences in cellular regulation of
–5,000
these two processes. LV relaxation, as controlled by Ca2+ han-
dling, appears to be resistant to aerobic training in many species,
including humans.70,71 These particular protein alterations may be
–dP/dt (mmHg/sec)

specific to the aging process and not influenced by physical activ-

–3,000 ity. LV compliance is regulated by a separate set of proposed
pathways, which warrant some detailed discussion.
The proposed pathophysiology of increased stiffness of the left
ventricle with aging is multifactorial. Much of the focus in this
–1,000

6
Estimated transmural pressure

Adult Senescent Senescent Senescent +

A + Ad.βgal Ad.SERCA2a
30 4
(mmHg)

25

20
τ (msec)

2
15 Sedentary
Athletes
10 Young
0
5
50 75 100 125 150
0 Left ventricular end-diastolic volume (ml)
Adult Senescent Senescent Senescent +
B Figure 30-11 End diastolic pressure-volume relationships in young
+ Ad.βgal Ad.SERCA2a
healthy sedentary subjects, healthy sedentary seniors, and senior
Figure 30-10 Restoration of diastolic function by adenoviral gene transfer Masters athletes. Normal sedentary aging results in a loss of ventricular
of SERCA2a in rat hearts. Ad.β-Gal is the reporter adenovirus. Ad.SERCA2a compliance, while lifelong aerobic exercise prevents this loss. Estimated
is the adenovirus containing the gene of interest. A, −dP/dT and B, Tau. Rat transmural pressure is equal to pulmonary capillary wedge pressure
hearts infected with Ad.SERCA2a demonstrate increased rate of ventricular minus right atrial pressure; left ventricular end diastolic volume is
relaxation. (Modified from Schmidt U et al: Restoration of diastolic function in measured by echocardiography. (Modified from Arbab-Zadeh A et al: Effect
senescent rat hearts through adenoviral gene transfer of sarcoplasmic reticu- of aging and physical activity on left ventricular compliance. Circulation
lum Ca(2+)-ATPase. Circulation 2000;101:790–796.) 2004;110:1799–1805.)
392 Chapter 30 • Aging and Diastolic Heart Failure

24 P = –Sln[(Vm–V)/(Vm–Vo)]
Fibrillar
ECM
Pulmonary capillary wedge pressure

20
dP/dV = S/(Vm–V)
@121 = 0.204
16 @139 = 0.582
(mmHg)

Post bedrest
12 Stress, strain
S = 5.65
Disruption
of fibrillar
8 ECM
Pre bedrest
S = 6.13
4 dP/dV = S/(Vm–V)
@139 = 0.374
* @121 = 0.178
0
Vo Vo
0 40 80 120 160
Stress, strain
LVEDV (ml)
Figure 30-13 The extracellular matrix (ECM) is composed of a basement
Figure 30-12 Bedrest deconditioning leads to decreased LV compliance. membrane and a fibrillar collagen network providing support and struc-
Shift of the end diastolic pressure-volume (LVEDV) relationship to the left tural integrity to myocytes. (Modified from Spinale FG: Matrix metallo-
after 2 weeks of strict bedrest. (Modified from Levine BD, Zuckerman JH, proteinases: Regulation and dysregulation in the failing heart. Circ Res
Pawelczyk JA: Cardiac atrophy after bed-rest deconditioning: A nonneural 2002;90:520–530.)
mechanism for orthostatic intolerance. Circulation 1997;96:517–525.)

TABLE 30-2
MMPS AND TIMPS IN VENTRICULAR REMODELING
ENZYME MMP ENZYME (KDA LATENT/ACTIVE) SUBSTRATE REMODELING*

Collagenases MMP-1 Interstitial collagenase (52/42) Collagen type I, II, III, VII, and X; gelatins; +
proteoglycans; entactin
MMP-8 Neutrophil collagenase (85/64) Collagen type I, II, and III +
MMP-13 Collagenase-3 (52/42) Collagen type I, II, and III +
Gelatinases MMP-2 Gelatinase A (72/66), type IV collagenase Gelatins (type I), collagen type I, II, III, IV, V, VII, and XI; +
fibronectin; laminin; elastin; proteoglycans
MMP-9 Gelatinase B (92/84), type V collagenase Gelatins (type I and V), collagen type I, II, III, IV, V, +
and VII; elastin; entactin; proteoglycans
Stromelysins MMP-3 Stromelysin 1 (57/45) Gelatins (type I, III, IV, and V), collagen type III, IV, IX, +
and X; collagen telopeptides; proteoglycans;
fibronectin; laminin; MMP activation
MMP-10 Stromelysin 2 (54/44) Collagen type IV; proteoglycans; laminin; fibronectin ?
MMP-11 Stromelysin 3 (64/46) Furin deavage −
Membrane type MMP-14 MT1-MMP (66/54) Collagen type I, II, III, and IV; gelatin; fibronectin; +
laminin; activation of proMMP-2 and proMMP-13
... (MT2-MT3-MT4-MMPs) (Not known) ?
Others MMP-7 Matrilysin, PUMP-1 (28/19) Proteoglycans, fibronectin, gelatins, collagen type IV, ?
elastin, entactin
MMP-12 Matalloelastase (54/22) Elastin (macrophage elastase) ?

*Role in cardiac remodeling was classified as documented (+), probable (?), or not known (-).
Modified from Jugdutt BT: Ventricular remodeling after infarction and the extracellular collagen matrix: When is enough enough? Circulation 2003;108:1395–1403.

field has centered on the extracellular matrix (ECM). The ECM in turn results in myocardial fibrosis, impairing both ventricular
is composed of a basement membrane and a fibrillar collagen relaxation and compliance.74
network providing support and structural integrity to myocytes Recently, it has been recognized that the regulation of the
(Fig. 30-13).72 The ECM is also highly metabolically active and ECM depends on an interplay between matrix metalloprotein-
serves as a source for anti-apoptotic signals and growth factors, a ases (MMPs), a family of enzymes present in the myocardium
substrate for cell adhesion, and a determinant of myocyte mechan- and responsible for degrading the matrix components of the
ics.72–74 The ECM undergoes extensive turnover and remodeling. heart, and specific tissue inhibitors of matrix metalloproteinases
Altering the balance between collagen synthesis and degradation (TIMPs) (Table 30-2).76,77 Activity of MMPs is regulated at both
results in myocardial collagen accumulation, stiffening, and cardiac pre- and posttranscriptional levels and may be modulated by
dysfunction.72,75 A common thread among diverse etiologies of inflammatory cytokines such as tumor necrosis factor (TNF)–
CHF appears to be the dynamic remodeling of the ECM, which alpha,76 as well as mechanical physiological signals such as load
 Chapter 30 • Aging and Diastolic Heart Failure 393

and stretch.78–80 Increased MMP activity has been associated with These data suggest the possibility of a “metabolic hypothesis”
LV enlargement and dilation,77 and inhibiting these enzymes of cardiac stiffening with sedentary aging. This hypothesis pro-
limits the severity of pacing-induced CHF in pigs.74,81 poses that the metabolic consequences of sedentary aging—
However, these changes (expected to augment proteolysis of relative insulin resistance and excess caloric intake relative to
collagen) do not readily explain the increased fibrosis and stiffness expenditure, with or without obesity—lead to “lipotoxicity” and
associated with end-stage CHF. In this regard, aged rats appear to the accumulation of abnormal metabolites such as triglycerides
have substantial decreases (40%–45%) in MMP activity.82 Trans- (TGs) and advanced glycation end-products (AGEs) that sepa-
genic mice that overexpress cardiac-specific TNF-alpha may help rately and/or together contribute to the stiffening of the aged
to reconcile this apparent contradiction with respect to aging.83 In heart. Studies in animal models of human obesity have led to the
this model, young mice initially demonstrated a significant increase development of this novel concept of “lipotoxicity,” which may
in MMPs associated with LV structural remodeling. However, as explain the multiple pathological features associated with
the mice aged, there was a time-dependent increase in TIMP-1 obesity.100 Specifically, in these animals the consequences of excess
levels, associated with an overall reduction in the MMP/TIMP fat mass develop secondary to the toxic effects of an accumulation
ratio and progressive fibrotic stiffening without further enlarge- of intracellular lipid within non-adipocytes.101,102 While few
ment.83 This time course and pattern of MMP/TIMP profiles has human data are available, evidence is emerging that an excessive
also been demonstrated in pressure overload hypertrophy84 due to accumulation of lipid within the myocardium develops in obesity
aortic banding. Thus the activity of MMPs and their TIMPs may and is associated with sedentary aging (Fig. 30-14). In animal
be time dependent, with differing effects dependent on the specific models of human obesity, myocardial TG increases 2.5- and 4-
pathophysiology and phase of the life cycle.77 fold by 7 and 14 weeks of age, respectively, while lean wild-type
Aging also has prominent effects on the balance between animals display no change in myocardial TG over the same time
myocyte volume and the ECM. For example, the aged heart has frame.102 This increase in myocardial TG content is associated
substantially fewer myocytes than the young heart, accompanied with a 15-fold increase in markers of apoptosis and profoundly
by significant increases in the volume fraction of collagen.85 In depressed LV systolic performance, implying that intramyocardial
rats, this reduced number of myocytes is associated with increases TG accumulation may explain the cardiac maladaptations that
in the size of each individual myocyte that may be adaptive.84,85 develop secondary to chronic obesity. When animals are treated
Increased myocardial fibrosis has also been noted in senescent with an agent that lowers tissue TG, intracellular lipid content is
animal hearts.86–89 In otherwise “healthy” but aged human hearts, effectively diminished, markers of apoptosis are attenuated, and
there appear to be focal areas of interstitial fibrosis, predomi- LV systolic performance is restored.102 In summary, substantial
nantly in the subendocardium of the left ventricle, that increase evidence from animal studies suggests that excessive myocardial
with age and may be related to the loss of myocyte volume as lipid accumulation is a key feature in the pathogenesis of obesity-
“replacement fibrosis.”90 related disorders and contributes to cardiac dysfunction.
The close association between TG accumulation and insulin
resistance/glucose intolerance in animal models as well as the
Metabolic Hypothesis of Cardiac Aging clinical “metabolic syndrome” raises the additional possibility that
The exact mechanism by which sedentary aging could lead to the long-term consequences of TG accumulation could be exac-
inhibition of MMPs with increases in TIMPs leading to fibrosis erbated by the accretion of AGEs within the heart.103 When
and cardiac stiffening is uncertain. Another, possibly interrelated reducing sugars (such as glucose) complex nonenzymatically with
mechanism could be that relative energy imbalance, specifically amino groups on proteins, the resulting protein-protein crosslinks
insufficient energy expenditure relative to caloric intake, may form a yellow-brown pigment that leads to the “browning” typi-
present a unifying hypothesis for why the heart stiffens with sed- cally associated with the roasting of a basted turkey or steak.103
entary aging, yet is preserved with lifelong exercise training. For First described by Louis Maillard almost a hundred years ago, the
example, aged rats show clear evidence of progressive increases in
collagen deposition in the left ventricle with age. However, this
fibrosis was substantially reduced in rats maintained on a calorie-
Myocardial triglyceride (F/W %)

1.4
restricted diet.91 More recently, gene chip array analysis has identi-
fied prominent alterations in transcription with aging in a mouse 1.2
model, including marked upregulation of the expression of ECM 1.0
genes, such as procollagens.92 Similar to the aged rat, these mice
0.8
demonstrated a 150% to 200% reduction in expression of these
genes when fed a hypocaloric diet.92 Progressive weight gain/ 0.6
obesity is one of the hallmarks of the aging process.93 For most 0.4
individuals, such weight gain with age is due predominantly to
0.2
reduced levels of physical activity and caloric expenditure,93 with
severe health consequences.94,95 Obesity is a particularly impor- 0.0
tant risk factor for the syndrome of heart failure with a normal Masters Sedentary- Sedentary Sedentary-
EF.19 For example, obese individuals display increased LV mass athlete vigorous moderate no training
training training
and wall thickness coupled with reduced LV filling dynamics—
maladaptations that may predispose individuals to heart failure, Figure 30-14 Intramyocardial triglyceride (TG) accumulation in elderly
particularly with advancing age.96–98 Interestingly, these adverse humans determined by 1H-MRS (magnetic resonance spectroscopy) calcu-
lations of fat/water ratio from a senior Masters athlete and three senior
LV adaptations appear to develop independently of hemody- sedentary subjects after various levels of training. Elevated TG accumula-
namic load,99 thus pointing to a metabolic cause for these cardiac tion is associated with sedentary aging and is sensitive to physical
consequences. activity.
394 Chapter 30 • Aging and Diastolic Heart Failure

Maillard reaction104 is driven by the concentration of available increased myocardial stiffness.120–123 It should be emphasized that
sugars and is thereby also responsible for the glycation of short- these AGEs do not act simply as structural scaffolding. Rather,
lived proteins such as hemoglobin; this process is widely used they appear to be metabolically active, binding to receptors for
clinically to monitor control of glucose in diabetic patients over AGEs (RAGEs), which may precipitate endothelial dysfunction
several weeks to months as the concentration of hemoglobin A1c by enhancing oxidative stress and exacerbating inflammatory
(Fig. 30-15). responses that may modify the ECM.124,125 Together, these mul-
These Maillard reaction products (also known as Amadori tifaceted effects of the accumulation of both vascular and myo-
products) form on other proteins in vivo and may accumulate over cardial crosslinked collagen have led to their being proposed as a
time in complex arrangements of crosslinked proteins, such as unifying hypothesis to explain ventriculovascular stiffening in the
AGEs.105 When AGEs form on long-lived proteins such as colla- elderly.120,121,126,127 As will be discussed later in this chapter, inhibi-
gen or lens crystallin proteins, they result in prominent stiffening tors of the crosslinking process may be potential treatments to
of the ECM and can lead to human pathology such as cataracts prevent or even reverse ventricular stiffening with aging.
or vascular and myocardial stiffening.106–110 Because AGEs are
very stable and virtually irreversible once formed, they accumulate Role of Comorbid Conditions in the
continuously with aging.111–113 This process therefore has been
proposed as one of the key mechanisms responsible for the stiff- Pathophysiology of Diastolic Heart Failure
ening of a variety of tissues as a primary manifestation of the The variety of cellular changes, discussed above, that occur during
aging process, which may be accelerated in diseases with chroni- normal aging lead to the abnormalities in LV relaxation and com-
cally high concentrations of blood glucose, such as diabetes.108,114 pliance, which are reflected as abnormal Doppler parameters of
Over the last 25 years, a substantial amount of evidence has diastolic function. It is clear, given the high prevalence of these
accumulated to support this hypothesis.103,112,113,115 For example, abnormalities in the senior population, that the presence of dia-
human dura mater108 and skin116 obtained at autopsy from other- stolic abnormalities alone is not sufficient to cause heart failure.
wise healthy individuals showed a clear, linear increase in pig- Instead, the superimposing of comorbid conditions upon a sub-
mented collagen typical of AGEs with advancing age, suggesting strate of altered diastolic function may be the etiology of DHF
that these products accumulate in human tissue over time. in the senior population.
Diabetic patients experienced an even greater accumulation of It is unclear whether these comorbid conditions are the direct
pigmented collagen, suggesting that the presence of diabetes inciting stimuli for the development of CHF in this population
“accelerated” the aging process.108 or rather coexisting disease processes accumulated during aging.
Diabetic patients also accumulate substantial amounts of There are ample data to suggest, however, that the former may be
crosslinked collagen in blood vessels, leading to increased vascular true. The presence of HTN, atrial fibrillation, diabetes, decon-
stiffening.117 More recently, it has been demonstrated that AGEs ditioning, and CAD are all known to negatively effect diastolic
crosslink not only collagen, but also elastin in the aorta, further function.128–131 Individual comorbid conditions may influence
reducing arterial distensibility.106,118 Myocardial collagen also particular deleterious effects on diastolic function. For example,
appears to be increasingly crosslinked with age,119 associated with atrial fibrillation may markedly impair late ventricular filling131;

THE MAILLARD REACTION

H O
C
–
(CHOH)4 NH

CH N N
NH
Glucose
+ (CHOH)4
CH2 O
–
Schiff base
AGE crosslink
Amadori product

Protein amine

Figure 30-15 The Maillard reaction. (Modi-

fied from Zieman SJ, Kass DA: Advanced
Δ glycation endproduct crosslinking in the car-
diovascular system: Potential therapeutic
target for cardiovascular disease. Drugs
2004;64:459–470.)
 Chapter 30 • Aging and Diastolic Heart Failure 395

diabetes, as noted earlier, is associated with increased LV stiff- 40%), echoed the data from these other studies.12 More impor-
ness132; and even short periods of subclinical ischemia are known tantly, a subanalysis based on the CHARM data demonstrated
to adversely impact Doppler measures of diastolic function.133 that atrial fibrillation in particular appeared to be a strong addi-
Based on these data, we can theorize that given a background of tive risk factor for cardiovascular mortality and hospitalization in
age-related slowed relaxation, loss of vigorous suction, and patients with DHF.11 The additional incremental risk imposed by
decreased static LV compliance, the presence of these comorbid atrial fibrillation appears to be greater for patients with preserved
disease states may further worsen the ability of the heart to fill EF, as opposed to those with reduced EF.
adequately at normal filling pressures, leading to pulmonary
edema and heart failure. The proposed paradigm for this process
is shown in Figure 30-16. The presence of these disorders in
DHF patients is not trivial, and their prevalence in several large CLINICAL RELEVANCE
studies is summarized in Table 30-3. Challenges in Designing Trials and Treatments for
In ADHERE, for example, which examined data from over
100,000 CHF hospitalizations (26,322 with preserved systolic
Diastolic Heart Failure
function), 77% of DHF patients had HTN, 45% had diabetes, The presence of the previously mentioned comorbid conditions
and 50% had CAD.9 When the data from the Olmsted County in patients with DHF has important implications for therapeutic
experience are examined, similar results are observed in individual drug development. The divergent pathophysiological pathways we
patients hospitalized for DHF, with 63% having HTN, 53% have discussed are not likely to respond to a single agent (like an
having atrial fibrillation, and one third having diabetes.8 The angiotensin receptor blocker [ARB] alone) that may be more
ancillary subset of the Digitalis Investigation Group (DIG) trial, useful in SHF by preventing or reversing ventricular dilation and
which examined the effect of digoxin versus placebo in 988 adverse remodeling. To date there are many more evidence-based
patients with EF greater than 45% on cardiovascular outcomes, therapies for SHF compared with DHF (Table 30-4) (see
demonstrated that the majority of patients had HTN and isch- Chapters 32 and 34). Few large clinical trials, with the notable
emic disease, and one third had diabetes.14 Finally, the CHARM- exception of CHARM and the ancillary DIG study, have exam-
Preserved study, which examined the effect of candesartan versus ined patients with normal systolic function. The CHARM-
placebo on similar outcomes in 3023 patients with DHF (EF > Preserved study demonstrated a moderate benefit in prevention

TABLE 30-3
PREVALENCE OF CONDITIONS KNOWN TO NEGATIVELY IMPACT DIASTOLIC DYSFUNCTION IN DHF SAMPLES
(% OF TOTAL PATIENTS)
OLMSTED COUNTY STUDY ADHERE ANCILLARY DIG TRIAL CHARM-PRESERVED TRIAL

Number of patients 4596 26322 988 3023

Hypertension, % 63 77 60 23
Hx MI or CAD, % 53 50 50 45
Diabetes, % 33 45 29 28
Valvular disease, % 3 21 No data No data
Atrial fibrillation, % 41 21 No data 29

DHF, diastolic heart failure; ADHERE, Acute Decompensated HEart Failure National REgistry; DIG, Digitalis Investigation Group; CHARM, Candesartan in Heart Failure: Assessment of
Reduction in Mortality and Morbidity; Hx, history; MI, myocardial infarction; CAD, coronary artery disease.

Healthy sedentary aging:

• Increased static ventricular end diastolic stiffness
Diastolic “dysfunction” • Slowed myocardial relaxation
• Loss of vigorous diastolic suction

Comorbid conditions:
• Hypertension (hypertrophy,
increased LV stiffness)
• Diabetes (increased LV stiffness)
• Ischemia (slowed relaxation)
• Atrial fibrillation (decreased time
for filling, loss of atrial kick)
• Valvular heart disease (impaired
filling in mitral stenosis, LV
hypertrophy in AS)
Figure 30-16 Proposed paradigm by which
comorbid conditions overlaid on a substrate of
• Pulmonary edema
slowed relaxation and decreased compliance
Diastolic heart failure • Dyspnea
could result in diastolic heart failure. LV, left ven-
• Exercise intolerance
tricular; AS, aortic stenosis.
396 Chapter 30 • Aging and Diastolic Heart Failure

of hospitalization for worsening CHF in the DHF population Association (NYHA) class. This study echoes prior data that
with the use of candesartan.12 In the ancillary DIG study, digoxin suggested a benefit of ACE inhibitors in DHF, but the role of
appeared to have little effect on any substantial cardiovascular such drugs in treating this disorder is far from settled.13
endpoint.14 More recently, there has been interest in the possible The PEP-CHF trial also provides several examples of the dif-
role of hydroxymethylglutaryl coenzyme-A (HMG-CoA) ficulty in designing DHF trials. The study was underpowered to
reductase inhibitors (“statins”) in DHF. The role of these drugs address the primary endpoint. Subject enrollment was difficult
in DHF is unclear, but there is some evidence to suggest improved and did not meet the target of 1000 patients. The authors noted
outcomes in DHF on statin therapy.134 Proposed mechanisms difficulty in confirmation of the diagnosis of CHF in this patient
have focused not only on low-density lipoprotein reduction population and suggested that the addition of an elevated level of
and reduction of ischemic events, but also on possible pleio- brain natriuretic peptide (BNP) might help make a more defini-
tropic effects involving regression or prevention of myocardial tive diagnosis. In addition, there was a significant withdrawal of
fibrosis.134,135 subjects during the study; 28% and 26% withdrew from the per-
More recently the angiotensin-converting-enzyme (ACE) indopril and placebo arms, respectively. Based on this and other
inhibitor perindopril was studied in the Perindopril in Elderly studies in the geriatric literature, recruitment into clinical trials of
People with Chronic Heart Failure (PEP-CHF) trial. This trial older persons who have numerous comorbid conditions and more
enrolled 850 DHF patients who were at least 70 years old with often are female can be quite challenging.138,139 The PEP-CHF
an EF of at least 45% and echo criteria for diastolic dysfunc- trial also noted fewer clinical events than had been predicted. The
tion.136,137 Patients were randomized to perindopril or placebo. relatively lower mortality in the DHF population makes it harder
The trial failed to show a significant benefit of the study drug in for investigators to show benefits in survival for potential drug
reaching the primary outcome of a decrease in a composite end- treatments.14 Lastly, the use of the presence of so-called diastolic
point of mortality and hospitalizations. However, the investiga- dysfunction by echocardiography as a requirement for enrollment
tors, using secondary endpoint data, suggested that this drug may is a matter of controversy, as previously discussed in this
have beneficial effects in those younger than 75 years of age, those chapter.17,140,141
with prior myocardial infarction, and those with HTN. Using Based on the experience of previous clinical trials, the treat-
such analyses, there appeared to be a benefit of perindopril in ment of comorbid conditions such as HTN alone may be of
improvement of the 6-minute walk distance and New York Heart limited benefit in the senior DHF patient. Years of ventricular
stiffening and slowed relaxation are unlikely to reverse easily.
These underlying changes in diastolic properties (whether pri-
TABLE 30-4 marily age associated or not) should therefore also be considered
as targets for direct therapy.
PAUCITY OF EFFECTIVE TREATMENT OPTIONS FOR
DIASTOLIC HEART FAILURE
Novel Therapies on the Horizon
SYSTOLIC HEART FAILURE DIASTOLIC HEART FAILURE
Treatments designed to improve static LV compliance may be of
ACE-I ARBs (candesartan) great benefit in patients with DHF, particularly in the sedentary
ARBs ACE-I (perindopril) senior population. A new agent was recently created to specifically
Beta blockers break already formed AGE crosslinks (see Chapter 34).112,142–144
Aldosterone antagonism (aldactone,
eplerenone) This drug, ALT-711, is a thiazolium derivative (3-phenyacyl-4,5-
Isrodil/hydralazine dimethylthiazolium chloride) that catalytically breaks established
Digoxin (symptomatic benefit) AGE crosslinks between proteins (Fig. 30-17).145 Preclinical,
whole animal studies using ALT-711 have been promising. In one
ACE-I, angiotensin-converting-enzyme inhibition; ARBs, angiotensin receptor blockers. study, for example, the hearts of diabetic rats developed increased

A.G.E. Modification Cleaved products

crosslinked imparted by +
proteins + Alagebrium alagebrium alagebrium

H O Ph CHO
[Protein] O O [Protein] N
N [Protein]
Ph + X
H H O
+ δ– + N HN COOH HO [Protein]
O HO
[Protein] δ– S +
X
S O
OH X [Protein]
* Ph
OH δ– +

δ–
S

Figure 30-17 ALT-711 is a novel advanced glycation end-product (AGE) crosslink breaker. (Modified from Alteon Corporation Company: R&D pipeline: AGE
crosslink breakers, 2006).
 Chapter 30 • Aging and Diastolic Heart Failure 397

BNP expression, decreased collagen solubility, and increased than placebo.145 A number of other multicenter Phase II clinical
accumulation of AGEs and connective tissue growth factors.132 trials have been either completed or initiated, with over 1000
When the AGE crosslink breaker ALT-711 was given 4 months patients receiving ALT-711 for up to 6 months (e.g., Patients with
after diabetes was induced, collagen solubility was restored, BNP Impaired Ejection Fraction and Diastolic Dysfunction: Efficacy
expression was reduced, and AGE accumulation was prevented.132 and Safety Trial of Alagebrium [PEDESTAL], Systolic and Pulse
In a similar experimental design, AGE crosslink breakers were Pressure Hemodynamic Improvement by Restoring Elasticity/
also shown to improve arterial compliance.146 Systolic Hypertension Interaction with Left Ventricular Remod-
One of the most promising animal studies researched the effect eling [SAPPHIRE/SILVER], Systolic Pressure Efficacy and
of ALT-711 on aged dogs (Fig. 30-18).147 The key data from this Safety Trial of Alagebrium [SPECTRA]).149–151 The safety of the
study demonstrated the following: drug has remained consistently high, with no increase in adverse
events compared with placebo, and relatively few side effects.
1. Aged dogs had dramatically increased cardiac stiffness, as
The focus of most of the clinical trials has been on patients
derived from LV end diastolic pressure-volume relation-
with HTN and SHF, but one clinical study has been performed
ships compared with young animals, similar to what we
in patients with heart failure and a normal EF, the Distensibility
have demonstrated in humans.
Improvement And reMOdeliNg in Diastolic Heart Failure
2. Four weeks of ALT-711 restored LV compliance and dis-
(DIAMOND) study.152 This open-label study used a relatively
tensibility about halfway to normal. Similarly, other studies
high dose of ALT-711 (210 mg b.i.d.) for 16 weeks. Primary
showed that nondiabetic aged primates had increases in
endpoints were changes in echocardiographically derived volumes
LV end diastolic diameter, systolic fractional shortening,
and Doppler indices of ventricular filling, NYHA functional
and stroke volume after ALT-711 treatment, associated
class, exercise capacity, and quality of life. The results were mixed.
with improved ventriculo-arterial coupling (50% reduc-
There were minor improvements in some Doppler variables, such
tion in LV end diastolic volume divided by stroke
as an increase in the tissue Doppler early mitral annular velocity
volume).148
by about 15%, but no change in either systolic or diastolic volumes,
Thus, breaking of AGE crosslinks improved ventricular function arguing against a physiologically meaningful alteration in static
and optimized ventriculovascular coupling in healthy older pri- ventricular compliance. The majority of patients who completed
mates without diabetes. the trial increased their NYHA functional class, and the Minne-
Initial Phase I and Phase II human studies with this drug have sota Living with Heart Failure questionnaire improved, though
been encouraging, both for their safety and for their efficacy. The these may be relatively soft endpoints in an open-label study.
first published multicenter clinical study examined 93 patients Exercise tolerance, blood pressure, and simple measures of aortic
older than 50 years with systolic HTN and elevated pulse pres- distensibility did not improve over the 16 weeks of the trial.
sure145 randomized to ALT-711 or placebo in a 2 : 1 distribution The relatively limited improvement in the noninvasive clinical
for 2 months. Precise measures of arterial compliance were con- indicators used in the DIAMOND study were somewhat disap-
ducted. These findings included: pointing, particularly in light of the more dramatic physiological
benefit in the preclinical studies. This outcome does, however,
❒ Greater decrease in pulse pressure in patients treated with
emphasize an important point: that is, the short-term use of
ALT-711 compared with placebo
crosslink breakers alone may not be sufficient to alter cardiovas-
❒ Increase in total arterial compliance by 15% with no change
cular compliance and improve functional capacity in hearts that
in placebo
have been stiffened by decades of accumulation of AGEs or other
❒ Decline in pulse wave velocity without any clear change in
toxic metabolites. In this regard, the role of exercise may be par-
cardiac output or systemic vascular resistance
ticularly important. Given the marked preservation of static
In addition, ALT-711 appeared to be well tolerated, with few chamber compliance with lifelong exercise, shorter-term intensive
serious adverse events, and actually fewer minor adverse events aerobic training coupled with these crosslink breakers may be a
potential treatment strategy in the senior DHF patient. Aerobic
training should also be considered a preventative strategy, espe-
cially when initiated at a younger age. Whether starting intensive
End diastolic pressure (mmHg)

40 training later in life confers the same benefits in static LV compli-

35 ance as does lifelong training is unclear. Further studies examining
30 4 weeks † both of these issues are currently under way.
25 2 ALT-711 †
20
2* §
15 † FUTURE RESEARCH
§ §
10
5 § 1
The population of seniors in the United States is growing, as is
0 the incidence of DHF in this age group. DHF imposes a signifi-
0 10 20 30 40 50 60 70 80 90 cant morbidity on these individuals. While the underlying cause
End diastolic volume index (ml/m2) of DHF remains controversial, the age-associated abnormalities
Figure 30-18 ALT-711 in dogs. Pressure-volume relationships among two of LV compliance and relaxation may provide the substrate upon
groups of dogs: group 1 = young; group 2 (solid line) = aged; and group 2* which a host of comorbidities, including diabetes, atrial fibrilla-
(dotted line) = aged dogs following 4 weeks of therapy with the advanced tion, HTN, and CAD, may be overlaid, resulting in progression
glycation end-product (AGE) crosslink breaker ALT-711. (Modified from
Asif M et al: An advanced glycation endproduct cross-link breaker can reverse
to CHF. Treatments are currently limited for DHF, and an unclear
age-related increases in myocardial stiffness. Proc Natl Acad Sci USA understanding of the pathophysiology and diagnosis of this dis-
2000;97:2809–2813.) order hampers investigational efforts.. Future therapies particu-
398 Chapter 30 • Aging and Diastolic Heart Failure

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properties with novel crosslink breakers. Prevention of this dis- ejection fractions than men independent of differences in left ventricular
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conditions such as HTN and ischemic disease during physical activity on Doppler measures of diastolic function. Am J Cardiol
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 Chapter 30 • Aging and Diastolic Heart Failure 401

APPENDIX
EFFECT OF AGING ON DOPPLER MEASURES OF DIASTOLIC FUNCTION
STUDY AGE RANGE (YEARS) E : A RATIO IVRT DT AFF

Framingham study (n = 127)

20–29 0.98–3.18 0.14–0.34
30–39 0.95–2.55 0.15–0.35
40–49 0.92–1.96 0.23–0.35
50–59 0.73–1.85 0.22–0.38
60–69 0.51–1.55 0.23–0.47
≥70 0.26–1.42 0.24–0.60
All ages 0.32–2.48 0.15–0.47
Cardiovascular health study (n = 980)
Overall (>65) 0.64–1.56
Women
65–69 0.50–1.62
70–74 0.50–1.42
75–79 0.52–1.28
>80 0.48–1.12
Men
65–69 0.52–1.64
70–74 0.44–1.48
75–79 0.47–1.39
>80 0.48–1.16
Mantero (n = 288)
20–29 0.9–2.9 41.2–94.8 97.2–194.4 0.04–0.44
30–39 0.9–2.5 45.3–97.7 94.2–283.8 0.07–0.47
40–49 0.8–2.0 49.0–97.8 93.2–218.8 0.10–0.50
50–59 0.6–1.8 51.7–102.9 87.5–222.3 0.14–0.54
60–69 0.6–1.4 51.0–107.8 103.5–241.1 0.17–0.57
70–80 0.2–1.4 44.7–117.5 86.5–269.7 0.19–0.59
Voutilainen (n = 93)
<40 1.0–3.0 101–177 0.11–0.35
40–60 0.6–1.8 100–204 0.20–0.48
>60 0.76–0.84 112–216 0.27–0.63
All 0.3–2.7 99–199 0.08–0.56
Klein (n = 117)
<50 0.7–3.1 54–98 139–219
>50 0.5–1.7 56–124 138–282
20–29 0.8–3.6 49–93 144–220
30–39 0.9–2.5 63–95 138–214
40–49 0.8–2.4 53–105 131–223
50–59 0.9–1.7 52–124 157–245
60–69 0.6–1.4 60–128 132–296
>70 0.2–1.8 56–116 135–303
European Study Group on Diastolic Heart Failure (review)
Age <30
IVRT >92
Age 30–50
IVRT >100
Age >50
IVRT >105
Cohen (n = 107)
21–49 1.9 (0.7–3.1*) 76 (54–98*) 179 (139–219*)
>50 1.1 (0.5–1.7*) 90 (56–124*) 210 (138–282*)
Bryg (n = 32)
24–29 0.92–3.04
30–49 0.80–2.24
51–68 0.25–1.89
Spirilo (n = 86)
20–29 1.3–4.1 48–96 158–278
30–49 0.8–3.2 56–104 166–274
50–74 0.4–2.0 60–108 155–287

Ranges calculated normal ranges ±2 SDs from mean and *occasional 95% confidence intervals.
A, peak atrial filling; AFF, atrial filling fraction; DT, deceleration time; E, peak rapid filling; IVRT, isovolumetric relaxation time.
Modified from Petrie MC, Hogg K, Caruana L, Mcmurray JJV: Poor concordance of commonly used echocardiographic measures of left ventricular diastolic function in patients with
suspected heart failure but preserved systolic function: Is there a reliable echocardiographic measure of diastolic dysfunction? Heart 2004;90:511–517.
 BARRY A. BORLAUG, MD
VOJTECH MELENOVSKY, MD, PhD
DAVID A. KASS, MD
31
Ventricular-Arterial
Interaction in Patients
with Heart Failure
and a Preserved
Ejection Fraction
INTRODUCTION Pathophysiology of Ventricular-Arterial
Stiffening
PATHOPHYSIOLOGY OF LEFT VENTRICULAR-
Ventricular-Arterial Stiffening and Exercise
ARTERIAL COUPLING
Reserve
Ventricular-Arterial Stiffening in Heart Failure
with a Preserved Ejection Fraction CLINICAL RELEVANCE: THERAPEUTIC
Mechanisms of Ventricular-Vascular STRATEGIES TARGETING STIFFNESS
Stiffening
FUTURE RESEARCH

INTRODUCTION arterial stiffness is about 1.5 mmHg/ml.1,2 These low values allow
relatively large changes in volume in both the heart and the vas-
The mammalian cardiovascular system is designed to provide cular bed to be achieved with only modest changes in ejected
adequate flow at physiologic pressures both at rest and under a pressures.
broad range of demands. Since blood flow is pulsatile, changes in With advancing age, both ventricular and arterial stiffness
cardiac output are accompanied by alterations in the arterial pulse increase, and these changes may be further exacerbated by
wave amplitude and peak systolic pressure. To prevent wide fluc- common disorders such as hypertension, diabetes mellitus, and
tuations in blood pressure that otherwise can lead to vascular and renal disease.3–6 Since the heart and arterial systems are coupled,
end-organ damage, the heart and arteries are compliant so that such stiffening results in amplification of systolic and pulse pres-
pulse and peak pressures can be buffered, while systemic diastolic sures during ejection, faster pressure decay during diastole, and
pressures are augmented. For the vasculature, this compliance is enhanced cardiac systolic loading. Stiff arteries facilitate rapid
largely contained within the proximal conduit vessels, while transit of the flow and pressure pulse through the vasculature,
within the heart, it is described by the end systolic stiffness (elas- increasing the velocity at which these waves encounter regions of
tance, inverse of compliance) that is achieved during contraction. impedance mismatch (e.g., distal arteriolar narrowings), which
The normal human heart develops a ventricular systolic stiffness then increases the amplitude of reflected pressure waves, further
of about 2.0 mmHg/ml of ventricular end systolic volume, while exacerbating systolic load. The net effect is an adverse impact on
403
404 Chapter 31 • Ventricular-Arterial Interaction in Patients with Heart Failure and a Preserved Ejection Fraction

cardiac systolic and diastolic functions, with increased myocardial function, which are typically determined in the time domain. One
oxygen consumption required to provide the body with blood approach to this problem involves the development of a vascular
flow, impaired cardiovascular reserve function, labile systemic parameter that shares units applicable to the heart, namely effec-
blood pressures, and diminished coronary flow reserve.2,6–8 Aging tive arterial elastance (Ea).15,16 Ea combines both mean and pul-
is also associated with endothelial dysfunction,9 which may in satile loading, providing a lumped parameter that reflects the net
part relate to mechanical stiffening, as reduced wall distensibility impact of arterial vascular load on the heart. This index was
can itself compromise endothelial-dependent responses to shear developed and validated by Sunagawa et al. in the mid 1980s and
stress stimulation10,11 and vasorelaxation. One can consider this then applied and verified in humans by Kelly et al.15 The latter
adverse interaction between heart and arteries as a form of cou- group confirmed that the simple ratio of end systolic pressure to
pling disease that ultimately limits the ability of the integrated stroke volume (Pes/SV) could serve to estimate Ea in both hyper-
cardiovascular system to respond to stress. tensive and normal humans. Graphically, Ea can be depicted as
Abnormal ventricular-arterial stiffening and thus coupling may the absolute value of the slope of a line linking the coordinate
play an important role in patients with heart failure symptoms points of (end systolic volume [Ves], Pes) and (end diastolic
but with apparent preservation of systolic function. Such patients volume [Ved], P = 0) (see Fig. 31-1).
are typically older and female, with histories of chronic hyperten- Coupling of heart and artery is often then depicted by the
sion and a high prevalence of diabetes, obesity, and renal dysfunc- interaction of these two relations and expressed as a ratio of Ea/
tion. They often develop marked systolic hypertension under Ees.17–19 The intersection of these lines determines Pes and Ves
conditions of stress, and both their arterial and ventricular systolic (see Fig. 31-1). As shown in Figure 31-2, the Ea/Ees ratio is fairly
pressures are very sensitive to blood volume status. While abnor- preserved with normal aging to maintain optimal efficiency,
mal diastolic function is thought to contribute to heart failure declining somewhat in women, while both the numerator (vascu-
symptoms by increasing congestion, it cannot explain the observed lar load) and the denominator (ventricular stiffness) increase.1 Ea
increases in systemic pressures, nor does it fully underlie limita- is dominated by mean ventricular load, namely systemic vascular
tions of cardiac reserve. Here, we review the pathophysiology of resistance,16,19 but it is also altered by artery stiffening to increase
ventricular-arterial stiffening and its role in the syndrome of heart pulse pressure. Blood pressure pulsatility rises with aging, and
failure with a preserved ejection fraction (HFpEF). this is reflected in the pressure-volume diagram in the elderly
individual (see Fig. 31-1B) and the HFpEF patient (see Fig.
31-1C) by the rise in systolic pressure throughout ejection
PATHOPHYSIOLOGY OF LEFT (arrows).2,20,21 Since Ea is determined by the ratio Pes/SV, the
VENTRICULAR-ARTERIAL COUPLING greater the disparity between Pes and mean arterial pressure (i.e.,
the more pulsatile or stiff the arterial system), the higher Ea will
The influence of increases in ventricular systolic and vascular be relative to mean resistance load. Ea also varies directly with
stiffness on net cardiovascular function is best depicted in the heart rate, since for any given cardiac SV, the systolic pressure will
pressure-volume plane. Ventricular end systolic chamber stiffness increase or decrease proportionally with the number of strokes
is expressed as end systolic elastance (Ees) (Fig. 31-1), defined by (i.e., cardiac output). It is important to keep these factors in mind
the slope of the end systolic pressure-volume relationship.12 Ven- when interpreting data reporting on Ea and Ea/Ees coupling.
tricular afterload can be represented as aortic input impedance, Effective coupling of heart to artery can be defined in several
derived from Fourier analysis of aortic pressure and flow waves.13,14 ways. One is the optimal transfer of blood from heart to periphery
Impedance is expressed in the frequency domain and thus is more without excessive increases in pulse or systolic pressures. Another
difficult to match with optimal measures of ventricular systolic is optimal cardiovascular flow reserve without compromise to

Ees = Pes/Ves-V0
Ea = Pes/SV CONTROL HF pEF
200 200 5.6 2.8
2.2 2.1
LV pressure

150
LV pressure

150
Pressure

100 100

50 50

0 0
0 40 80 120 160 0 40 80 120 160

Volume LV Volume LV Volume

A B C
Figure 31-1 A, Idealized pressure-volume loop in a young person. Contractility is expressed as end systolic elastance (Ees), the slope of the end systolic
pressure-volume relationship. Afterload is defined by effective arterial elastance (Ea), the negative slope passing through the end systolic and end diastolic
pressure-volume points. Note the loop’s rectangular shape, with little increase in pressure during systole. B, Typical pressure-volume loops obtained from
a normal 65-year-old man during preload reduction. Note that the coupling ratio (Ea/Ees) is close to unity. C, Example loops from a subject with heart
failure with a preserved ejection fraction (HFpEF). Ea and Ees are elevated, the coupling ratio is lower, and the loops have a more trapezoidal shape due
to the gradual increase in systolic pressure during ejection (reflecting increased arterial pulse pressure), related to a decrease in arterial compliance and
increase in wave reflections (arrow). Pes, end systolic pressure; Ves, end systolic volume; V0, volume intercept; SV, stroke volume. (Modified from Kawaguchi
M et al: Combined ventricular systolic and arterial stiffening in patients with heart failure and preserved ejection fraction: Implications for systolic and diastolic
reserve limitations. Circulation 2003;107:714–720.)
 Chapter 31 • Ventricular-Arterial Interaction in Patients with Heart Failure and a Preserved Ejection Fraction 405

2.5 3.5 1.0

r = 0.25, p<0.0001
3.0 0.9

Ees (mmHg/ml)
Ea (mmHg/ml)

2.0
r = 0.26, p<0.0001 2.5 0.8

Ea/Ees
r = 0.01, p = 0.66

2.0 0.7
1.5
r = 0.17, p<0.0001 r = –0.10, p = 0.002
1.5 0.6
r = 0.21, p<0.0001
1.0 1.0 0.5
40 50 60 70 80 90 100 110 40 50 60 70 80 90 100 110 40 50 60 70 80 90 100 110
Age Age Age
A B C
Figure 31-2 A, B, Arterial and ventricular systolic stiffness increase with aging in both men (blue) and women (red). At each age level, stiffness is higher
in women, in whom the age-dependent increase in ventricular-arterial stiffness is accentuated. C, The increase in ventricular and arterial stiffness is
matched with aging in men, resulting in a stable coupling ratio, while in women this ratio decreases with age. (Modified from Redfield MM et al: Age- and
gender-related ventricular-vascular stiffening: A community-based study. Circulation. 2005;112:2254–2262.)

6 3
*
*
Ees (mmHg/ml)

Ea (mmHg/ml)
4 † 2

Figure 31-3 A, Ventricular systolic stiffness

is elevated in hypertensive patients com- 2 1
pared with younger and age-matched con-
trols, but significantly higher in heart failure
with a preserved ejection fraction (HFpEF). 0 0
B, Arterial elastance is higher in HFpEF
patients than in both hypertensive and non- Con-y Con-o Con-HTN HFpEF Con-y Con-o Con-HTN HFpEF
hypertensive controls. C, Increases in vascu-
A B
lar stiffness are correlated with increased 8
ventricular systolic stiffness in all groups, Con-y 1.2
with HFpEF showing an exaggerated increase Con-O
in ventricular stiffness. D, Coupling ratio is
6 Con-HTN 1.0
Ees (mmHg/ml)

lower to a similar extent in both hyperten-

Ea/Ees ratio

sive patients and HFpEF patients compared HFpEF

with controls. HFpEF is thus distinguished
from hypertension by the extent of ventricu- 4 0.8
lar and arterial stiffening, not simply by the
* *
ratio of Ea/Ees. Con-y, young controls; Con-o,
older age-matched controls; Con-HTN, 2 0.6
hypertension-matched controls. (Modified
from Kawaguchi M et al: Combined ventricular
0 0.4
systolic and arterial stiffening in patients with
heart failure and preserved ejection fraction: 0 1 2 3 4 Con-Y Con-o Con-HTN HFpEF
Implications for systolic and diastolic reserve
limitations. Circulation 2003;107:714–720.) C Ea (mmHg/ml) D

arterial pressures. One can mathematically express optimal cou- Ventricular-Arterial Stiffening in Heart Failure
pling as the interaction that best enhances the work performed with a Preserved Ejection Fraction
by the heart on the body (i.e., optimal external work). Lastly, one
must consider the efficiency of the heart in performing this In patients with HFpEF, the Ea/Ees ratio falls compared with
work—the energy consumption required to effect this external younger individuals but is similar to that of nonsymptomatic
work. All of these are reasonable definitions, although prior hypertensive elderly patients.2,20 Importantly, it still falls in a range
experimental and clinical studies have tended to focus on the where external work and efficiency are not likely compromised.
latter two: optimizing external work and efficiency. For this, one However, while the ratio itself is reduced, the absolute values of
can both predict22 and observe experimentally18,22 that an Ea/Ees both numerator and denominator are significantly elevated (Fig.
coupling ratio of 0.6–1.2 achieves near optimal work and effi- 31-3). Thus, HFpEF patients have elevated vascular stiffness,2,25
ciency. This range is normally maintained under various physio- as well as increased ventricular stiffness in both systole2 and dias-
logic stresses, as shown elegantly some years back in exercising tole.26,27 The net interaction of ventricular and arterial stiffness is
animals.23 It can become very high, particularly in dilated cardio- important because it can significantly affect the first two compo-
myopathy, where depressed heart function (low Ees) is coupled nents of what we can consider optimal coupling—blood pressure
to a high arterial impedance (high Ea).24 homeostasis and preservation of adequate cardiovascular reserve.
406 Chapter 31 • Ventricular-Arterial Interaction in Patients with Heart Failure and a Preserved Ejection Fraction

As displayed in Figure 31-4, an increase in both Ea and Ees means erties of muscle cell size, wall geometry, intrasarcomeric protein
that systolic pressures are much more sensitive to changes in composition, cytosolic and membrane distensibility, and extracel-
cardiac preload, and thus central vascular blood volume. Small lular matrix composition, fibrillar crosslinking, and biophysical
changes in volume that might accompany dietary indiscretion or properties. These are discussed in detail in Chapters 2, 6, and 30.
diuretic usage will translate to more exaggerated changes in arte- Systolic ventricular stiffness is related to the same determinants
rial pressure.20 This also predicts higher pressures during stress, of stiffness in diastole, as well as activated myofilament properties,
which, in addition to requiring a greater amount of energy to changes in structural protein behavior shortened to smaller
deliver a given SV, can also alter both ejection and relaxation. A lengths, and interactions of the activated myocytes with the
higher resting Ees means that there can be less effective contractile matrix. As mentioned, the latter is typically measured as chamber
reserve to call upon during stress demands (Fig. 31-5A). Higher stiffness or elastance (pressure/volume), but has also been assessed
combined ventricular and vascular stiffening leads to greater invasively by transverse indentation methods or estimated based
cardiac energy demands to provide the body with a given amount on stress-strain analysis.30,31 Vascular stiffening also stems from
of blood flow (see Fig. 31-5B).2 Lastly, increased vascular stiffness structural and muscle-tone–dependent factors. Smooth muscle
and thus pulsatile loading can affect vascular homeostasis, coro- tone plays an important role, as does the geometry of the vessel
nary perfusion, and flow reserve.6 We next discuss each of these (e.g., dilation), elastin and collagen content, crosslinking of matrix
mechanisms in more detail. components, and other factors. This has been recently reviewed
in detail.32
How do these mechanisms relate to patients with HFpEF?
Mechanisms of Ventricular-Vascular Stiffening Many HFpEF patients have left ventricular hypertrophy (LVH),
Ventricular stiffening is a product of both passive and active concentric chamber remodeling, or both.33–36 While in some, this
muscle properties. Passive behavior is somewhat of a misnomer, may develop from a primary sarcomeric protein defect (as with
since diastolic tone is regulated in part by calcium and also by the genetic hypertrophic cardiomyopathies), this cause is uncommon
phosphorylation state and isoforms of various sarcomeric pro- compared with the maladaptive response to chronically increased
teins.28,29 Nonetheless, we can ascribe diastolic stiffening to prop- ventricular load, and we will focus on the latter here. In a large
Peak systolic pressure (mmHg)

180
Young
Elderly
ΔP 150

ΔP 120

90

60
A B 40 60 80 100 120
E LV end diastolic volume (ml)

y = 0.01x + 0.3
p = 0.001, r = 0.41
2
SBPEDV (mmHg/ml)

ΔP
ΔP 1

0
C D 0 20 40 60 80 100
F Age (yrs)
Figure 31-4 The effects of varying preload and afterload on systolic blood pressure (SBP) in the presence or absence of increased ventricular systolic
stiffening. A, In a normal patient, an increase in end diastolic volume (EDV) (arterial elastance [Ea] constant) leads to a corresponding increase in SBP (ΔP).
B, In a typical patient with heart failure with a preserved ejection fraction with increased end systolic elastance (Ees), the same increase in preload causes
a much greater increase in SBP. Similarly, while an increase in Ea causes an increase in SBP (C), this increase is amplified in the setting of elevated Ees (D),
causing a much greater increase in SBP. With normal aging, the dependence of SBP on preload becomes increased, as shown by a typical younger and
older patient (E). The slope of the SBP-preload relation plotted in E increases significantly with aging (F), related to increases in ventricular and arterial
stiffness. LV, left ventricular. (Modified from Chen C-H et al: Coupled systolic-ventricular and vascular stiffening with age: Implications for pressure regulation and
cardiac reserve in the elderly. J Am Coll Cardiol 1998;32:1221–1227.)
 Chapter 31 • Ventricular-Arterial Interaction in Patients with Heart Failure and a Preserved Ejection Fraction 407

100
700
Ea = 1.4
Percent change in stroke volume

unit change in stroke volume

Ea = 1.9 600

Change in cardiac work per

80 Ea = 2.5
with a doubling in Ees

500

(mmHg)
60 400
HFpEF
300
40
200 Con y/o HTN/o

100
20
0 6
5 5
4 4
3 3
0 2 2
Ea (mmHg/ml) 1 1 Ees (mmHg/ml)
0 2 4 6 8 10
Baseline Ees (mmHg/ml)
A B
Figure 31-5 The effects of basal end systolic elastance (Ees) on cardiovascular reserve function. A, The percent increase in stroke volume for a 100%
increase in Ees (i.e., contractility increase) is quite low when the baseline Ees is high. This hyperbolic relationship shifts in parallel with changes in arterial
load (arterial elastance, Ea), but this shift is modest compared to the effect of the baseline Ees value. B, The energetic cost for a given increase in cardiac
stroke volume is greatly increased in the setting of increased ventricular-arterial stiffness, as is seen in HFpEF. This increases myocardial oxygen demand
and may promote ischemia in addition to reducing reserve capacity. HTN/o refers to older-aged hypertensives, and Con y/o refers to young and old non-
hypertensive, healthy controls, respectively. For this prediction model, oxygen consumption is estimated based on the total pressure-volume area (PVA =
stroke work + potential area = SV × ESP + 0.5 × (ESV − Vo) × ESP), and this equation is resolved in terms of Ees, Ea by using two additional primary equa-
tions, one for the end-systolic elastance: ESP = Ees (ESV − Vo), and the other for effective arterial elastance: Ea = ESP/SV. SV, stroke volume; ESV, end-systolic
volume; Ees, end-systolic elastance; ESP, end-systolic pressure; Vo, volume axis intercept of the end-systolic pressure-volume relationship. More complete
details of the mathematics can be found in Suga H. Physiol Rev 1990;70:247–277. (Modified from Kawaguchi M, et al: Combined ventricular systolic
and arterial stiffening in patients with heart failure and preserved ejection fraction: Implications for systolic and diastolic reserve limitations. Circulation
2003;107:714–720.)

observational study of consecutive patients presenting with In addition to being older and often hypertensive, the majority
HFpEF, the mean LV mass index was 66.5 g/m2.7, well above of HFpEF patients are female,35,36,44 and this factor may also influ-
cutoff partition values for defining LVH (46.7 g/m2.7 in women ence abnormal ventricular-arterial stiffening. Women develop
and 49.2 g/m2.7 in men).36 Myocyte hypertrophy has been docu- concentric LVH in the setting of pressure overload more
mented, along with a modest rise in myofibrillar content and often compared with men.1,45,46 In addition, in a large population-
increases in passive myocyte stiffness in triton-skinned cells.37,38 based study of largely asymptomatic individuals, age-dependent
Myocardial fibrosis is also frequently observed, although this is increases in ventricular systolic and arterial stiffness were found
less clearly different from hearts displaying dilated cardiomyopa- to be more marked in women compared with men (see Fig. 31-2).
thy.38 Ventricular cellular passive stiffness has been found to cor- This may underlie part of the increased prevalence of HFpEF in
relate with estimates of diastolic chamber stiffness37 in HFpEF older women.1 The precise cause for this remains unknown but
subjects, and indeed diastolic stiffening is reported in these may in part relate to hormonal factors and differences in ventricu-
patients.27 Not all diastolic stiffening is intrinsic to the chamber, lar and aortic size and length. In contrast to vascular and ventricu-
however, as external loading factors also appear to contribute lar systolic stiffening, mean peripheral vascular resistance does not
importantly to observed diastolic stiffening, as indicated by inva- show this age-dependent rise and is greater in men. Thus women
sive pressure-volume analysis.2,39 are more likely to display accentuated increases in pulsatile loading
Diastolic stiffening alone can contribute to fluid redistribution with age, associated with greater coupled ventricular-arterial
into the lungs and limit net cardiac filling, but it cannot explain stiffening.
why patients with HFpEF typically present with severe, uncon-
trolled hypertension when they develop pulmonary edema40 and
often display marked blood pressure sensitivity to vasodilator or Pathophysiology of Ventricular-Arterial Stiffening
diuretic therapy. The latter more directly relates to increased left There are several important physiologic consequences of com-
ventricular (LV) systolic stiffening (Ees).2,41 In addition to arterial bined ventricular and arterial stiffening, as summarized in Table
systolic pulse pressure and stiffness, which are known to increase 31-1, and while each of the two components confers morbidity,
with age,1,21,42,43 Ees also has been shown to rise in tandem (see the combination of both leads to synergistic effects. One major
Fig. 31-2).1,41 In subjects who develop hypertension and cardiac repercussion is increased blood pressure lability and sensitivity to
hypertrophy, and those who further develop HFpEF, this stiffen- volume and vascular loading.2,20 In a normal heart-artery system,
ing is more pronounced over age-matched controls (see Fig. a rise in Ved results in a given rise in Pes (see Fig. 31-4A).
31-1B, Fig. 31-3). Since Ees also has been viewed as a measure of However, in a typical HFpEF patient, even if the coupling ratio
systolic contractile function, one might conclude that this reflects is normal, the same increase in Ved will lead to an accentuated
enhanced contractility. However, this seems unlikely, as other increase in systolic pressure (see Fig. 31-4B). The pressure-volume
parameters less dependent on chamber geometry do not increase area or stroke work to achieve this given SV therefore also is
with aging. higher in the HFpEF patient. Conversely, a given decrease in Ved
408 Chapter 31 • Ventricular-Arterial Interaction in Patients with Heart Failure and a Preserved Ejection Fraction

TABLE 31-1
PATHOPHYSIOLOGY OF VENTRICULAR-ARTERIAL STIFFENING
UNDERLYING ABNORMALITY HEMODYNAMIC CONSEQUENCES CLINICAL RELEVANCE

Increased Ventricular Systolic Stiffness 1. Amplified change in blood pressure for a 1. Hypotension and oliguria with slight overdiuresis or
given change in preload or afterload the addition of a new vasodilator agent
2. Lower contractile reserve 2. Modest volume infusion leads to hypertension and/
3. Lower stroke volume reserve or acute pulmonary edema
4. Greater energetic cost to eject a given 3. Impaired exercise tolerance and functional disability
stroke volume 4. Increased myocardial oxygen demand and ischemia
Increased Arterial Stiffness 1. Amplified change in blood pressure for a 1. Hypotension and oliguria with slight overdiuresis or
given change in preload or contractility the addition of a new vasodilator agent
2. Greater dependence upon systolic 2. Modest volume infusion leads to hypertension and/
pressure for coronary flow or acute pulmonary edema
3. Increased wave reflections and late 3. Greater degree of ischemia and larger infarct size for
systolic load given decrease in systolic blood pressure
4. Abnormal endothelial 4. Prolonged systole, abbreviated diastole, impaired
mechano-transduction relaxation
5. Endothelial dysfunction, further limiting vasodilation
in response to stress

will also lead to exaggerated drops in systolic pressure in this has consequences, as it can render the heart more sensitive to
stiffly coupled system. Similarly, an isolated increase in afterload declines in systolic performance. Consider a heart exposed to
(Ea) in an HFpEF patient will lead to a much more exaggerated coronary artery occlusion to induce acute ischemia (Fig. 31-6).
increase in blood pressure because of the higher baseline Ees (see When the heart ejects into a compliant arterial system, the occlu-
Fig. 31-4C and D). Increased ventricular-arterial stiffening sion is well compensated for by moderate chamber dilation, and
explains why systolic blood pressure is much more preload depen- there is little decline in systolic pressure. However, when the same
dent in older versus younger patients (see Fig. 31-4E and F). heart ejects into a stiff system by means of an in vivo aortic bypass
In addition to increased preload and afterload sensitivity, sys- tube,7 the results are markedly different. In this case, the heart
tolic reserve also becomes limited with increased stiffening. A dilates much more with the same occlusion, and the magnitudes
high basal Ees means that there is less effective change in systolic of both the ischemic bed size and the resulting decline in function
performance for a given percent rise in Ees during stress demands. are exacerbated.
Increases in Ees reflect contractility reserve, but the effect of a Cardiac interaction with a stiff arterial system also amplifies
change in Ees on net cardiac output is nonlinear, being much late systolic pressure loading, and this can affect both the net
greater when the starting value is low than when it rises (see Fig. amount of volume ejected and diastolic processes.49 Elevation of
31-5). If you link a heart with a high Ees to a stiff arterial system, afterload prolongs relaxation,50–53 an effect that can be mitigated
the net effect on systolic pressure is exacerbated,20 and thus ejec- in the setting of β-adrenergic activation.54 Progressive increases
tion is further compromised. Since exercise duration is deter- in late systolic load, induced by timed inflation of intra-aortic
mined predominantly by cardiac output reserve,47 combined balloons in animal models, have been shown to prolong LV
systolic ventricular and vascular stiffening can be an important relaxation.53 The increase in loading required to elicit a
contributor to exertional incapacity. prolongation was rather marked, at nearly 80% of maximum
A third consequence of combined arterial-ventricular systolic (i.e., isovolumic contraction). However, we have found that in
stiffening is that the cardiac work required to deliver a given patients with HFpEF, acute increases in afterload induced by
cardiac output increases. As shown in Figure 31-5B, using a previ- isometric handgrip can also slow isovolumic relaxation rate,2 and
ously validated model, one can estimate the required rise in cardiac this could contribute to elevated diastolic pressures and disease
work to achieve a given change in SV (heart rate constant) as a pathophysiology.
function of ventricular (Ees) and arterial (Ea) properties.2 This is A sixth mechanism whereby loss of arterial compliance and
depicted as a three-dimensional surface—with the lowest cost to thus distensibility with vascular stiffening may contribute to
the heart when both ventricular and arterial net elastances are low, disease pathophysiology lies in endothelial mechanosignaling.
and increasing cost as these rise. Mean values for both parameters The endothelium is a major physical force transducer that regis-
are depicted for four patient groups, including subjects with ters local changes in shear stress (flow) and vessel distension
HFpEF, who have double or more the energetic cost to the heart (stretch) and translates these signals to alterations in endothelial
compared with younger controls, and age-matched hypertensive function and vascular tone. Pulsatile perfusion combines both
subjects without LVH. Patients with chronic LVH and hyperten- stimuli, and recent studies from our laboratory have revealed that
sion but without heart failure symptoms had elevation of both25 these two signals combined provide additive stimulation for nitric
and an increased energy cost to the heart (data not shown). oxide synthase (NOS), a primary upstream kinase activator
The heart normally depends upon diastolic arterial pressure as (Akt), and cytoprotective effects against oxidant stress.10,11 The
the driving force for coronary artery perfusion, with more than latter appear mediated primarily by the augmented rise in Akt
70% of coronary flow provided during diastole. However, when activation. However, pulse perfusion in the relative absence of wall
the heart ejects into a stiff vasculature, it becomes more depen- cyclic distension yields a different response. Here, Akt activation
dent upon flow entering the circulation during systole.7,48 Animal is blunted and there is correspondingly less rise in NOS activation
studies have revealed that this change in pulse perfusion pattern and a substantial blunting of the protection to oxidant stress. This
 Chapter 31 • Ventricular-Arterial Interaction in Patients with Heart Failure and a Preserved Ejection Fraction 409

200 200

150 150

Pressure (mmHg)

Pressure (mmHg)
100 100

50 50

0 0
0 30 60 90 0 30 60 90

A Volume (ml) B Volume (ml)

Figure 31-6 The effects of acute ischemia in the setting of increased arterial stiffening. A, If the heart ejects into a normally compliant system, acute
occlusion of the left anterior descending induces a rightward shift in the pressure-volume loop, with an increase in end diastolic and systolic volumes,
and a slight decrease in systolic pressure. B, If the same experiment is performed with the heart ejecting into a stiff vasculature, the heart dilates more,
end systolic volume shifts more to the right, and there is a greater diminution in the systolic blood pressure developed. (Modified from Kass DA et al: Adverse
influence of systemic vascular stiffening on cardiac dysfunction and adaptation to acute coronary occlusion. Circulation 1996;93:1533–1541.)

signaling appears specifically coupled to stretch stimulation group was significantly older than the healthy older volunteers).
(rather than shear), and although the exact cascade responsible The authors went on to show that changes in aortic distensibility
remains to be elucidated, it has intriguing implications. One is and cross-sectional area strongly predict exercise performance
that reduced arterial compliance can blunt the normal flow- (peak oxygen consumption) (Fig. 31-7), even after adjusting for
mediated dilatory response that is a central component of vaso- age and gender in multivariate regression analysis. Aortic wall
dilator reserve under stress. While this direct link has yet to be thickness was significantly greater in HFpEF subjects compared
proven in vivo, it may indeed contribute to vasodilator reserve with both groups, supporting the notion that exaggerated vascular
limitations in the elderly, and in particular in individuals with remodeling contributes to increased arterial stiffening in these
HFpEF, who require such reserve as a compensation for the loss patients, independent of or in addition to normal aging.
of other cardiovascular mechanisms.55 We recently showed that compared with hypertensive subjects
with LVH, patients with HFpEF display a markedly blunted
ability to augment cardiac output with upright exercise, despite a
Ventricular-Arterial Stiffening and similar increase in LV Ved.55 Their inability to increase cardiac
Exercise Reserve output with stress correlated with chronotropic incompetence
Increases in ventricular and vascular stiffness affect cardiovascular and an inability to properly vasodilate and reduce systemic vascu-
reserve function with exercise stress. Warner et al. studied the lar resistance during exercise. Baseline blood pressure and vascu-
effects of losartan on exercise performance in 20 asymptomatic lar stiffness were similarly elevated in both groups, and only by
hypertensive subjects with echo-Doppler diastolic dysfunction measuring changes with exercise was the deficit in vasodilator
and a hypertensive response to exercise, suggesting increased reserve function observed.
ventricular-vascular stiffness.56 While losartan had no effect on
resting blood pressure, it decreased peak systolic pressure during
exercise, increased the time for blood pressure to exceed CLINICAL RELEVANCE: THERAPEUTIC
190 mmHg, and was associated with an approximately 10% STRATEGIES TARGETING STIFFNESS
increase in peak oxygen consumption. The authors speculated
that losartan therapy improved diastolic performance, but this Ventricular-vascular stiffening can be treated with agents that
was not directly demonstrated. An equally plausible explanation acutely modulate ventricular systolic and diastolic performance,
is that losartan provided for a greater reduction in aortic input vascular smooth muscle tone, and endothelial function. Interven-
impedance during stress, improving the cardiac output response tions such as verapamil that acutely reduce ventricular and vascu-
to exercise. In a more recent study from this group, 6 months of lar stiffness have been shown to improve exercise capacity in
losartan compared with hydrochlorothiazide treatment found patients with HFpEF59 and hypertrophic cardiomyopathy60,61 and
similar reductions in exercise-induced hypertension in this popu- in elderly patients with hypertension and hypertrophy.62 A large
lation, while only losartan improved exercise performance and part of the mechanistic benefit has been believed to be related to
quality of life measures, suggesting that direct ventricular and improvements in ventricular peak filling rate (PFR), assessed by
vascular effects, rather than blood pressure change per se, are nuclear gated blood pool study.59–61 However, a more recent trial
critical in determining cardiovascular reserve function.57 in older hypertensive patients found that verapamil did not
Hundley et al. studied the relationship between proximal produce a consistent increase in PFR.62 In contrast, it was associ-
aortic distensibility derived from magnetic resonance imaging ated with significant reductions in ventricular systolic stiffness
(MRI) and exercise performance in 10 young, 10 older, and 10 (contractility/peak cardiac power index) and vascular stiffness
HFpEF subjects.58 They demonstrated that aortic distensibility is (Ea, pulse wave velocity, augmentation index), and these changes
highest in the young and most compromised in HFpEF patients, were in turn associated with a 50% improvement in aerobic exer-
even compared with healthy older subjects (although the HFpEF cise performance. In subjects with lower resting PFR, verapamil
410 Chapter 31 • Ventricular-Arterial Interaction in Patients with Heart Failure and a Preserved Ejection Fraction

7 150

6 125
Distensibility (10–3 mmHg–1)

Area change (mm2)

5
100
Figure 31-7 Increased vascular stiffness
4
impairs metabolic exercise performance in
75
heart failure with a preserved ejection fraction
3 (HFpEF). Both A, aortic distensibility and B,
50 change in cross-sectional area correlate strongly
2 with peak oxygen consumption (PkVO2) during
y = 0.003x – 1.54 y = 0.056x – 21.08
metabolic exercise testing in young (green dia-
r = 0.79 25 r = 0.82
1 monds), older (red squares), and HFpEF subjects
(blue triangles). (Modified from Hundley WG et al:
0 0 Cardiac cycle–dependent changes in aortic area
and distensibility are reduced in older patients
0 1000 2000 3000 4000 0 1000 2000 3000 4000 with isolated diastolic heart failure and correlate
PkV02 (ml/min) PkV02 (ml/min) with exercise intolerance. J Am Coll Cardiol
A B 2001;38:796–802.)

tended to increase it, but if PFR was higher at rest, verapamil Drugs specifically targeting ventricular hypertrophy may also
tended to diminish it. However, it is important to note that exer- prove very useful. An emerging player in hypertrophy signaling,
cise performance improved similarly in both groups of patients. rho kinase,71 is a key downstream effector of Gq-protein–coupled
In a recent study of HFpEF subjects, we found that resting PFR angiotensin-II signaling. Rho kinase increases vascular smooth
was elevated compared with hypertensive/LVH controls because muscle cell tone, and the rho kinase inhibitor fasudil is being eval-
of volume overload, suggesting that verapamil may have less uated as an anti-anginal drug. Fasudil also attenuates angiotensin-
benefit in this population.55 It is noteworthy that all of these trials II–induced cardiac hypertrophy, thus therapies interfering with
were limited by relatively small sample sizes and did not involve rho kinase may prove synergistically useful relative to its vasodila-
chronic administration of study drug. tory and antihypertrophic properties.72 Intriguingly, hydroxy-
Pure vasodilators may have more variable effects. Two weeks methylglutaryl coenzyme-A (HMG-CoA) reductase inhibitors
and 6 months of treatment with the angiotensin receptor antago- (statins), which are known to inhibit rho kinase activation,73
nist losartan improved exercise performance in subjects with a have also been shown to be associated with improved survival in
hypertensive response to exercise,56,57 while acute vasodilation a retrospective analysis of patients with HFpEF.74 We recently
with sodium nitroprusside did not share such beneficial effects.63 demonstrated that the phosphodiesterase (PDE)-5 inhibitor
The latter is somewhat predictable, since a given reduction in Ea sildenafil markedly attenuated the hypertrophic response to
results in more exaggerated decreases in blood pressure with rela- pressure overload in mice.75 In humans, sildenafil suppresses acute
tively less increase in stroke volume in the setting of high baseline β-adrenergic–stimulated contractility,76 and ongoing studies,
Ees (see Fig. 31-4D). Propranolol, which decreases Ees but including an NIH-sponsored multicenter trial (RELAX trial), are
increases Ea, also does not improve net exercise performance.64 evaluating whether it can blunt or even reverse hypertrophic
However, none of these small trials were performed in patients responses in patients with HFpEF. Since both rho kinase and
with HFpEF. Given the extent of chronotropic incompetence in PDE-5 inhibitors can reduce LVH and arterial stiffness and cause
HFpEF patients,55,65 drugs such as calcium channel antagonists modest vasodilation, they present attractive approaches to treat
and beta blockers require more study to compare offsetting effects multiple potentially synergistic abnormalities in HFpEF patients.
on ventricular and arterial stiffness and heart rate. As basic research continues to define more of the cellular mech-
anisms contributing to increases in ventricular and arterial stiff-
ness, remodeling, and hypertrophy, we will increasingly be able
FUTURE RESEARCH to target HFpEF more specifically and efficaciously at its
pathophysiologic foundations. Such basic findings will be more
Many of the increases in ventricular-arterial stiffness in HFpEF effectively translated to the bedside as additional clinical
are chronic in nature, due to changes in the material properties of hemodynamic studies are performed to distill how each compo-
the cardiovascular system.6 In the largest randomized trial of nent of ventricular-arterial stiffening specifically modifies systolic
heart failure with near-normal EF (Candesartan in Heart Failure: and diastolic performance in patients with HFpEF.
Assessment of Reduction in Mortality and Morbidity [CHARM]–
Preserved), there was a borderline-significant treatment effect
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27. Zile MR, Baicu CF, Gaasch WH: Diastolic heart failure—abnormalities in in myocardial relaxation: A mechanism for diastolic dysfunction. Cardiovasc
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28. Kass DA, Bronzwaer JG, Paulus WJ: What mechanisms underlie diastolic dependent cardiac modulation in vivo by troponin I with constitutively
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29. Granzier HL, Labeit S: The giant protein titin: A major player in myocardial 55. Borlaug BA, Melenovsky V, Russell SD, et al: Impaired chronotropic
mechanics, signaling, and disease. Circ Res 2004;94:284–295. and vasodilator reserves limit exercise capacity in patients with heart
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57. Little WC, Zile MR, Klein A, et al: Effect of losartan and hydrochlorothia- 67. Pitt B, Reichek N, Willenbrock R, et al: Effects of eplerenone, enalapril, and
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diastolic dysfunction. Am J Cardiol 2006;98:383–385. tricular hypertrophy: The 4E-left ventricular hypertrophy study. Circulation
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elderly individuals. J Am Coll Cardiol 1999;33:1602–1609. 73. Liao JK: Statin therapy for cardiac hypertrophy and heart failure. J Investig
63. Nussbacher A, Gerstenblith G, O’Connor FC, et al: Hemodynamic effects Med 2004;52:248–253.
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during dynamic exercise. Circulation 1994;90:2333–2341. 75. Takimoto E, Champion HC, Li M, et al: Chronic inhibition of cyclic GMP
65. Brubaker PH, Joo KC, Stewart KP, et al: Chronotropic incompetence and phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med
its contribution to exercise intolerance in older heart failure patients. J Car- 2005;11:214–222.
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 ANNE S. KANDERIAN, MD
AJAY BHARGAVA, MD
GARY S. FRANCIS, MD
32
General Treatment of
Diastolic Heart Failure
INTRODUCTION BACKGROUND
BACKGROUND
There are several trials that are ongoing or under consideration
PATHOPHYSIOLOGY to test different therapies in patients with diastolic heart failure.
CLINICAL RELEVANCE Only two large trials have been completed. The Candesartan
General Treatment Guidelines in Heart Failure: Assessment of Reduction in Mortality and
Treatment of Underlying Disease and Morbidity (CHARM-Preserved) trial5 demonstrated a trend
Contributing Factors toward improvement as measured by fewer hospitalizations for
Specific Therapies heart failure when candesartan was added to conventional therapy.
More recently, the perindopril in elderly people with chronic heart
FUTURE RESEARCH failure (PEP-CHF) study was published. This study did not show
SUMMARY a mortality benefit with perindopril, but similarly, there was a
significant reduction in heart failure related hospitalizations at
one year.5a However, the cardiovascular event rate in patients with
diastolic heart failure is relatively low compared with patients
INTRODUCTION with systolic heart failure. There are more noncardiovascular
deaths and non–heart failure hospitalizations in patients with
Even the language of “diastolic heart failure” is controversial.1 The diastolic heart failure, as they tend to be older and have more
phrase “heart failure with preserved left ventricular function” is comorbid conditions. Elderly women with hypertension, LV
preferred by many. When there is uncertainty about the name of hypertrophy (LVH), and ischemic heart disease are the proto-
a disorder and ambiguity regarding its pathophysiology, you can typical patients. This makes it much more difficult to demonstrate
be almost certain that there will be little agreement about its a clear reduction in all-cause death and all-cause hospitalizations
treatment. However, there is general, although not universal, in a clinical trial that focuses on treatment of diastolic heart
agreement that the fundamental problem of diastolic heart failure failure, unless the sample size is very large and the follow-up is
is impaired left ventricular (LV) filling. The left ventricle is often quite long. Recognition of this problem has probably hampered
thickened and stiff, and the filling pressures are increased relative the design and implementation of large clinical trials for the treat-
to the LV volume. This leads to the cardinal features of heart ment of diastolic heart failure.
failure, including pulmonary congestion, dyspnea, exercise intol- Because the language and pathophysiology of diastolic heart
erance, and edema. In fact, systolic and diastolic failure are usually failure are complex,6–8 it is not unexpected that the treatment
clinically indistinguishable at the bedside. In most cases, a detailed would also be ambiguous. Nevertheless, certain general principles
imaging or even a hemodynamic study is necessary to understand of treatment can be applied. One should initially target therapy
the underlying structural and functional distinction between sys- toward reducing pulmonary congestion, maintaining synchro-
tolic and diastolic heart failure. Moreover, systolic and diastolic nous atrial contraction, and increasing the duration of diastole by
functions are intertwined and usually don’t occur in isolation.2 reducing heart rate. Sodium restriction, reduction of total blood
These observations have in part obscured the development of volume, and reduction of central blood volume are generally
a specific therapy designed to treat diastolic heart failure. useful. Blunting neurohormonal activation (both the sympathetic
There currently is no targeted therapy for diastolic heart failure. nervous system [SNS] and the renin-angiotensin-aldosterone
This may change as old concepts of pathophysiology are system [RAAS]) seems helpful. Hypotension should be avoided
challenged.3,4 by cautious use of low-dose diuretics, so as to maintain blood
415
416 Chapter 32 • General Treatment of Diastolic Heart Failure

pressure and cardiac output. Interventions should include drugs myocardial mass and changes in the extracellular matrix caused by
designed to prevent and treat myocardial ischemia and foster excess fibrillar collagen.7,10 Ventricular relaxation is an energy-
prevention and regression of LVH. Preservation of exercise toler- dependent process and is often impaired when myocardial isch-
ance is an important clinical goal.7 Nevertheless, it should be emia is present.11 Hypertension, LVH, and fibrosis caused by
reiterated that there are no large randomized clinical trials to scarring from myocardial infarction (MI), dilated cardiomyopa-
guide our therapy, with the exception of CHARM-Preserved and thy, or aging all lead to increased myocardial stiffness.12 Additional
PEP-CHF, and both of these trials failed to show a survival etiologies include pericardial diseases, infiltrative cardiomyopa-
benefit. thies, and hypertrophic cardiomyopathy. Each increases myocar-
Despite a lack of clinical trial data, physicians are faced on a dial stiffness and produces diastolic dysfunction.9
daily basis with patients who have severe diastolic heart failure. Just as in heart failure with impaired LV function, neurohor-
The question remains, how should we manage them? This chapter monal and endothelial activity play important roles in diastolic
will outline a number of conventional treatment options currently heart failure.7,13 Activation of the RAAS contributes to increased
available. We may lack objective data from large clinical trials, but myocardial stiffness, partly by increasing reactive collagen deposi-
we have years of observational data. These treatment options are tion.7 The collagen matrix is particularly active in heart failure,
outlined in Table 32-1. leading to both enhanced collagen synthesis and a higher turnover
of collagen.7 The ratio of myocardial fibroblasts to myocytes is
4 : 1, implying the important role of collagen in myocardial growth
PATHOPHYSIOLOGY and hypertrophy. Angiotensin II and aldosterone stimulate hyper-
trophy and proliferation of cells and stimulate collagen synthesis
To date, the pathophysiology of diastolic heart failure is incom- by fibroblasts, leading to LV remodeling, including hypertro-
pletely understood and is not directly addressed by any drugs cur- phy.7,14 Therefore, one could postulate that reducing RAAS activ-
rently available. The core feature of diastolic heart failure is ity with agents such as angiotensin-converting-enzyme (ACE)
inadequate LV diastolic filling, which is a consequence of both inhibitors, angiotensin receptor blockers (ARBs), and aldosterone
impaired LV relaxation and increased LV stiffness.6,8–10 Several receptor blockers is beneficial in patients with diastolic heart
mechanisms contribute to these processes, including increased failure, just as in systolic heart failure.

TABLE 32-1
MANAGEMENT OF PATIENTS WITH DIASTOLIC HEART FAILURE
OBJECTIVE TREATMENT DAILY MEDICATION DOSE

Control congestion Salt restriction <2 g of sodium per day

Diuretics Furosemide 10–120 mg
Hydrochlorothiazide 12.5–25 mg
Control hypertension and regress LVH Diuretics Chlorthalidone 12.5–25 mg
Hydrochlorothiazide 12.5–25 mg
Beta blockers Atenolol 12.5–100 mg
Metoprolol 12.5–200 mg
Propranolol 20–80 mg
Carvedilol 3.126–50 mg
ACE inhibitors Enalapril 2.5–40 mg
Lisinopril 10–40 mg
Ramipril 5–20 mg
Captopril 25–150 mg
ARBs Losartan 50–100 mg
Candesartan 4–32 mg
Aldosterone blockers Spironolactone 25–75 mg
CCBs Amlodipine 2.5–10 mg
Felodipine 2.5–20 mg
Maintain sinus rhythm and control tachycardia Cardioversion of atrial fibrillation
Radiofrequency ablation of atrial fibrillation
Beta blockers Atenolol 12.5–100 mg
Metoprolol 12.5–200 mg
CCBs Verapamil 120–360 mg
Diltiazem 120–540 mg
Treat myocardial ischemia Coronary revascularization (coronary artery bypass surgery
or percutaneous coronary intervention)
Nitrates Isosorbide dinitrate 30–180 mg
Isosorbide mononitrate 30–90 mg
Beta blockers Atenolol 12.5–100 mg
Metoprolol 12.5–200 mg
CCBs Amlodipine 2.5–10 mg
Verapamil 120–360 mg
Diltiazem 120–540 mg

LVH, left ventricular hypertrophy; ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; CCB, calcium channel blocker.
Modified from Aurigemma GP, Gaasch WH: Diastolic heart failure. NEJM 2004;351:1097–1105.
 Chapter 32 • General Treatment of Diastolic Heart Failure 417

Increased LV stiffness and decreased compliance of the ventri- TABLE 32-2

cle are reflected in the pressure-volume loop curve such that for
any given LV volume, a higher LV diastolic pressure is observed. AMERICAN COLLEGE OF CARDIOLOGY/AMERICAN
Likewise, for any pressure, the LV end diastolic volume is HEART ASSOCIATION RECOMMENDATIONS FOR
much smaller.8,12 Pulmonary congestion ensues when the TREATMENT OF PATIENTS WITH HEART FAILURE AND
higher pressures are transmitted back to the lungs.12,13 All these NORMAL LEFT VENTRICULAR EJECTION FRACTION
lead to the typical symptoms of heart failure, including exer-
Class I Level of Evidence
tional dyspnea and diminished exercise tolerance. An exaggerated 1. Control of systolic and diastolic A
hypertensive response to exercise is often observed when patients hypertension in accordance with published
with diastolic heart failure undergo exercise stress testing.11 This guidelines
may be due to the high frequency of concomitant systemic 2. Control of ventricular rate in patients with C
atrial fibrillation
hypertension. 3. Use of diuretics to control pulmonary C
congestion and peripheral edema
Class IIa Level of Evidence
CLINICAL RELEVANCE 1. Coronary revascularization in patients with C
coronary artery disease in whom
General Treatment Guidelines symptomatic or demonstrable myocardial
ischemia is judged to be having an adverse
The goals of treatment of diastolic heart failure are similar to effect on cardiac function
those of systolic heart failure. Not only do we seek to improve Class IIb Level of Evidence
survival in our patients, but we also aim to improve our patients’ 1. Restoration and maintenance of sinus C
rhythm in patients with atrial fibrillation
quality of life by reducing symptoms, increasing exercise toler- 2. Use of beta blockers, ACE inhibitors, ARBs, or C
ance, and decreasing hospitalizations. Like most disease states, CCBs in patients with controlled
treatment should be based on evidence derived from clinical trials. hypertension to minimize symptoms of
Practice guidelines are generally data driven, but when there are heart failure
few data, consensus or expert opinion is provided. Most of the 3. Use of digitalis to minimize symptoms of C
heart failure is not well established.
data from clinical trials have been exclusive to systolic heart
failure. Although the mortality rate of patients with diastolic
ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; CCB, calcium
heart failure is not quite as high as that of systolic heart failure, channel blocker.
it is nevertheless higher than in patients without heart failure.8,13,15
Moreover, there is significant morbidity associated with diastolic
heart failure, and the hospitalization rate in the elderly remains The Heart Failure Society of America (HFSA) also produced
close to that of systolic heart failure.8,10,16 Approximately one an executive summary on its Heart Failure Practice Guidelines.19
third to one half of all patients with manifest heart failure have These too include a section on evaluation and management of
preserved ejection fraction (EF).8,10,13,16,17 The incidence of dia- patients with heart failure and preserved LVEF (Table 32-3). The
stolic heart failure depends on the local demographics. Hospitals guidelines highlight the necessity to obtain a differential diagnosis
in large inner-city neighborhoods will see much more diastolic in these patients, as treatment may vary for differing conditions.
heart failure, as poorly treated hypertension and elderly people The HFSA recommendations are similar to those of the ACC/
are more common. Therefore it remains crucial that we learn AHA task force and stress the importance of evaluating for myo-
more about effective treatment strategies for patients with dia- cardial ischemia, controlling blood pressure, and counseling on
stolic heart failure. However, lack of data from large clinical trials salt restriction. Diuretic therapy is recommended in those patients
is reflected in the practice guidelines set forth by the experts. with evidence of volume overload. ACE inhibitors are recom-
The practice guidelines on chronic heart failure of the Ameri- mended in all patients with heart failure and preserved EF who
can College of Cardiology/American Heart Association (ACC/ have diabetes or atherosclerotic cardiovascular disease and
AHA) were revised in 200518 and include a section on patients one additional risk factor. The guidelines recommend that ARBs
with heart failure and normal LVEF. The recommendations listed be used in patients who are intolerant of ACE inhibitors.
by the task force are presented in Table 32-2. Beta blockers are recommended in patients who have a history of
Class I recommendations include control of hypertension, MI, hypertension, or atrial fibrillation with rapid ventricular
control of ventricular rate in patients with atrial fibrillation, and rate. CCBs are recommended in those patients who have atrial
use of diuretics to control pulmonary congestion and peripheral fibrillation but are intolerant to beta blockers, those with
edema. Coronary revascularization in patients with heart failure symptom-limiting angina, and those with hypertension. Finally,
and normal EF and coronary artery disease is a class IIa recom- the guidelines recommend that sinus rhythm be restored and
mendation. Restoration and maintenance of sinus rhythm in maintained in patients who have symptomatic atrial fibrillation
patients with atrial fibrillation, heart failure, and normal EF may or flutter.
improve symptoms and is a class IIb recommendation. Due to a These guidelines are essentially based on observational
paucity of data to guide management of patients with diastolic studies. Other than for the ACC/AHA and HFSA guidelines,
heart failure, a class IIb recommendation is given to beta blockers, there are few recommendations to offer patients with diastolic
ACE inhibitors, ARBs, and calcium channel blockers (CCBs). heart failure. While there is no standardized treatment, attention
Efficacy of digitalis to minimize symptoms of heart failure in needs to be paid to the individual patient and to potential
patients with a normal EF is not well established, and its use is etiologies of diastolic heart failure. Since no patient is quite like
also a class IIb recommendation. The task force emphasized the another, treatment strategies should be targeted to underlying
need to eliminate other conditions that may contribute to heart mechanisms that could be contributing to heart failure in each
failure with a normal EF. individual.
418 Chapter 32 • General Treatment of Diastolic Heart Failure

18
TABLE 32-3
16

Reduction in left ventricular

THE HEART FAILURE SOCIETY OF AMERICA
14 *
RECOMMENDATIONS FOR MANAGEMENT OF

mass index (%)

PATIENTS WITH HEART FAILURE AND PRESERVED 12 * †
LEFT VENTRICULAR EJECTION FRACTION 10
8
STRENGTH OF
RECOMMENDATION EVIDENCE 6
4
1. Detailed approach to differential diagnosis C
by use of echocardiography, 2
electrocardiography, and stress imaging 0
2. Evaluate for possible myocardial ischemia C
3. Aggressive blood pressure management C ARBs CCBs ACE Diuretics Beta
4. Low sodium diet C inhibitors blockers
5. Diuretic recommended in all patients with C Figure 32-1 Reduction in left ventricular (LV) mass index (percentage
clinical evidence of volume overload from baseline) associated with antihypertensive therapy from different
(thiazide or loop diuretic), with avoidance drug classes. The results are based on a meta-analysis of eight trials
of excessive diuresis and over 4100 patients. The reduction of LV mass index was significantly
6. ARBs or ACE inhibitors should be B or C respectively higher with angiotensin II receptor blockers (ARBs) (13%), calcium channel
considered blockers (CCBs) (11%), and angiotensin-converting-enzyme (ACE) inhibi-
7. ACE inhibitors should be considered in C tors (10%) compared with beta blockers (6%). * indicates p < 0.05 versus
patients with symptomatic atherosclerotic beta blockers; † indicates p < 0.01 versus beta blockers. (From Klingbeil AU
cardiovascular disease or diabetes and 1 et al: A meta-analysis of the effects of treatment on left ventricular mass in
additional risk factor essential hypertension. Am J Med 2003;115:41–46.)
8. ARBs should be considered in patients who C
meet the above criteria but are intolerant
to ACE inhibitors to LVH, causing impaired LV compliance because of a stiffer
9. Beta blockers recommended in patients
with: ventricle. Antihypertensive therapy is critical in diastolic heart
a. Prior MI C failure, as it induces LVH regression, improving diastolic perfor-
b. Hypertension B mance and LV distensibility.11
c. Atrial fibrillation requiring rate control B Klingbeil et al. published a meta-analysis of the effects of treat-
10. CCBs should be considered in:
a. Atrial fibrillation requiring rate control in C
ment on LV mass in essential hypertension.21 This meta-analysis
patients intolerant to beta blockers of 80 clinical trials and over 4000 patients showed that anti-hyper-
(diltiazem or verapamil) tensive drug classes had differing effects on LV mass reduction.
b. Symptom-limiting angina A ARBs produced a 13% reduction of LV mass index; CCBs, 11%;
c. Hypertension (amlodipine) C ACE inhibitors, 10%; diuretics, 8%; and beta blockers, 6% (Fig.
11. Restore and maintain sinus rhythm in C
patients with symptomatic atrial flutter/ 32-1). ARBs, CCBs, and ACE inhibitors all reduced LV mass
fibrillation index more significantly than beta blockers. It is intuitive that with
LVH regression, diastolic function might improve; however, it
ARB, angiotensin receptor blocker; ACE, angiotensin converting enzyme; MI, myocardial remains to be determined whether a greater reduction in LV mass
infarction; CCB, calcium channel blocker. improves clinical outcomes. Nevertheless, in the Losartan Inter-
vention For Endpoint Reduction in Hypertension (LIFE) study,
Treatment of Underlying Disease and regression of Cornell product LVH was associated with 35% to
45% reductions in the risk of cardiovascular death, stroke, or MI,
Contributing Factors a 37% reduction in the composite endpoint, and a 28% reduction
There are several conditions that contribute to or exacerbate dia- in all-cause mortality.22 It is very infrequent that single drug
stolic heart failure. These include hypertension, LVH, myocardial therapy is effective in reducing blood pressure, and we are often left
ischemia, increased vascular stiffness, diabetes mellitus, renal to employ multiple agents to achieve goal blood pressure, espe-
failure, anemia, obesity, and pulmonary diseases.12,20 Furthermore, cially in patients with concomitant diabetes mellitus.
there may be external constraints on the myocardium and peri- While medical therapy and lower blood pressure contribute to
cardium that render the left ventricle incapable of filling ade- LVH regression, one must not forget that weight loss, reduced
quately,11 thereby mimicking diastolic heart failure. It is crucial to salt intake, and exercise can also play roles in managing hyperten-
consider these conditions, as treatment of constrictive pericarditis sion. A recent cross-sectional study showed that long-term caloric
is obviously quite different than that of systemic hypertension restriction ameliorates the decline in diastolic function in
with LVH. humans.23 Twenty-five patients with caloric restriction were com-
pared with 25 age- and gender-matched healthy subjects on a
standard Western diet and were found to have lower body mass
Hypertension index, systolic and diastolic blood pressures, and levels of inflam-
Hypertension is associated with an increase in left atrial (LA) matory markers. Indices of diastolic function were improved in
pressure that contributes to increased LV diastolic pressure and patients with caloric restriction compared with the matched con-
delays early diastolic filling (see Chapter 19).11 Lowering the trols on a Western diet; however, no change was found with
blood pressure allows the ventricle to relax more adequately, respect to systolic function. It is unclear whether the effect of
thereby increasing early diastolic filling.11 Furthermore, treating caloric restriction on diastolic function is independent of blood
hypertension may reduce myocardial ischemia, which can also pressure; nevertheless, emphasis should be placed on targeting
contribute to diastolic heart failure. Chronic hypertension leads dietary modifications when advising patients.
 Chapter 32 • General Treatment of Diastolic Heart Failure 419

Coronary Artery Disease Some experimental studies have been conducted on diabetic
animal models. Studies in prediabetic rats as well as in advanced
Myocardial ischemia or infarction is a major contributor to dia- diabetic rats have consistently demonstrated that peroxisome pro-
stolic heart failure (see Chapter 22). One of the first hemody- liferator–activated receptor (PPAR) ligands improve glucose and
namic parameters observed when a coronary artery is acutely lipid metabolism, as well as prevent LV diastolic dysfunction.37–39
occluded by angioplasty is a reduction in negative change in pres- PPAR-α agonists such as pioglitazone or rosiglitazone not only
sure versus time (−dp/dt). This change is manifested by an abrupt improve insulin resistance but facilitate endothelial function.40–42
increase in LV end diastolic pressure before there are any changes Recent studies have confirmed the existence of endothelial dys-
in systolic function.11 These observations suggest that diastolic function in patients with systolic heart failure,43 and we can
relaxation, known to be energy dependent, is exquisitely sensitive perhaps assume that this is altered in patients with diastolic heart
to myo-cardial ischemia, even more so than systolic function.11 failure as well. Nonetheless, endothelial dysfunction has been
The pressure-volume relationship is shifted up and to the left.24 implicated in the pathophysiology of hypertension,43 which is
The chamber stiffness constant, k, achieves a greater slope. Fibro- closely associated with development of diastolic heart failure. It is
sis produced by scarring from a prior infarction also contributes plausible that PPAR ligands may be useful in diabetic patients
to LV stiffening.9,25 Diastolic heart failure is primarily a disease with diastolic heart failure, although randomized double-blind
of the elderly, and it is in this population that the prevalence of studies are needed, especially since PPAR agonists have been
coronary artery disease is most high. There are no data demon- noted to promote fluid retention and exacerbation of heart
strating that coronary revascularization leads to an improvement failure.
in diastolic heart failure outcomes. Revascularization alone, Patients with impaired diastolic function can remain asymp-
without further medical therapy, has not been shown to reduce tomatic for years without evident heart failure. LA hypertrophy
the incidence of pulmonary edema.10,11 In fact, one study showed and forceful LA contraction can augment late diastolic filling.11
that pulmonary edema occurred in 50% of patients within 6 However, in patients with atrial fibrillation, this useful mecha-
months after revascularization.26 Despite this, it is essential that nism is absent, invoking an augmentation of LA pressure. The left
screening for coronary artery disease be performed, either by inva- atrium then acts more as a simple conduit and cannot propel
sive or noninvasive techniques, as myocardial ischemia is a well- blood easily into the thickened, nondistensible left ventricle. Pul-
established cause of diastolic heart failure. monary congestion ensues and consequently symptomatic heart
failure. Therefore, it is usually advantageous to restore and main-
Diabetes tain sinus rhythm in patients with diastolic heart failure. When
Diabetes mellitus and impaired glucose metabolism contribute to this is not feasible, it is important to at least control ventricular
LVH and arterial stiffness, which impair LV relaxation and dis- rate, as tachycardia reduces the time for complete relaxation and
tensibility (see Chapter 26).11,27 Furthermore, the prevalence of may be hazardous to patients with diastolic dysfunction. Slowing
coronary artery disease is higher in patients with diabetes, and the heart rate enables more time for diastolic filling and thus
there may be more underlying microvascular disease. The advanced better coronary perfusion and LV performance.10
glycation of proteins forms complex compounds known as
advanced glycation end-products (AGEs), which cross-link and
polymerize with other proteins. These cross-links with collagen Specific Therapies
alter vascular compliance, resulting in loss of elasticity and
increased vascular stiffness.28 This process occurs with normal
Diuretics
aging but is often accelerated in the presence of diabetes. In hyper- Life-threatening pulmonary edema can occur in patients with
tensive patients without diabetes, fasting plasma glucose is associ- diastolic heart failure. It can be a dramatic presentation and
ated with adverse diastolic function independent of LVH.29 should be promptly treated, as in any case of acute pulmonary
Several studies have reported that insulin resistance in nondia- edema. Severe systemic hypertension is frequently present and
betic patients with hypertension is associated with diastolic dys- must be aggressively treated. Acute myocardial ischemia, mycar-
function.30–33 In fact, hypertension and diabetes mellitus are a dial infarction, and rapid atrial fibrillation must also be identified,
dominant force in the development of systolic and diastolic heart and if evident, promptly treated. Intravenous diuretics, nitrates,
failure, and the combination of the two is associated with more oxygen, and in some cases morphine sulfate are frequently
severe abnormal LV relaxation.27 employed. Intubation and ventilatory support may be necessary,
It is not unreasonable to conclude that treating diabetes and and patients with chronic or acute renal failure may sometimes
improving glucose control may be favorable in patients with dia- need urgent dialysis. Intravenous furosemide and nitrates should
stolic heart failure. Nevertheless, some studies have shown that be employed judiciously, as patients with diastolic heart failure
an improvement in glycemic control in patients with type II dia- and small LV chambers may be more easily volume depleted than
betes mellitus does not ameliorate diastolic function in spite of patients with large, dilated, poorly contracting hearts.11 This is
regression of LVH.34,35 It may be that improved glycemic control particularly the case when there is an absence of systemic hyper-
has little effect on the already present AGEs responsible for col- tension, making diastolic heart failure difficult to treat. The dia-
lagen cross-linking and fibrosis. The LIFE study noted that stolic pressure-volume curve is steep, implying that small changes
patients with diabetes have less regression of LVH than those in volume result in large changes in pressure, and therefore a
without diabetes in response to antihypertensive therapy.36 Addi- significant drop in cardiac volume can produce hypotension and
tionally, regression of Cornell product LVH with antihyperten- reduced cardiac output.
sive therapy was associated with a reduction in the composite Diuretics have no direct effect on actual diastolic function, but
endpoint in the nondiabetic population, but this did not appear they can reduce central blood volume. Loop diuretics preferen-
to be the case in patients with diabetes. These observations stress tially are utilized in treating volume overload, whereas thiazide
the importance of prevention, early strict glycemic control, and diuretics are more useful for control of blood pressure. The Anti-
blood pressure control. hypertensive and Lipid-Lowering Treatment to Prevent Heart
420 Chapter 32 • General Treatment of Diastolic Heart Failure

Attack Trial (ALLHAT) demonstrated that chlorthalidone was losartan with regard to the composite primary endpoint of car-
superior to both amlodipine and lisinopril in hypertensive diovascular death, stroke, and MI, supports the contention that
patients.44 Interestingly, this benefit was even more prominent in beta blockers are less effective in LVH regression than ARBs.22
African-American participants. Several studies have confirmed Although there are no large-scale randomized trials assessing
that African-American patients do not respond as well to blockers the efficacy of beta blockers in patients with heart failure and
of the RAAS; this may be due to inherent lower plasma renin preserved EF, a few smaller-scale trials have been performed.
levels.45,46 However, a substantial number of patients with heart Differing patient populations and small sample sizes have
failure have some degree of renal insufficiency, and thiazide produced conflicting results, and there are essentially no serious
diuretics are well known to be ineffective when there is reduced outcomes data.
glomerular filtration. One of the earlier studies randomized 158 elderly patients with
a prior history of MI, heart failure, and an EF greater than 40%
to propranolol or placebo.55 All patients were treated with ACE
Nitrates inhibitors and diuretics and followed for 32 months. The authors
Nitrates are frequently used along with diuretics in the treatment demonstrated that there was a 35% reduction in total mortality
of acute pulmonary edema. They assist in alleviating pulmonary and a 37% reduction in combined total mortality and nonfatal MI
congestion while acting primarily as venodilators. Unlike diuret- in patients randomly allocated to propranolol. The mortality
ics, however, nitrates may also exert their action on the ventricle by reduction seems quite high in the face of the small sample size
releasing endothelial nitric oxide, thereby improving ventricular and portrays a higher benefit of beta blockers than was reported
distensibility. Nitrates are predominantly useful in cases of hyper- in the larger-scale Study of Effects of Nebivolol Intervention on
tensive pulmonary edema and are often used either sublingually or Outcomes and Rehospitalizations in Seniors with Heart Failure
intravenously. Like diuretics, nitrates must be cautiously used, as (SENIORS). It may very well be that the mortality benefit
hypotension can occur. Large doses of nitroglycerin must be given observed with propranolol is attributable to these patients having
to achieve arteriolar dilation (i.e., to lower blood pressure), whereas underlying coronary artery disease, with improvement of myocar-
smaller doses of nitroglycerin (i.e., 40 μg/min) lower venous pres- dial ischemia driving the benefit rather than direct improvement
sure through dilation of large-capacitance veins and thereby reduce in actual diastolic function.
pulmonary congestion without reducing blood pressure. The SENIORS trial randomized 2128 elderly patients with
heart failure to nebivolol versus placebo.56 Nebivolol is a beta-1-
selective blocker that modulates nitric oxide and serves as a vaso-
Beta Blockers dilator but is not yet approved for use in the United States. This
It has become standard practice to incorporate beta blockers into study was not exclusive to diastolic heart failure, with a mean EF
the treatment of coronary artery disease, hypertension, and more of 36%. Only 35% of patients had an EF greater than 35%. The
recently systolic heart failure. Prior studies have shown that beta primary outcome consisted of a composite of all-cause mortality
blocker treatment in patients with systolic heart failure is associ- or cardiovascular hospitalizations. These endpoints occurred in
ated with improved ventricular performance, a higher EF, and 31.1% of patients receiving nebivolol compared with 35.3% of
increased survival.47–50 Despite the paucity of data with beta patients receiving placebo. The hazard ratio in favor of nebivolol
blockade and diastolic heart failure, it is not unreasonable to infer was 0.86, with a p value of nominal significance (p = 0.039). In
that beta blockade is also valuable in the treatment of diastolic SENIORS, 68% of patients had documented coronary artery
heart failure. disease. Subgroup analyses were performed in patients with EFs
Beta blockade may exert its actions on diastolic heart failure less than and greater than 35%. The hazard ratios for the primary
via several distinct mechanisms. Coronary artery disease is a outcome were 0.87 and 0.82, respectively, indicating no differen-
common comorbidity in the elderly hypertensive patient mani- tial effect on preserved or low EF. The benefit of nebivolol was
festing with heart failure and a preserved EF. Myocardial ischemia not as robust as that observed with beta blockers in systolic heart
may instigate heart failure, and it has been shown that beta block- failure, such as was demonstrated with carvedilol in the Carve-
ers improve symptoms and survival in patients with coronary dilol Prospective Randomized Cumulative Survival Study
artery disease.51–54 Administration of beta blockers likely relieves (COPERNICUS)49 and bisoprolol in the Cardiac Insufficiency
ischemia and may play a role in preventing diastolic heart failure. Bisoprolol Study (CIBIS) II.50 The population studied in the
Additionally, beta blockers are effective in reducing tachycardia. SENIORS trial was older; the inclusion criteria was age older
Tachycardia is generally not well tolerated in patients with dia- than 70 years, which produced a mean age of 76 years. Subgroup
stolic dysfunction, as it reduces diastolic time, thereby reducing analysis demonstrated that patients younger than 75 years had a
the time for complete relaxation and LV filling, thus contributing greater reduction in all-cause mortality or cardiovascular hospi-
to elevated diastolic pressure. Furthermore, tachycardia is not well talizations with nebivolol (17.4%) than placebo (22.5%) com-
tolerated in myocardial ischemia, due to increased myocardial pared with those older (24.6% vs. 26.7%). These observations
oxygen demand and decreased time allowed for coronary perfu- support the contention that large clinical trials in older patients
sion. For these reasons, beta blockers are also advantageous in the will have many noncardiovascular deaths, making “all-cause mor-
setting of atrial fibrillation and a rapid ventricular rate. tality” a poor choice for an endpoint.
As with systolic heart failure, beta blockers can suppress the These studies looked primarily at clinical outcomes of patients
deleterious effects of chronic activation of the sympathetic nervous with diastolic heart failure and did not focus on actual diastolic
system, thereby improving autonomic balance and reducing ven- function. However, there are studies that sought to ascertain this
tricular wall stress. Beta blockers, still useful as effective anti- notion. Echocardiographic parameters are utilized to determine
hypertensive agents, elicit LVH regression, though not to the stages of diastolic dysfunction, and studies have consistently con-
same degree as other antihypertensive agents.21 The analysis of firmed that beta blocker usage is associated with improved dia-
the LIFE study, in which atenolol was shown to be inferior to stolic function. A study published in 2000 showed that in 45
 Chapter 32 • General Treatment of Diastolic Heart Failure 421

patients with depressed EF, administration of carvedilol signifi- heart failure. ACE inhibitors may be beneficial in that they
cantly increased deceleration time of early diastolic filling.57 The improve compliance of blood vessels, cause regression of LVH,
authors demonstrated an improvement in diastolic function: restore flow-mediated dilation in blood vessels, and improve
77% of patients with a baseline restrictive filling pattern reverted endothelial function in patients with heart failure. Additionally,
to normal or pseudonormal filling patterns after carvedilol ACE inhibitors play a vital role in modifying myocardial remodel-
therapy, and 71% of patients with an abnormal relaxation pattern ing that occurs with systolic heart failure, LVH, post-MI, and
changed to a normal filling pattern. The Swedish Doppler- activation of the RAAS.64 Theoretically, agents that block the
echocardiographic study (SWEDIC) was comprised solely of RAAS should likewise be beneficial in patients with heart failure
patients with heart failure and preserved systolic function.58 In and preserved EF.
this study, 113 patients were randomized to carvedilol or placebo Very little data exist on the utility of ACE inhibitors in heart
for 6 months. The primary endpoint was change in the integrated failure patients with preserved EF. Despite this, several observa-
quantitative assessment of all four Doppler variables of diastolic tional studies have demonstrated that patients with diastolic heart
function. These are (1) E/A ratio (early diastolic filling velocity failure prescribed ACE inhibitors had longer survival as well as a
to atrial late diastolic filling velocity), (2) mitral atrial (A)-wave shorter length of stay during index hospitalization.65,66
duration compared with pulmonary venous atrial duration, (3) To address this issue, the Perindopril for Elderly People with
isovolumic relaxation time, and (4) pulmonary venous systolic/ Chronic Heart Failure (PEP-CHF) clinical trial is under way.67
diastolic velocity. Although there was no effect on the primary In the PEP-CHF study, 850 elederly patients with LVEF between
endpoint, there appeared to be a trend toward improved diastolic 40% and 50% and a history of heart failure and abnormal diastolic
function in patients treated with carvedilol. A statistically signifi- dysfunction were randomized either to perindopril or to placebo.
cant improvement in E/A ratio was found in patients treated with The primary endpoint was a composite of all-cause mortality and
carvedilol (p = 0.046). This finding may be purely a result of heart failure hospitalizations and was achieved in 25.1% of
lowering the heart rate. As expected, heart rate decreased signifi- patients randomized to placebo versus 23.6% of patients random-
cantly in the carvedilol group (from 74 to 60 bpm), although there ized to perindopril (p = 0.545). However, when analysis was
was no significant reduction in systolic and diastolic blood pres- conducted at one-year follow-up, patients randomized to perin-
sure. When subgroup analysis was performed, the benefit of dopril had significantly fewer heart failure hospitalizations,
carvedilol on E/A ratio was exclusive to patients with baseline improvement in NYHA class, and an increase in six minute
heart rates greater than 71 bpm (p = 0.002). In those with low walking distance. The mean follow-up of the study was 26.2
heart rates (<71 bpm), there was no effect. Although the study months; however, after one year, a large percentage of the patients
was not powered for mortality, other measurements were assessed. were unblinded, and over one third of patients were taking open-
A trend toward worsening New York Heart Association (NYHA) label ACE inhibitors by the end of the study. This could explain
class with carvedilol treatment was observed, though it was not why there was no statistical difference in the overall primary end-
statistically significant. point in spite of a difference in subgroup analysis at one year
Patients likely to benefit from beta blocker therapy include follow-up.
those with known coronary artery disease, myocardial ischemia, A small study conducted in 1993 examined the effect of enala-
and tachycardia. Lowering the heart rate to less than 71 bpm may pril on congestive heart failure in elderly patients with prior MI
not provide any incremental benefit of improved diastolic filling and normal LVEF.68 In this study, 21 patients with NYHA class
and diastolic function as seen in the SWEDIC trial. Beta blockers III heart failure who required diuretics were randomized to 3
may also be valuable in patients with atrial fibrillation to control months treatment with enalapril or placebo. Enalapril was found
heart rate, lower blood pressure, and alleviate myocardial isch- to significantly improve NYHA functional class, systolic and dia-
emia. Finally, beta blockers are still widely used in the treatment stolic blood pressure, EF, and exercise tolerance and to reduce LV
of hypertension, though other agents have been shown to provide mass. Enalapril also led to improvement in diastolic parameters
more LVH regression. such as increased peak mitral E/A ratios.
Another trial examined the long-term Effects of Amlodipine
and Lisinopril on LV Mass and Diastolic Function: E/A Ratio
Angiotensin-Converting-Enzyme Inhibitors (ELVERA) in elderly, previously untreated hypertensive patients.69
It has been well established that ACE inhibitors are beneficial in This study randomized 166 patients to either amlodipine or
patients with chronic heart failure and reduced EF. Landmark lisinopril. Both drug therapies led to equivalent reductions in
trials such as the Studies of Left Ventricular Dysfunction systolic and diastolic blood pressures, reduction in the LV mass
(SOLVD)59 and the Cooperative North Scandinavian Enalapril index, and improvement in the E/A ratio. The authors demon-
Survival Study (CONSENSUS)60 demonstrated that ACE strated that even when blood pressures were stabilized in the
inhibitors improve survival as well as slow the progression of second year of drug treatment, reduction of LV mass continued
heart failure in patients with depressed EF.59–61 Most of the clini- to take place. Although there appeared to be an improvement in
cal trials that have shown a benefit in patients with heart failure diastolic function based on echocardiographic parameters, clinical
have excluded those with preserved EF, as a low EF was usually outcomes were not assessed in this study.
a criteria for entry. Several randomized studies have also shown a It is well known that patients with chronic kidney disease have
benefit of ACE inhibitors in patients post-MI, as in the Survival a propensity to develop LVH and diastolic heart failure.70,71 In
and Ventricular Enlargement (SAVE) trial,61 as well as in patients fact, several reports have documented that diastolic dysfunction
with high-risk factors, as in the European Trial of Reduction of exists in children with chronic kidney disease on hemodialysis.72
Cardiac Events with Perindopril in Stable Coronary Artery Diastolic dysfunction poses a problem for the individual with
Disease (EUROPA)62 and the Heart Outcomes Prevention Eval- chronic kidney disease, since hypotension during dialysis is a
uation (HOPE) study.63 These trials have consistently demon- common occurrence.70 There are conflicting reports on whether
strated an improvement in survival and EF and a reduction in kidney transplantation serves to improve diastolic dysfunction or
422 Chapter 32 • General Treatment of Diastolic Heart Failure

not. Nevertheless, there may be a role for drug therapy. ACE use in those who are intolerant of ACE inhibitors. There is little
inhibitors have been shown to be effective in slowing the progres- evidence to support one or the other in heart failure with pre-
sion of renal disease in both the diabetic and nondiabetic popula- served EF. The ACC/AHA guidelines give both drug classes a
tions, as well as reducing protein excretion in diabetics by 35% to class IIb recommendation.18 To date, the largest randomized clini-
40%. Additionally, ACE inhibitors have been shown to induce cal trial in patients with heart failure and preserved EF conducted
regression of LVH that is associated with a significant improve- is the CHARM-Preserved trial.5
ment in diastolic function in hypertensive patients with chronic CHARM-Preserved examined the effects of candesartan in
renal failure.73 It may be challenging to interpret diastolic dys- patients with chronic heart failure and preserved LVEF. This trial
function in patients with renal failure because the Doppler indices was part of the overall CHARM program. CHARM-Preserved
of diastolic dysfunction are preload dependent and have been enrolled 3023 patients, randomizing them to either candesartan
known to change during hemodialysis.74–77 Controversy exists or placebo with a mean follow-up of 36.6 months. The primary
over whether ACE inhibitors are equally efficacious in differing endpoint consisted of combined cardiovascular death and hospi-
population subgroups. Most of the patients enrolled in clinical talizations related to heart failure. There was a slight relative risk
trials are Caucasian males, and we should not assume that these reduction of 11% in the primary outcome among LV preserved
benefits will apply to women and non-Caucasians. Several studies patients treated with candesartan; however, this improvement was
have indicated that African-American patients are less likely to marginal (unadjusted p = 0.118, covariate adjusted p = 0.051)
benefit from monotherapy with ACE inhibitors and ARBs than (Fig. 32-2). Although cardiovascular death did not differ between
diuretics and CCBs compared with Caucasians.78,79 A pooled the two groups, there did appear to be a significant reduction in
analysis from the SOLVD prevention and treatment trials dem- heart failure hospitalizations with use of candesartan (p = 0.017).
onstrated that enalapril therapy was associated with a significant There was also a trend toward reduced cardiovascular events with
reduction of heart failure hospitalizations among Caucasian candesartan, although the results were not significant.
patients with LV dysfunction, but not among African-American The CHARM-Preserved trial failed to demonstrate a survival
patients.78 Additionally, this analysis showed that both systolic benefit because of several possible reasons, the most likely being
and diastolic blood pressure reduction was more effective in Cau- that the study was insufficiently powered. The number of cardio-
casian patients, whereas there was no significant difference in vascular events was relatively small. The curves were beginning to
African-American patients. separate, and had the study a larger sample size or a longer follow-
A meta-analysis of the ACE inhibitor trials indicates that up period, the results may have unambiguously favored candesar-
women are not as likely to benefit from these agents as men.79 It tan. Patients were enrolled if they had heart failure based on a
appears that men have a significant mortality reduction from physician’s judgment rather than absolute diagnostic criteria. It is
treatment with ACE inhibitors (relative risk, 0.82), whereas conceivable, therefore, that some enrolled patients might not have
women have a more modest mortality benefit (relative risk, 0.92). had heart failure and therefore were not as likely to benefit from
Women with symptomatic LV dysfunction have a slight mortality drug intervention. Another observation is that the patients studied
benefit (relative risk, 0.90), although not to the same degree as in this trial were younger, with a mean age of 67 years. The
men. Mortality benefit is not observed in women with asymptom- increased morbidity and mortality that is associated with diastolic
atic LV dysfunction (relative risk, 0.96). In men, there is a signifi- heart failure generally affects the elderly more than their younger
cant mortality benefit in both symptomatic and asymptomatic LV counterparts. The younger age of the patients and fewer end-
dysfunction groups. It is unclear why these differences exist, and points may have contributed to the lack of survival benefit
evidently future studies are warranted. observed with candesartan in the CHARM-Preserved trial.
Despite the paucity of data on ACE inhibitors in patients with A smaller, randomized study of surrogate endpoints by Little
heart failure and preserved EF, we still advocate their use in the et al. demonstrated that treatment with losartan significantly
treatment of diastolic heart failure. ACE inhibitors are effective improved exercise tolerance and quality of life in patients with
in patients with hypertension as well as in those with vascular diastolic dysfunction and a hypertensive response to exercise.83 As
disease, both of which associate with diastolic heart failure. ACE
inhibitors may be effective tools for primary prevention in that
their use has been related to prevention of heart failure, diabetes,
hospital admission for CHF (%)

50 Hazard ratio 0.89

and even new or recurrent atrial fibrillation.62,63,80–82 Efficacy of
cardiovascular death or

(95% CI 0.77–1.03), p = 0.118

ACE inhibitors is related to higher dosages. However, it is best 40 Adjusted hazard ratio 0.86, p = 0.051
Proportion with

to start at a lower dose and carefully uptitrate monthly, as hypo-

tension continues to remain a risk in patients with diastolic heart 30
failure receiving vasodilator therapy. Similarly, renal function Placebo
must be closely monitored, as a substantial rise in blood urea 20
Candesartan
nitrogen (BUN) and creatinine can occur when there is baseline
10
renal insufficiency or simultaneous renovascular disease. Serum
potassium should also be monitored frequently as hyperkalemia 0
can frequently occur. Special consideration should be given in the 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
elderly, as their creatinine clearance is usually lower, with even
mild elevations in serum creatinine levels. Time (years)
Number at risk
Candesartan 1514 1458 1377 833 182
Placebo 1509 1441 1359 824 195
Angiotensin Receptor Blockers Figure 32-2 The CHARM-Preserved trial: Kaplan-Meier curve of the time
to cardiovascular death or hospital admission for congestive heart failure
ACE inhibitors are historically preferred over ARBs when treat- (CHF). (From Effects of candesartan in patients with chronic heart failure and
ing patients with heart failure and depressed EF because the preserved left-ventricular ejection fraction: The CHARM-Preserved Trial. Lancet
former have been available longer. ARBs are usually reserved for 2003;362:777–781. With permission from Elsevier.)
 Chapter 32 • General Treatment of Diastolic Heart Failure 423

angiotensin II impairs LV relaxation, the authors decided to failure hospitalizations. Patients require careful monitoring as
ascertain whether losartan, an ARB, could improve diastolic func- they tend to develop more hyperkalemia and renal dysfunction
tion during exercise, and thereby improve exercise tolerance. They with the combined use of ACE inhibitors and ARBs, even in the
noted that at baseline, the mitral E/A ratio increased with a absence of aldosterone antagonists. The use of concomitant ACE
shortened mitral deceleration time after exercise. Although there inhibitors and ARBs needs to be validated in patients with
did not appear to be any significant change in echocardiographic diastolic heart failure. In the CHARM-Preserved trial, less than
diastolic parameters with administration of losartan, there was an 20% of patients were on ACE inhibitors, so an effective analysis
increase in exercise tolerance as well as quality of life. Losartan could not be conducted.5 A recent animal study demonstrated
did not alter the resting blood pressure and slightly decreased that addition of an ARB to an ACE inhibitor in hypertensive rats
peak systolic blood pressure during exercise, although this was not induced more regression of LVH and myocardial fibrosis.88 This
significant. In this study, losartan was administered for only 2 led to reduced myocardial stiffening and improved ventricular
weeks, and this duration of treatment may have been insufficient relaxation that was independent of blood pressure.
to show any meaningful clinical change, yet exercise tolerance and Although we do not have data to suggest that ARBs provide a
quality of life did improve. clear and unambiguous survival benefit to patients with diastolic
The initial LIFE study demonstrated that for equivalent blood heart failure, we advocate their use, as they have been shown to
pressure reduction, losartan was superior to atenolol in preventing effectively lower blood pressure and reduce LVH and heart failure
cardiovascular morbidity and death in hypertensive patients, a hospitalizations and to enhance exercise tolerance. These are all
group known to be at risk to develop diastolic heart failure. A important goals in the treatment of heart failure. Additionally, like
substudy from LIFE examined the changes in diastolic LV filling ACE inhibitors, ARBs have been shown to consistently reduce
after one year of antihypertensive treatment.84 Echocardiograms the development of new-onset diabetes mellitus, a determinant
and Doppler measurements were performed at baseline and one of diastolic dysfunction. The cardioprotective effects of ARBs are
year in 728 patients. The authors demonstrated that antihyper- wide in that they block the actions of angiotensin II and the
tensive therapy reduced mean LV mass by 12% and LA diameter RAAS, leading to improved hemodynamics, reduced LV remod-
by 3% and improved diastolic LV filling patterns significantly. The eling, improved endothelial function, arterial compliance, and
E/A ratio and the deceleration time both increased, and there tone. Either an ACE inhibitor or an ARB is a reasonable treat-
appeared to be an improvement in flow patterns. The LIFE sub- ment option for diastolic heart failure.
study also noted that improvement in diastolic function was
related only to reduction in LV mass. There appeared to be no
changes in diastolic filling parameters in patients without LV Aldosterone Receptor Blockers
mass reduction. Since the study was blind and the main LIFE Aldosterone is released from the adrenal glands in response to
study was still in progress, no comparison was made between angiotensin II and multiple other stimuli, including hyperkale-
losartan and atenolol. Nevertheless, the study confirms that blood mia. It plays an important role in promoting myocardial fibrosis.11
pressure control by losartan or atenolol can promote regression ACE inhibitors and ARBs have only a partial effect on aldoste-
of LVH and improve diastolic function. rone release inhibition, since other factors, such as serum potas-
ARBs have consistently demonstrated an improvement in sium levels, catecholamines, endothelin, and corticotrophin, are
LVH regression; in fact, the greatest reduction (13%) of LV mass not blocked. There are no current studies regarding aldosterone
index in a meta-analysis on antihypertensive therapy was observed receptor blockers in patients with diastolic heart failure, though
with ARBs.21 A study of hypertensive patients confirmed that one is currently being planned. However, aldosterone blockers
there is a strong association between myocardial collagen content improve mortality in patients with heart failure and depressed EF,
and LV chamber stiffness.85 In this study, all patients were given as in the case of spironolactone in the Randomized Aldactone
losartan for 12 months, and endomyocardial biopsies were Evaluation Study (RALES)89 and eplerenone in post-MI patients
obtained. The authors demonstrated that losartan caused signifi- in the Eplerenone Post-Acute Myocardial Infarction Heart Failure
cant regression of myocardial fibrosis (reduced collagen content) Efficacy and Survival Study (EPHESUS).90 Based on this, it is
and that this was associated with reduction of LV chamber stiff- attractive to consider aldosterone blockers to be likewise benefi-
ness, assessed echocardiographically. This further confirms the cial in patients with heart failure and preserved EF. Although
role of angiotensin II in invoking myocardial fibrosis. these agents are clearly appealing, we have no compelling data for
Differing opinions exist on whether ARBs should be added to their use in patients with diastolic heart failure. They require
ACE inhibitors in the treatment of heart failure. Several studies regular monitoring of serum potassium and renal function and
of systolic heart failure, such as the Randomized Evaluation of should probably not be used in patients with serum creatinine
Strategies for LV Dysfunction (RESOLVD) pilot study, the levels greater than 2.5 mg/dL. We have little information about
CHARM-Added trial,86 and the Valsartan in Chronic Heart the combined use of ACE inhibitors, ARBs, and aldosterone
Failure Trial (Val-HeFT),87 demonstrated that addition of an receptor blockers, and this triple combination cannot be recom-
ARB to treatment of patients already being treated with ACE mended until the safety record of their coadministration is
inhibitors further reduced mortality or morbidity or both in those established.
with heart failure and depressed EF. However, there appears to
be a discrepancy between the latter two trials. In Val-HeFT, 35%
of patients were treated with beta blockers, and the addition of Calcium Channel Blockers
valsartan to patients treated with an ACE inhibitor and a beta One of the first studies looking at treatment effects in patients
blocker was associated with adverse effects of morbidity and mor- with diastolic heart failure utilized a CCB, verapamil.91 This study
tality. This was probably a statistical anomaly and was not observed was a placebo-controlled, double-blind, 5-week crossover trial in
in the CHARM-Added trial, in which 55% of patients were 20 men with EFs greater than 45%, heart failure, and documented
treated with beta blockers, and addition of candesartan was asso- abnormal LV peak filling rates. Verapamil improved the LV peak
ciated with a further reduced risk of cardiovascular death or heart filling rate by 30%. Furthermore, there seemed to be an improve-
424 Chapter 32 • General Treatment of Diastolic Heart Failure

ment in the mean congestive heart failure score. The small sample A retrospective analysis by Little’s group evaluated 137 patients
size and the fact that all patients were men greatly limit the study, with heart failure and a preserved EF.111 Use of statin therapy was
as diastolic heart failure is particularly prevalent in elderly women. associated with an improvement in survival, with a relative risk of
The study was likely too brief to measure an effect on LVH death of 0.22. Interestingly, treatment with an ACE inhibitor,
regression. Another study showed that verapamil was effective in ARB, beta blocker, or CCB had no significant effect on survival.
improving LV diastolic filling and exercise tolerance in patients Propensity analysis confirmed that statin therapy was indeed
with hypertrophic cardiomyopathy.92 associated with improved survival. Nevertheless, these studies
CCBs are valuable agents that also ameliorate angina. The non- should be considered exploratory or hypothesis generating, not
dihydropyridine CCBs may be of utility in diastolic heart failure definitive.
in that like beta blockers, they serve to lower the heart rate and
increase ventricular diastolic filling. One must be mindful when
prescribing verapamil in the elderly, as it tends to cause constipa- FUTURE RESEARCH
tion. In animal models with diastolic heart failure, amlodipine was
shown to prevent myocardial stiffening through amelioration of Diastolic heart failure is common and lethal. As the population
collagen remodeling.93 CCBs are highly effective antihypertensive continues to age and coronary revascularization becomes more
agents, and since control of high blood pressure is a major goal in readily available, we are seeing more patients with heart failure
the treatment of diastolic heart failure, they are widely used in who have preserved EF. Clearly, it would be advantageous to have
this syndrome. large-scale clinical trials to guide our therapy with this condition.
To date, most large-scale clinical trials in patients with heart
failure have focused on those with depressed EF. The largest trial
Digitalis of patients with heart failure and preserved EF is the CHARM-
The ACC/AHA practice guidelines state that the usefulness of Preserved trial, which indicated only a marginal benefit of cande-
digitalis to minimize symptoms of heart failure in patients with sartan, probably because it was underpowered. There are several
normal EF is not well established and is given a class IIb recom- ongoing large-scale clinical trials. These include the Irbesartan in
mendation. The Digitalis Investigation Group (DIG) examined Heart Failure with Preserved EF trial (I-Preserve) and Treatment
the effect of digoxin on mortality and morbidity in patients with of Preserved Cardiac function heart failure with an Aldosterone
heart failure.94 The overall study showed that digoxin did not antagonist (TOPCAT), a trial of spironolactone in patients with
reduce overall mortality but did reduce the rate of overall hospi- heart failure and preserved EF funded by the National Heart,
talizations, as well as hospitalizations for worsening heart failure. Lung, and Blood Institute. However, it should be reiterated that
The main study randomized patients with EFs less than 45%; patients with diastolic heart failure likely have fewer lethal cardio-
however, an ancillary trial was conducted in 988 patients with EFs vascular endpoints and more noncardiovascular morbidity end-
greater than 45%. The results were similar to the main trial in that points than patients with systolic heart failure. As such, trials
there was no significant difference with respect to overall mortal- focusing on diastolic heart failure will require large sample sizes
ity. There was, however, a reduction in the combined outcome of and very long follow-ups to provide an unambiguous conclusion.
death or hospitalization due to worsening heart failure, with a risk Such trials may be beyond the reach of contemporary designs and
ratio of 0.82. The subpopulation studied in DIG may have been costs.
too small, and a false positive result may have been observed.
Despite the subset findings in the DIG trial, digitalis is not widely
used to treat patients with diastolic heart failure, and other agents SUMMARY
may be more beneficial.
Heart failure is one of the most common causes for elderly patients
to be admitted to the hospital, and diastolic heart failure probably
Statins accounts for one half of all these patients. To date, treatment of
The use of statins in the last decade has been expanding, mainly heart failure has focused primarily on patients with a depressed
because of the vast number of clinical trials that demonstrate EF. Although the mortality of diastolic heart failure is perhaps not
their efficacy in various disease states. The contemporary think- as severe as systolic heart failure, it is nevertheless high and should
ing is that statins have pleiotropic effects that go beyond be taken into account. In the absence of clinical trial data, we are
pure lipid-lowering mechanisms.95–97 In addition to their anti- without clear guidelines regarding effective therapy. The practice
inflammatory and antioxidant properties, statins may reduce LV guidelines provided by the ACC/AHA and HFSA serve as road-
remodeling, increase arterial distensibility, improve endothelial maps of how to approach patients with diastolic heart failure but
function, and favorably affect the neurohormonal systems.98–103 cannot recommend definitive drug treatment. As with systolic
Additionally, few animal studies have shown that statins heart failure, treatment of acute symptoms of heart failure should
reduce or prevent LVH and fibrosis.104–106 One clinical study be targeted at reducing congestion and volume overload with the
also demonstrated that use of statins induced regression of aid of diuretics and possibly nitrates. Several known causes of
LVH in patients with angina.107 Several retrospective analyses of diastolic heart failure, such as hypertension, underlying ischemia,
large databases have observed that statins improve survival in atrial fibrillation, valvular heart disease, and diabetes need to be
patients with heart failure and depressed EF, irrespective of considered, as their management may differ. Every effort should be
whether the heart failure is due to ischemia.108–110 Although no made to ensure that patients are compliant with medications and
large prospective trials in diastolic heart failure have been per- that they maintain salt restriction. Up to 80% of patients with
formed, an observational study demonstrated that statin therapy diastolic heart failure have evidence of LVH determined echocar-
may be associated with lower mortality in patients with diastolic diographically,14 and treatment of hypertension should always be
heart failure.111 a primary concern. It usually takes more than one drug to effec-
 Chapter 32 • General Treatment of Diastolic Heart Failure 425

tively control blood pressure. Beta blockers may be useful to slow 15. McCullough PA, Khandelwal AK, McKinnon JE, et al: Outcomes and prog-
heart rate, prolong diastole, and allow for enhanced ventricular nostic factors of systolic as compared with diastolic heart failure in urban
America. Congest Heart Fail 2005;11:6–11.
diastolic filling. ACE inhibitors and ARBs may be beneficial, as 16. Wu EB, Yu CM: Management of diastolic heart failure—a practical review
they block the RAAS and the deleterious effects of angiotensin II, of pathophysiology and treatment trial data. Int J Clin Pract 2005;59:1239–
which has been implicated in the pathophysology of diastolic 1246.
heart failure. Even though the largest trial conducted to date, 17. Yancy CW, Lopatin M, Stevenson LW, et al: Clinical presentation, manage-
ment, and in-hospital outcomes of patients admitted with acute decompen-
CHARM-Preserved, did not demonstrate a clear survival benefit sated heart failure with preserved systolic function: A report from the Acute
with candesartan, there was a reduction in heart failure hospital- Decompensated Heart Failure National Registry (ADHERE) database.
izations; this remains a valid goal in the chronic treatment of heart J Am Coll Cardiol 2006;47:76–84.
failure. Just as in the treatment of hypertension and systolic heart 18. Hunt SA: ACC/AHA 2005 guideline update for the diagnosis and man-
failure, various agents with differing mechanisms of action should agement of chronic heart failure in the adult: A report of the American
College of Cardiology/American Heart Association Task Force on Practice
be employed in the treatment of diastolic heart failure (see Table Guidelines (Writing Committee to Update the 2001 Guidelines for the
32-1). It bears mentioning that the pathophysiology of diastolic Evaluation and Management of Heart Failure). J Am Coll Cardiol 2005;46:
heart failure is not similar to that of systolic heart failure, and new e1–e82.
molecular mechanisms in diastolic heart failure are being uncov- 19. Executive summary: HFSA 2006 Comprehensive Heart Failure Practice
Guideline. J Card Fail 2006;12:10–38.
ered.112,113 Caution should be exercised in assuming that treatment 20. Massie BM, Fabi MR: Clinical trials in diastolic heart failure. Prog Cardio-
of systolic heart failure produces the same effects as in diastolic vasc Dis 2005;47:389–395.
heart failure. Clearly, novel agents that target the underlying 21. Klingbeil AU, Schneider M, Martus P, et al: A meta-analysis of the effects
molecular mechanisms in diastolic heart failure should be sought. of treatment on left ventricular mass in essential hypertension. Am J Med
That being said, the management of patients with diastolic heart 2003;115:41–46.
22. Dahlof B, Devereux RB, Kjeldsen SE, et al: Cardiovascular morbidity and
failure is complex and not always effective. Careful follow-up is mortality in the Losartan Intervention For Endpoint reduction in hyperten-
warranted, and control of concomitant problems such as hyper- sion study (LIFE): A randomised trial against atenolol. Lancet
tension and diabetes mellitus is essential. In the final analysis, pre- 2002;359:995–1003.
vention will prove to be the most powerful interdiction. If we can 23. Meyer TE, Kovacs SJ, Ehsani AA, et al: Long-term caloric restriction ame-
liorates the decline in diastolic function in humans. J Am Coll Cardiol
prevent hypertension and LVH, ischemic heart disease, and type 2006;47:398–402.
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 STEVEN J. LESTER, MD
A. JAMIL TAJIK, MD
33
Echo-Based Approach to
the Management of
Diastolic Heart Failure
INTRODUCTION those of systolic function from 2D variables. This may create the
illusion that individuals with heart failure have “normal systolic
PATHOPHYSIOLOGY
function.” The interrogation of cardiac function with derived
CLINICAL RELEVANCE parameters of deformation such as strain and strain rate confirm
Primary Prevention of Diastolic Dysfunction the illusion despite frequent pronouncements and mutual cita-
Secondary Prevention and Treatment of Diastolic tion. Despite its incipient limitations, for the purpose of further
Heart Failure discussion the term diastolic heart failure (DHF) will be used in
this chapter to refer to the syndrome of heart failure in the setting
FUTURE DIRECTIONS
of normal ejection fraction.
Individuals with heart failure, whether associated with a normal
or a reduced ejection fraction, may be equally disabled and have
INTRODUCTION a similarly poor prognosis.1–3 In individuals with heart failure,
independent of etiology, the New York Heart Association
Heart failure is a clinical syndrome of signs and symptoms result- (NYHA) functional classification is useful in defining prognosis
ing from cessation of normal heart function whereby the heart is and monitoring response to treatment. Similarly, a comprehensive
not able to pump enough blood to meet the body’s energy evaluation and staging of diastolic function, independent of
demands. Hence, heart failure is not a specific disease entity; disease, is useful in defining prognosis, monitoring response to
instead, the development of heart failure represents the final treatment, and developing new treatment strategies.4–10
common pathway of any and all forms of cardiovascular disease. Diagnosis and staging of diastolic dysfunction provide a frame-
The diagnosis of heart failure is incomplete without assignment work for the approach to management of individuals with DHF
of a specific etiology. The components of the cardiac cycle provide (see Chapter 10). The echocardiogram is a powerful tool enabling
an intellectual framework for the appropriation of the breakdown the clinician to noninvasively obtain parameters of flow, pressure,
in heart function. As a result, terms such as “diastolic heart failure” and resistance and thus evaluate intracardiac hemodynamics
or heart failure in the setting of “normal systolic function” have influenced by ailments in the diastolic phase of the cardiac cycle.
crept into the medical nomenclature.
Although it is practical to classify heart failure patients as those
with either normal or abnormal systolic function, such a classifica- PATHOPHYSIOLOGY
tion is based on physiologic principles destitute of virtue. Each
component of the cardiac cycle is functionally dependent on the The mitral valve is the door that when opened exposes the left
other. Unlike two-dimensional (2D) echocardiography, where atrium to the hemodynamic elements of the left ventricle. Pro-
crude parameters of cardiac performance such as ejection fraction longed exposure to elevated filling pressure results in structural
are used, Doppler echocardiography is able to detect and quanti- remodeling of the left atrium. Therefore, the comprehensive
tatively display minor amplitude and temporal subtleties that may evaluation of diastolic function should begin with a measure of
occur in ventricular mechanical function. Traditionally, parame- left atrial (LA) size. The anteroposterior dimension of the left
ters of diastolic function have been derived from Doppler, and atrium obtained by M-mode echocardiography was initially the
429
430 Chapter 33 • Echo-Based Approach to the Management of Diastolic Heart Failure

only available method to determine LA size. However, for this ologies and potential precipitating conditions, as mentioned
unidimensional measurement to accurately represent the true LA above, must be the goal of short- and long-term management
size, it must be assumed that it bears a consistent relation to other strategies. Neurohormonal modulation of the renin-angiotensin-
LA dimensions. This assumption is not accurate, and thus LA size aldosterone system (RAAS) has a proven salutary effect on each
should be represented by a volume-based method of evaluation.11,12 of the above-mentioned conditions.18–33
As diastolic function is staged from mild to moderate to severe, so Angiotensin-converting-enzyme inhibitors (ACEIs), angioten-
will there be mild, moderate, and severe increases in LA volume in sin I receptor antagonists (ARBs), and aldosterone receptor antag-
the absence of atrial arrhythmias or valvular heart disease. LA onists (ARAs), independently of their hemodynamic effect,
volume may therefore be considered the “morphophysiologic” mediate potentially favorable effects of reduced smooth muscle
expression of left ventricular (LV) diastolic function.13 LA volume cell growth, prevention of collagen deposition, and reduced growth
reflects the cumulative effect of exposure to increased LV filling factor expression.34–37 Statins have touted similar pleiotropic
pressure over time. An increase in LA volume has profound clinical effects.38,39 Intellectually intriguing is the low threshold to the use
implications. LA volume has been found to be a robust predictor of statins and consideration of therapy targeting the RAAS in
of cardiovascular outcomes, not the least of which is an increased individuals with an increased LA volume and/or a subclinical
risk for the development of heart failure.14–17 history of coronary disease (positive coronary artery calcification
score by computed tomography or increased carotid intima-media
thickness) or prediabetes in an effort to prevent eventual develop-
CLINICAL RELEVANCE ment of DHF. Limited data in patients with hypertension suggest
that favorable remodeling of the left atrium can be influenced.40
Primary Prevention of Diastolic Dysfunction ACEIs may also result in favorable remodeling of the left atrium
Identification of risk and intervention prior to overt disease is essen- (the morphophysiologic expression of diastolic function) inde-
tially the first therapeutic target for all disease and no less our first pendently of their influence on blood pressure.41 Opportunities
strategy in the management of DHF. The age distribution of DHF exist for these hypotheses to be tested in clinical trials (see
incidence is skewed toward the elderly, and in individuals over 70 Chapters 32 and 34). Until furnished with data, definitive thera-
years of age the incidence of DHF exceeds that of heart failure with peutic recommendations are null, and potential therapeutic
reduced ejection fraction.1 A primary prevention strategy becomes approaches are based on prophecy.
even more germane as society is faced with a burgeoning elderly
population creating a social and health care economic crisis. Echo- Secondary Prevention and Treatment of
cardiography, with its ability to reliably and reproducibly measure
LA volume, provides a window of opportunity to identify individu- Diastolic Heart Failure
als at risk for DHF and potentially provide therapeutic intervention. In individuals with DHF, the question is generally not what the
The intervention for prevention is based on little clinical trial data cumulative effect of filling pressure over time has been, but rather
and requires the art of medicine to intervene. what the filling pressures at the instant in time of the evaluation
DHF is a pathophysiologic manifestation of a heterogeneous are. The echocardiogram reliably provides us with this informa-
group of diseases. Common underlying etiologies of DHF include tion through the integration of data obtained from blood flow
hypertension, ischemic and diabetic heart disease, metabolic syn- velocities with those of wall motion analysis. This integrative
drome, and obesity. Less common but important considerations evaluation also allows for staging of disease severity (Fig. 33-1)
are diagnoses of valvular heart disease, infiltrative and storage (see Chapter 10). Here the evaluation often begins with measures
diseases, hypertrophic cardiomyopathy, pericardial disease, and of the mitral inflow velocity profile (Fig. 33-2). Annular excursion
other restrictive cardiomyopathies. Another very important but interrogated generally with Doppler tissue imaging techniques
underappreciated etiology for DHF is sleep apnea. Ventricular- provides an evaluation of wall motion (Fig. 33-3). Notwithstand-
arterial stiffening contributes importantly to the development of ing constrictive pericarditis, ubiquitous to individuals with dia-
DHF. Precipitating factors (acute decompensation) of DHF may stolic dysfunction is a relaxation abnormality of the left ventricle.
include sudden elevation in blood pressure, tachycardia (com- This is characterized by a low early mitral inflow velocity (E) and
monly atrial fibrillation with an uncontrolled ventricular response), E/A ratio (A = the atrial component of mitral inflow), with a
acute ischemia, renal failure, anemia, the institution of nonsteroi- prolonged deceleration time and a low early mitral annular veloc-
dal antiinflammatory medication, and other factors, such as ity (E′). With progression to more severe diastolic dysfunction,
excessive salt load that may increase intravascular volume. Early the association of reduced LV compliance with increased LA
identification and aggressive targeted treatment of underlying eti- pressure will result in an increase in the E velocity and E/A ratio

Normal Abnormal Pseudorestrictive Restrictive

relaxation normalization (reversible) (irreversible)

Figure 33-1 Natural history of diastolic dysfunction.

Mean LAP Normal ↑ ↑↑ ↑↑↑ ↑↑↑ Wave form represents the mitral inflow velocity profile.
A “restrictive (reversible)” condition would represent a
Grade of conformational change in the mitral inflow velocity
diastolic I II III IV profile during the strain phase of the Valsalva maneuver
dysfunction from III to I. LAP, left atrial pressure.
 Chapter 33 • Echo-Based Approach to the Management of Diastolic Heart Failure 431

E vel = 90cm/sec velocity, and a measure of the isovolumic relaxation time may also
A vel = 40cm/sec be helpful in the evaluation and staging of diastolic dysfunction.
E/A = 2.2 The absence of clinical trial data makes treatment of DHF
DT = 222msec
largely empirical and generally based on therapeutic strategies
thought to favorably target the underlying causative etiologies and
precipitating factors. As the etiologic classification of individuals
with DHF is varied, so are recommended treatment strategies.
E
For example, the need to individualize the therapeutic approach
to DHF is highlighted by judicious blood pressure control in
hypertensive patients, anti-ischemic therapy (pharmacologic and/
or revascularization) in patients with ischemic heart disease,
treatment of sleep apnea, definitive management of valvular heart
A disease, gradient reduction therapy in individuals with hypertro-
phic cardiomyopathy, surgical treatment of constrictive pericardi-
tis, control of ventricular rate, restoration and maintenance of
sinus rhythm in individuals with atrial fibrillation, and appropri-
ate targeted therapies for disorders such as hemachromatosis,
Fabry’s disease, and amyloidosis.
As one cannot categorize individuals with DHF into a homo-
geneous etiologic classification, should one create a simple unify-
Figure 33-2 Mitral inflow velocity profile with the pulsed wave sample ing treatment strategy? This is a consideration often overlooked
volume placed at the mitral leaflet tips. E, early rapid filling wave; A, late in the design of heart failure trials. The Candesartan in Heart
filling wave due to atrial contraction; DT, deceleration time, the time inter-
val from the peak of the E velocity to its extrapolation to baseline. Failure: Assessment of Reduction in Mortality and Morbidity
(CHARM-Preserved) trial, a prospective outcome trial evaluat-
ing a treatment strategy (candesartan) solely for individuals with
DHF, included a heterogeneous etiologic classification of DHF.42
The findings, however, were promising, showing a significant
reduction in hospitalization for heart failure and a strong trend
toward significance in the primary outcome of death or hospital
admission for heart failure. We await the results of the Irbesartan
in Heart Failure with Preserved Systolic Function (I-Preserve)
trial, in which inclusion defined a more discriminate patient
population.43
A number of small studies have evaluated the efficacy of ACEIs,
ARBs, beta blockers, digoxin, and calcium channel blockers in the
A¢
management of patients with DHF. These studies have yielded
dichotomous outcomes and little conclusive insight into definitive
E¢ treatment strategies. The echocardiographic staging of diastolic
dysfunction (see Fig. 33-1) may provide a useful guide for
therapeutic intervention. Congestive symptoms can often be ame-
liorated with the judicious use of venodilators and diuretics.
Medications that modify atrioventricular (AV) nodes can be used
to slow heart rate and increase the diastolic filling time. Addi-
Figure 33-3 Septal annular Doppler tissue image. E′, early diastolic annular tional neurohormonal modulation is intellectually intriguing.
velocity (away from the apex or transducer); A′, late diastolic annular veloc-
ity secondary to atrial contraction.
Treatment may be tailored to a defined success of a reduction in
diastolic dysfunction grade and NYHA functional class.
Individuals with grade 1 diastolic dysfunction are generally
and a reduction in deceleration time. The mitral blood flow veloc- asymptomatic at rest but may complain of dyspnea on mild exer-
ity profile may now appear normal. However, the E′ velocity will tion. In the normal heart, as heart rate increases, there is an
remain reduced, identifying the underlying LV relaxation abnor- increase in contractility and faster relaxation. In myocardial
mality. The E/E′ ratio can therefore be used to discriminate an disease, there is incomplete restitution, less LV pressure decline,
individual with normal versus grade II diastolic dysfunction. reduced coronary flow reserve, and thus higher LV diastolic pres-
Similarly, individuals with a restrictive mitral inflow pattern, sure (Fig. 33-4). For these individuals, the duration of diastole is
E/A greater than 2, and deceleration time less than 150 msec who critical, and beta blockers or rate-slowing calcium channel block-
are able to favorably influence the mitral inflow velocity profile ers often provide a favorable symptomatic response. In Figure
with hemodynamic manipulation (often the Valsalva maneuver) 33-5, intracardiac hemodynamics are favorably influenced with
declare themselves of less severe diastolic dysfunction than diuresis, and better blood pressure control is characterized echo-
those with an irreversible restrictive pattern. The former are des- cardiographically by a change to a grade I mitral inflow velocity
ignated with grade III diastolic dysfunction and the latter are profile and reduced E/E′ ratio. The persistent and unchanged
designated with grade IV. Beyond the scope of this chapter but reduced E′ velocity suggests that myocardial mechanical proper-
worthy of note is that the evaluation of the pulmonary venous ties are in fact unaltered, but with hemodynamic manipulation a
blood flow velocity profile, the mitral inflow flow propagation more favorable position of the end diastolic pressure-volume rela-
432 Chapter 33 • Echo-Based Approach to the Management of Diastolic Heart Failure

50 W

40 Normal
B

LV pressure (mmHg)
30

20

10

0
0 50 100 150 200 250
LV end diastolic volume (ml)
Figure 33-6 The left ventricular (LV) end diastolic pressure-volume rela-
Figure 33-4 Top, unfavorable mitral inflow velocity profile with fusion of tionship (EDPVR). W, worsening of the EDPVR; B, better EDPVR. (Modified
the mitral E and A waves. Bottom, with heart rate slowing there is now a from Maurer MS et al: Diastolic dysfunction: Can it be diagnosed by Doppler
more favorable mitral inflow velocity profile. echocardiography? J Am Coll Cardiol 2004;44:1543–1549.)

diagnosis of heart failure must not be made without appropriation

E=1.4m/sec E¢=.04m/sec E/E¢=35 of the underlying etiology and precipitant cause. This is the fun-
damental limitation of many heart failure trials, where patient
inclusion is granted based on signs and symptoms of heart failure
and either an ejection fraction of greater than 40%–45% or less
than 35%–40% without consideration of an underlying causative
mechanism. This limits the external validity of much of the pub-
e¢ lished literature defining management of patients with heart
failure. The need for more rigid criteria defining study populations
for heart failure trials is needed, and as we embark on defining
E=.40m/sec E¢=.04m/sec E/E¢=10 therapeutic strategies for DHF, this consideration is paramount.
In clinical medicine there are fundamentally only two thera-
peutic targets; improvement in symptoms and quality of life and
improvement in survival. The salutary effects on symptoms as a
result of strategies that merely alter loading conditions (see Figs.
33-4 and 33-5) do not directly influence the diastolic properties
e¢ of the myocardium but rather direct the myocardium to a more
favorable position on the end diastolic pressure-volume curve. A
true change in diastolic function is characterized by a rightward/
Figure 33-5 Top two images, before treatment; and bottom two images, downward shift in the end diastolic pressure-volume relationship
posttreatment. Following treatment, there has been a conformational
change in the mitral inflow velocity profile to a grade 1 pattern and a (Fig. 33-6). Either a more favorable position on a defined end
marked reduction in the E/E′ ratio. Note that before and after treatment, diastolic pressure-volume curve or a true change in the end dia-
the E′ velocity remains unchanged and significantly depressed. stolic pressure-volume relationship will result in improvement in
symptoms. It is difficult, however, to conceptualize how survival
may be affected without a true change in myocardial performance.
tionship has been achieved. In patients with grade 3 or 4 diastolic Therefore, as treatment strategies evolve for DHF, endpoints need
dysfunction, LV filling may be complete in middiastole. Such to include not only symptoms but also the influence on myocar-
patients have a fixed stroke volume, and empirically slowing the dial mechanics. Echocardiography is evolving novel mechanisms
heart rate to between 50 and 70 bpm may result in a further reduc- with which to evaluate subtle changes in myocardial performance.
tion in cardiac output and a worsening of the clinical symptom The paradigm of myocardial motion is shifting from simple uni-
complex. Therefore, in these patients, the initiation of beta blocker directional comments of longitudinal, circumferential, or radial
therapy should be monitored closely and done with small doses. motion to those of rotation, twist, and torsion, which better
reflect the complexity of myocardial mechanics (see Chapter 12).
Along with standard Doppler techniques, this may prove echo-
FUTURE DIRECTIONS cardiography to be an even more important tool in the evaluation
of new treatment strategies.
It must be emphasized that heart failure is not a diagnosis but The heart is not a pump that works in isolation. The heart
rather a constellation of signs and symptoms representing a final has an intimate relationship with the arterial vasculature (see
common pathway of a heterogeneous group of diseases.10 The Chapters 7 and 31). Increases in vascular and ventricular stiffness
 Chapter 33 • Echo-Based Approach to the Management of Diastolic Heart Failure 433

along with DHF appear to be associated with the privilege of 20. Tsouli SG, Liberopoulos EN, Kiortsis DN, et al: Combined treatment
aging.44 Vascular stiffness results in an increase in pulse pressure. with angiotensin-converting enzyme inhibitors and angiotensin II receptor
blockers: A review of the current evidence. J Cardiovasc Pharmacol
The decrease in diastolic pressure may decrease coronary blood Ther 2006;11:1–15.
flow, incite microvascular abnormalities, and begin a cascade result- 21. Pitt B, Fonarow GC, Gheorghiade M, et al: Improving outcomes in post–
ing in abnormal diastolic function.45 Insight into these mechanisms acute myocardial infarction heart failure: Incorporation of aldosterone
may influence novel therapeutic strategies targeting the vascula- blockade into combination therapy to optimize neurohormonal blockade.
Am J Cardiol 2006;97:26F–33F.
ture with endpoints of stiffness and central aortic pressure. Pre- 22. Al-Mallah MH, Tleyjeh IM, Abdel-Latif AA, et al: Angiotensin-
liminary strategies focused in this direction hold promise.46 converting enzyme inhibitors in coronary artery disease and preserved
left ventricular systolic function: A systematic review and meta-analysis
of randomized controlled trials. J Am Coll Cardiol 2006;47:1576–
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434 Chapter 33 • Echo-Based Approach to the Management of Diastolic Heart Failure
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 W. H. WILSON TANG, MD
34
Future Therapies in
Diastolic Heart Failure
INTRODUCTION PATHOPHYSIOLOGY AND CLINICAL RELEVANCE
PATHOPHYSIOLOGY AND CLINICAL RELEVANCE Targeting Extrinsic Factors: Antagonizing
Targeting Extrinsic Factors: Antagonizing Neurohormonal Upregulation
Neurohormonal Upregulation
Targeting Intracellular Intrinsic Factors: Metabolic It has been postulated that neurohormonal upregulation in the
Modulation heart failure syndrome is a nonspecific homeostatic response to
Targeting Extracellular Intrinsic Factors: Inhibiting adverse hemodynamic perturbations in both preserved and
Collagen, Crosslinks, and Matrix Deposition impaired systolic function.3 Although current guidelines have rec-
Novel Device Therapies ognized the potential benefit of angiotensin-converting-enzyme
(ACE) inhibitors and aldosterone receptor blockers in the treat-
FUTURE RESEARCH ment of diastolic heart failure,4 outcome trials are still ongoing. The
modest benefits of add-on aldosterone receptor blockers to ACE
inhibitors or β-adrenergic blockers in the Candesartan in Heart
Failure: Assessment of Reduction in Mortality and Morbidity
(CHARM)–Preserved study has provided some reassurance that
INTRODUCTION this approach is safe and potentially beneficial.5 Results from the
European Perindopril for Elderly Persons with Chronic Heart
The treatment of diastolic heart failure (also known as “heart Failure (PEP-CHF) study have recently been reported.6 However,
failure with preserved systolic function”) has been challenging, enrollment and event rates were lower than anticipated and many
partly because there is a lack of consensus regarding the definition subjects withdrew from the study or started to take open-label
of the disease entity, as well as a paucity of large-scale clinical trials ACE inhibitors, thereby reducing the power of the study to show
to demonstrate effective therapeutic strategies.1 Diastolic and sys- a difference in the primary endpoint to 35%. Nevertheless, by
tolic heart failure may have certain similar pathophysiologic pro- one year follow-up, reductions in the primary outcome (HR
cesses in common, but there are also distinct differences in 0.692: 95% CI 0.474–1.010; P = 0.055) and hospitalization for
myocardial structure and function.2 Most treatment strategies for heart failure (HR 0.628: 95% CI 0.408–0.966; P = 0.033) were
diastolic heart failure strive to alleviate signs and symptoms or observed, and functional class (P < 0.030) and six minute
prevent exacerbating factors, rather than alter the underlying corridor walk distance (P = 0.011) improved in those assigned to
pathophysiologic abnormalities (such as improving active relax- perindopril. Meanwhile, the Valsartan in Diastolic Dysfunction
ation or reducing passive stiffness). (VALIDD) study did not show statistically significant differences
Several lines of new investigations have identified regression of in changes of diastolic relaxation velocity between valsartan or
left ventricular (LV) hypertrophy as a potential target of therapy, matched placebo when similar target blood pressure lowering was
while others hope to improve outcomes in patients with features achieved.7 This raised a question of reliability regarding echocar-
of diastolic heart failure via novel targets. Some of these drugs diographic variables as surrogate endpoints and the benefits of
have already been approved for other indications, and improve- these agents beyond their blood pressure control. The Irbesartan
ment in diastolic dysfunction is considered an ancillary property in Heart Failure with Preserved Ejection Fraction (I-PRESERVE)8
that may have potential for further clinical development. This study is still underway, and we hope it will shed important insight
chapter summarizes the ongoing efforts to develop future thera- into whether ACE inhibitors and aldosterone receptor blockers
pies targeting extrinsic or intrinsic factors in diastolic heart improve clinical outcomes in this population. However, the wide
failure. acceptance of these agents in the treatment of hypertension and
435
436 Chapter 34 • Future Therapies in Diastolic Heart Failure

diabetes already may have lessened the impact of these large-scale and abnormal diastolic function on echocardiography. Although
clinical trials on changing the treatment patterns in this popula- the primary objective of this exploratory study is to demonstrate
tion, since the majority of patients suffering from diastolic heart improvement in impaired exercise tolerance with sitaxsentan
failure may already be treated with ACE inhibitors, aldosterone sodium in patients with diastolic heart failure, it will provide
receptor blockers, or both. Ongoing clinical developments of renin valuable data to assess the safety of a drug class that has previously
inhibitors and aldose reductase inhibitors will likely provide more raised concerns in the systolic heart failure population.
complete blockade of the renin-angiotensin-aldosterone system
and potential therapies for diastolic heart failure.
Vasopressin Receptor Antagonists
Arginine vasopressin levels have been found to be elevated in
Aldosterone Receptor Antagonists patients with clinical evidence of both systolic and diastolic heart
A growing body of evidence suggests that aldosterone plays an failure (see Chapter 27). Since patients with diastolic heart failure
important role in the pathophysiology of diastolic heart failure (see demonstrate the same clinical presentation of fluid retention and
Chapters 27 and 32). Myocardial aldosterone has been implicated functional impairment, antagonizing vasopressin V2 receptors
in myocyte hypertrophy and cardiac fibrosis leading to diastolic may provide some added benefits. However, current clinical trials
dysfunction.9 In patients with systolic heart failure, treatment with of vasopressin receptor antagonists such as tolvaptan and lixivap-
aldosterone receptor antagonists resulted in reduction in collagen tan are limited either to those with LV systolic dysfunction or to
turnover and in cardiac fibrosis.10,11 Several small-scale investiga- those with evidence of hyponatremia. If beneficial in these set-
tions have demonstrated that in hypertensive subjects, treatment tings, it will be logical to explore the potential benefits of these
with spironolactone can lead to improvement in myocardial strain agents in patients with diastolic heart failure, although there have
and strain rate, measured by echocardiography,12 as well as reduc- been no specific studies to address the role of vasopressin and its
tion in LV mass, measured by magnetic resonance imaging.13 antagonist in diastolic heart failure.
These results appear to be synergistic with the use of ACE inhibi-
tors, or even with angiotensin receptor blockers (ARBs).
For now, aldosterone receptor antagonists are not indicated for Targeting Intracellular Intrinsic Factors:
treating diastolic heart failure, and their broad adoption has been Restoring Calcium Homeostasis
hampered by their risks of developing hyperkalemia and renal Targeting calcium homeostasis to improve lusitropy has been a
insufficiency. Several mechanistic clinical studies are under way to long-standing goal in treating diastolic heart failure. During
better identify changes in various clinical and echocardiographic cardiac ischemia, an increase in intracellular calcium is proposed
features with either spironolactone or eplerenone. A large, National to impair myocyte contraction and may alter myocyte recovery
Institutes of Health–sponsored multicenter clinical trial is cur- following reperfusion. Many of the agents that improve calcium
rently under way to study whether spironolactone can reduce sensitization have demonstrated improvement in lusitropy in
morbidity and mortality. The Treatment of Preserved Cardiac animal models and in mechanistic studies.
Function Heart Failure with an Aldosterone Antagonist
(TOPCAT) study will enroll 4500 adult patients with heart
failure and preserved systolic function (LV ejection fraction >45%, MCC-135 (Calderet)
plus heart failure hospitalization within 12 months or elevated MCC-135 is an agent for cardiac diseases, including heart failure
natriuretic peptides). Patients will be recruited over 21/2 years, or myocardial infarction, that demonstrates improving effects for
treated, and followed for a minimum of 2 years, with the primary cardiac diastolic dysfunction and protective effects for cardiac
endpoint being a composite of cardiovascular mortality, aborted necrosis by enhancing Ca2+ uptake by the sarcoplasmic reticulum
cardiac arrest, and hospitalization for the management of heart and inhibiting the sarcolemmal Na+/Ca2+ exchange.20 These
failure (i.e., hospitalization for nonfatal myocardial infarction or effects have been shown mainly in animal models21 and were
nonfatal stroke). This is, however, quite a challenging task, because thought to reduce calcium overload at the sarcoplasmic reticulum,
the study population will primarily be elderly patients with a wide thereby preserving myocardial function in diastolic heart failure
range of comorbid conditions that may confound the endpoints. and reducing the incidence of fatal reperfusion arrhythmias in the
setting of ischemia. However, published human data on this
compound is limited. The Phase II randomized, double-blind,
Endothelin Receptor Antagonists
placebo-controlled, parallel-assignment, safety/efficacy MCC-
Researchers have had a long-standing interest in the development 135 GO1 study has been performed in patients with symptom-
of endothelin receptor antagonists for the treatment of heart atic diastolic heart failure22; the results of the study have not yet
failure (see Chapter 27). However, attempts to use bosentan, been presented. The future clinical development of MCC-135 for
darusentan, and tezosentan in patients with systolic heart failure diastolic heart failure is currently unclear.
have not been successful.14–16 More recently, it has been recog-
nized that endothelin may play an important role in the develop-
ment of diastolic dysfunction. Endothelin interacts with the Ranolazine
renin-angiotensin-aldosterone system and matrix metalloprotein- Ranolazine has been safe and effective in reducing angina in
ases (MMPs) in the development of diastolic dysfunction, and patients with refractory chronic stable angina (currently approved
this pathophysiology can be attenuated by endothelin type A indication) without any alterations in hemodynamic profiles.23
receptor antagonists.17–19 Sitaxsentan sodium, a potent antagonist Ranolazine also has inhibitory effects on the late sodium channel,
of the endothelin receptor (isoform ETA), is currently being evalu- which has prompted interest in using ranolazine for treatment of
ated in a Phase II multicenter clinical trial in patients with dia- diastolic dysfunction.24 Animal studies have identified improve-
stolic heart failure, defined as symptoms of chronic heart failure, ments in LV function following ranolazine therapy,25 and early
with a left ventricular ejection fraction (LVEF) greater than 50% human studies have shown improvement in diastolic indices fol-
 Chapter 34 • Future Therapies in Diastolic Heart Failure 437

lowing intravenous administration of ranolazine in humans.26 hypertension.43 However, no clinical studies have been performed
Through its inhibition of the late sodium current, ranolazine to specifically examine the role of these agents in improving dia-
reduces the activity of sodium-calcium exchange (NCX) and stolic indices beyond the setting of diabetes mellitus.
lowers intracellular calcium overload.23 However, such effects While there are limited peroxisome proliferator-activated
have been limited to in vitro and animal studies,27 and their ben- receptors–gamma (PPARγ) in the myocardium, abundant recep-
efits are yet to be confirmed in humans. Nevertheless, as an tors for another “sensitizer,” glucagon-like peptide 1 (GLP-1),
approved drug, there is good potential for ranolazine to be devel- may indicate potential direct metabolic effects on the myocar-
oped in the area of diastolic heart failure. dium. Short-term infusion of GLP-1 in diabetic patients with no
history of heart failure has also resulted in improvement in inva-
sive hemodynamic measurements of diastolic dysfunction44;
Gene Therapy
mechanistic human trials are currently ongoing in patients with
Direct gene transfer has yielded some success in experimental advanced systolic heart failure, and an injectable form of GLP-1
models of diastolic heart failure. The concept is straightforward: is currently approved for glycemic control in patients with diabe-
Overexpression of a gene that encodes a specific protein to tes mellitus.
enhance or replace an abnormality in calcium handling may
improve excitation-contraction coupling and result in improve-
ment in diastolic function.28,29 Genes that improve calcium Fatty Acid Oxidation Inhibitor
homeostasis, such as Ca2+-ATPase (SERCA2a)30,31 and parvalbu- Improving cardiac metabolism can also be achieved by reducing
min,32 phospholamban (S16EPLN),33 protein phosphatase 1,34 fatty acid oxidation, thereby restoring the balance of glucose and
and NCX,35 have been prime targets for this type of strategy fatty acid utilization in the failing heart. Both perhexiline and
in animal models. Most of the studies demonstrated hemody- oxfenicine inhibit fatty acid oxidation and reduce the rise in dia-
namic improvement of LV relaxation but not necessarily reduc- stolic tension during ischemia.45 Several existing drugs, such as
tion in LV end diastolic pressures. Various other cell therapies, trimetazidine and perhexiline, have been tested in patients with
antisense therapies,36 and other targets, such as Akt and ryano- heart failure in the setting of impaired LVEF, and echocardio-
dine receptor–stabilizing proteins (FKBP12.6), have also been graphic indices of diastolic dysfunction (E/A ratio, diastolic strain,
reported.37,38 However, human data regarding the safety and effi- or strain rate) improved in parallel with alterations in phosphocre-
cacy of gene therapy remain scarce. atine/ATP ratios.46 While there have been some safety concerns
It should be emphasized that not all strategies targeting calcium with renal and hepatic drug toxicities for perhexiline, trimetazi-
homeostasis can result in diastolic improvement. One such inno- dine has been widely used in Europe for treating angina.
vative device therapy modulates intracellular calcium levels using
noncontractile repetitive pacing, so-called cardiac contractility
modulation.39 Clinical trials are currently under way to determine Copper Chelating Therapy (Trientine)
its efficacy in improving cardiac performance, but so far there has Another intriguing concept that has emerged over the past
not been any noticeable improvement in diastology, despite an few years is the role of copper metabolism in the development
impressive increase in cardiac contractility in symptomatic patients of diabetic cardiomyopathy. Cooper et al. published several
with impaired cardiac function. key papers illustrating the efficacy of trientine, a copper chelat-
ing agent for Wilson’s disease, in reversing LV remodeling
Targeting Intracellular Intrinsic Factors: (predominantly regression of hypertrophy) without lowering
blood sugar.47,48 It was also shown to substantially improve car-
Metabolic Modulation
diomyocyte structure and to reverse elevation in LV collagen and
The role of metabolic derangements in progression of the heart β-1 integrin. These data are believed to implicate accumulation of
failure syndrome is not well understood despite decades of basic elevated loosely bound copper in the mechanism of diabetic car-
science research. Hyperglycemia has been associated with wors- diomyopathy and to support the use of selective copper chelation
ening diastolic dysfunction in patients with type 1 diabetes mel- in the treatment of this condition. This hypothesis is now being
litus.40 Metabolism, contraction, and relaxation of the heart are tested in a new formulation of trientine (under the name
inseparably linked, and a constant resynthesis of adenosine tri- LaszarinTM, Protemix Inc). Early-phase reports of oral treatment
phosphate (ATP) by oxidative phosphorylation in the mitochon- with trientine show elevations in copper excretion in humans with
dria is a prerequisite for normal cardiac function. In heart failure, type 2 diabetes, and following 6 months of treatment, it caused
the heart adapts by switching from fatty acid to glucose oxida- elevated LV mass to decline significantly toward normal.48 To
tion.41 Restoring the balance between fatty acid and glucose date, trientine has been well tolerated by patients in clinical trials,
metabolism represents an exciting and promising novel strategy and it has a long safety profile in the treatment of Wilson’s disease.
in heart failure, although the effects of metabolic modulation in A Phase IIb clinical trial of trientine administration in patients
diastolic heart failure have not been explored. with diabetic heart failure with a quality of life (exercise tolerance)
outcome is currently under way. Larger clinical trials are in the
planning stages. Nevertheless, our understanding of why copper
Insulin Sensitizers chelation may work is rudimentary; it is unclear whether it will
Several new diabetic medications have been evaluated in the work outside the setting of diabetes mellitus, and whether struc-
improvement of diastolic dysfunction in long-term therapy (see tural changes may directly translate into clinical benefits.
Chapter 26). The number of studies on this topic is limited.
Hyperglycemia has been associated with increased diastolic
abnormalities, and metformin has been shown to reduce diastolic Statins and Coenzyme Q10
dysfunction in diabetic myocardium.42 Pioglitazone has also been Statins have been widely used to treat hypercholesterolemia.
shown to improve diastolic indices in patients with essential Interestingly, their anti-inflammatory and pleiotropic effects have
438 Chapter 34 • Future Therapies in Diastolic Heart Failure

been considered as potential treatments in the setting of diastolic teins, lipids, and DNA (see Chapter 30). Many proteins, including
heart failure (see Chapter 32). Treatment with statins in non– the structural proteins collagen and elastin, play an integral role
heart failure patients has been associated with reduction in in the architecture of tissues and organs and in the maintenance
markers of oxidative and nitrosative stress.49 Fukuta et al. con- of cardiovascular elasticity and vascular wall integrity. By irrevers-
ducted an exploratory study of statin therapy in patients with ibly crosslinking collagen molecules in the setting of aging or
diastolic heart failure.50 This study evaluated 137 patients with diabetes, AGEs may increase the tensile strength of the collagen
heart failure and preserved LV function. Use of statin therapy was and also may make it less susceptible to degradation by MMPs.
associated with an improvement in survival and a relative risk of The formation of AGE “crosslink” therefore leads to increased
death of 0.22. In contrast, treatment with an ACE inhibitor, aldo- stiffness, and abnormal protein accumulation may cause further
sterone receptor blocker, beta blocker, or calcium channel blocker complications of aging and diabetes. AGEs are also known to
had no significant effect on survival. induce oxidative stress, in which reactive molecules provoke the
Propensity analysis confirmed that statin therapy was associ- underlying component of inflammation.
ated with improved survival and a trend toward improved survival Pharmacologic intervention with alagebrium, the prototype
without cardiovascular hospitalization.50 Interpretation of these AGE crosslink breaker, directly targets the biochemical pathway
results must take into consideration that this was not a random- leading to myocardial and vascular stiffness. Removal of the AGEs
ized clinical trial. Nevertheless, other prospective studies have by cleavage of the abnormal crosslinking bonds has been associ-
identified potential benefits of statin use on LV remodeling.51 ated with diminished inflammatory and sclerotic signaling
There have been several plausible explanations for the potential pathways. These pathways are responsible for the deposition of
benefits of statins in this population, including prevention of abnormal amounts of matrix proteins that physically stiffen
hypertrophy and fibrosis, providing ancillary anti-inflammatory tissues. The presence of AGE crosslinks also renders tissues and
and antioxidative effects, and of progression of coronary ischemia. organs less susceptible to normal turnover, thus enhancing the
With broad use of statins in the at-risk population (particularly presence of these abnormal bonds on various molecules. Impor-
in diabetic patients), large-scale exploration of efficacy with statin tantly, alagebrium does not disrupt the natural carbohydrate
therapy in this setting will be challenging. It will be interesting to modification to proteins, intramolecular crosslinking, or peptide
see if the ongoing clinical trials using rosuvastatin have any effects bonds that are responsible for maintaining the normal integrity
on diastolic remodeling or mortality benefits. of the collagen chain. Thus, normal structure and function are
The issues are further complicated by the phenomenon known preserved, while abnormal crosslinking is reduced. Preliminary
as “statin cardiomyopathy.” In some studies diastolic parameters studies have indicated that alagebrium can partially reverse some
have become more impaired following statin therapy and can be of the constellation of functional deficits and structural abnor-
improved by coenzyme (Co) Q10 administration.52 Indeed, malities of diastolic dysfunction and may be able to modify some
CoQ10 has been widely used as a nutriceutical agent due to its aspects of chronic heart failure. Most importantly, alagebrium
antioxidant effects. Claims have been made that CoQ10 may modifies the underlying disease pathology rather than treating the
possess some effects on improving diastolic dysfunction in small symptoms of disease.
clinical studies,53 but no definitive evidence for diastolic improve- Distensibility Improvement and Remodeling in Diastolic
ment is available. Heart Failure (DIAMOND), a Phase IIa clinical study, was con-
ducted to evaluate the potential effects of alagebrium in patients
with diastolic heart failure.57 In this open-label study, 23 patients
Thyroid Hormone Analog (New York Heart Association [NYHA] classes II–III, LVEF
The connection between thyroid hormone and the cardiovascular >50%, age ≥60 years) received 210 mg of alagebrium twice daily
system has been well recognized. In hyperthyroidism, cardiac con- for 16 weeks in addition to their current medications. Patients
tractility and cardiac output are enhanced and systemic vascular who received alagebrium had a statistically significant reduction
resistance is decreased, whereas the opposite is true in hypothyroid- in LV mass, as well as a marked improvement in the initial phase
ism. Furthermore, significant correlations were found between of LV diastolic filling and better quality of life in the absence of
pulse-wave tissue Doppler imaging parameters and serum-free T3 blood pressure reduction. The results from the parallel, open-label
and T4 and concentrations of thyroid-stimulating hormone in both Patients with Impaired Ejection Fraction and Diastolic Dysfunc-
subclinical hypothyroid and in euthyroid patients.54 Treatment with tion: Efficacy and Safety Trial of Alagebrium (PEDESTAL)
thyroid hormones and their analogs may restore diminished expres- study on patients with systolic heart failure and diastolic dysfunc-
sion of sarcoplasmic reticulum proteins, including GLUT-4 and tion were presented at the 2005 American Heart Association
SERCA2.55 A recently developed T3 analog, 3,5-diiodothyropro- scientific sessions and showed trends consistent with the
pionic acid (DITPA), has been shown to improve diastolic indices,56 DIAMOND study results. However, recent safety concerns have
but current ongoing Phase II heart failure studies have been limited emerged regarding liver toxicity in male rats treated with
to those with chronic systolic heart failure. alagebrium, and the clinical development of this drug class in
hypertension and erectile dysfunction has been discontinued.
Nevertheless, if the benefits outweigh the risks, this novel approach
Targeting Extracellular Intrinsic Factors: will be highly promising.
Inhibiting Collagen, Crosslinks, and
Matrix Deposition
Matrix Metalloproteinase Inhibitors
Advanced Glycation End-Product
Collagen deposition leading to increased stiffness can result from
Crosslink Breakers alterations in the balance of promoters and inhibitors of MMPs.58
Advanced glycation end-products (AGEs) are permanent carbo- However, this concept of inhibiting MMPs to reduce collagen
hydrate structures that form when carbohydrates bind to pro- deposition suffers from the problem of using a therapeutic target
 Chapter 34 • Future Therapies in Diastolic Heart Failure 439

that has widespread effects that extend beyond the failing gies are highly invasive, with potential complications that can
myocardium. Recent results from the Prevention of Myocardial be extensive and devastating, which has limited their broad
Infarction Early Remodeling (PREMIER) study showed that adoption.
the prototype MMP inhibitor, PG-116800, did not show Two devices specifically designed to enhance diastolic filling are
significant benefits in preventing LV remodeling over placebo now in preclinical phases of testing. Although these devices
following myocardial infarction.59 This inhibitor has yet to be require invasive surgical implantation through a simple off-pump
tested in the setting of diastolic heart failure. Several other drugs closed-heart procedure, preclinical data have been promising. The
are also being considered to target MMPs and tissue inhibitors ImCardia (CorAssist Cardiovascular Inc.) is an elastic, self-
of metalloproteinases (TIMPs) in this population; but until a expanding device with a special silicon lattice material attached to
more specific target can be identified, this strategy remains largely the external surface of the left ventricle.64 The ImCardia harnesses
theoretical. the heart’s systolic energy during recoil from systole in order to
reduce diastolic intracardiac pressure. The device operates without
the need for an external source of energy. In contrast, the Levram
Novel Device Therapies Physiological Cardiac Assist Device (PCAD) (Levram Medical
Cardiac Resynchronization Therapy Systems) utilizes a single blood displacement chamber and a
single cannula.65 The cannula is inserted into the failing ventricle
As in many other areas in cardiology, innovative device therapies cavity via the LV apex and is connected to a blood displacement
have emerged. One of them is cardiac resynchronization actuator. Instead of the traditional “rerouting” concept of ventricu-
therapy (CRT), for patients with systolic heart failure with dys- lar assist devices, the Levram PCAD utilizes the residual power
synchrony (see Chapter 29). When properly optimized, CRT has of the cardiac muscle and works with its dynamics in a synchro-
been shown to improve systolic as well as diastolic dysfunction.60 nized manner, thereby providing direct add-on mechanical
We still have very limited experience regarding the role of dyssyn- pumping assistance during systole and diastole. Both studies will
chrony in pure diastolic heart failure, and the significance of dys- begin human feasibility trials in the near future, but the concept
synchrony (especially diastolic dyssynchrony) in patients with for surgical interdiction is still in early development, largely due
preserved systolic function remains unclear. While studies to date to its invasive nature.
have limited CRT to patients with systolic heart failure, patients
with atrial fibrillation who may be dependent on cardiac pacing
have been shown to benefit in the Post Atrioventricular Nodal FUTURE RESEARCH
Ablation Evaluation (PAVE) LV-based cardiac stimulation trial.61
Furthermore, regional wall thickness62 and diastolic indices63 Drugs and devices developed to treat diastolic heart failure are
appear to improve following CRT, especially in non-ischemic thought to hold limited commercial promise because they are
cardiomyopathy. primarily add-on therapies in a study population in which
treatment goals and treatment outcomes are not well defined. The
Implantable Hemodynamic Monitoring Devices therapeutic options discussed in this chapter are just some of
the examples on which there are published data or that are cur-
One strategy to improve care for patients with diastolic heart rently in active clinical development. The fact that there are a
failure targets improved monitoring of diastolic parameters to limited number of “pipeline” drugs that specifically target
guide therapy. Since the common end result of passive diastolic heart failure brings home the point that we are still in
stiffness and abnormal relaxation is elevated LV end diastolic the infancy of understanding the underlying pathophysiology of
pressure, proactive intracardiac hemodynamic monitoring is a diastolic heart failure. Furthermore, the association between
theoretical solution to guide optimal drug therapy. Over the improvements of echocardiographic indices of diastolic dysfunc-
past two decades, implantable hemodynamic monitoring tion may not relate directly to clinical efficacy. Although LV
(IHM) devices have undergone significant refinements, and the hypertrophy regression appears to be a good surrogate endpoint
recent multicenter Chronicle Offers Management to Patients for diastolic heart failure, definitive proof for this is not yet
with Advanced Signs and Symptoms of Heart Failure available.
(COMPASS-HF) safety study, utilizing the Chronicle From what we understand now, drugs that affect calcium
device (Medtronic Inc.), resulted in significant reduction in homeostasis will emerge as important players in this field, although
heart failure hospitalizations and mortality in patients with existing neurohormonal antagonists will maintain their presence
NYHA class III heart failure (approximately 30% of the study in the diastolic heart failure regimen. New targets will emerge,
population had preserved cardiac function).59 Several other and new drug classes (like AGE crosslink breakers) will be tested
hemodynamic monitoring devices are currently undergoing early as we broaden our understanding of the diversity of diastolic
clinical development, and it is likely that IHM devices will guide heart failure. Metabolic modulation has also shown great promise
drug management in selected patients with diastolic heart as we begin to understand the close connections between myo-
failure. cardial and vascular metabolic derangements and diastolic dys-
function. Device implantation for treating diastolic heart failure
will need further development to reduce the procedural risks,
Novel Mechanical Assist Devices invasiveness, and expense. Nevertheless, intracardiac hemody-
Mechanical assist devices have focused on improving forward flow namic monitoring devices will likely play an important role in
by providing either pulsatile or nonpulsatile pumps as “replace- guiding therapy in this population. The road to clinical develop-
ments” for myocardial function. However, currently available ment in diastolic heart failure is tortuous and demanding, but at
mechanical devices are invasive and focus mainly on salvaging the same time exciting and rewarding, as it brings new ideas, new
patients with end-stage systolic dysfunction. Most of these strate- challenges, and new hopes.
440 Chapter 34 • Future Therapies in Diastolic Heart Failure

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Index

Page numbers followed by b denote boxes, those followed by f denote figures, and those followed by
t denote tables.

A Angina, 424
Angiotensin II, 253, 347
Biopsy, endomyocardial
description of, 250
ACE inhibitors. See Angiotensin-converting enzyme Angiotensin II inhibitors, 268 in restrictive cardiomyopathy, 310
(ACE) inhibitors Angiotensin receptor blockers, 210, 422–423 Biventricular pacing, 374, 375t
Action potential, 5–6 Angiotensin-converting enzyme (ACE) inhibitors B-mode echocardiography, 163
Acute aortic insufficiency, 240 angiotensin receptor blockers and, 423 Brain natriuretic peptide
Acute chamber dilation, 30 indications for, 338t, 353, 396, 417, 421–422, administration of, 357–358
Acute coronary syndromes, 357 435 in chronic renal failure, 358
Acute decompensated diastolic heart failure, 24 Annular velocity, 187f in constrictive pericarditis, 304–305, 358
Acute heart failure, 356–357 Annulus paradoxus, 308 description of, 67, 148, 190, 345
Acute ischemia Aortic distensibility, 208, 208f diastolic dysfunction and, 355
description of, 55, 278 Aortic insufficiency, 240–241 exogenous administration of, 357–358
transmitral inflow in, 280t Aortic stenosis half-life of, 351
Acute myocardial infarction diastolic dysfunction in, 241 in heart failure, 351–352
Doppler filling profiles in, 282–285, left ventricular untwisting delays associated with, immunoassays for, 352
283t 157 left ventricular function and, 351f, 354f, 355t
left ventricular remodeling after, 278 Tei index affected by, 195 left ventricular remodeling and, 351
Acute pulmonary edema, 20 Apical acoustic window, 153 NT-proBNP, 351, 357
Adrenergic receptors, 4 Arginine vasopressin, 346, 348 plasma levels of, 351, 353, 356, 359
Adrenergic signaling abnormalities, 4 Arterial compliance, 208, 209f restrictive cardiomyopathy levels of, 304–305
Adrenocorticotropic hormone, 348 Arterial elastance, 78, 82 secretion of, 351
Adrenomedullin, 345, 349 Arterial stiffening. See also Ventricular-arterial structure of, 350f
Advanced glycation end-products (AGEs), 160, stiffening synthesis of, 350–351
393–394, 419, 438 age-associated increase in, 84 Brain perfusion, 84
Aerobic exercise training, 211 description of, 78, 82–83 Buffered beat acquisition, 108
Afterload Arterial-ventricular coupling, 82
arterial, age-associated increases in, 85 Arterial-ventricular stiffening. See Ventricular-
in chronic aortic regurgitation, 240
ejection fraction affected by, 63
arterial stiffening
Arteriovenous oxygen, 204
C
left ventricular geometry affected by increases in, Ascites, 304 Calcium
323 Atenolol, 416t early diastole influenced by reuptake of, 390f,
systolic blood pressure affected by, 406f Athlete’s heart, 293 390–391
tissue Doppler imaging affected by increases in, Atrial conduit function, 37 homeostasis of, 334–335, 436
324t Atrial fibrillation mitochondrial sequestration of, 84
AGEs. See Advanced glycation end-products constrictive pericarditis and, 308 in myocardial relaxation impairments, 3
Aging. See also Seniors description of, 138 myofilament responsiveness to, 6–7
arterial stiffening and, 84 hypertrophic cardiomyopathy and, 290–291 regulation abnormalities, 4
Doppler measures of diastolic function affected Atrial flutter, 138 Calcium channel blockers, 294–296, 417,
by, 401 Atrial natriuretic peptide 423–424
left ventricular diastolic function and, description of, 237, 346 Calcium release
84 NT-proANP, 358 calcium-induced, 4
left ventricular filling and, 111, 120 structure of, 350f sarcoplasmic membrane protein regulation of, 6
left ventricular relaxation affected by, 111, Atrial septal defects, 323 Calcium sensitizers, 7
388–389 Atrial systole, 106 Calcium-induced calcium release, 4
metabolic hypothesis of, 393–394 Atrioventricular conduction disease, 378 Calmodulin-dependent protein kinase II, 6
mitral flow velocity and, 120t, 120–121 Atrioventricular delay, 377–379, 379, 379f Candesartan, 210, 211f, 338, 386, 395, 415, 416t,
pulmonary venous flow velocity and, 123 Atrioventricular synchrony, 378 431
sedentary, 388, 393 Augmentation index, 236 Capillary basement membrane, 335
A-kinase anchoring proteins, 4 Capillary resistance, 83
Alagebrium, 438 Capillary wedge pressure, 148
Aldosterone, 253, 296, 348, 435
Aldosterone inhibitors, 210
B Captopril, 416t
Carbon dioxide, 203–204
Aldosterone receptor antagonists, 339, 423, Bernoulli equation, 46, 134 Cardiac amyloid, 358
435–436 Beta blockers Cardiac amyloidosis
ALT-711, 396f, 396–397 diastolic heart failure treated with, 420–421 case study of, 262
Amlodipine, 416t, 421 dilated cardiomyopathy treated with, 254 classification of, 262–263
Amyloid deposits, 305 hypertrophic cardiomyopathy treated with, clinical presentation of, 263–264
Amyloidosis. See Cardiac amyloidosis 294–295 description of, 100, 100f

443
444 Index
Cardiac amyloidosis (Continued) Children Constrictive pericarditis (Continued)
diagnosis of, 265–266 diastolic dysfunction in, 313–319 case studies of, 308–311
echocardiography of, 264–265 dilated cardiomyopathy in, 324 chest x-ray evaluations, 308, 309f, 310f
end-stage chronic heart failure caused by, 193, hypertrophic cardiomyopathy in, 323–324, 325f clinical presentation of, 304
194f left ventricular diastolic function in computed tomography of, 308, 309f
etiology of, 262 color M-mode flow propagation velocity, description of, 98–99, 99f
familial, 262–263 318–319 diagnosis of, 302
flow diagram of, 267f description of, 314 diastolic dysfunction in, 158
forms of, 263t mitral inflow Doppler assessments, 314–316 diastolic forward flow in, 306f
left atrial strain in, 168 pulmonary venous Doppler assessments, 316 echocardiography evaluations
orthostatic hypotension in, 263 tissue Doppler imaging of, 316–318 M-mode, 305f
secondary, 263 left ventricular hypertrophy in, 323 pulsed Doppler, 305–307, 306f, 307f
senile systemic, 263 single ventricle palliation, 325–326, 327f tissue Doppler, 307–308
Cardiac cachexia, 263 tetralogy of Fallot in, 324–325 two-dimensional, 305, 305f
Cardiac cycle, 13f, 116 Chlorthalidone, 416t effusive-, 311
Cardiac natriuretic peptides. See Natriuretic peptides Chronic aortic insufficiency, 240–241 electrocardiographic findings, 304–305
Cardiac output Chronic renal failure, 358, 421 future research of, 311
exercise-related increases in, 16–17 Chronotropic incompetence, 209f, 211 hepatic vein diastolic flow in, 306, 307f
Fick principle used to determine, 204 Chronotropic response, 208–209, 209f interventricular dependence in, 303–304
left ventricular relaxation effects on, 119 C-hump, 248 intrathoracic-intracardiac pressures, dissociation
Cardiac resynchronization therapy Circulation in, 303
basics of, 374 lumped parameter model of, 49–50 jugular venous pressure in, 304
description of, 157–158, 439 neurohormonal regulation of, 346 left ventricular filling in, 317
diastolic dysfunction affected by, 377t Coenzyme Q10, 437–438 magnetic resonance imaging of, 308
diastolic function affected by, 376–377 Colchicine, 268 mitral annulus velocity, 307, 310
diastolic heart failure treated with, 381 Collagen mitral inflow velocity in, 305, 306f
mechanisms of, 374 aldosterone blockade effects on, 348 occult, 307
modalities, 381 crosslinked, 394 pathology of, 302, 302f
Tei index affected by, 376 in diastolic heart failure, 17, 19f pathophysiology of, 302–308
Cardiac sarcoidosis, 100, 101f Color kinesis, 250 pericardial thickness associated with, 305
Cardiac tamponade Color M-mode Doppler echocardiography physical examination findings, 304
acute, 301 background of, 145–148 pulmonary capillary wedge pressure fluctuations
constrictive pericarditis and, 311 in children, 318–319 in, 303–304, 304f
Cardiac transplantation clinical uses of, 148–149 restrictive cardiomyopathy versus, 303–304, 358
cardiac noncompliance after, 251 description of, 145 tissue Doppler imaging of, 158, 307–308
description of, 178, 179f diastolic function evaluations, 148 treatment of, 308
diastolic dysfunction in, 250–252 flow propagation, 146 ventricular septal motion in, 305
hemodynamic abnormalities associated with, flow propagation velocity measurements, 322f Continuous wave Doppler
254 future research of, 149–150 isovolumic relaxation time measurement, 217
pulmonary capillary wedge pressure after, 251 intraventricular pressure gradients, 146–147, 149 pulmonary regurgitation, 173
rejection after, 196, 251–252 left atrial pressure estimates using, 148 tricuspid regurgitation, 173
survival rates after, 250 left ventricular filling evaluations, 219 Contractility
technique of, 251 left ventricular inflow evaluation, 219f, 219–220, myofilament responsiveness to calcium effects on,
Cardiomyocytes. See also Myocytes 220f 6
age-related changes in, 390 mitral inflow, 146f sympathetic stimulation effects on, 3
calcium regulation in, 390f pathophysiologic evaluations, 147–148 Convective deceleration, 80–81
diastolic disorders caused by dysfunction of, pseudonormal filling patterns, 148 Copper chelating therapy, 437
81 technique of, 216 Coronary artery disease
diastolic function, 19 Computational fluid models, 53–54 diabetes mellitus and, 336
hypertrophy of, 86 Computed tomography, 308, 309f Doppler echocardiography diagnosis of, 278–285
stiffness of, 86 Concentric left ventricular hypertrophy, 23–24, 65, equilibrium radionuclide angiocardiography
in systolic heart failure, 17 182, 235 detection of, 109–110
Cardiomyopathy. See Diabetic cardiomyopathy; Conduit stiffness, 85 magnetic resonance imaging applications, 98
Dilated cardiomyopathy; Hypertrophic Congenital heart disease prevalence of, 277
cardiomyopathy atrial septal defects, 323 radionuclide techniques for, 110–111
Cardiopulmonary exercise testing left ventricular diastolic function in children treatment of, 110–111, 419
hemodynamic alterations during color M-mode flow propagation velocity, Coronary circulation, 84
arterial compliance, 208, 209f 318–319 Coronary perfusion, 84–85
chronotropic response, 208–209, 209f description of, 314 Corticotrophin-releasing factor, 349
left ventricular compliance, 206 mitral inflow Doppler assessments, 314–316 Coupling disease, 82
left ventricular filling pressures, 206 pulmonary venous Doppler assessments, 316 Crosslink breakers, 438
stroke volume, 205–206, 207f tissue Doppler imaging of, 316–318 Crosslinked collagen, 394
submaximal exercise capacity, 204 left ventricular hypertrophy in, 323 C-type natriuretic peptide, 350–351
variables measured during, 203 patent ductus arteriosus, 320 Cyclic adenosine monophosphate, 4
Cardiotrophin-1, 349 postoperative, 326–327
Cardiovascular risk, 85–86 single ventricle palliation, 325–326
Cardiovascular system
arterial-ventricular coupling, 82
tetralogy of Fallot, 324–325
ventricular pressure overload in, 323
D
description of, 82 ventricular septal defects, 320 Danon’s disease, 270
stiffening of, 82 ventricular volume overload in, 319–323 Decompensated diastolic heart failure
Carvedilol, 197, 416t Constrictive pericarditis acute, 24
Central pulse pressure, 84–85 ascites in, 304 causes of, 21
Chamber stiffness, 43–44 atrial fibrillation and, 308 comorbid conditions, 21–22
CHARM, 338, 386, 395, 415, 422, 431, 435 brain natriuretic peptide in, 304–305, 358 diastolic function abnormalities in, 20–22
Chest x-rays, 308, 309f, 310f cardiac tamponade and, 311 trigger mechanisms of noncardiac factors in, 24
 Index 445
Deconditioning, 391–393 Diastolic dysfunction (Continued) Diastolic heart failure (Continued)
Deferoxamine, 271 natural history of, 430f diuretics, 416t, 419–420
Deformation of myocardium, 223 pericardium and, 27–30 goals, 417
Delayed hyperenhancement, 96, 97f prevalence of, 68 guidelines for, 417
Demand ischemia, 22 primary prevention of, 430 nitrates, 420
Diabetes mellitus prognosis of, 68–69 overview of, 416t
cardiovascular disease associated with, 333 reperfusion as cause of, 22 statins, 424
complications of, 337 secondary prevention of, 430–432 summary of, 424
coronary artery disease and, 336 in seniors. See Seniors, diastolic dysfunction in ventricular myocardium in, 373
crosslinked collagen in, 394 stages of, 65t, 216t Diastolic mitral regurgitation, 138
diastolic heart failure in systolic dysfunction and, 79 Diastolic pressure-volume relationships, 45f
angiotensin-converting enzyme inhibitors for, tachycardia effects on, 338 Diastolic stiffening, 407
338t in transplanted heart, 250–252 Diastolic suction
prevalence of, 339 Diastolic function description of, 80
risks of, 333–334 atrioventricular delay and, 377–379 left ventricular, 17
studies of, 339 cardiac resynchronization therapy effects on, left ventricular geometry abnormalities and, 81
treatments for, 337–338, 419 376–377 models of, 81
epidemiology of, 333 definition of, 355 pericardial contribution to, 29
glycemic control in, 419 in hypertrophic cardiomyopathy, 159, 296 ventricular filling affected by, 80
hypertension and, 336 left ventricular. See Left ventricular diastolic Diastolic tricuspid regurgitation, 138
tissue Doppler evaluations, 160 function Digital filtering, 108
treatment of, 419 pacing effects on, 375–376 Digitalis, 424
Diabetic cardiomyopathy right ventricular, 138–9 Digoxin, 338
calcium homeostatic regulation abnormalities in, Diastolic heart failure Dihydropyridine receptors (DHPRs), 3–4
334–335 cardiac resynchronization therapy for, 381 3,5-Diiodothyropropionic acid, 438
cardiac autonomic dysfunction in, 336 cardiac structure in, 367–368 Dilated cardiomyopathy
cellular mechanisms involved in, 335f cardiomyocytes in beta blockers for, 253–254
clinical relevance of, 336–339 diastolic function, 19 cardiac resynchronization therapy for, 157–158
free fatty acid metabolism in, 334 gene products from, 86 in children, 324
insulin resistance in, 336 hypertrophy of, 86 definition of, 247
left ventricular diastolic dysfunction in, 336–337 remodeling of, 17 diuretics for, 254
metabolic disturbances associated with, 334–335 characteristics of, 11, 65, 277, 368t, 373 exercise tolerance in, 252
myocardial fibrosis, 335 collagen in, 17, 19f familial, 247
pathophysiology of, 334f, 334–335, 335f conditions associated with, 64, 339 incidence of, 247
progression of, 336, 337t decompensated, 20–21 left ventricular diastolic dysfunction in
small vessel disease in, 335–336 definition of, 12, 12b, 64, 74, 85, 233, 367, description of, 98, 247–248
stages of, 337t 429 echocardiographic indices of, 248–250
Diastasis, 106, 117 in diabetes mellitus. See Diabetes mellitus prognostic significance of, 252–253
Diastole diagnostic criteria for, 12b, 65–66, 70, 386 tissue Doppler imaging of, 250
atrial contraction at end of, 12–13 Doppler echocardiography findings, 15f left ventricular end diastolic pressure in, 248
definition of, 4 epidemiology of, 69–70, 81, 373 magnetic resonance imaging applications, 98
description of, 313 during exercise, diastolic function abnormalities pathogenesis of, 248
left ventricular chamber, 43–44 in, 22 pressure-volume relationship abnormalities in,
left ventricular stiffness and, 16, 83 exercise intolerance in, 205 248, 249f
measurements of, 13 hospitalization rates for, 339 right ventricular diastolic dysfunction in, 253
myocardial relaxation during, 12 incidence of, 430 survival rate for, 254
phases of, 12–13, 106 left ventricular ejection fraction in, 367 Tei index in, 195
Diastolic distensibility, 17 left ventricular filling in, 338 tissue Doppler evaluations, 157–158, 250
Diastolic dysfunction. See also Left ventricular left ventricular remodeling in, 17, 18f, 21f, 367 treatment of, 253–254
diastolic dysfunction; Right ventricular left ventricular systolic function in, 19–20, 367– Diltiazem, 295–296, 416t
diastolic dysfunction 371, 368t Direct His bundle pacing, 381
arterial stiffness and, 82 mechanical asynchrony in, 375f Disopyramide, 296
assessment of, 132 mortality rates, 277 Diuretics, 254, 416t, 419–420
brain natriuretic peptide and, 355 with normal ejection fraction, 85–86 DHRs. See Dihydropyridine receptives
cardiac resynchronization therapy effects on, 377t novel therapies for, 396–397 Dobutamine stress echocardiography, 196
in cardiac transplantation, 250–252 pathophysiology of, 416–417, 430 Doppler echocardiography
causes of, 3 precipitating factors, 430 acute myocardial infarction, 282–285, 283t
cellular mechanisms of, 4, 5f prevalence of, 69–70, 386f aging effects on, 401
characteristics of, 374 prognosis of, 70 cardiac transplantation rejection, 250
in children, 313–319 in seniors. See Seniors, diastolic heart failure in color M-mode. See Color M-mode Doppler
in constrictive pericarditis, 158 stroke volume alterations in, during exercise, 206, echocardiography
definition of, 11–12, 12b, 64, 74, 85, 367 207f description of, 429
in dilated cardiomyopathy, 98 substrate in, 21 diastolic dysfunction assessments, 67–68
Doppler echocardiography assessments, 67–68 systolic heart failure versus, 65, 66t, 86 diastolic function assessments, 70, 135–136
epidemiology of, 68–69, 116 treatment of diastolic heart failure findings, 15f
exercise intolerance associated with, 205, 337 ACC/AHA recommendations for, 417t hypertrophic cardiomyopathy, 291–293
grading of, 121–123, 124f, 431 aldosterone receptor blockers, 423 isovolumic relaxation time, 217, 218f, 313
in hypertrophic cardiomyopathy, 97, 296 angiotensin receptor blockers, 422–423 left atrial size evaluations, 216, 216f
ischemic causes of, 22 angiotensin-converting enzyme inhibitors, left ventricular filling assessments using, 13
left atrial size and, 166–168 421–422 left ventricular inflow measurements, 216–217,
left ventricular end diastolic pressure, 78–79 background, 415–416 217f, 219–220
manifestations of, 313 beta blockers, 420–421 leg raising maneuver, 228, 228f
mitral filling pattern associated with, 14 calcium channel blockers, 423–424 limitations of, 140
myocardial relaxation abnormalities associated description of, 396t, 396–397 management uses of, 429–433
with, 77 digitalis, 424 maneuvers used with, 226–228
446 Index
Doppler echocardiography (Continued) Endothelin-1, 348–349 Glucosidase acid alpha trinucleotide repeat
myocardial velocity gradients, 308 Endothelin receptor antagonists, 436 expansion, 159
noninvasive, 78 Endothelium, 408 Glycemic control, 419
preload increase effects on, 322t End-stage chronic heart failure, 193, 194f, Glycogen storage disorders, 269–270
pulsed wave 349 Glycated hemoglobin, 160, 333
constrictive pericarditis evaluations, 305–307, Energy-dependent diastolic relaxation, 86 GNB3 gene, 237
306f, 307f Energy-dependent myocardial relaxation, 81 Gradient echo sequences, 94–95
hepatic veins, 221–222 Equilibrium radionuclide angiocardiography
pulmonary venous flow evaluations, 217–218, buffered beat acquisition, 108
219f
right ventricular inflow, 221, 222f
coronary artery disease evaluations, 109–110
data analysis, 108–109
H
superior vena cava, 223, 223f description of, 105 Heart
waveform, 218, 219f diastolic function analysis using, 107–109 anatomic features of, in diastolic heart failure,
respiratory maneuvers, 228 digital filtering, 108 367–368
respirometer use, 225, 226f, 228 frame mode, 107 compliance of, 403
in seniors, 387 list mode acquisition, 107–108 diastolic arterial pressure in, 408
technique of, 215–216 mathematical curve fitting, 108 lumped parameter model of, 49–50
Tei index measurements, 194 E/Vp, 187–188 Heart failure
tetralogy of Fallot, 324–325 E-wave velocity acute, 356–357
tissue. See Tissue Doppler description of, 47, 128–129 brain natriuretic peptide levels in, 351–352
Dual-chamber implantable cardioverter- in mitral regurgitation and stenosis, 136 conditions that cause, 64
defibrillators, 381 Excitation-contraction coupling, 3–4 definition of, 11, 63, 203, 429
Dual-chamber pacemakers, 374, 378 Exercise demographic features of, 352
Dyspnea, 191 diastolic function during, 16–17, 118–119 diagnosis of, 356–357, 432
Dyssynchronous pacing, 376t left ventricle response to, 370–371 diastolic. See Diastolic heart failure
left ventricular filling effects, 13f ejection fraction in, 81, 405–406
myocyte relaxation during, 17 epidemiology of, 215, 373
E Exercise intolerance
description of, 203, 211
incidence of, 3
left ventricular hypertrophy and, 346
E/A wave velocity ratio in diastolic heart failure, 205 model of, 346f
aging effects, 388f pathophysiology of, 204–209, 211 monitoring of, 357
description of, 131–132, 136, 430 severity of, 203 mortality rates, 81
pseudonormalization of, 238 in systolic heart failure, 205 after myocardial infarction, 357, 358f
Ea/Ees ratio, 404 Exercise tolerance natural history of, 203
Early annular diastolic velocity, 186 in diastolic dysfunction, 337 neurohormonal model of, 345
Eccentric left ventricular hypertrophy, 235 in dilated cardiomyopathy, 252 normal systolic function in, 111
Echocardiography interventions to increase, 210–211 predictors of, 277
amyloidosis evaluations, 264–265 Exercise training, 211 with preserved ejection fraction, 405–406, 417,
color kinesis, 250 Expired ventilation/carbon dioxide generation, 421
color M-mode Doppler. See Color M-mode 203 renin-angiotensin system in, 347–348
Doppler echocardiography Extracellular matrix symptoms of, 81
description of, 105 composition of, 392, 392f systolic. See Systolic heart failure
Doppler. See Doppler echocardiography myocyte volume and, 393 treatment of, 357
left atrial area measurement using, 163, 164f, 164t regulation of, 392 Heart transplantation. See Cardiac transplantation
myocardial contrast, 225–226 remodeling of, 17, 19f Hemochromatosis, 100, 101f, 270–271
E/Ea ratio, 188–189, 318 Hepatic venous flow, 175–176, 177f
Effective arterial elastance, 78, 82 HMG-CoA reductase inhibitors, 396, 410, 424. See
Effusive-constrictive pericarditis, 311
Ejection fraction
F also Statins
Hydrochlorothiazide, 210, 416t
definition of, 63 Fabry’s disease, 268–270 Hydropericardium, noncompressing, 29
determinants of, 75, 368 Familial amyloidosis, 262–263 Hyperglycemia, 335
diastolic heart failure prognosis and, 70 Fatty acid oxidation inhibitors, 340, 437 Hyperinsulinemia, 336
in heart failure, 81, 405–406, 417 Felodipine, 416t Hypertension
left ventricular. See Left ventricular ejection Fibrosis, myocardial, 235, 239, 241, 335 antihypertensive therapies for, 354, 418–419
fraction Fibrous pericardium, 301, 302f aortic stiffness in, 236–237, 237f
left ventricular filling pressure measurements and, Fick equation, 204, 206f cardiac fibrosis in, 239
190 Filling. See Left ventricular filling cardiac natriuretic peptide and, 352
limiting factors, 75 First pass radionuclide angiography, 105, description of, 111
preserved, 352 109–110 diabetes mellitus and, 336
timing of measurements, 66 Flow propagation velocity, 187f diastolic dysfunction in, 235, 242
in women, 386, 387f Fluid-structure interaction models, 54 epidemiology of, 237–238
Ejection phase, 35 Fontan operation, 326, 327f future research for, 242
Elastance index, 237 Forward continuity disease, 85 left atrial function in, 235–236
Electrocardiogram, 304–305 Frank-Starling relationship, 29, 116, 166 left atrial pressure affected by, 418
Enalapril, 416t Free fatty acid metabolism, 334 left ventricular geometry and, 235
End diastolic pressure volume, 75, 76f, 279f, 289, Furosemide, 416t left ventricular hypertrophy, 238–239, 293
391f left ventricular mass in, 234–235
End systolic elastance, 78 left ventricular remodeling secondary to,
End systolic pressure to stroke volume ratio, 404
End systolic volume, 17
G 233
mitral inflow parameters, 238–239
Endomyocardial biopsy Gene expression profiling, 254 neurohormones for, 354
description of, 250 Gene therapy, 7, 436–437 renin-angiotensin system in, 347–348
in restrictive cardiomyopathy, 310 Glucagon-like peptide 1, 437 signaling pathways activated in, 237
End-organ pulsatility, 83–84 Glucose cross-link breakers, 210 systolic heart failure and, 397
Endothelin, 345 Glucose cross-linkers, 339 treatment of, 239, 242, 418–419
 Index 447
Hypertensive hypertrophic cardiomyopathy of the Ischemia (Continued) Left atrium
elderly, 238 in hypertrophic cardiomyopathy, 289 area of, echocardiography measurement of, 163,
Hypertrophic cardiomyopathy left ventricular hypertrophy and, 23 164f, 164t
athlete’s heart versus, 293 pulmonary symptoms induced by, 23 booster pump function, 34
atrial fibrillation in, 290–291 subendocardial, 23 conduit function, 37
beta blockers for, 294–295 supply, 22 contractility of, 236
calcium Ischemic heart disease, 157 definition of, 163
diastolic levels, 287–288 Isometric hand exercise, 227–228 distensibility of, 85
sensitivity changes, 288–289 Isosorbide dinitrate, 416t enlargement of, 167, 294
calcium channel blockers for, 294–296 Isosorbide mononitrate, 416t function of, 34
in children, 323–324, 325f Isovolumic relaxation future research of, 168
clinical presentation of, 290–291 duration of, 106 physiologic functions of, 165–166
definition of, 287 initiation of, 106 pressure-volume loops, 38f
diagnosis of, 291–293 quantification of, 13 pressure-volume relations of, 34–35, 64, 166f
diastolic dysfunction in, 97, 296 Isovolumic relaxation time reservoir function, 36–37
diastolic function in, 159, 296 cardiac transplant rejection effects on, 251 tissue velocity of, 168f
differential diagnosis, 293 definition of, 182, 217, 313 Left hepatic vein, 172
Doppler echocardiographic indices, 291–293 description of, 126–127 Left ventricle
dual-chamber pacing in, 378 Doppler measurement of, 174, 217, 218f, 313 chronic hemodynamic loading adaptation, 37
exercise-induced ischemia in, 289 duration of, 127 circumferential shortening of, 370
hypertensive left ventricular hypertrophy versus, left ventricular intracavitary flow during, 127–128 contractile behavior of, 368–370
293 in mid-left ventricular cavity, 128f contractility of, 369
hypertrophy associated with, 97, 289 contraction of, 79
left atrial enlargement and, 294 distensibility of, 248
left ventricular hypertrophy and, 358
left ventricular outflow tract obstruction, 287
J exercise response by, 370–371
flow propagation inside, 54
longitudinal strain in, 294f J-receptors, 209 longitudinal shortening of, 370
magnetic resonance imaging of, 97–98 Jugular venous pressure, 304 narrowing of, 128
mitral flow velocity in, 291, 292f pacing effects on, 374–375
mortality causes, 291 passive diastolic properties of, 48–49
mutations in, 287–288, 288f
myocardial velocity gradients in, 291–292, 293f
K pressure propagation inside, 54–55
pressure-volume loops, 240f
myosin heavy chain mutations in, 287–288, 290 Kirchoff ’s first law, 49 pumping ability of, 368
obstructive, 290 Kussmaul sign, 304 regional contractile behavior of, 369–370
phenotypic heterogeneity of, 290 relaxation of, 44
prognosis of, 291 systolic performance of, 63–64
progression of, 290
radionuclide techniques for, 111 L Left ventricular chamber diastole, 43–44
Left ventricular compliance, 119
rapid filling volume index in, 289 LAMP2, 269 Left ventricular diastolic dysfunction. See also
subclinical disease, 293–294 Laplace’s law, 234 Diastolic dysfunction
symptoms of, 290–291 Left atrial appendage cellular bases of, 237
tissue annular velocities in, 292f description of, 33, 39f in diabetes cardiomyopathy, 336–337
tissue Doppler evaluations, 159 distensibility of, 85 in dilated cardiomyopathy. See Dilated
treatment of, 294–296 Left atrial diameter cardiomyopathy, left ventricular diastolic
Hypotension, 415 measurement of, 164f, 164t, 167 dysfunction in
in obese patients, 236 grading of, 121–123, 124f
Left atrial dimension, 182f hypertension and, 235
I Left atrial function left atrial function and, 38–39
left atrial pressure in, 316
assessment of, 165–166
Implantable hemodynamic monitoring devices, 439 diastolic left ventricular dysfunction and, metabolic risk factors, 236
Infective endocarditis, 240 38 molecular bases of, 237
Inferior vena cava diameter, 172–173, 173f, 222– in hypertension, 235–236 symptoms of, 11
223, 223f left ventricular systolic dysfunction and, Left ventricular diastolic function
Insulin resistance, 334, 336 38–39 abnormalities in, 18
Insulin sensitizers, 437 Left atrial pressure age-related changes, 84
Interventricular interval, 379 color M-mode Doppler echocardiography assessment of, 64, 66, 74–76, 79
Interventricular septum, 317f estimation of, 148 in children
Intracardiac blood flow determinants, 44–46 description of, 80–81 color M-mode flow propagation velocity,
Intracellular calcium, 4 diastolic filling rates affected by, 279 318–319
Intraventricular flow diastolic properties that affect, 117, 118f description of, 314
description of, 50–51 hypertension effects on, 418 mitral inflow Doppler assessments, 314–316
fluid-mechanical computer modeling of, 53–55 mean, 117, 189 pulmonary venous Doppler assessments, 316
Intraventricular pressure gradients in restrictive cardiomyopathy, 305 tissue Doppler imaging of, 316–318
color M-mode Doppler echocardiography of, transmitral velocity affected by, 182–183 definition of, 64
146–147, 149 Left atrial relaxation, 123 in diastolic heart failure, 17–19
description of, 54–55, 57, 207 Left atrial size Doppler echocardiography assessments
left ventricular torsion and, 156 diastolic dysfunction and, 166–168 color M-mode, 148
Irbesartan, 339 Doppler echocardiography of, 216, 216f, description of, 70, 135–136, 313–314
Ischemia 429–430 equilibrium radionuclide angiocardiography
acute. See Acute ischemia prognosis associated with, 167 assessment of, 107–109
demand, 22 quantification of, 163–165 exercise effects, 16–17, 119
diastolic dysfunction caused by, 22 Left atrial strain, 168 heart failure symptoms and, 67
Doppler inflow patterns affected by, 279, Left atrial systolic force, 235 hypertension effects on, 111
281–282 Left atrial volume, 164–165, 165f, 167, 291 measurement of, 66–67
experimental studies of, 55 Left atrial volume index, 167t metabolic risk factors on, 236
448 Index
Left ventricular diastolic function (Continued) Left ventricular hypertrophy (Continued)
obesity on, 236 in hypertrophic cardiomyopathy, 97, 358 M
radionuclide assessments of, 106, 106b ischemia and, 23 Magnetic resonance imaging
time-activity curve, 106, 107f M-mode echocardiography of, 133 amyloidosis, 100, 100f
tissue Doppler imaging assessments, 254 ventricular time-volume curves in, 98 artifacts, 100
Left ventricular diastolic pressure, 12 Left ventricular inflow constrictive pericarditis, 98–99, 99f, 308
Left ventricular diastolic pressure-volume relation, color M-mode Doppler measurement of, 220f contraindications, 100, 101t
368 Doppler measurement of, 216–217, 217f coronary artery disease evaluations, 98
Left ventricular diastolic suction effect, 17 Left ventricular intracavitary flow, 127–128 delayed hyperenhancement, 96, 97f
Left ventricular dilation, 54, 55f Left ventricular isovolumic relaxation time. See description of, 93
Left ventricular ejection fraction Isovolumic relaxation time dilated cardiomyopathy evaluations, 98
description of, 337, 357 Left ventricular mass, 233–235 gradient echo sequence, 94–95
in diastolic heart failure, 367 Left ventricular mass-to-volume ratio, 326 hemochromatosis, 100, 101f
“normal,” 386t Left ventricular outflow tract hypertrophic cardiomyopathy evaluations,
Left ventricular ejection time, 194 obstruction of, 323 97–98
Left ventricular end diastolic pressure time-velocity integral, 128 imaging sequences of, 94–97
description of, 74, 75f, 76f, 78, 117, 181 verapamil effects on, 295 limitations of, 100, 102
in dilated cardiomyopathy, 248 Left ventricular pacing, 375t myocardial tagging, 95–96, 96f
estimation of, 184 Left ventricular pressure pericardium, 98, 99f
Left ventricular end diastolic pressure-volume declines in, 13, 250 phase contrast, 95
relationship, 279f volume and, 78f phase velocity, 95
Left ventricular end systolic elastance, 370f Left ventricular relaxation physics of, 93–94
Left ventricular filling abnormal, 374 restrictive cardiomyopathy, 99–100
age-related changes in, 111 aging effects on, 111, 388–389 sarcoidosis, 100, 101f
cardiac loading conditions effect on, 121 cardiac output affected by, 119 spin-echo sequence, 94, 94f
color M-mode Doppler echocardiography of, diastolic filling time affected by, 118 Magnetic resonance spectroscopy, 96–97
219 impaired, 184t Maillard reaction, 394, 394f
computer modeling of, 54f isovolumic period of, 55 Matrix metalloproteinases
determinants of, 117f in seniors, 388–389 description of, 236, 392t, 392–393, 436
diagram of, 80f slowing of, 117 inhibitors of, 438
diastolic function measurements, 13–14 tissue Doppler assessments, 156–157 MCC-135, 436
in diastolic heart failure, 338 transmitral velocity and, 185–186 Mean arterial blood pressure, 84
diastolic suction effects, 80 Left ventricular remodeling Mechanical assist devices, 439
Doppler echocardiographic assessment of, brain natriuretic peptide and, 351 Mechanoreceptors, 28
13, 64 concentric, 235–236 Metabolic equivalents, 203
exercise effects on, 13f definition of, 278 Metabolic hypothesis, 393–394
historical perspectives of, 116–117 in diastolic heart failure, 17, 18f, 21f, 367 Metoprolol, 416t
left ventricular relaxation effects on, 118f hypertension as cause of, 233 Microalbuminuria, 337
pseudonormalized, 64 post-infarction, 278 Middiastolic flow reversal, 326
relaxation during, 49, 134 Left ventricular stiffness Mineralocorticoid receptors, 348
right ventricular filling and, 303 abnormal, 404 Mitral annular velocity
sinus tachycardia effects on, 136 age-related increases in, 403, 405f in constrictive pericarditis, 307, 310
variations in, 137 assessment of, 77–78 septal ablation effects on, 296, 297f
velocity of, 46–47 definition of, 374 tissue Doppler imaging of, 133–134
Left ventricular filling patterns diastolic function and, 16, 83 Mitral A-wave
abnormal, 81, 120f noninvasive assessment of, 78 duration of, 130–131
age-related changes in, 120 quantification of, 16 velocity of, 130
baseline, 54, 56f Left ventricular stroke volume, 36 Mitral deceleration time, 129
natural history of, 121f Left ventricular stroke work, 369f Mitral E wave, 314, 316
normal, 120f Left ventricular suction, 80–81 Mitral filling
patient management uses of, 139 Left ventricular systolic dysfunction in diastolic dysfunction, 14
preload effects, 227 definition of, 63 pseudonormal, 148
Left ventricular filling pressures left atrial function and, 38 Mitral flow
definition of, 181 symptoms of, 11 acceleration of, 46–47
description of, 78–79 Left ventricular systolic function, 19–20, deceleration of, 47
ejection fraction and, 190 367–371 Doppler tracings of, 316f
estimation of, 184–191 Left ventricular torsion, 156, 223–224 modeling of, 47–49
exercise-related alterations in, 206 Left ventricular untwisting peak, 80
noninvasive measures of, 206–207 catecholamines and, 156 preload effects on, 49
tissue Doppler evaluation of, 157 delayed, 156 relaxation effects on, 48, 48f
two-dimensional echocardiography of, 181–182 description of, 55, 57f Mitral flow velocity
Left ventricular geometry Left ventricular wall age-related changes in, 120t, 120–121
afterload increase effects on, 323 segments of, 225f disease effects on, 120–121
description of, 55, 57f stress, 359 Doppler measurement of, 130f
hypertension and, 235 thickness of Doppler patterns, 119–123
Left ventricular hypertrophy description of, 193, 238 in hypertrophic cardiomyopathy, 291,
angiotensin receptor blockers for regression of, in restrictive cardiomyopathy, 303 292f
423 Left ventricular-arterial coupling, 404–409 left ventricular diastolic dysfunction graded by,
in children, 323 Leg raising maneuver, 228, 228f 121–122
chronic kidney disease and, 421 Lisinopril, 416t, 421 patterns
concentric, 23–24, 65, 182, 235 List mode acquisition, 107–108 abnormal, 137
in congenital heart disease, 323 Loop diuretics, 420 interpretation of, 136–138
eccentric, 235 Losartan, 210, 409, 416t M-mode echocardiography of, 132–133
heart failure and, 346 Lumped parameter model, 49–50 tricuspid flow velocity patterns versus,
hypertensive, 233–235, 238–239, 293 Lungs, fluid redistribution into, 407 133
 Index 449
Mitral flow velocity (Continued) Pacing (Continued)
two-dimensional echocardiography of, N synchronous, 376t
132–133 Na+-Ca2+ exchanger ventricle-to-ventricle timing, 379
at start of atrial contraction, 129–130 calcium regulation by, 7 ventricular dyssynchrony, 380
variables of description of, 4–5 Parvalbumin, 437
description of, 119f in reverse mode, 5, 7 Passive relaxation, 77
left ventricular isovolumic relaxation time, sarcolemmal, 5 Patent ductus arteriosus, 320
126–127 summary of, 7 Peak E/A wave velocity ratio, 131–132
Mitral inertance, 46, 49, 49f sympathetic stimulation regulation of, 5 Peak filling rate, 94, 106, 409
Mitral inflow Natriuretic peptide(s) Peak forward flow velocity in early systole, 123
ischemia effects on, 279, 281–282 atrial. See Atrial natriuretic peptide Peak mitral A-wave velocity, 130
left ventricular dilation effects on, 54, 55f brain. See Brain natriuretic peptide Peak mitral E-wave velocity, 47, 128–129, 133
Mitral inflow velocity, 305, 306f, 431f cardiac dysfunction screening and, 354–356 Peak oxygen consumption, 203
Mitral peak E/A wave velocity ratio, 131–132 C-type, 350–351 Peak systolic blood pressure, 210f
Mitral regurgitation description of, 349–350 Percutaneous coronary interventions, 284
acute, 241 hypertension and, 352 Percutaneous transluminal coronary angioplasty,
chronic, 241–242 structure of, 350 279, 281
diastolic, 138 Natriuretic peptide receptor, 350 Pericardial effusion, 301–302
diastolic dysfunction in, 241–242 Navier-Stokes equations, 44 Pericardial knock, 304
E-wave velocities in, 129, 136 Neonatal myocardium, 314 Pericardiectomy
Mitral respiratory flow velocity, 137 Neurohormones description of, 27–28
Mitral stenosis adrenomedullin, 349 pathophysiologic effects of, 28
E-wave velocities in, 129, 136 aldosterone, 253, 296, 348 transmural pressures after, 29
pulmonary hypertension secondary to, 242 arginine vasopressin, 346, 348 Pericardiocentesis, 311
Mitral time-velocity integral, 128 blockade of, 359 Pericardium
Mitral to pulmonary venous A-wave duration, 124, cardiotrophin-1, 349 anatomy of, 301
126, 126f circulation regulation by, 346 calcified, 308, 309f
Mitral valve regurgitation, 50 endothelin-1, 348–349 fibrous, 301, 302f
M-mode echocardiography future research of, 359 historical studies of, 302
color. See Color M-mode Doppler in heart failure, 352–354 magnetic resonance imaging of, 98, 99f
echocardiography natriuretic peptides. See Natriuretic peptides pathophysiology of, 27–30
constrictive pericarditis, 305f overview of, 345–346 serous, 301, 302f
inferior vena cava diameter measurements, 222– prostaglandins, 352 ventricular volume and, 301
223, 223f renin-angiotensin system, 345, 347–348 Perindopril, 338, 396, 421, 435
left atrial size measurement using, 163 summary of, 359 Peroxisome proliferator-activated receptor-γ, 236,
mitral flow velocity patterns evaluated with, sympathetic nervous system, 345–347 419, 437
132–133 tissue necrosis factor-alpha, 349 Phase contrast imaging, 95
strain rate, 156f types of, 345 Phosphodiesterase-5A, 237, 410
Myocardial compliance, 30 urocortin, 349 Phospholamban, 6, 237, 391, 437
Myocardial contrast echocardiography, 225–226 ventricular hypertrophy transition to heart failure, Post-infarction left ventricular remodeling, 278
Myocardial fibrosis, 235, 239, 241, 335 346 P-R interval, 131
Myocardial infarction, 357, 358f, 419 Nicorandil, 296 Preload
Myocardial ischemia, 419 Nitrates, 420 description of, 49
Myocardial relaxation Noncompressing hydropericardium, 29 Doppler echocardiography affected by increases
assessment of, 76–77 Norepinephrine, 347, 353 in, 322t
causes of, 44 left ventricular filling patterns affected by,
factors that affect, 375 227
impaired, 98
magnetic resonance spectroscopy of, 96–97
O systolic blood pressure affected by, 406f
during Valsalva maneuver, 121
mitral flow affected by, 48 Obesity, 236 Pre-pro-endothelin, 348
myocyte control of, 3 Obstructive hypertrophic cardiomyopathy, 290 Pressure half-time, 313
noninvasive assessment of, 77 Oxygen consumption, 204–205 Pressure pulsatility, 84
pressure decrease during, 44 Pressure relaxation, 76
ventricular compliance and, 49 Pressure-volume loop, 74, 75f, 404f
Myocardial strain, 155, 223, 292–293
Myocardial tagging, 95–96, 96f
P Pressure-volume relations
description of, 34–35
Myocardial velocity gradients, 291–292, 293f, 308 Pacing diastolic, 45f
Myocardium adverse effects of, 379–381 in dilated cardiomyopathy, 248, 249f
atrial, 33 atrial, 375t Primary pulmonary hypertension, 197, 242
deformation of, 223 basics of, 374 Propranolol, 416t
neonatal, 314 biventricular, 374, 375t Prostaglandins, 352
Myocyte relaxation cardiac condition effects on, 380 Protein kinase A, 4
diastolic dysfunction caused by, 3 cardiac function affected by, 374–375 Protein phosphatase 1, 437
during exercise, 17 diastolic dysfunction, 374 Pseudonormal mitral filling, 148, 248
Myocytes. See also Cardiomyocytes diastolic function and, 375–376 Pulmonary artery pressures, 134
action-potential duration in, 5–6 direct His bundle, 381 Pulmonary artery systolic pressure, 191
in atrial myocardium, 33 dual-chamber, 374, 378 Pulmonary capillary wedge pressure
hypertrophy of, 278 duration of, 380 after cardiac transplantation, 250–251
remodeling of, 17, 19f dyssynchronous, 376t in constrictive pericarditis, 303–304
Myofilaments, 6 left ventricular, 375t description of, 181, 184, 185f, 188f, 198f, 391
Myosin binding protein C, 288 mechanism of action, 374 intrathoracic-intracardiac dissociation effects on,
Myosin heavy chains modes of, 381 303, 303f
description of, 37 right ventricular, 375, 375t Pulmonary congestion, 66
mutations, 159, 287–288, 290 right ventricular outflow tract, 381 Pulmonary edema, 419
Myosin regulatory light chains, 289 sites of, 376t, 380–381 Pulmonary regurgitation, 173
450 Index
Pulmonary vein(s) Right atrial appendage, 33 Stiffening
description of, 33 Right atrial pressure, 176f, 177t arterial-ventricular. See Ventricular-arterial
modeling of, 52f Right atrium, 172 stiffening
velocity Right ventricle cardiovascular system, 82–83
description of, 183–184 dimension of, 172 left ventricular. See Left ventricular stiffness
limitation of, 185 isovolumic acceleration, 323 Storage cardiomyopathies, 268–269, 272
Pulmonary vein flow, 49, 316f pressure-volume loops, 35 Strain, 155, 223
Pulmonary vein–left atrial pressure gradient, 50 Right ventricular diastolic dysfunction, 253. See also Strain rate, 155, 168, 191, 223, 292–293
Pulmonary venous diastolic flow velocity, 123 Diastolic dysfunction Strain rate imaging, 224, 225t, 292
Pulmonary venous flow Right ventricular diastolic function Stroke volume
Doppler measurement of, 217–218, 219f, 226f, description of, 138–139 diastolic distensibility and, 17
316 determinants of, 171 exercise-related alterations in, 205–206,
velocity evaluation of, 178–179 207f
age-related changes in, 123 Right ventricular end diastolic pressure-dimension, Subendocardial ischemia, 23
mitral to pulmonary venous A-wave duration, 28 Submaximal exercise capacity
124, 126, 126f Right ventricular filling, 171, 303 description of, 204
Pulmonary venous stiffness, 85 Right ventricular function, 197 heart rate, 205
Pulse pressure, 84–85 Right ventricular inflow, 221, 222f Superior vena cava, 223, 223f, 307f
Pulse wave velocity, 236 Right ventricular outflow tract pacing, 381 Supply ischemia, 22
Right ventricular pacing, 375, 375t Sympathetic nervous system, 345–347
Right ventricular relaxation, 171 Synchronous pacing, 376t
Q Ryanodine receptor 2, 4–5 Systolic anterior motion, 266
Systolic arterial pressure, 66, 67f
Q-Ea, 189 Systolic blood pressure, 406f
QRS prolongation, 374 S Systolic dysfunction
definition of, 85
Sarcoidosis, 100, 101f left ventricular
R Sarcolemma, 5
Sarcolemmal receptors, 5–6
definition of, 63
left atrial function and, 38
Radionuclide techniques Sarcoplasmic membrane proteins, 6 symptoms of, 11
advantages of, 105 Sarcoplasmic reticulum Systolic function
coronary artery disease applications, 110–111 calcium release from, 4, 7 assessment of, 75–76
diastolic function assessments, 106, 106b description of, 6 echocardiographic measures of, 319–320
equilibrium radionuclide angiocardiography. See Sarcoplasmic/endoplasmic reticulum Ca2+-ATPase, in heart failure, 111
Equilibrium radionuclide angiocardiography 7, 237, 288, 334, 391 heart failure symptoms and, 67
first pass radionuclide angiography, 105, 109–110 Secondary amyloidosis, 263 Systolic heart failure
future research for, 112 Sedentary aging, 388, 393 aldosterone and, 348
history of, 105–106 Senile systemic amyloidosis, 263 cardiomyocytes in, 17, 86
hypertension evaluations, 111 Seniors. See also Aging characteristics of, 11, 65, 86, 368t
hypertrophic cardiomyopathy evaluations, 111 coronary artery disease in, 419 definition of, 64, 85–86
limitations of, 111–112 diastolic dysfunction in diastolic heart failure versus, 65, 66t, 86
Ramipril, 416t description of, 388 endothelial dysfunction in, 419
Ranolazine, 436 left ventricular compliance decreases, 391–393 epidemiology of, 70
Rapid filling volume index, 289 slowing of myocardial relaxation as cause of, exercise intolerance in, 205
Receptor activator modifying proteins, 349 388–391 hypertension and, 397
Regulatory light chains, 289 diastolic heart failure in treatment of, 396t
Remodeling. See Left ventricular remodeling clinical presentation of, 385–386 ventricular myocardium in, 373
Renal perfusion, during diastole, 84 comorbid conditions, 394–395, 395f Systolic performance, 63–64
Renin, 347 diagnosis of, 386–387 Systolic strain, 369
Renin-aldosterone-angiotensin system, 416 Doppler echocardiography, 387 Systolic torsion, 55
Renin-angiotensin system, 345, 347–348 future research of, 397–398
Reperfusion, 22 hypertension and, 395–396
Repolarization-relaxation coupling, 3–4 prognosis of, 387–388
trials and treatments for, 395–396
T
Reservoir function, 36–37
Respiratory collapse, 172–173 epidemiology of, 385 Tachycardia, 136, 198, 338
Respiratory maneuvers, 228 myocardial relaxation in, 388–389 Tc-99m radiolabeled agents, 109, 112
Respirometer, 225, 226f, 228 population growth of, 385 Tei index
Restrictive cardiomyopathy Septal ablation, 296 aortic stenosis effects on, 195
brain natriuretic peptide levels in, 304–305 SERCA, 5–6 cardiac resynchronization therapy effects on,
constrictive pericarditis versus, 303–304, 358 Serous pericardium, 301, 302f 376
definition of, 303 Sildenafil, 237, 410 carvedilol effects on, 197
description of, 99–100 Simpson’s method, 164, 165f definition of, 250
endomyocardial biopsy in, 310 Single photon emission computed tomography, description of, 193–194
hemodynamics of, 302 107 in dilated cardiomyopathy, 195
hepatic vein diastolic flow in, 306, 307f Single ventricle palliation, 325–326 Doppler echocardiography measurements, 194
idiopathic, 310 Sinus tachycardia, 136 formula for, 194
left atrial pressure in, 305 Sitaxsentan sodium, 436 left ventricular diastolic filling pressure, 196
left ventricular filling in, 317 Sleep apnea, 430 limitations of, 198
left ventricular wall thickness in, 303, 305 Small vessel disease, 335–336 load dependency of, 195
morphologic features of, 302f, 303 Speckle tracking, 224 measurement of, 194–195
secondary causes of, 303 Sphygmomanometer, 227, 227f primary pulmonary hypertension and, 197
tissue Doppler evaluations, 158 Spin-echo sequence, 94, 94f prognostic utility of, 195–196
Restrictive filling, 248 Spironolactone, 416t pulmonary capillary wedge pressure and, 198f
Reverse continuity disease, 84 Statins, 424, 430, 437–438. See also HMG-CoA right ventricular function evaluations, 197
Rho kinase, 410 reductase inhibitors tachycardia evaluations, 198
 Index 451
Tetralogy of Fallot, 324–325 Transmitral velocity (Continued) Ventricular compliance, 49
Thermodilution catheter, 284 left ventricular relaxation and, 185–186 Ventricular contractility, 369
Thiazide diuretics, 420 limitation of, 185 Ventricular dyssynchrony, 380
Thyroid hormone analog, 438 relaxation effects on, 182–183 Ventricular function
Tissue Doppler imaging Transmural pressures, 28 definition of, 368
afterload increase effects on, 323, 324t Transplant rejection, 160 left ventricular ejection fraction. See Left
age effects on, 320f Transplantation. See Cardiac transplantation ventricular ejection fraction
in children, 316–318 Transthyretin, 262 Ventricular hypertrophy. See also Left ventricular
constrictive pericarditis evaluations, 158, Treppe effect, 17, 119 hypertrophy
307–308 Tricuspid annular plane systolic excursion, 253 in congenital heart disease, 323
conventional Doppler versus, 220 Tricuspid flow velocity, 133 drugs that target, 410
definition of, 220 Tricuspid inflow, 174–175, 175f Ventricular remodeling. See Left ventricular
description of, 16, 16f Tricuspid regurgitation remodeling
diabetes mellitus evaluations, 160 continuous wave Doppler of, 173 Ventricular septal defects, 320
diastolic function evaluations, 220 description of, 134 Ventricular stiffness
dilated cardiomyopathy evaluations, 157–158, diastolic, 138 abnormal, 404
250 hepatic venous flow in, 177f age-related increases in, 403, 405f
formats of, 220 jet velocity, 173, 174f assessment of, 77–78
hypertrophic cardiomyopathy evaluations, 159 Trientine, 437 causes of, 406
ischemic heart disease evaluations, 157 Triglycerides, 393 definition of, 374
left ventricular diastolic function assessments, α-Tropomyosin, 289 diastolic function and, 16, 83
254 Troponin C, 4 future research of, 410
left ventricular end diastolic dimension effects on, Troponin I, 289 noninvasive assessment of, 78
321f Troponin T, 288–289 quantification of, 16
left ventricular filling pressure evaluations, Troponin-tropomyosin complex, 4 therapeutic strategies for, 409–410
157 T-tubules, 5 Ventricular-arterial stiffening. See also Arterial
left ventricular relaxation assessments, Tumor necrosis factor-alpha, 392 stiffening
156–157 Two-dimensional echocardiography abnormal, 404
mitral annular velocities evaluated with, 133–134 constrictive pericarditis evaluations, 305, 305f cardiac work affected by, 408
myocardial velocities, 158 Fabry’s disease, 270f endothelial mechanosignaling, 408
myocardial velocity recording using, 176 left ventricular filling pressure evaluations, exercise reserve and, 409
parameters, 160 181–182 future research of, 410
preload increase effects on, 322t mitral flow velocity patterns evaluated with, in heart failure with preserved ejection fraction,
restrictive cardiomyopathy evaluations, 158 132–133 405–406
subclinical disease versus hypertrophic pathophysiology of, 407–409
cardiomyopathy, 293 Ventricular-vascular stiffening
transplant rejection evaluations, 160
velocities, 153–155, 154f
U mechanisms of, 406–407
treatment of, 409–410
Tissue inhibitors of metalloproteinases, 236, 392, Urocortin, 349 Verapamil, 111, 210, 211f, 295, 416t, 423
392t, 438 Voltage-gated L-type channels
Tissue necrosis factor-alpha, 349 calcium influx through, 4
Titin, 86
Torsion imaging, 224
V description of, 3
phosphorylation of, 4
Transesophageal echocardiography, 175 Valsalva maneuver, 121, 226f, 227f, 226–227
Transmitral A velocity, 184 Valvular heart disease
Transmitral E velocity, 186
Transmitral flow, 51f
aortic insufficiency, 240–241 W
aortic stenosis, 241
Transmitral gradient, 47, 49 description of, 239–240, 358 Wilson’s disease, 437
Transmitral velocity mitral stenosis, 242 Women
deceleration time, 77 Vascular stiffness, 82, 84 angiotensin-converting enzyme inhibitor use in,
determinants of, 182–183 Vasoactive hormones, 345 422
Doppler recording of, 183f Vasodilators, 352, 410 ejection fraction in, 386, 387f
inflow, 65f Vasopressin, 347 heart failure with preserved ejection fraction in,
left atrial pressure effects on, 182–183 Vasopressin receptor antagonists, 436 407