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23. IMAGING OF MYOCARDIAL INNERVATION 486 30. USE OF ARTIFICIAL INTELLIGENCE INCLUDING
DECISION SUPPORT SYSTEMS IN CARDIAC IMAGING 637
Atsuro Masuda, Masanao Naya,
Keiichiro Yoshinaga, and Nagara Tamaki Ernest V. Garcia

24. IMAGE-BASED MEASUREMENTS OF MYOCARDIAL

BLOOD FLOW 500 SECTION FIVE CHALLENGES
Heinrich R. Schelbert FOR NUCLEAR CARDIOLOGY
25. IMAGING OF MYOCARDIAL METABOLISM 518
31. PHYSICIAN CERTIFICATION AND LAB ACCREDITATION 659
Robert J. Gropler William A. Van Decker
26. INFLAMMATORY AND INFILTRATIVE DISEASES
32. COST EFFECTIVENESS OF IMAGING
AND TUMORS 540
WITH NUCLEAR CARDIOLOGY 669
Sharmila Dorbala and Katarina H. Nelson Lawrence M. Phillips and Leslee J. Shaw
27. RADIONUCLIDE IMAGING IN HEART FAILURE 574
33. GUIDELINES AND APPROPRIATE USE CRITERIA 677
Prem Soman George R. Marzouka, Lynda Otalvaro-Orozco,
and Robert C. Hendel

SECTION FOUR ADVANCES IN CARDIAC 34. RADIATION CONSIDERATIONS 694

IMAGING Andrew J. Einstein

28. HYBRID CARDIAC IMAGING 589 35. PRACTICAL ISSUES: ASK THE EXPERTS 713
Philipp A. Kaufmann and Oliver Gaemperli Ami E. lskandrian and Ernest V. Garcia

29. CARDIOVASCULAR MOLECULAR IMAGING 601

Index 733
Alan R. Morrison, Joseph C. Wu,
and Mehran M. Sadeghi

xiv CONTENTS
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Nuclear Cardiac Imaging: Principles and

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9780199392094.001.0001

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Preface

Oxford Medicine Online

Nuclear Cardiac Imaging: Principles and

Applications (5 ed.)
Edited by Ami E. Iskandrian and Ernest V. Garcia

Free access to supplementary online-only videos is also available

for print readers. To access this content, please expand the End
Matter heading in the table of contents below by clicking on the
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Publisher: Oxford University Press Print Publication Date: Oct 2015

Print ISBN-13: 9780199392094 Published online: Oct 2015
DOI: 10.1093/med/
9780199392094.001.0001

Preface

Author(s): Ami E. Iskandrian and Ernest V. Garcia

This edition is prompted by the many innovations and advances that have
occurred in the field of nuclear cardiology since the prior edition (the
fourth edition) was published in 2008.

In keeping with the original objective of this book, we sought to publish

the most comprehensive and definitive document of detailed and precise
information for years to come. We sought to change where changes are
due, update when new information is available and delete when obsolete.
This meant looking at each chapter and deciding on direction and
authorship. We asked the writers to be concise, informative,
comprehensive, and authoritative. Since the chapters of the fourth edition
were superb, we asked the authors either to update them or start de novo
— and the result is a combination of both. We solicited the help of many
authors; most are on the editorial board of the Journal of Nuclear
Cardiology or are Board members.

Page 1 of 3
Preface

As both of us read each and every word the authors wrote, we were
impressed by how well explained and detailed the chapters were and by
how much new information we were discovering in each of these topics,
even the ones we thought we had mastered! We are very grateful to our
contributors because we realize how much time and effort it takes to
produce such a high-quality contribution.

Our objective was also to produce a book that was easy to read and
understand, both from the aesthetic and intellectual points of view. In this
edition, for the first time, we are presenting most figures in color and
providing access to an online collection of videos.

We edited the chapters to be consistent with each other in both format

and function. We encouraged the authors, in addition to providing us with
up-to-date information, to also indicate to the reader their honest
appraisal of the status of each specific topic. This proved to be
particularly useful in controversial and in fast-changing topics. We asked
authors to provide 10 key points for each chapter and one or two case
presentations to capture the essence of the chapter and its clinical
application. Finally, in the last chapter, we provided straightforward
answers to the most commonly asked questions regarding practical,
technical, and clinical issues.

The book is divided into five sections. The first section has 10 chapters
dealing with historical, technical, and physiologic considerations. The
second section has 11 chapters dealing with diagnosis and prognosis. The
third section has 6 chapters dealing with conditions other than coronary
artery disease. The fourth section has three chapters on advanced cardiac
imaging. The fifth and last section deals with challenges and
opportunities.

This book validates the concept that the whole is greater than the sum of
its parts. Although each chapter can be considered an excellent reference
source for any specific topic, this book is not meant to be sitting on your
shelf. We encourage neophytes and experts alike to read it cover to cover.
We expect that you will get as much pleasure from reading it as we have
in bringing it to you. As in any book with so many chapters and authors,
some repetition and controversy exist. We purposely have allowed that to
give the readers different perspectives or even different viewpoints.

We are grateful to our families for their sacrifices in allowing us to pursue

this monumental undertaking. We are happy with the final product; it is
our way to thank the brilliant minds in the field that made this all possible
and our gift to the students who will carry the torch in the future. We are
grateful to the staff of Oxford University Press and especially to the
efforts of Andrea Knobloch, Rebecca Suzan, and Joseph Lurdu Antoine for
advice and flexibility.

Ami E. Iskandrian, MD, MACC, FASNC

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Contributors

Oxford Medicine Online

Nuclear Cardiac Imaging: Principles and

Applications (5 ed.)
Edited by Ami E. Iskandrian and Ernest V. Garcia

Free access to supplementary online-only videos is also available

for print readers. To access this content, please expand the End
Matter heading in the table of contents below by clicking on the
plus symbol.

Publisher: Oxford University Press Print Publication Date: Oct 2015

Print ISBN-13: 9780199392094 Published online: Oct 2015
DOI: 10.1093/med/
9780199392094.001.0001

Contributors

Wael AlJaroudi, MD, FACC, FASNC

Assistant Professor of Medicine and Radiology
Director of Cardiovascular Imaging
Division of Cardiovascular Medicine
Clemenceau Medical Center
Beirut, Lebanon
Sameer Ather, MD, PhD
Division of Cardiovascular Disease
Department of Medicine
University of Alabama at Birmingham
Birmingham, Alabama
Rob S. B. Beanlands, MD
National Cardiac PET Centre
Division of Cardiology
Department of Medicine
University of Ottawa Heart Institute

Page 1 of 8
Contributors

Ottawa, Canada
Daniel S. Berman, MD
Professor of Medicine
UCLA School of Medicine
Director, Nuclear Cardiology/Cardiac Imaging
Cedars-Sinai Medical Center
Los Angeles, California
Vikas Bhatia, MD
Division of Cardiovascular Disease
Department of Medicine
University of Alabama at Birmingham
Birmingham, Alabama
Todd M. Brown, MD, MSPH, FACC
Assistant Professor of Medicine
Division of Cardiovascular Diseases
University of Alabama at Birmingham
Birmingham, Alabama
Manuel D. Cerqueira, MD
Professor of Medicine and Radiology
Cleveland Clinic Learner School of Medicine
Case Western Reserve University
Chairman of Nuclear Medicine, Imaging Institute
Staff Cardiologist, Heart and Vascular Institute
Cleveland Clinic
Cleveland, Ohio
Ji Chen, PhD, FACC, FASNC
Assistant Professor of Radiology
Department of Radiology and Imaging Sciences
Emory University
Atlanta, Georgia
Alberto Cuocolo, MD
Department of Advanced Biomedical Sciences
School of Medicine
University of Naples Federico II
Naples, Italy
Robert A. deKemp, PhD
National Cardiac PET Centre
Division of Cardiology
Department of Medicine
University of Ottawa Heart Institute
Ottawa, Canada
E. Gordon DePuey, MD
Director of Nuclear Medicine
Department of Radiology
Mt. Sinai St. Luke’s and Roosevelt Hospitals
Clinical Professor of Radiology
Mt. Sinai Icahn School of Medicine

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Contributors

New York, New York

Vasken Dilsizian, MD
Professor of Medicine and Radiology
University of Maryland School of Medicine
Chief, Division of Nuclear Medicine
University of Maryland Medical Center
Baltimore, Maryland
Sharmila Dorbala, MBBS, MPH, FACC
Noninvasive Cardiovascular Imaging Program
Departments of Radiology and Medicine
Division of Nuclear Medicine and Molecular Imaging
Harvard Medical School
Department of Radiology
Brigham and Women’s Hospital
Boston, Massachusetts
Andrew J. Einstein, MD, PhD
Herbert Irving Associate Professor of Medicine (in Radiology)
Victoria and Esther Aboodi Cardiology Researcher
Director, Cardiac CT Research
Co-Director, Cardiac CT and MRI
Department of Medicine, Cardiology Division, and Department of
Radiology
Columbia University Medical Center/New York-Presbyterian Hospital
New York, New York
Fabio Peroba Esteves, MD
Adjunct Professor of Radiology
Emory University School of Medicine
1364 Clifton Road NE - Radiology
Atlanta, Georgia
Ayman Farag, MD
Division of Cardiovascular Disease
Department of Medicine
University of Alabama at Birmingham
Birmingham, Alabama
Oliver Gaemperli, MD
Department of Cardiac Imaging and Interventional Cardiology
University Hospital Zurich
Zurich, Switzerland
James R. Galt, PhD
Assistant Professor of Radiology
Department of Radiology and Imaging Sciences
Emory University School of Medicine
Atlanta, Georgia
Guido Germano, PhD
Director, Artificial Intelligence in Medicine Program
Professor of Medicine
UCLA School of Medicine

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Contributors

Cedars-Sinai Medical Center

Los Angeles, California
Robert J. Gropler, MD
Division of Radiological Sciences
Edward Mallinckrodt Institute of Radiology
Washington University School of Medicine
St. Louis, Missouri
Ankur Gupta, MD
Division of Cardiovascular Disease
Department of Medicine
University of Alabama at Birmingham
Birmingham, Alabama
Fadi G. Hage, MD, FASH, FACC
Associate professor of Medicine
Chief, Section Nuclear Cardiology
Division of Cardiovascular Disease
Department of Medicine
University of Alabama at Birmingham
Section of Cardiology
Birmingham Veterans Affairs Medical Center
Birmingham, Alabama
Robert C. Hendel, MD
Cardiovascular Division
Professor of Medicine and Radiology
University of Miami Miller School of Medicine
Miami, Florida
Philipp A. Kaufmann, MD
Zurich Center for Integrative Human Physiology
University of Zurich
Department of Cardiac Imaging and Interventional Cardiology
University Hospital Zurich
Zurich, Switzerland
George R. Marzouka, MD
Cardiovascular Division
University of Miami Miller School of Medicine
Miami, Florida
Atsuro Masuda, MD
Department of Nuclear Medicine
Hokkaido University Graduate School of Medicine
Sapporo, Japan
Brian A. Mc Ardle, MB, BCh
National Cardiac PET Centre
Division of Cardiology
Department of Medicine
University of Ottawa Heart Institute
Ottawa, Canada
Alan R. Morrison, MD, PhD

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Contributors

Assistant Professor of Medicine

Division of Cardiology
Yale University School of Medicine
New Haven, Connecticut
Paul H. Murphy, PhD
Professor Emeritus of Radiology
Baylor College of Medicine
Houston, Texas
Masanao Naya, MD, PhD
Department of Cardiovascular Medicine
Hokkaido University Graduate School of Medicine
Sapporo, Japan
Katarina H. Nelson, MD
Noninvasive Cardiovascular Imaging Program
Departments of Radiology and Medicine
Harvard Medical School
Brigham and Women’s Hospital
Boston, Massachusetts
Lynda Otalvaro-Orozco, MD
Cardiovascular Division
University of Miami Miller School of Medicine
Miami, Florida
Lawrence M. Phillips, MD
New York University Langone Medical Center
New York, New York
Jennifer M. Renaud, MSc
National Cardiac PET Centre
Division of Cardiology
Department of Medicine
University of Ottawa Heart Institute
Ottawa, Canada
Mehran M. Sadeghi, MD
Associate Professor of Medicine
Division of Cardiology
Yale University School of Medicine
New Haven, Connecticut
Rupa Mehta Sanghani, MD, FACC, FASNC
Assistant Professor of Medicine
Department of Medicine, Section of Cardiology
University of Chicago Medicine
Chicago, Illinois
Heinrich R. Schelbert, MD, PhD
George V. Taplin Professor of Molecular and Medical Pharmacology
David Geffen School of Medicine at UCLA
University of California
Los Angeles, California
Thomas H. Schindler, MD

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Contributors

Associate Professor of Radiology and Radiological Science

Division of Nuclear Medicine
Johns Hopkins University School of Medicine
Baltimore, Maryland
Leslee J. Shaw, PhD
Professor of Medicine
Division of Cardiology
Emory Program in Cardiovascular Outcomes Research and
Epidemiology
Emory University School of Medicine
Atlanta, Georgia
Piotr J. Slomka, PhD
Scientist, Artificial Intelligence in Medicine Program
Professor of Medicine
UCLA School of Medicine
Cedars-Sinai Medical Center
Los Angeles, California
Prem Soman, MD, PHD, FRCP, FACC
Associate Professor of Medicine (Cardiology)
Clinical & Translational Science
Director of Nuclear Cardiology
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania
Raymond Taillefer, MD, FRCPC
Professor of Nuclear Medicine
Department of Radiology
University of Montréal
Director of Nuclear Medicine
University of Montreal for Hospital St-Jean-sur-Richelieu
CISSS Montérégie-Centre
Montréal, Canada
Nagara Tamaki, MD, PhD
Department of Nuclear Medicine
Hokkaido University Graduate School of Medicine
Sapporo, Japan
Joshua A. Turner, MD
Division of Cardiovascular Diseases
University of Alabama at Birmingham
Birmingham, Alabama
James E. Udelson, MD
Professor of Medicine
Tufts University School of Medicine
Chief, Division of Cardiology
Tufts Medical Center
Boston, Massachusetts
Ines Valenta, MD
Department of Diagnostic Radiology and Nuclear Medicine

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Nuclear Cardiology: History and Milestones

Oxford Medicine Online

Nuclear Cardiac Imaging: Principles and

Applications (5 ed.)
Edited by Ami E. Iskandrian and Ernest V. Garcia

Free access to supplementary online-only videos is also available

for print readers. To access this content, please expand the End
Matter heading in the table of contents below by clicking on the
plus symbol.

Publisher: Oxford University Press Print Publication Date: Oct 2015

Print ISBN-13: 9780199392094 Published online: Oct 2015
DOI: 10.1093/med/
9780199392094.001.0001

Nuclear Cardiology: History and Milestones

Chapter: Nuclear Cardiology: History and Milestones

Author(s): Barry L. Zaret
DOI: 10.1093/med/9780199392094.003.0001

Key Points

1. The initial application of radioisotopes to cardiac studies

occurred in the mid-1920s.
2. Ventricular function was evaluated in the 1960s and 1970s by
first-pass and equilibrium techniques.
3. Myocardial stress perfusion imaging was first performed
using potassium-43 and exercise in 1973.

Page 1 of 18
Nuclear Cardiology: History and Milestones

4. Stress imaging rapidly evolved thereafter with new tracers

(thallium-201 and technetium-labeled agents) and from planar to
SPECT approaches.
5. Perfusion imaging rapidly proved its value diagnostically and
in assessing prognosis.
6. Infarct imaging reached its peak use in the 1970s but is now
no longer employed.
7. Advances in hybrid imaging, combining CT with radionuclide
imaging, have recently allowed attenuation correction as well as
providing the combination of anatomic and physiologic data.
8. PET myocardial perfusion studies have recently become a
standard approach for evaluating perfusion, absolute coronary
blood flow, and coronary reserve.
9. PET FDG studies of cardiac sarcoidosis have recently been
established as a new approach for defining myocardial
inflammation.
10. New SPECT systems provide high-sensitivity, high-resolution
studies, allowing for radiation dose reduction and high-quality
imaging studies.

Abbreviations

CT
computed radiologic tomography
ERNA
radionuclide angiocardiography
FDG
(F-18)-fluorodeoxyglucose
LV
left ventricular
MI
myocardial infarction
PET
positron emission tomography
SPECT
single-photon emission computed tomography

Introduction

Nuclear cardiology is generally considered a clinical phenomenon

of the past four decades. However, the field has its roots in earlier times.
This chapter focuses on these historical roots as they have evolved into
the present era. Space constraints mandate focusing solely on the
highlights. My apologies to the many highly productive investigators and

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Nuclear Cardiology: History and Milestones

laboratories whose contributions helped the field grow to its current

level, but who could not be included.

Heart Function and Circulatory Dynamics

The initial application of radioisotopes to the study of the

circulation occurred in the mid-1920s (Table 1.1). The famous cardiologic
investigator of that era, Hermann Blumgart, in an elegant series of
studies employing radon gas dissolved in saline as the radionuclide
marker and a modified Wilson cloud chamber as the radiation detector,
measured central circulation transit times in humans.1 These studies,
which were well ahead of their time, resulted in substantial improvement
in the general understanding of cardiovascular function in a variety of
disease states. They were early forerunners of the studies of the 1950s
and 1960s, in which substantial attention was given to hemodynamic
characterization in both health and human disease states. Blumgart’s
laboratory in Boston also served as fertile ground for training the next
generation of cardiovascular investigators.

Table 1.1 Major Advances: Before 1970

Decade Investigator Advance

1920s H Blumgart Circulation times with radioisotopes

1940s M Prinzmetal Radiocardiography

1960s EA Carr Perfusion imaging in experimental MI

EA Carr Hot spot imaging in experimental MI

HO Anger Development of scintillation camera

J Kriss Quantitative first-pass radionuclide

angiocardiography

Not until the 1940s did Myron Prinzmetal build on this concept for
potential clinical use, employing a simple sodium iodide probe to record
transit of radiolabeled albumin through the central circulation.
Prinzmetal, a practicing cardiologist, made important clinical
observations using nonimaging Geiger tubes and scintillation detectors in
a procedure called radio-cardiography to define cardiac output,
pulmonary blood volume, and pulmonary transit time.2

However, the major impetus for the development of nuclear medicine

technology occurred when Hal O. Anger, working in Berkeley, California,
developed the first practical widely used high-resolution dynamic imaging
device, the gamma (Anger) camera.3 With this device, early pioneers in

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Nuclear Cardiology: History and Milestones

the field (such as Joseph Kriss) demonstrated the ability to visualize

cardiac structures from rapid sequential radionuclide images following
injection of a bolus of technetium-99m (Tc-99m)-labeled radioactive
tracers.4,5 From these serial images, a number of inferences could be
made concerning cardiac pathophysiology and cardiac chamber and great
vessel size. Following these qualitative studies, quantitative techniques
were developed for assessing left and right ventricular ejection fraction
as well as the degree of left:right intracardiac shunting.6,7 For over a
decade, first-pass approaches to ejection fraction were widely used.
Extensive studies were subsequently performed by many laboratories,
particularly at Duke and Yale Universities, establishing efficacy and
clinical utility.8,9,10,11

In 1971, the principle of electrocardiographic gating of the stable labeled

(equilibrium) blood pool to evaluate cardiac performance was first
proposed by Zaret and Strauss12,13 (Table 1.2). This forerunner of current
equilibrium radionuclide angiocardiography (ERNA) required separate
manual gating of end-systole and end-diastole for subsequent
measurement of left ventricular (LV) ejection fraction and assessment of
regional function. This was a cumbersome and time-consuming
procedure. However, once efficacy had been established, it was only a
short time before automation of this technique occurred; using relatively
simple computerized techniques, the entire cardiac cycle could be
visualized in an endless loop display with automated calculation of
ejection fraction and visualization of the entire ventricle volume curve.
For over a decade, this technique was the standard for measuring
ventricular function noninvasively. In 1977, Borer et al. at the National
Institutes of Health first reported combining ERNA with exercise to
evaluate regional and global LV function under stress conditions in
coronary artery disease as well as other disease states, such as valvular
heart disease.14 In large part, echocardiography has superseded ERNA in
this context. However, for precise serial measurements of ejection
fraction, such as in the situation involving monitoring cardiotoxicity in
patients receiving chemotherapy, the radionuclide technique remains the
procedure of choice.15

Table 1.2 Major Advances: 1970–2000

Date Investigators Advance

1971 B Zaret, HW ECG gating of cardiac blood pool in

Strauss humans (ERNA) for LV ejection
fraction and regional wall motion
abnormality

1973 B Zaret, HW Exercise perfusion imaging (K-43)

Strauss in humans

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