Cardiac Repolarization Basic Science and Clinical

Management

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Editor
Nabil El-Sherif
Department of Medicine and Physiology
State University of New York Downstate Medical Center
VA New York Harbor Healthcare Center
Brooklyn, NY
USA

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Foreword

Normal cardiac repolarization is vital to maintain optimal mechanical and

electrical cardiac function. Repolarization that is too long or too short, or
otherwise abnormal, puts the patient at risk for developing life-threatening
cardiac arrhythmias. It is essential that scientists and clinical electrophysiolo-
gists understand cardiac repolarization. The textbook Cardiac Repolarization:
Basic Science and Clinical Management, edited by Nabil El-Sherif, provides
information critical to that understanding.
Chapter 1, “Physiology and Molecular Biology of Ion Channels Underlying
Ventricular Repolarization of the Mammalian Heart,” reviews the key ion
channels that underlie cardiac repolarization and focuses on critical potas-
sium ion channels, while the Chap. 2, “Neuromodulation of Cardiac
Repolarization and Arrhythmogenesis,” explores autonomic modulation of
this activity at the cardiac channel, cellular, and organ levels.
Heart failure can predispose to the development of potentially fatal
arrhythmias via multiple mechanisms including altered calcium handling,
stretch, and changes in myocyte electrical and metabolic properties, as
explored in Chap. 3, “Repolarization Remodeling in Structural Heart
Disease.” A major advance in studying mechanisms impacting repolarization
has been the use of pluripotent stem cell-derived cardiomyocytes to model
cardiac disease states, a major advance presented in Chap. 4, “Cardiac
Repolarization and Stem Cells: An Emerging Path Toward Precision
Medicine.”
Voltage-gated sodium channels, responsible for the rapid upstroke of the
action potential, are vital to maintain electrical excitability and coordinate
excitation-contraction coupling, as explored in Chap. 5, “Role of Late Sodium
Current during Repolarization and Its Pathophysiology.” How age, sex, and
race impact cardiac repolarization and arrhythmogenesis is presented in
Chap. 6, “Age, Sex, and Racial Differences in Cardiac Repolarization and
Arrhythmogenesis,” emphasizing that testosterone appears to shorten the
QTc interval in males, while in females, there is a more complex interaction
between progesterone and estrogen.
With the initial chapters serving as a scientific foundation for clinical
events involving repolarization, the text now turns to the clinical arena, begin-
ning with a consideration of the standard electrocardiogram (ECG), still one
of the most useful methods for risk stratification for sudden cardiac death,
and an analysis of the QT interval, as explained in Chap. 7, “ECG-derived
Evaluation of Cardiac Repolarization.” Microvolt T-wave analysis represents

v
vi Foreword

another approach for investigating the QT interval to track T-wave alternans,

a beat-to-beat fluctuation in ST-segment or T-wave morphology, and is dis-
cussed in Chap. 19, “Microvolt T-Wave Alternans: Pathophysiology and
Clinical Aspects.”
The next several chapters feature clinical manifestations of the long QT
interval. Chapter 8 delves into the phenotype-genotype relationship of clini-
cal presentations, ECG patterns, risk stratification for cardiac events, and
therapy in “Genotype-Phenotype Correlation in Congenital LQTS:
Implications for Diagnosis and Risk Stratification,” concentrating on the
three genes KCNQ1, KCNH2, and SCN5A underlying LQT1, LQT2, and
LQT3, respectively, which account for about 95% of patients with an identi-
fied genetic cause. Chapter 9 discusses the clinical management of patients
with the inherited long QT syndrome, “Clinical Management of LQTS
Patients,” focusing on minimizing the adrenergic response, shortening the
QTc, decreasing the dispersion of refractoriness, and improving the function
of dysfunctional ion channel.
Chapter 10, “Drug-Induced Long QT Syndrome and Torsades de Pointes,”
emphasizes drug-induced LQTS and its ventricular arrhythmia, noting that
QT prolongation is a useful but imperfect predictor of patients at high risk of
developing the serious and life-threatening arrhythmia, torsades de pointes.
Chapter 11, “Acquired Long QT Syndrome and Electrophysiology of Torsade
de Pointes,” stresses the electrophysiological mechanisms of acquired LQTS,
its electrocardiographic (ECG) characteristics, clinical presentation, and
management of the acquired long QT interval.
New mechanisms of QT prolongation are explored in Chap. 12, “Pathogenesis
of Autoimmune-Associated Long QT Syndrome,” and Chap. 13, “The Role of
Inflammation and Autoimmunity in Long-QT Syndrome.”
The QTc interval can be too short (<340 ms) as well as too long and pro-
voke ventricular arrhythmias, as discussed in Chap. 18, “The Short QT
Syndrome.”
A relatively newly described entity, the J-wave syndromes, appears to be a
constellation of several clinical entities characterized by J-wave abnormali-
ties, such as the early repolarization syndrome associated with variants in
seven different genes, discussed in Chap. 14, “Genetics, Molecular Biology
and Emerging Concepts of Early Repolarization Syndrome.” Chapter 15,
“Electrocardiographic J-wave and Cardiovascular Risk in the General
Population,” presents the prevalence and significance of the ECG pattern of
early repolarization in the general population, while Chap. 16, “Benign
Versus Malignant Early Repolarization Patterns,” differentiates benign from
arrhythmogenic J waves, emphasizing the J-wave proper, the ST-segment,
and the ensuing T-waves.
Brugada syndrome appears to be part of the J-wave group and is discussed
in Chap. 17, “Genetic Architecture, Pathophysiology, and Clinical
Management of Brugada Syndrome,” in which the authors stress the under-
standing of the pathophysiological mechanism(s), the ongoing efforts to
reappraise the genetic architecture, and the advances in risk stratification and
therapeutic approaches.
Foreword vii

Chapter 20, the final chapter, “Action Potential Dynamics in Human Atrial
Fibrillation,” explores the action potential variability in the most common
sustained arrhythmia that affects more than 30 million people worldwide,
atrial fibrillation.
This textbook, ably edited by Nabil El-Sherif and written by him along
with a multitude of electrophysiology experts, is a must for basic and clinical
electrophysiologists interested in cardiac repolarization.

Douglas P. Zipes, MD
Distinguished Professor
Indiana University School of Medicine
Krannert Institute of Cardiology
Indianapolis, IN, USA
Preface

Cardiac repolarization is a vital aspect for understanding normal cardiac

rhythm, and its abnormal modulation is the basis of many potentially lethal
cardiac arrhythmias. The last book that dealt exclusively with cardiac repolar-
ization was published in 2003. It is overdue to readdress the many significant
changes in the field.
This book was designed to provide a comprehensive up-to-date coverage
of clinical and research aspects of cardiac repolarization, with several sec-
tions that are the domain of practicing physicians. The 20 chapters are sub-
grouped into 4 parts. Part I deals with the basic, molecular biology and
clinical aspects of cardiac repolarization at large, including the influence of
the autonomic system, remodeling in organic heart disease, racial and gender
difference in cardiac repolarization and arrhythmic risk, ECG-derived evalu-
ation of cardiac repolarization, and future role of stem cells studies of cardiac
repolarization.
Part II provides a comprehensive coverage of pathophysiology, molecular
biology, and clinical aspects of long QT syndromes. While basic and clinical
aspects of congenital long QT syndrome and torsade de pointes are usually
the domain of academic cardiologists and cardiac electrophysiologists,
acquired and drug-induced long QT syndrome should be of interest to a
majority of medical professionals who prescribe drugs and take care of
patients.
Part III provides updated basic and clinical coverage of the subject of early
repolarization (ER), also called J-wave syndromes, and expound currently
controversial aspects such as benign versus malignant ER in the 12-lead ECG
and in the general population at large. Finally, Part IV covers the pathophysi-
ology and clinical aspects of special cardiac repolarization syndromes that
include short repolarization syndrome, repolarization alternans, the impor-
tant role of microvolt T-wave alternans in arrhythmia risk stratification, and
the recently recognized role of atrial repolarization and arrhythmogenesis.
The wide-ranging features of the book should be of interest not only to
academic and clinical cardiologists and cardiac electrophysiologists but also
to a much larger group of practicing internists and other medical profession-
als who would like to keep abreast of the important developments in this field.

Brooklyn, NY, USA Nabil El-Sherif

ix
Contents

Part I Pathophysiology, Molecular Biology, and Clinical Aspects

of Cardiac Repolarization
1 Physiology and Molecular Biology of Ion Channels
Underlying Ventricular Repolarization of the Mammalian
Heart��������������������������������������������������������������������������������������������������   3
Thomas W. Comollo, Chuangeng Zhang, Xinle Zou,
and Robert S. Kass
2 Neuromodulation of Cardiac Repolarization and
Arrhythmogenesis���������������������������������������������������������������������������� 49
Fabrice Extramiana and Pierre Maison-Blanche
3 Repolarization Remodeling in Structural Heart Disease ������������ 77
Andreas S. Barth and Gordon F. Tomaselli
4 Cardiac Repolarization and Stem Cells: An Emerging
Path Toward Precision Medicine���������������������������������������������������� 87
Massimiliano Gnecchi, Luca Sala, and Peter J. Schwartz
5 Role of Late Sodium Current During Repolarization
and Its Pathophysiology������������������������������������������������������������������ 109
Mohamed Chahine
6 Age, Sex and Racial Differences in Cardiac
Repolarization and Arrhythmogenesis������������������������������������������ 119
Arja Suzanne Vink, Sally-Ann B. Clur, Pieter G. Postema,
Nico A. Blom, and Arthur A. M. Wilde
7 ECG-Derived Evaluation of Cardiac Repolarization ������������������ 131
Gioia Turitto and Nabil El-Sherif
Part II Pathophysiology, Molecular Biology, and Clinical
Aspects of Long QT Syndromes
8 Genotype-Phenotype Correlation in Congenital LQTS:
Implications for Diagnosis and Risk Stratification ���������������������� 141
Ilan Goldenberg
9 Clinical Management of LQTS Patients���������������������������������������� 165
Wojciech Zareba

xi
xii Contents

10 Drug-Induced Long QT Syndrome and Torsades

de Pointes������������������������������������������������������������������������������������������ 185
Raymond L. Woosley and Peter J. Schwartz
11 Acquired Long QT Syndrome and Electrophysiology
of Torsade de Pointes ���������������������������������������������������������������������� 201
Nabil El-Sherif, Gioia Turitto, and Mohamed Boutjdir
12 Pathogenesis of Autoimmune-­Associated Long
QT Syndrome ���������������������������������������������������������������������������������� 217
Mohamed Boutjdir, Pietro Enea Lazzerini,
Pier Leopoldo Capecchi, Franco Laghi-Pasini,
and Nabil El-Sherif
13 The Role of Inflammation and Autoimmunity
in Long QT Syndrome �������������������������������������������������������������������� 227
Pietro Enea Lazzerini, Franco Laghi-Pasini, Nabil El-Sherif,
Mohamed Boutjdir, and Pier Leopoldo Capecchi
Part III Pathophysiology, Molecular Biology, and Clinical
Aspects of Early Repolarization Syndromes
14 Genetics, Molecular Biology, and Emerging Concepts
of Early Repolarization Syndrome������������������������������������������������ 255
Charles Antzelevitch and Gregory Dendramis
15 Electrocardiographic J Wave and Cardiovascular Risk
in the General Population��������������������������������������������������������������� 269
Heikki V. Huikuri
16 Benign Versus Malignant Early Repolarization Patterns������������ 277
Raphael Rosso and Sami Viskin
17 Genetic Architecture, Pathophysiology, and Clinical
Management of Brugada Syndrome���������������������������������������������� 285
John R. Giudicessi and Michael J. Ackerman
Part IV Pathophysiology and Clinical Aspects of Special
Cardiac Repolarization Syndromes
18 The Short QT Syndrome ���������������������������������������������������������������� 303
Chiara Scrocco, Fiorenzo Gaita, and Carla Giustetto
19 Microvolt T-Wave Alternans: Pathophysiology
and Clinical Aspects������������������������������������������������������������������������ 313
Richard L. Verrier
20 Action Potential Dynamics in Human Atrial Fibrillation������������ 333
Junaid Ahmed Bakhtiyar Zaman, Sanjiv M. Narayan,
and Michael R. Franz
Index���������������������������������������������������������������������������������������������������������� 347
Contributors

Michael J. Ackerman, MD, PhD Departments of Cardiovascular Medicine,

Pediatric and Adolescent Medicine, and Molecular Pharmacology and
Experimental Therapeutics, Mayo Clinic Genetic Heart Rhythm Clinic and
the Windland Smith Rice Sudden Death Genomics Laboratory, Rochester,
MN, USA
Charles Antzelevitch, PhD, FACC, FHRS, FAHA Department of
Cardiovascular Research, Lankenau Institute for Medical Research,
Wynnewood, PA, USA
Lankenau Heart Institute, Wynnewood, PA, USA
Sidney Kimmel Medical School, Thomas Jefferson University, Philadelphia,
PA, USA
Andreas S. Barth, MD, PhD, FAHA Department of Cardiac
Electrophysiology, Johns Hopkins University, Baltimore, MD, USA
Nico A. Blom, MD, PhD Department of Pediatric Cardiology, Emma
Children’s Hospital, Amsterdam UMC, University of Amsterdam,
Amsterdam, The Netherlands
Department of Paediatric Cardiology, Willem-Alexander Children’s Hospital,
Leiden University Medical Centre, Leiden, The Netherlands
Mohamed Boutjdir, PhD Department of Medicine and Physiology, SUNY
Downstate Medical Center, Brooklyn, NY, USA
State University of New York Downstate Medical Center, New York, NY, USA
NYU School of Medicine, New York, NY, USA
Pier Leopoldo Capecchi, MD, PhD Department of Medical Sciences,
Surgery and Neurosciences, University of Siena, Siena, Italy
Mohamed Chahine, PhD CERVO Research Center, Institut Universitaire
en Santé Mentale de Québec, Quebec City, QC, Canada
Department of Medicine, Université Laval, Quebec City, QC, Canada
Sally-Ann B. Clur, MBBCh, MSc, FCP(SA)Paed, PhD Department of
Pediatric Cardiology, Emma Children’s Hospital, Amsterdam UMC,
University of Amsterdam, Amsterdam, The Netherlands
Thomas W. Comollo, PhD Department of Pharmacology, Columbia
University Irving Medical Center, Vagelos College of Physicians and
Surgeons, New York, NY, USA
xiii
xiv Contributors

Gregory Dendramis, MD Cardiovascular Division, Pietro Cosma Hospital,

Padova, Italy
Nabil El-Sherif, MD Department of Medicine and Physiology, State
University of New York Downstate Medical Center, VA New York Harbor
Healthcare Center, Brooklyn, NY, USA
Fabrice Extramiana, MD, PhD Arrhythmia unit, Department of Cardiology,
Bichat Hospital, APHP, Paris University, Paris, France
Michael R. Franz, MD, PhD Division of Cardiology, Veterans Affairs
Medical Center, Washington, DC, USA
Fiorenzo Gaita, MD Department of Medical Sciences, University of Turin,
and Clinica Pinna Pintor, Turin, Italy
John R. Giudicessi, MD, PhD Department of Cardiovascular Medicine,
Mayo Clinic, Rochester, MN, USA
Carla Giustetto, MD Division of Cardiology, Department of Medical
Sciences, University of Turin, “Città della Salute e della Scienza” Hospital,
Turin, Italy
Massimiliano Gnecchi, MD, PhD Coronary Care Unit, and Laboratory of
Experimental Cardiology for Cell and Molecular Therapy, IRCCS Policlinico
San Matteo Foundation, Pavia, Italy
Department of Molecular Medicine – Unit of Cardiology, University of Pavia,
Pavia, Italy
Department of Medicine, University of Cape Town, Cape Town, South Africa
Ilan Goldenberg, MD Cardiology Division, Clinical Cardiovascular
Research Center, University of Rochester Medical Center, Rochester, NY, USA
Heikki V. Huikuri, MD Research Unit of Internal Medicine, University
Hospital of Oulu, Oulu, Finland
Robert S. Kass, PhD Department of Pharmacology, Columbia University
Irving Medical Center, Vagelos College of Physicians and Surgeons, New
York, NY, USA
Franco Laghi-Pasini, MD, PhD Department of Medical Sciences, Surgery
and Neurosciences, University of Siena, Siena, Italy
Pietro Enea Lazzerini, MD Department of Medical Sciences, Surgery and
Neurosciences, University of Siena, Siena, Italy
Pierre Maison-Blanche, MD Arrhythmia unit, Department of Cardiology,
Bichat Hospital, APHP, Paris University, Paris, France
Sanjiv M. Narayan, MD, PhD Department of Medicine, Stanford
University, Stanford, CA, USA
Pieter G. Postema, MD, PhD Department of Clinical and Experimental
Cardiology, Amsterdam UMC, University of Amsterdam, Heart Center,
Amsterdam, The Netherlands
Raphael Rosso, MD Department of Cardiology, Tel-Aviv Medical-Center
and Sackler School of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel
Contributors xv

Luca Sala, PhD Center for Cardiac Arrhythmias of Genetic Origin –

Laboratory of Cardiovascular Genetics, Istituto Auxologico Italiano IRCCS,
Milan, Italy
Peter J. Schwartz, MD Center for Cardiac Arrhythmias of Genetic Origin
– Laboratory of Cardiovascular Genetics, Istituto Auxologico Italiano IRCCS,
Milan, Italy
Chiara Scrocco, MD Clinical Cardiology Academic Group, Molecular and
Clinical Sciences Research Centre, St George’s University of London,
London, UK
Gordon F. Tomaselli, MD The Albert Einstein College of Medicine,
Department of Medicine, Bronx, NY, USA
Gioia Turitto, MD Cardiac Electrophysiology Services, Department of
Medicine, New York-Presbyterian Brooklyn Methodist Hospital, Brooklyn,
NY, USA
Richard L. Verrier, PhD Department of Medicine, Harvard Medical
School, Beth Israel Deaconess Medical Center, Boston, MA, USA
Arja Suzanne Vink, MSc, MD Department of Clinical and Experimental
Cardiology, Amsterdam UMC, University of Amsterdam, Heart Center,
Amsterdam, The Netherlands
Department of Pediatric Cardiology, Emma Children’s Hospital, Amsterdam
UMC, University of Amsterdam, Amsterdam, The Netherlands
Sami Viskin, MD Department of Cardiology, Tel-Aviv Medical-Center and
Sackler School of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel
Arthur A. M. Wilde, MD, PhD Department of Clinical and Experimental
Cardiology, Amsterdam UMC, University of Amsterdam, Heart Center,
Amsterdam, The Netherlands
Raymond L. Woosley, MD, PhD Department of Medicine, Division of
Clinical Data Analytics and Decision Support, University of Arizona, College
of Medicine-Phoenix, Phoenix, AZ, USA
Junaid Ahmed Bakhtiyar Zaman, MA, BMBCH, MRCP Royal Brompton
Heart and Vascular Institute, London, UK
Department of Medicine, Stanford University, Stanford, CA, USA
Wojciech Zareba, MD, PhD Cardiology Division, Clinical Cardiovascular
Research Center, University of Rochester Medical Center, Rochester, NY, USA
Chuangeng Zhang, PhD Department of Pharmacology, Columbia
University Irving Medical Center, Vagelos College of Physicians and
Surgeons, New York, NY, USA
Xinle Zou, PhD Department of Pharmacology, Columbia University Irving
Medical Center, Vagelos College of Physicians and Surgeons, New York,
NY, USA
 Part I
Pathophysiology, Molecular Biology, and
Clinical Aspects of Cardiac Repolarization
 Physiology and Molecular Biology
of Ion Channels Underlying
1
Ventricular Repolarization
of the Mammalian Heart

Thomas W. Comollo, Chuangeng Zhang,

Xinle Zou, and Robert S. Kass

Introduction reticulum, the sarcoplasmic reticulum (SR),

through Ca2+-sensitive ryanodine receptor chan-
The proper mechanical pumping of the mamma- nels [7]. This triggers the excitation-contraction
lian heart depends upon a precise, cyclic cascade (EC) coupling relationship that triggers calcium-­
of electrical events, with each player from the dependent muscle contraction [7, 8]. Calcium
anatomical region, down to the ion channels ions bind a protein called trophin, exposing a
responsible for each ionic current playing its myosin-binding site on the actin filaments, and
exact role in this symphonic-like mechanism. myosin moves the actin by an adenosine triphos-
Cells in the sinoatrial note, the “pacemaker” phate (ATP)-dependent mechanism [9]. Thus, the
region of the heart, are first activated and propa- electrical signaling of the heart translates into
gate the electrical activity through the remainder mechanical pumping via rhythmic contraction of
of the heart. This signal spreads due to the cou- the myocardium.
pling of cardiac cells at gap junctions [1–5], Ventricular action potential waveforms reflect
inciting “action potentials” in each of the cells the coordinated activity of multiple ion channels
(cardiomyocytes), as the cell is electrically that open, close, and inactivate on different time
excited. The surface electrocardiogram (ECG) scales (Fig. 1.1). The rapid upstroke of the action
reflects the differences in voltage across different potential (phase 0) is caused by a large inward
regions of the heart as this electrical cascade current through voltage-gated Na+ channels. It is
spreads through the organ. followed by a transient repolarization (phase 1),
The “action potentials” generated in each cell reflecting Na+ channel inactivation and the acti-
as the electrical signals spread throughout the vation of voltage-gated outward potassium (K+)
heart are the result of activation and subsequent currents (Fig. 1.1). This transient repolarization
inactivation of both depolarizing, inward sodium or “notch” influences the height and duration of
(Na+) and calcium (Ca2+) currents that are then the plateau phase (phase 2) of the action poten-
countered by repolarizing, outward K+ currents tial, which depends on the delicate balance of
[4, 6]. During this action potential cascade of inward (Ca2+ and Na+) currents and outward (K+)
events, the influx of Ca2+ triggers release of more currents. Although Ca2+ influx through high-­
Ca2+ from the myocyte version of the endoplasmic threshold, L-type voltage-gated Ca2+ channels is
the main contributor of inward current during the
T. W. Comollo · C. Zhang · X. Zou · R. S. Kass (*) plateau phase, this current declines during phase
Department of Pharmacology, Columbia University 2 as the (L-type Ca2+) channels undergo Ca2+
Irving Medical Center, Vagelos College of Physicians and voltage-dependent inactivation. The driving
and Surgeons, New York, NY, USA
e-mail: [email protected] force for K+ efflux through the voltage-gated

© Springer Nature Switzerland AG 2020 3

N. El-Sherif (ed.), Cardiac Repolarization, https://doi.org/10.1007/978-3-030-22672-5_1
4 T. W. Comollo et al.

Phase 1 These currents determine the heights and the

durations of ventricular action potentials. In con-
trast to the Na+ and Ca2+ currents, there are mul-
Phase 2
tiple types of K+ currents in ventricular myocytes.
Phase 3 Of the various K+ currents, the voltage-gated K+
currents are the most numerous and diverse. At
Phase 0

least two types of transient outward currents, Ito,f

and Ito,s, and several components of delayed recti-
100 ms
Phase 4 fication, including IKr (IK(rapid)) and IKs (IK(slow)),
lNa have been distinguished in ventricular myocytes
in a variety of different species (Table 1.1). In
lCa.L addition, there are marked regional differences in
the expression patterns of these (voltage-gated)
lNCX
K+ currents. These differences contribute to the
observed variability in ventricular action poten-
lto,f tial waveforms [10–12]. The time- and voltage-­
lto,s dependent properties of the various repolarizing
currents in myocytes isolated from different spe-
lKs
cies and/or from different regions of the ventri-
lKr cles in the same species are similar, suggesting
lK,slow that the molecular correlates of the underlying
lSS channels are also the same [13]. A rather large
lKl number of pore-forming (α) and accessory (β, δ,
and γ) subunits that coassemble as Na+, Ca2+, and
lKATP K+ channels have been identified in mammalian
ventricles, and considerable progress has been
Fig. 1.1 Schematic of the action potential and underlying
ionic currents in adult human ventricular myocytes. The
made in defining the relationships between these
contributions of some K+ currents, such as IK,slow and ISS subunits and functional ventricular Na+, Ca2+, and
which are expressed in other species, have not been K+ channels. Importantly, these studies have
defined in human ventricular cells revealed that distinct molecular entities underlie
the various ion channels contributing to ventricu-
(and other) K+ channels, however, is high during lar action potential repolarization.
the plateau, and, as the Ca2+ channels inactivate, Importantly, voltage-gated channels change
the outward K+ currents predominate resulting in between at least three different conformations.
a second, rapid phase (phase 3) of repolarization These are open, closed, and inactivated [14–16].
back to the resting potential (Fig. 1.1). The height In the closed state, the channel pore is closed.
and the duration of the action potential plateau, Upon activation, due to rising intracellular volt-
as well as the time- and voltage-dependent prop- age, the pore opens due to movement of the volt-
erties of the underlying voltage-gated Na+, Ca2+, age sensor and the channel enters the “open”
and K+ currents, therefore, also influence action conformation. After time that varies from chan-
potential durations. As a result, modifications in nel to channel, the voltage-gated ion channel will
the properties or the densities of any of these enter the “inactivated” conformation, a noncon-
channels could have dramatic effects on ventricu- ducting state. Eventually, the channel will recover
lar action potential waveforms, refractory peri- from the inactivated state and become capable of
ods, and cardiac rhythms. conducting ionic current again [14–16].
Electrophysiological studies have detailed the The densities and the properties of voltage-­
properties of the major voltage-gated inward Na+ gated Na+, Ca2+, and K+ currents change during
and Ca2+ and outward K+ currents (Table 1.1). normal ventricular development, reshaping