Basic Cardiac Electrophysiology for the Clinician E-Book

Jose Jalife

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 621

Veröffentlichungsjahr: 2011

Beschreibung

This book translates fundamental knowledge in basic cardiac electrophysiology from the bench to the bedside. Revised and updated for its second edition, the text offers new coverage of the molecular mechanisms of ion channel behavior and its regulation, complex arrhythmias, and the broadening roles of devices and ablation. Clear, straightforward explanations are illustrated by plentiful diagrams to make the material accessible to the non-specialist.

Leseprobe

Contents

Acknowledgments

Foreword to the First Edition

Foreword to the Second Edition

Introduction

CHAPTER 1 Bioelectricity

On the Electricity of Biological Membranes

Parallel RC Circuits

Origin of the Membrane Potential

Active Currents

Excitability

Cardiac Action Potential

Basic Action Potential Parameters

Voltage Clamp

Methods of Resolving Currents through Ion Channels

Some Basic Terminology

Summary

CHAPTER 2 Ion Channels

Mechanisms of Ion Permeation

Ionic Currents in Cardiac Cells

Molecular Structure of Cardiac Ion Channels

Summary

CHAPTER 3 Ion Channel Regulation

Mechanisms of Ion Channel Regulation

Autonomic Regulation of Ionic Currents in Cardiac Cells

Summary

CHAPTER 4 Impulse Initiation and Propagation in Cardiac Muscle

Electrotonic Propagation

Pacemaker Synchronization in the Sinus Node

Resistive Coupling and Mutual Entrainment

The Phase–Response Curve Predicts Entrainment

Interaction of Two Pacemakers (Mutual Entrainment)

Mutual Entrainment and the Generation of the Heartbeat

Propagation of the Cardiac Impulse

Cable Equations

Propagation of the Action Potential: “Sink” and “Source”

Current Load and the Concept of Liminal Length

Factors Regulating Action Potential Propagation in Cardiac Tissues

Concept of “Safety Factor” for Propagation

Propagation in Two Dimensions and the Concept of Curvature

Anisotropic Propagation

Propagation in Three-Dimensional Cardiac Muscle

Propagation at Junctional Sites

Heterocellular Interactions and Their Role on Propagation

Summary

CHAPTER 5 Rate Dependency of Discontinuous Propagation

Continuous versus Discontinuous Propagation

Postrepolarization Refractoriness

Cellular Mechanisms of Discontinuous Propagation

Unidirectional Block

Cellular Mechanisms of Wenckebach Periodicity

Recovery Curve

Recovery Curve Predicts Nonlinear Dynamics of Rate-Dependent Propagation

Ionic Mechanism of Wenckebach in Ventricular and Atrioventricular Nodal Myocytes

Nonlinear Recovery and Complex Excitation Dynamics

Role of Gross Anatomic Structure in Discontinuous Propagation

The Phenomenon of Fibrillatory Conduction

Summary

CHAPTER 6 Basic Mechanisms of Cardiac Arrhythmias

Abnormal Impulse Formation

Alterations in the Conduction of the Impulse: Reentry

Summary

CHAPTER 7 Rotors, Spirals, and Scroll Waves in the Heart

Self-Organization in Excitable Media

Lessons about Cardiac Reentry from the B–Z Reaction

The Concept of “Wavebreak”

The Ever-Increasing Curvature of a Spiral Wave Front

Wavebreaks and “Singularities”

Lines of Block in Anisotropic Reentry

Spiral Waves and Wavelets

Wavebreak Precedes the Initiation of Reentry

Excitability and Core Size

The Excitable Gap

Figure-of-8 Reentry and the Common Pathway

Drifting Spirals

Drifting Spirals and Electrocardiographic Patterns

Doppler Effect and Torsades de Pointes

Anchoring and the Transition from Polymorphic to Monomorphic Activation

Effects of Externally Applied Waves on Spiral Wave Dynamics

Three-Dimensional Scrolls

Dynamics of Scroll Waves

Experimental Detection of Three-Dimensional Vortex-like Reentry in Cardiac Muscle

Summary

CHAPTER 8 Rotors and the Mechanisms of Atrial Fibrillation

Mechanism of Atrial Fibrillation: Multiple Wavelets versus Mother Rotor

The Sheep Model of Atrial Fibrillation

Wavebreak and Initiation of Reentry in the Atria

A Single Reentrant Source may Drive Atrial Fibrillation

Left Atrium-to-Right Atrium Frequency Gradients

Dispersion of Activation Rate during Atrial Fibrillation

Stretch and Activation in the Left Atrium during Atrial Fibrillation

Vagal Effects on Rotors during Atrial Fibrillation

Ionic Mechanisms of Parasympathetic Modulation of Atrial Fibrillation

Remodeling of the Atrial Substrate in Chronic Atrial Fibrillation

Atrial Fibrillation in Humans: The Spatial Distribution of Dominant Frequencies

Activation Frequency and Rotors as Atrial Fibrillation Drivers in Humans

Summary

CHAPTER 9 Molecular Mechanisms of Ventricular Fibrillation

Wavebreaks and Rotors

Fibrillatory Conduction

The Guinea Pig Heart Model of Ventricular Fibrillation

Nature of the Fastest Dominant Frequencies

Action Potential Abbreviation and Rapid Rotation Frequency

Background Current in Left Ventricle versus Right Ventricle

An Ionic Mechanism of Stable Ventricular Fibrillation

The Kir Family of Channel Proteins

Inward Rectification and Kir2.x Channels

Kir2.x Channels in the Right and Left Ventricle

Why the Kir2.x Channels?

IK1 Up-Regulation in the Mouse Heart

IKs and Fibrillatory Conduction

The Universal Law of Ventricular Fibrillation Frequency Scaling Across Species

Scaling of Ventricular Fibrillation Frequency

Mechanism of Ventricular Fibrillation Scaling

What Is the Significance of Ventricular Fibrillation Frequency Scaling?

Summary

CHAPTER 10 Inheritable Arrhythmogenic Diseases

Congenital Long QT Syndrome

Acquired Long QT Syndrome

Arrhythmia Mechanisms and the Long QT Syndrome

Brugada Syndrome

Short QT Syndrome

Catecholaminergic Polymorphic Ventricular Tachycardia

Arrhythmogenic Right Ventricular Cardiomyopathy

Summary

Bibliography

Index

Dedications

To Paloma, Andrea, David, Marina, Obi, Kachi, Celina, Sofía, Ilán, Sebastián, Josyane, Jean-Pierre and Late Chief C.N. Anumonwo, the Iyase of Ogwashi-Uku, Delta State, Nigeria.

This edition first published 2009, © 2009 by José Jalife, Mario Delmar, Justus Anumonwo, Omer Berenfeld and Jérôme Kalifa

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Library of Congress Cataloging-in-Publication Data

Basic cardiac electrophysiology for the clinician/Jose Jalife... [et al.]. – 2nd ed.

p.; cm.

Includes bibliographical references and index.

ISBN 978-1-4051-8333-8

1. Heart-Electric properties. 2. Electrophysiology. 3. Arrhythmia. 4. Heart conduction system.

I. Jalife, Jose.

[DNLM: 1. Heart–physiology. 2. Electrophysiology. WG 202 B3107 2009]

QP112.5.E46B37 2009

612.1′71–dc22

2008045638

Acknowledgments

Special thanks to the Jalife, Delmar, Anumonwo, Berenfeld and Kalifa families for their love, patience and unconditional support. We are also deeply indebted to all students, postdoctoral fellows, and technicians who throughout the years have contributed their work and ideas to our research program. Many of the concepts presented in this book are direct results of such contributions. We particularly thank all the current scientists, technicians, and clerical staff of the Center for Arrhythmia Research of the University of Michigan for their exceptional courage in following our lead and for sharing our vision for a bright future in the study of intercellular communication and cardiac impulse propagation. The unreserved support of our fearless administrator, Laurie Lebouef, is greatly appreciated. Thanks to Sherry Morgenstern, our in-house artist who helped with the figures. Our thanks go also to Doug Zipes, who generously took time from his busy schedule to read the manuscripts and write the forewords for the two editions of this book. We are obliged to Dr. David Pinsky, Dr. Hakan Oral, and Dr. Fred Morady and to the leadership of the University of Michigan Health System for helping make our dream for a Center for Arrhythmia Research a reality with a bright outlook. Much of the work presented was made possible by generous grants from the National Heart, Lung and Blood Institute; National Institutes of Health; the American Heart Association, Inc.; and the Heart Rhythm Society for the last 28 years.

José Jalife, MD

Mario Delmar, MD, PhD

Justus Anumonwo, PhD

Omer Berenfeld, PhD

Jérôme Kalifa, MD, PhD

Foreword to the First Edition

Finally a book for the clinician that explains basic cardiac electrophysiology! Pepe Jalife and his colleagues have done it at last, based on a series of lectures they presented to residents, fellows, and faculty members of the divisions of cardiology and pediatric cardiology at SLTNY Health Science Center in Syracuse, New York. Their course, “Basic Cardiac Electrophysiology for Clinical Fellows,” became exceedingly popular as clinicians realized the importance of what they were learning and that this information could help them make decisions, which directly impacted on choices for patient care. This type of lecture series, with its subsequent book, could only be given by a group of scientists with feet firmly planted in the animal laboratory and at the bedside. Indeed this group of electrophysiologists represent precisely that skill set. Further, they do this in a fashion that eschews the jargon of the profession that ordinarily is certain to drive off would-be students. The importance of their teaching is underscored by the breakthrough observations over the past several years on the genetic basis for the “ionopathy” responsible for the congenital Long QT Syndrome. Knowledge of this type will increment and include more and more diseases as we hurdle toward the 21st century and the practice of genetic-based medicine. A firm grasp of the electrophysiological basis of the principles for the normal and abnormal heartbeat will be required, and Basic Cardiac Electrophysiology for the Clinician provides this information. Their work is very much “all you need to know, as clinicians, about basic cardiac electrophysiology but were afraid to ask.” Each chapter has a similar format, beginning with an introduction and ending with a summary. I found that very helpful, and so should the clinician. Further, the figures avoid complexity and vividly make the points the authors seek to convey.

Chapter 1 deals with the bioelectricity of cardiac electrophysiology and discusses how the laws of electricity apply to movement of ions across cell membranes, using standard concepts about voltage, current, resistance, and capacitance. Basic concepts of action potentials and their differences in muscle, sinus and AV nodes, and Purkinje fibers help explain many of the clinical phenomena observed. There is a useful discussion on methodology to understand which currents flow through the various ion channels, such as use of voltage clamp method. Finally, the concept of rectification can be understood!

Chapter 2 introduces the various components responsible for the currents underlying cardiac excitation that are carried by ion channels, pumps or exchangers, and the differences between them. Gating and ion selectivity are discussed along with the various currents and the molecular structure of cardiac ion channels. The M and H gates, postulated by Hodgkin and Huxley, are explained in the light of the three confirmational states of closed, open and inactivated ion channels.

In Chapter 3 the authors present mechanisms of ion channel regulation, including enzyme systems, signaling pathways and autonomic regulation of ionic currents. Understanding control of ion channel regulation may provide insight into methods of therapeutic intervention when these systems go awry.

Chapter 4 offers a critical discussion of the concept of propagation of the cardiac impulse, explaining how the electrical signal spreads from cell to cell through the cardiac synctium to induce electrical activation of the entire heart. This chapter capitalizes on the basic information presented in the previous three chapters. A key concept, electrotonus, is clearly explained.

Intrinsic to the heartbeat is the concept of pacemaker activity, with the sinus node as the obvious prototypic example. Chapter 5 considers in-depth sinus node function, the synchronization of all of the sinus node cells to discharge in unison, phase response curves and entrainment and resetting, along with vagal modulation of sinus node activity. Many of these concepts are then applied to parasystolic foci and electrotonic modulation.

Chapter 6 focuses on rate dependent modulation of discontinuous action potential propagation, a concept underlying complex patterns of propagation such as Wenckebach and development of arrhythmias such as fibrillation. Most investigators are unaware that propagation, when viewed microscopically, is actually step wise as electrotonic currents propagate from cell to cell. Macroscopically, the action potential appears to travel uniformly and continuously. Differences in cell geometry and ionic currents, as well as nonuniform distribution of gap junctions connecting neighboring myocytes, contribute to non-uniform discontinuous propagation.

Chapter 7 is “bread and butter” for any clinical electrophysiologist and discusses clearly and at length the cellular mechanisms underlying the basic for cardiac arrhythmias. Thus, abnormal impulse formation, including normal and abnormal automaticity and triggered activity, along with alterations in conduction of the cardiac impulse that provide the basis for reentry, underlie all the therapeutic interventions used to treat patients with arrhythmias.

Chapter 8 extends these concepts by focusing in on spiral wave activity, which may be the basis for functional reentry. This chapter, to me, emphasizes a major aspect of the contributions from the Syracuse group of electrophysiologists: their insights into mechanisms of cardiac electrophysiology are rooted in “biological laws of nature,” from phase response curves and resetting of parasystolic foci to spiral wave activity. One can only do this if the investigators have a clear understanding of the fundamental electrical phenomena responsible for the genesis of the heartbeat. Jalife and his group clearly demonstrate this breathtaking expanse of knowledge and it comes through vividly to the reader in chapter after chapter. This book is an exciting contribution for anyone interested in cardiac electrophysiology.

Douglas P. Zipes, MD

Distinguished Professor of Medicine, Pharmacology and Toxicology

Director, Division of Cardiology and Krannert Institute of Cardiology

Indiana University School of Medicine

Foreword to the Second Edition

A popular series of books includes the words for dummies in the title, to indicate the information contained has been modified so that readers—certainly not dummies, just less knowledgeable about the topic—can more easily understand the subject matter presented. In fact, writing such a book requires the authors to have an even greater grasp of the material than other experts in the field because they must be able to explain complex concepts in ways the uninitiated can understand. This is accomplished by eliminating jargon and superfluous information characteristic of usual scientific writing, and explaining the “taken for granted” information in detail, i.e., focusing on the core of the topic for the less sophisticated student. Judging by the enormous success of the series, the concept is effective. In fact, Dr. Jalife and his colleagues wrote such a book about basic cardiac electrophysiology 10 years ago and have now updated and richly illustrated it with the wealth of new information attained in the last decade. As they indicate in the Introduction, the book is for all types of students of the heart—medical students, residents, fellows, postdocs, and faculty, whether basic or clinical—to educate and interest them in understanding cardiac electrophysiology and arrhythmias. It goes without saying that the basic scientist early in his or her career would be interested in such a book: I wish I had one when I started 40 years ago. But what needs to be said is that the clinician should be interested in this topic as well because acquiring this knowledge, even in its rudimentary form, will enable him or her to be more effective in critically evaluating published literature, understanding the basis of various clinical syndromes and arrhythmias, and, in the end, making more intelligent diagnostic and therapeutic decisions. From a personal perspective, I think I have been a better clinician because of my understanding of basic cardiac electrophysiology, knowledge “from cell to bedside.” In the final analysis, the goal of virtually every medical scientist and physician is to provide better care for patients. This book brings the doctor closer to achieving that end and I recommend it to every student of the heart.

Douglas P. Zipes, MD

Distinguished Professor of Medicine, Pharmacology and Toxicology

Director, Division of Cardiology and Krannert Institute of Cardiology

Indiana University School of Medicine

Introduction

The genesis of the heartbeat is a biological process that depends on electrical phenomena that are intrinsic to the heart itself. The study of the fundamental basis of such phenomena is essential to cardiology, not only because it serves as the source from which current knowledge in clinical cardiac electrophysiology (EP) is based but, most importantly, because electrical diseases of the heart are a major health problem in society and clinical practice. In this regard, the rate of increase in our knowledge of cardiac EP has accelerated dramatically over the past 40 years. A wide variety of basic mechanisms is already well described in the experimental laboratory. Furthermore, the field has been enriched by concepts derived from other disciplines, including genetics, molecular biology, cell biology, biochemistry, biophysics, and computer modeling. Yet although several tools have been developed for the identification of the cellular mechanisms of clinical arrhythmias (mapping systems, pharmacologic agents, pacing, etc.), the understanding of the mechanisms and the appropriate treatment of such arrhythmias continue to be very difficult tasks. Nevertheless, many patients benefit annually from the use of devices or other advanced treatments aimed at diagnosis and therapy of electric diseases, and many of such advances can be traced directly to research in the basic EP laboratory.

Future progress may depend on enhanced understanding of the fundamental mechanisms underlying the heart’s electrical behavior and on improved methods for detection of bioelectric phenomena and mathematical approaches to analyze more accurately the complex nonlinear processes underlying normal and abnormal cardiac rhythms. Thus, a precise quantitative understanding of electrical diseases is a major challenge faced by both basic scientists and clinicians. Achieving that understanding should have significant health benefits and should be greatly accelerated by multidisciplinary approaches that bring clinical and basic investigators to work together on such a common goal. Then basic cardiac EP will play a major role in the future of clinical EP, including applications to diagnosis and therapy.

The original idea for the first edition of this book, published in 1998, materialized many years ago as a result of many informal but enlightening conversations with our dear friend and colleague, Dr. Winston Gaum, now at the University of Rochester, when he was Chief of Pediatric Cardiology at the SUNY Upstate Medical University in Syracuse, NY. This led to a series of lectures given by the authors in the 1990s to pediatric and adult cardiology residents, fellows, and faculty members at SUNY Upstate. The course, entitled “Basic Cardiac Electrophysiology for Clinical Fellows,” was designed as a review of fundamental principles of EP and cellular mechanisms of arrhythmias, with the goal of refreshing our students’ memories about long forgotten academic material seen during the first and second years of medical school. In addition, we had a hidden, more selfish agenda in mind. First, we wished to demonstrate to those students that such basic principles were not useless esoteric “stuff” in which only basic scientists were interested but in fact represented a solid basis for the rational management of their patients in their daily clinical practice. Second, and more important for us, we wished to spread the virus of our enthusiasm for basic cardiac EP and biophysics among those students and to entice at least a few of them to spend some time working in the basic EP laboratory. Fortunately, we succeeded on both counts. In fact, shortly after the course started, our students began to make the connection between the newly refreshed basic concepts and their knowledge of clinical electrocardiography and EP. Henceforth, the course became a series of scholarly and interesting discussions between basic scientists and clinicians. Most importantly, our success in infecting our students with the enthusiasm-forbasic-EP virus became clearly apparent shortly after completion of the course, when our clinical faculty began to encourage their fellows in cardiology and pediatric cardiology to spend 6 months to 1 year working on basic research projects under the supervision of one of us. This led to a steady flow of fellows through our laboratories, which continues to this date and is likely to continue for years to come.

This second edition of Basic Cardiac Electrophysiology for the Clinician represents a significant enhancement over the first edition. Outdated material has been omitted and previously existing chapters have been updated and carefully revised for errors (we thank Prof. Ketaro Hashimoto and his students for kindly pointing out some of those errors to us). In addition, three completely new chapters (Chapters 8–10) have been added.

In Chapter 1, we discuss some of the basic principles for applying concepts of basic electricity to the movement of ions across cell membranes. We start with the concept that the transmembrane flow of ions leads to electric currents and the displacement of charges across the cell membrane capacitor establishes the membrane potential. We review also some fundamental principles that determine the electric properties of the cell at rest and during activation, as well as the technology and concepts that have made it possible to unravel the ionic basis of the cardiac action potential. In the chapters that follow, we make repeated use of those concepts when discussing the properties of various membrane currents and the propagation of currents along tissues in the normal as well as the diseased heart.

In Chapter 2, we review the fundamental properties of ion channels, which, together with other protein macromolecules that include pumps and exchangers, act as “molecular machines” for the various ion translocation mechanisms across the cardiac cell membranes and that underlie cardiac excitation. A wide variety of ion channels are involved in the cardiac excitation process. These channels can be characterized by their gating mechanisms, e.g., voltage or ligand, as well as by their ion selectivity. Clearly, the determination of the molecular architecture of ion channels and the determination of structural correlates of ion channel key functions of gating and selectivity are important questions. A combination of tools of molecular and structural biology and of electrophysiology is providing important insight into ion channel function at the molecular level, and a fascinating picture is beginning to emerge. The studies implicate elements of the sequence of the ion channel protein in the two fundamental tasks of gating and ion selectivity.

Chapter 3 reviews current knowledge about how ionic currents in heart cells are regulated by several agents under physiological and pathophysiological conditions. Each regulatory agent, such as a neurotransmitter or a hormone, acts on a specific membrane receptor to affect the biophysical characteristics of several membrane currents in cardiac cells. Ion channel function is also dependent on the amount of the channel protein on the cell membrane. Overall, these changes in ion channel function will, in turn, affect the electrophysiological properties of the heart cell, with an ultimate effect on cardiac function.

In Chapter 4, we move from the ion channel and the cell to the study of intercellular communication by focusing on the role of electrical coupling on pacemaker synchronization and impulse propagation in the heart. We introduce the reader to basic concepts of electrotonic propagation and local circuit currents and their role in ensuring sinus pacemaker synchronization for the generation of the cardiac impulse as well as for successful impulse conduction. Based on those principles, the chapter discusses the concepts of phase resetting and mutual entrainment as well as the manner in which thousands of pacemaker cells in the sinus node synchronize to initiate together each cardiac impulse. In addition, the text brings attention to the fact that, although the unidimensional cable equations provide a good analytical tool to characterize the various electric elements involved in the propagation process, the heart is a highly complex 3-D structure, and its behavior commonly departs from that predicted by simple cable models. In this regard, some of the possible mechanisms by which active propagation may fail are discussed. The concept of wave front curvature, with its potential to lead to conduction slowing, the property of anisotropic propagation and the case of propagation across the Purkinje-muscle junction, as well as the presence of heterocellular interactions between myocytes and non-myocyte cells, all serve to illustrate the fact that cardiac impulse transmission does depart from simple unidimensional models.

The focus of Chapter 5 is the pathophysiology of cardiac impulse propagation, particularly in regard to the rate dependency of discontinuous action potential propagation in one-, two- and three-dimensional cardiac muscle. The chapter also discusses the dynamics and ionic mechanisms of complex patterns of propagation, such as Wenckebach periodicity and fibrillatory conduction, which provides a framework for understanding cellular and tissue behavior during high-frequency excitation and arrhythmias. Given the structural complexities of the various cardiac tissues and the complex nonlinear dynamics of cardiac cell excitation, it seems reasonable to expect that any event leading to very rapid activation of atria or ventricles may result in exceedingly complex rhythms, including fibrillation.

Chapter 6 deals with the cellular mechanisms of arrhythmias with emphasis placed on those aspects that may be relevant to the analysis of ECG manifestations. We review in detail well-established arrhythmia mechanisms and provide some insight into the appropriate tools to diagnose an arrhythmia in the clinical setting, which should reflect in our ability to provide a more rational therapeutic approach. The current focus on the development of new 3-D mapping techniques as well as the long-term recording of spontaneously occurring rhythm disturbances most likely will broaden our knowledge and offer new clues for diagnosing and managing cardiac arrhythmias.

In Chapter 7, we introduce the concept of rotors and spiral waves as a mechanism of the most complex arrhythmias. Some of the clinical manifestations of these arrhythmias are poorly explained by more conventional electrophysiological models of reentry. The theory of spiral waves, on the other hand, offers a new approach for the study of arrhythmias. Spontaneously occurring complex patterns of activation, as well as various dynamics resulting from external stimulation, are clearly predicted by theoretical and experimental studies on spiral waves. In addition, this approach offers new clues for the understanding of reentrant processes occurring in the complex three-dimensionality of the heart.

In Chapter 8, we present a brief review of contemporary ideas on atrial fibrillation (AF) mechanisms, from the bench to the bedside. We explore how studies in the isolated sheep heart enhance our understanding of AF dynamics and mechanisms by showing that high-frequency reentrant sources in the left atrium can drive the fibrillatory activity throughout both atria. Following those results and based on a large body of work investigating how measurements of AF cycle length in patients can contribute to its treatment, we focus our analysis on the organization of dominant frequency (DF) of the activity during AF in humans. We also emphasize how AF sources may be identified in human patients undergoing radio frequency ablation by the use of electroanatomic mapping and Fourier methods to generate 3-D, whole-atrial DF maps. In patients with paroxysmal AF, those sites are often localized to the posterior left atrium near the ostia of the pulmonary veins (PVs). We also contrast patients with paroxysmal vs. permanent AF by demonstrating that in the latter, high DF sites are more often localized to either atria than the posterior left atrium–PV junction. Finally, we review evidence showing how the response of the local AF frequency to adenosine tested for the mechanistic hypothesis that reentry is the mechanism that maintains human AF.

Chapter 9 reviews the most significant work demonstrating that the molecular mechanism of wave propagation dynamics during VF in the structurally and electrophysiologically normal heart may be explained in part on the basis of chamber-specific differences in the level of expression of cardiac potassium channels, particularly the inward-rectifier potassium channels responsible for IK1. In addition, we review some recent experiments in 2-D rat cardiomyocyte monolayers strongly suggesting that the slow component of the delayedrectifier current, IKs, plays an important role in the mechanism of fibrillatory conduction. We also summarize recent exciting data demonstrating that the inter-beat interval of VF scales according to a universal allometric scaling law, spanning over four orders of magnitude in body mass, from mouse to horse. Overall, a clearer picture of VF dynamics and its molecular mechanisms is emerging that might eventually lead to more effective prevention of sudden cardiac death.

Chapter 10 briefly addresses clinical manifestations, genetic bases, and cellular mechanisms of arrhythmias seen in some heritable arrhythmogenic diseases. Arguably, the intense amount of scrutiny given to these relatively rare diseases over the past 20 years has led to an explosion of new knowledge about the molecular and ionic bases of normal cardiac excitation and propagation. However, recent work has led to the conclusion that identifying a mutation in a given gene need not establish the diagnosis of a single disease and that discovering a mutation in an individual with a known disease is not enough to predict the phenotype of that individual. Therefore, important challenges remain in the understanding of the relationship between genetic defects and their clinical consequences. Nevertheless, we introduce the reader to original studies on the functional consequences of specific protein mutations in systems that approximate the physiological environment of these proteins which have been useful not only in the characterization of individual mutations, but also in the elucidation of the events underlying the initiation and maintenance of the arrhythmias in question.

In each chapter, the reader will find that most items of discussion in the text are accompanied by a substantial amount of graphic material, including simplified diagrams, color figures, and graphs, as well as schematic representations and cartoons. Whenever possible, we have intentionally avoided using original data, and, in most cases, individual concepts are explained in the simplest possible terms. Moreover, in general, we give no specific citations to original papers; rather, in the last few pages of the book, we provide a bibliography, where original articles, reviews, chapters, and monographs are presented to aid the reader interested in gaining a more in-depth knowledge of the subject matter. We are fully aware that our approach sacrifices detail and that some of our learned colleagues and critics may find such an approach offensive; we apologize for that. Yet we feel that, because our goal as educators is to spread the “gospel” of basic EP among clinicians, we needed to be didactic rather than absolutely precise.

Ten years have passed since the first edition was published and the authors of this book have moved to a new research environment with new students, fellows, and staff. Yet the same philosophy and excitement for basic and translational EP continues to drive our daily work. It is with that same excitement that we continue to teach basic cardiac electrophysiology at the University of Michigan. Thus, we have written the second edition of Basic CardiacElectrophysiology for the Clinician with one major objective in mind: to give our graduate students, postdocs, and clinical EP fellows as well as clinicians everywhere a broad general outline of modern knowledge in cardiac EP from the point of view of the basic scientist. It is our hope that this edition will have a similar effect as the previous one and as that described for students who have attended our lectures. We also hope that this book will contribute somewhat to reducing the ever-expanding intellectual gap between basic and clinical electrophysiologists. Hence, the book is not written as a scholarly text and is not directed to the technically expert basic researcher. In fact, because our primary goal is to reach as broad an audience as possible, we have again written each chapter as if it were the script for one of our lectures to graduate students, postdocs, and clinical fellows.