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CONTRIBUTORS
MICHAEL J. ACKERMAN, MD, PHD
Assistant Professor of Medicine, Pediatrics, and Molecular
Pharmacology, Mayo Medical School; Director, Long QT
Syndrome Clinic and Sudden Death Genomics
Laboratory, Mayo Clinic, Rochester, Minnesota
lntracellular Signaling and Regulation of Cardiac Ion
Channels
FELIPE AGUEL
Research Fellow, Department of Biomedical Engmeering,
Johns Hopkins University School of Medicine,
Baltimore, Maryland
Modeling Cardiac Defibrillation; Rotors and Spiral
Waves in Two Dimensions
CESAR ALBERTE-LISTA, MD
Assistant Professor of Medicine, University of Wisconsin;
Director
of Electrophysiology Laboratory, W. S.
Middleton Veterans Affairs Hospital; Staff Physician,
Division of Cardiology, University of Wisconsin Hospital
and Clinics, Madison, Wisconsin
Differential Diagnosis of Wide QRS Complex
Tachycardia
MATTHIAS ANT2
11. Medizinische Abteilung, Allgemeines Krankenhaus
St. Georg, Hamburg, Germany
Catheter Ablation of Atrioventricular Reentry
CHARLES ANTLELEVITCH, PHD
Executive Director/Director of Research, Gordon K.
Moe Scholar, Masonic Medical Research Laboratory,
Utica, New York
Drug-induced Channelopathies; The Brugada
Syndrome
JUSTUS M. B. ANUMONWO, PHD
Assistant Professor, Department of Pharmacology, SUNY
Upstate Medical University, Syracuse, New York
Biophysical Properties of Inward Rectifier Potassium
Channels
RlSHl ARORA, MD
Assistant Professor of Medicine, Northwestern
University School of Medicine, Northwestern Memorial
Hospital, Northwestern Medical Faculty Foundation,
Chicago, Illinois
Differential Diagnosis of Wide QRS Complex
Tachycardia
PETER H. BACKX, DVM, PHD
Professor of Physiology and Medicine, Faculty of
Medicine, University
of Toronto;
Senior Scientist, Division of Molecular and Cellular
Medicine, University Health Network, Toronto, Ontario,
Canada
Voltage Regulated Potassium Channels
JEFFREY R. BALSER, MD, PHD
Chairman, Department of Anesthesiology, Professor of
Anesthesiology and Pharmacology, Vanderbilt University
School of Medicine, Nashville, Tennessee
Biophysics of Normal and Abnormal Cardiac Sodium
Channel Function
KAREN BECKMAN, MD
Professor, Department of Medicine, Cardiovascular
Section, The University of Oklahoma Health Sciences
Center, Oklahoma City, Oklahoma
Electrophysiologic Characteristics of Atrioventricular
Nodal Reentrant Tachycardia: Implications for the
Reentrant Circuits
DAVID G. BENDITT, MD, FACC, FRCP(C)
Professor of Medicine, Co-Director, Cardiac Arrhythmia
Center, Cardiovascular Division, Department of Medicine,
University of Minnesota, Minneapolis, Minnesota
Head-up Tilt Table Testing
EDWARD J. BERBARI, PHD
Professor of Biomedical Engineering and Medicine,
Indiana University, Purdue University, Indianapolis,
Indianapolis, Indiana
High-resolution Electrocardiography
OMER BERENFELD, PHD
Research Assistant Professor, Institute for Cardiovascular
Research, Department
of Pharmacology, SUNY Upstate
Medical University, Syracuse, New York
Theory of Reentry; Mechanisms of Maintenance of
Atrial Fibrillation
iii

iv Contributors
DONALD M. BERS, PHD
Professor and Chair, Department of Physiology, Loyola
University, Chicago, Stritch School
of Medicine,
Maywood, Illinois
Cardiac Calcium Channels
ERIC C. BEYER, MD, PHD
Professor, Department of Pediatrics, Chief, Section of
Pediatric Hematology/Oncology and Stem Cell
Transplantation, University
of Chicago, Chicago, Illinois
Homomeric and Heteromeric Gap Junctions
MARTIN BlEL
Department Pharmazie, Zentrum fiir Pharmaforschung,
Pharmakologe fiir Natunvissenschaftler, Ludwig-
Maximilians-Universitat, Miinchen, Germany
HCN Channels: From Genes to Function
NEIL E. BOWLES, PHD
Assistant Professor, Pediatrics (Cardiology), Baylor
University College of Medicine, Houston, Texas
Human Molecular Genetics and the Heart
MARK R. BOYETT, BSC, PHD
Professor of Physiology, School of Biomedical Sciences,
University
of Leeds, Leeds, United Kingdom
Cellular Mechanisms of Sinoatrial Activity
JosEP BRUGADA, MD, PHD
Associate Professor of Medicine, University of Barcelona;
Director
of the Arrhythmia Unit, Cardiovascular
Institute, Hospital Clinic, Barcelona, Spain
The Brugada Syndrome
PEDRO BRUGADA, MD, PHD
Professor of Cardiology, OLV Hospital, Aalst, Belgium
The Brugada Syndrome
RAMON BRUGADA, MD, FACC
Director, Molecular Genetics Program, Masonic Medical
Research Laboratory, Utica, New York
The Brugada Syndrome
NENAD BURSAC, PHD
Assistant Professor, Department of Biomedical
Engineering, Duke University, Durham, North Carolina
Rotors and Spiral Waves in Two Dimensions
ALFRED E. BUXTON, MD
Professor of Medicine, Brown University Medical
School; Director of Arrhythmia Services and Clinical
Electrophysiology Laboratory, Rhode Island and Miriam
Hospitals, Providence, Rhode Island
Results of Clinical Trials of Automatic External
Defibrillators and Implantable Cardioverter-
Defibrillators in Patients at Risk for Sudden Death
MICHAEL E. CAIN, MD
Tobias and Hortense Lewin Professor of Medicine,
Director, Cardiovascular Division, Washington
University School of Medicine; Director, Cardiovascular
Division, Barnes-Jewish Hospital, St. Louis, Missouri
Class 111 Antiarrhythmic Drugs: Amiodarone, Ibutilide,
and Sotalol
HUGH CALKINS, MD
Professor of Medicine, Johns Hopkins University School
of Medicine; Director
of the Arrhythmia Service and
Clinical Electrophysiology Laboratory, Johns Hopkins
Hospital, Baltimore, Maryland
Syncope
DAVID J. CALLANS, MD
Associate Professor, Division of Cardiovascular Medicine,
University
of Pennsylvania Health System, Philadelphia,
Pennsylvania
Sinus Rhythm Abnormalities; Ventricular Tachycardia
in Patients with Coronary Artery Disease
RICCARDO CAPPATO, MD
Director, Center of Clinical Arrhythmia and
Electrophysiology, Istituto Policlinico San Donato,
Milan, Italy
Catheter Ablation of Atrioventricular Reentry
SHEILA J. CARROLL, MD
Post-Doctoral Fellow, Pediatric Cardiology, College of
Physicians and Surgeons of Columbia University, New
York, New York
KCNQ I/KCNE I Macromolecular Signaling Complex:
Channel Microdomains and Human Disease
AGUSTIN CASTELLANOS, MD, FACC, FAHA
Professor of Medicine, Division of Cardiology,
University
of Miami School of Medicine; Director,
Clinical Electrophysiology, University of Miami/Jackson
Memorial Medical Center, Miami, Florida
Sudden Cardiac Death; Parasystole
LAN S. CHEN, MD
Associate Professor of Clinical Neurology, Keck School
of Medicine, University of Southern California; Director,
Clinical Neurophysiology Program, Childrens Hospital
Los Angeles, Los Angeles, California
Nerve Sprouting and Cardiac Arrhythmias
PENG-SHENG CHEN, MD
Pauline and Harold Price Chair in Cardiac
Electrophysiology Research, Division
of Cardiology,
Department of Medicine, Cedars-Sinai Medical Center;
Professor of Medicine, David Geffen School
of Medicine,
University
of California, Los Angeles, Los Angeles,
California
Nerve Sprouting and Cardiac Arrhythmias
SHIH-ANN CHEN, MD
Professor of Medicine, National Yang Ming University,
School of Medicine; Director of Cardiac
Electrophysiology Laboratory, Taipei Veterans General
Hospital, Taipei, Taiwan
Catheter Ablation of Atrial Tachycardia

Contributors v
XIONGWEN CHEN
Temple University School of Medicine, Philadelphia,
Pennsylvania
Pharmacology of L-Type and T-Type Channels in the
Heart
DAVID E. CLAPHAM, MD, PHD
Professor of Neurobiology, Aldo R. Castafieda Professor
of Cardiovascular Research, Harvard Medical School;
Investigator, Howard Hughes Medical Institute; Director
of Cardiovascular Research, Children’s Hospital Boston,
Boston, Massachusetts
lntracellular Signaling and Regulation of Cardiac Ion
Channels
JACQUES CLEMENTY, MD
Professor of Cardiology, University of Bordeaux 11,
HBpital Cardiologique du Haut-LCveque, Bordeaux-
Pessac, France
Catheter Ablation of Atrial Fibrillation: Triggers and
Substrate
HARRY J. CRIJNS, MD, PHD
Professor of Cardiology, University of Maastricht;
Professor and Chairman of the Department
of
Cardiology, University Hospital, Maastricht, The
Netherlands
Ventricular Tachycardia in Patients with Hypertrophy
and Heart Failure
EMILE G. DAOUD, MD
MidOhio Cardiology and Vascular Consultants, MidWest
Research Foundation, Riverside-Methodist Hospital,
Columbus, Ohio
Bundle Branch Reentry
MlTHlLESH K. DAS, MD, MRCP, FACC
Assistant Professor of Medicine, Krannert Institute of
Cardiology; Assistant Professor
of Clinical Medicine,
Roudebush VA Medical Hospital, Methodist Hospital,
University Medical Center, Wishard Hospital,
Indianapolis, Indiana
Differential Diagnosis of Wide QRS Complex
Tachycardia
MARIO DELMAR, MD, PHD
Professor of Pharmacology, SUNY Upstate Medical
University, Syracuse, New York
Molecular Organization and Regulation of the Cardiac
Gap Junction Channel Connexin43; Prospects for
Pharmacologic Targeting of Gap Junction Channels
DARIO DIFRANCESCO, PHD
Department of Biomolecular Sciences and Biotechnology,
Laboratory of Molecular Physiology and Neurobiology,
University
of Milano, Milano, Italy
Pacemaker Channels and Normal Automaticity
JOHN P. DIMARCO, MD, PHD
Professor of Medicine, Cardiovascular Division, Director,
Clinical Electrophysiology Laboratory, University
of
Virginia Health System School of Medicine,
Charlottesville, Virginia
Adenosine and Digoxin
HALINA DOBRZYNSKI, BSC, PHD
Research Fellow, University of Leeds, School of
Biomedical Sciences, Leeds, United Kingdom
Cellular Mechanisms of Sinoatrial Activity
HEATHER s. DUFFY, PHD
Research Associate, Department of Neuroscience,
Albert Einstein College of Medicine, Bronx, New York
Molecular Organization and Regulation of the
Cardiac Gap Junction Channel Connexin43; Prospects
for Pharmacologic Targeting of Gap Junction
Channels
IGOR R. EFIMOV, PHD
Associate Professor of Biomedical Engineering,
Physiology, and Biophysics, Case Western Reserve
University, Cleveland, Ohio
Mechanisms of AV Nodal Excitability and
Propagation
JOACHIM R. EHRLICH, MD
Department of Medicine, Division of Cardiology, J.W.
Goethe University, Frankfurt, Germany
Atrial Fibrillation
NABIL EL-SHERIF, MD
Cardiology Division, Department of Medicine, SUNY
Downstate Medical Center, Brooklyn, New York
Torsade de Pointes
KENNETH A. ELLENBOGEN, MD
Kontos Professor of Medicine, MCVNCU School of
Medicine; Director, Clinical Electrophysiology Laboratory,
Medical College of Virgha, Richmond, Virginia
Atrial Tachycardia
ANDREW E. EPSTEIN, MD, FACC, FAHA
Professor of Medicine, Division of Cardiovascular
Disease, University of Alabama
at Birmingham,
Birmingham, Alabama
Ventricular Fibrillation
CENGIZ ERMIS, MD
EP Fellow, University of Minnesota, Minneapolis,
Minnesota
Head-up Tilt Table Testing
SABINE ERNST, MD
Director of Magnetic Navigation, 11. Medizinische
Abteilung, St. Georg General Hospital, Hamburg,
Germany
Catheter Ablation of Atrioventricular Reentry
N. A. MARK ESTES 111, MD
Professor of Medicine, Tufts University School of
Medicine; Director
of Cardiac Arrythmia Service,

vi Contributors
Tufts-New England Medical Center, Boston,
Massachusetts
New Antiarrhythmic Drugs
VLADIMIR G. FAST, PHD
Associate Professor, Department of Biomedical
Engineering, University
of Alabama at Birmingham,
Birmingham, Alabama
Cellular Mechanisms of Defibrillation
VADlM V. FEDOROV, PHD
Senior Research Scientist, Laboratory of Heart
Electrophysiology, Institute of Experimental Cardiology,
Moscow, Russia
Cholinergic Atrial Fibrillation
GUY FONTAINE, MD, PHD
Research Director, Department of Rhythmology, Lnstitut
de Cardiologie, Hbpital de la Salpetriere, Paris, France
Ventricular Tachycardia in Arrhythmogenic Right
Ventricular Cardiomyopathies
SARA FORESTI, MD
Research Fellow, Electrophysiology, Department of
Cardiology, Policlinico S. Matteo IRCCS, Oklahoma
City, Oklahoma
Electrophysiologic Characteristics of Atrioventricular
Nodal Reentrant Tachycardia: Implications for the
Reentrant Circuits
PAUL FORNES, MD, PHD
Associate Professor of Forensic Sciences, Medical School
Cochin Port Royal, University of Paris
0; Associate
Professor
of Pathology, Department of Pathology,
Hbpital EuropCen Georges Pompidou, Paris, France
Ventricular Tachycardia in Arrhythmogenic Right
Ventricular Cardiomyopathies
ROBERT FRANK, MD
Director, Department of Rhythmology, Institut de
Cardiologie, Hbpital PitiC-SalpCtrikre, Paris, France
Ventricular Tachycardia in Arrhythmogenic Right
Ventricular Cardiomyopathies
MICHAEL R. FRANZ, MD, PHD, FACC
Professor of Medicine and Pharmacology, Department of
Cardiology, Georgetown University Medical Center;
Director of Electrophysiology, Department of
Cardiology/Medicine, Veteran Affairs Medical Center,
Washington, D.C.
Monophasic Action Potential Recording
JOSEPH M. GALVIN, MB, BCH, MRCPI,
FACC
Senior Lecturer in Medicine, Royal College of Surgeons
in Ireland; Consultant Cardiologist, Co-Director, Cardiac
Unit, James Connolly Memorial Hospital, Dublin, Ireland
Ventricular Tachycardia in Patients with Dilated
Cardiomyopathy
ALAN GARFINKEL, PHD
Professor of Medicine (Cardiology) and Physiological
Science, University of California, Los Angeles,
Los
Angeles, California
Nonlinear Dynamics of Excitation and Propagation in
Cardiac Muscle
ANNE M. GILLIS, MD
Professor of Medicine, University of Calgary; Medical
Director or Pacing and Electrophysiology, Calgary
Health Region, Calgary, Alberta, Canada
Class I Antiarrhythmic Drugs: Quinidine,
Procainamide, Disopyramide, Lidocaine, Mexiletine,
Flecainide, and Propafenone
MICHAEL R. GOLD, MD, PHD
Michael Assey Professor of Medicine; Chief of
Cardiology; Medical Director, Heart and Vascular
Center, Medical University of South Carolina,
Charleston, South Carolina
Newer Applications of Pacemakers
JEFFREY GOLDBERGER, MD
Associate Professor, Department of Cardiology, The
Feinberg School of Medicine, Northwestern University,
Chicago, Illinois
Impact of Nontraditional Antiarrhythmic Drugs on
Sudden Cardiac Death
RICHARD A. GRAY, PHD
Associate Professor, Department of Biomedical
Engmeering, University of Alabama
at Birmingham,
Birmingham, Alabama
Global Mechanisms of Defibrillation
WOLFRAM GRIMM, MD
Professor of Internal Medicine and Cardiology; Director
of the Electrophysiology Laboratory, Department of
Cardiology, Philipps University, Marburg, Germany
Accelerated ldioventricular Rhythm and Bidirectional
Ventricular Tachycardia
WILLIAM J. GROH, BS, MD, MPH
Associate Professor of Medicine, Indiana School
of Medicine, Indiana University; Associate Professor
of Medicine, Methodist Hospital, Cardiology
Department; Wishard Hospital, Cardiology Department;
VA Medical Center, Cardiology Department,
Indianapolis, Indiana
Arrhythmias in Patients with Neurologic Disorders
DAVID E. HAINES, MD
Director, Heart Rhythm Center, William Beaumont
Hospital, Royal Oak, Michigan
The Biophysics and Pathophysiology of Lesion
Formation during Radiofrequency Catheter Ablation
MICHEL HAYSSAGUERRE, MD
Professor of Cardiology, University of Bordeaux 11,
H8pital Cariologique du Haut-LCvZque, Bordeaux-
Pesssac, France

Contributors vii
Catheter Ablation of Atrial Fibrillation: Triggers and
Substrate
CARLOS HARO, BS
Research Assistant, Department of Biomedical
Engineering, Tulane University, New Orleans, Louisiana
Modeling Cardiac Defibrillation
DAVID L. HAYES, MD
Professor of Medicine, Mayo Medical School;
Consultant, Division
of Cardiovascular Diseases and
Internal Medicine, Mayo Clinic, Rochester, Minnesota
Implantable Pacemakers
VOLODYA HAYRAPETYAN, PHD
Research Associate, Krannert Institute of Cardiology,
Indiana University, Indianapolis, Indiana
Homomeric and Heteromeric Gap Junctions
JEAN-LOUIS HEBERT, MD, PHD
Assistant Professor, Faculty of Medicine, University of
Paris XI; Chief, Cardiac Catheterization Laboratory,
Department of Cardiovascular and Lung Physiology,
University Hospital of BicEtre, Le Kremlin-BicEtre,
Paris, France
Ventricular Tachycardia in Arrhythmogenic Right
Ventricular Cardiomyopathies
CRAIG S. HENRIQUEZ, PHD
W. H. Gardner Jr. Associate Professor of Biomedical
Engineering and Computer Science, Department
of
Biomedical Engineering, Duke University, Durham,
North Carolina
Three-dimensional Propagation in Mathematical
Models
STEFAN HERRMANN, PHD
Assistant, Institut fur Pharmakologie und Toxikologie,
Technical University Munchen, Munchen, Germany
HCN Channels: From Genes to Function
GERHARD HINDRICKS, MD
University Leipzig, Heart Center; Co-Director,
Department of Electrophysiology, Leipzig, Germany
MELEZE HOCINI, MD
Clinical and Research Associate, HSpital Cardiologique
du Haut-LCvEque, Bordeaux-Pessac, France
Catheter Ablation of Atrial Fibrillation: Triggers and
Substrate
Catheter Ablation of Atrial Flutter
FRANZ HOFMANN
Professor and Chair in Pharmacology, Institut fur
Pharmakologie und Toxikologie, Technical University
Munchen, Munchen, Germany
HCN Channels: From Genes to Function
STEFAN H. HOHNLOSER, MD, FACC, FESC
Professor of Medicine, Department of Medicine,
Division of Cardiology,
J. W. Goethe University,
Frankfurt, Germany
T-Wave Alternans
HARUO HONJO, MD
Associate Professor, Department of Humoral Regulation,
Research Institute of Environmental Medicine, Nagoya
University, Nagoya, Japan
Cellular Mechanisms of Sinoatrial Activity
STEVEN R. HOUSER, PHD, FAHA
Laura H. Carnell Professor of Physiology, Director,
Cardiovascular Research Center, Temple University
School of Medicine, Philadelphia, Pennsylvania
Pharmacology of L-Type and T-Type Channels in the
Heart
LARRY V. HRYSHKO, BSC, PHD
Associate Professor of Physiology, Institute of
Cardiovascular Sciences, St. Boniface Hospital Research
Centre, University
of Manitoba, Winnipeg, Manitoba,
Canada
Membrane Pumps and Exchangers
EDWARD w. HSU, PHD
Assistant Professor, Department of Biomedical
Engineering, Duke University, Durham, North Carolina
Three-dimensional Propagation in Mathematical
Models
JIAN HUANG, MD, PHD
Assistant Professor of Medicine, Department of
Medicine, University
of Alabama at Birmingham,
Birmingham, Alabama
Defibrillation Waveforms
JEAN-SEBASTIEN HULOT, MD
Fellow, Service de Pharmacologie, HSpital de la
Salpetriere, Paris, France
Ventricular Tachycardia in Arrhythmogenic Right
Ventricular Cardiomyopathies
GARY D. HUTCHINS, PHD
John W. Beeler Professor, Vice Chairman for Research,
Department of Radiology, Indiana University School
of
Medicine, Indianapolis, Indiana
Neurocardiac Imaging
RAYMOND E. IDEKER, MD, PHD
Professor of Cardiology, Department of Medicine,
University
of Alabama at Birmingham, Birmingham,
Alabama
Defibrillation Waveforms
ALBERT0 INTERIAN, JR, MD
Professor of Medicine, Associate Chief, Division of
Cardiology and Electrophysiology, University
of Miami
School of Medicine, Miami, Florida
Sudden Cardiac Death
SEI IWAI, MD
Assistant Professor of Medicine, Division of Cardiology,
New York Presbyterian Hospital, Cornell University
Medical Center, New York, New York
Ventricular Tachycardia in Patients with Structurally
Normal Hearts

viii Contributors
WARREN M. JACKMAN, MD
Professor of Medicine, George Lynn Cross Research
Professor, Director, Clinical Electrophysiology, Co-
Director, Cardiac Arrhythmia Research Institute,
University of Oklahoma Health Sciences Center,
Oklahoma City, Oklahoma
Electrophysiologic Characteristics of Atrioventricular
Nodal Reentrant Tachycardia: Implications
for the
Reentrant Circuits
PIERRE JAYS, MD
Research Associate, University of Bordeaux 11; Staff
Physician, HBpital Cardiologique du Haut-LCvtque,
Bordeaux-Pessac, France
Catheter Ablation of Atrial Fibrillation: Triggers and
Substrate
JOSE JALIFE, MD
Professor and Chair, Department of Pharmacology;
Professor of Medicine and Pediatrics, Director, Institute
for Cardiovascular Research,
SUNY Upstate Medical
University, Syracuse, New York
Dynamics and Molecular Mechanisms of Ventricular
Fibrillation
in Normal Hearts
CRAIG T. JANUARY, MD, PHD
Professor of Medicine and Physiology, University of
Wisconsin Hospital and Clinics, Madison, Wisconsin
Pharmacology of the Cardiac Sodium Channel
CHRISTOPHER R. JOHNSON, PHD
Director, School of Computing, Director, Scientific
Computing and Imaging Institute, Distinguished
Professor of Computer Science, University of Utah, Salt
Lake City, Utah
Three-dimensional Propagation in Mathematical
Models
MARK E. JOSEPHSON, MD
Chief, Cardiovascular Division, Herman Dana Professor
of Medicine, Harvard Medical School; Director,
Harvard-Thorndike Electrophysiology Institute and
Arrhythmia Service, Boston, Massachusetts
Ventricular Tachycardia in Patients with Coronary
Artery Disease
XAVIER JOUVEN, MD, PHD
Epidemiologist, University of Paris V; Cardiologist,
Electrophysiologist, HBpital EuropCen Georges
Pompidou, Paris, France
Ventricular Tachycardia in Arrhythmogenic Right
Ventricular Cardiomyopathies
ALAN H. KADISH, BA, MD
Chester and Deborah C. Cooley Professor of Medicine,
Feinberg School of Medicine, Northwestern University;
Senior Associate Chief, Division of Cardiology,
Department
of Medicine, Northwestern Memorial
Hospital, Chicago, Illinois
Impact of Nontraditional Antiarrhythmic Drugs on
Sudden Cardiac Death
JONATHAN M. KALMAN, MBBS, PHD, FACC
Professor of Medicine, Director of Cardiac
Electrophysiology, Royal Melbourne Hospital,
Melbourne, Australia
Catheter Ablation of Atrioventricular Nodal
Reentrant Tachycardia
TIMOTHY J. KAMP, MD, PHD
Associate Professor of Medicine and Physiology,
University of Wisconsin Medical School, Madison,
Wisconsin
Pharmacology of the Cardiac Sodium Channel
ROBERT s. KASS, PHD
David Hosack Professor of Pharmacology and Chairman,
Columbia University, College of Physicians and
Surgeons, New York, New York
KCNQ I/KCNE7 Macromolecular Signaling Complex:
Channel Microdomains and Human Disease
HAROLD L. KENNEDY, MD, MPH, FACC,
FESC
Professor, Department of Medicine, Division of
Cardiology, University of South Florida, Tampa, Florida;
Chief of Medicine, Chief
of Cardiology and
Cardiovascular Research, Bay Pines VA Medical Center,
St. Petersburg, Florida
Use of Long-term (Holter) Electrocardiographic
Recordings
RICHARD E. KERBER, MD
Professor of Medicine, University of Iowa Hospitals and
Clinics, University of Iowa College of Medicine; Staff
Physician, University of Iowa Hospitals and Clinics, Iowa
City, Iowa
Transthoracic Cardioversion and Defibrillation
ANANT KHOSITSETH, MD
Fellow, Pediatric Cardiology, Mayo Graduate School of
Medicine, Mayo Clinic, Rochester, Minnesota
lntracellular Signaling and Regulation of Cardiac Ion
Channels
MICHAEL J. KILBORN
Clinical Senior Lecturer, University of Sydney; Staff
Cardiologist, Royal Prince Alfred Hospital, New South
Wales, Australia
Electrocardiographic Manifestations of Supernormal
Conduction, Concealed Conduction, and Exit Block
ANDRE G. KLEBER, MD
Professor of Physiology, Department of Physiology,
University of Bern, Bern, Switzerland
Intercellular Communication and Impulse
Propagation
GEORGE J. KLEIN, MD
Head, Division of Cardiology, University of Western
Ontario, London, Ontario, Canada
The Use of Implantable Loop Recorders; Wolff-
Parkinson-White Syndrome

Contributors ix
BRADLEY P. KNIGHT, MD
Associate Professor of Medicine, Director of Cardiac
Electrophysiology, Center for Advanced Medicine,
University of Chicago, Chicago, Illinois
Atrioventricular Reentry and Variants
ITSUO KODAMA, MD
Professor, Department of Circulation, Research Institute
of Environmental Medicine, Nagoya University, Nagoya,
Japan
Cellular Mechanisms of Sinoatrial Activity
HANS KOTTKAMP, MD
Professor of Medicine, Department of Electrophysiology,
University of Leipzig Heart Center, Leipzig, Germany
Catheter Ablation of Atrial Flutter
ANDREW D. KRAHN, MD
Associate Professor, Division of Cardiology, University of
Western Ontario; Cardiologist, London Health Sciences
Centre, London, Ontario, Canada
The Use of Implantable Loop Recorders
JAN P. KUCERA, MD
Senior Research Assistant, Department of Physiology,
University of Bern, Bern, Switzerland
Cardiac Tissue Architecture Determines Velocity and
Safety of Propagation
KARL-HEINZ KUCK, MD
Chief Cardiologist, St. Georg General Hospital, I1 Med.
Abteilung, Kardiologie, Electrophysiologie, Hamburg,
Germany
Catheter Ablation of Atrioventricular Reentry
JOHN D. KUGLER, MD
Chief, Joint Division of Pediatric Cardiology, University
of Nebiaska College of MedicineKreighton University
School
of Medicine; D.B and Paula Varner Professor of
Pediatrics, University of Nebraska College of Medicine;
Director, Cardiology, Children’s Hospital, Omaha,
Nebraska
Catheter Ablation in Pediatric Patients
CHI-TAI Kuo, MD
Associate Professor in Medicine, Chang-Gung
University, Taoyuan, Taiwan; Professor in Cardiology,
Chief
of the First Cardiovasular Division, Department of
Medicine, Chang-Gung Memorial Hospital, Linkou,
Taiwan
Exercise-induced Cardiac Arrhythmias
JUNKO KUROKAWA, PHD
Associate Research Scientist, Department of
Pharmacology, College of Physicians and Surgeons of
Columbia University, New York, New York
KCNQ I/KCNEI Macromolecular Signaling Complex:
Channel Microdomains and Human Disease
MAX J. LAB, MD
Professor Emeritus and Senior Research Investigator,
Division of Medicine, National Heart and Lung Institute,
London, United lngdom
Mechanoelectric Transduction/Feedback Prevalence
and Pathophysiology
WEN-TER LAI, MD
Professor of Internal Medicine, Kaohsiung Medical
University; Chief, Cardiovascular Center, Chung
Ho
Memorial Hospital, Kaohsiung, Taiwan
Exercise-induced Cardiac Arrhythmias
CLAIRE LARSON, 6s
Research Assistant, Department of Biomedical
Engineering, Tulane University, New Orleans, Louisiana
Modeling Cardiac Defibrillation
KENNETH R. LAURITA, PHD
Assistant Professor of Medicine & Biomedical
Engineering, The Heart
& Vascular Research Center,
MetroHealth Campus
of Case Western Reserve
University, Cleveland, Ohio
Restitution, Repolarization, and Alternans as
Arrhythmogenic Substrates
RALPH LAZZARA, MD
Natalie 0. Warren Professor of Medicine, George Lynn
Cross Research Professor, University of Oklahoma
Health Sciences Center; Director, Cardiac Arrhythmia
Research Institute, Oklahoma City, Oklahoma
Electrophysiologic Characteristics of Atrioventricular
Nodal Reentrant Tachycardia: Implications for the
Reentrant Circuits
BRUCE B. LERMAN, MD
H. Altschul Master Professor of Medicine, Chief,
Division
of Cardiology, Director, Cardiac
Electrophysiology Laboratory, Cornell University
Medical Center,
New York Presbyterian Hospital, New
York, New York
Ventricular Tachycardia in Patients with Structurally
Normal Hearts
DEBORAH L. LERNER, MD
Instructor in Pediatrics, Division of Critical Care
Medicine, Washington University School of Medicine,
St. Louis, Missouri
Gap junction Distribution and Regulation in the Heart
SAMUEL LEVY, MD
Professor of Cardiology, University of Marseille, School
of Medicine; Chief of Division of Cardiology, HGpital
Nord, Marseille, France
Implantable Atrial Defibrillators for Atrial Fibrillation
RONALD A. LI, PHD
Assistant Professor of Medicine, Institute of Molecular
Cardiobiology, Johns Hopkins University School of
Medicine, Baltimore, Maryland
Sodium Channels

x Contributors
DAVID LIN, MD
Assistant Professor, University of Pennsylvania, Hospital
of the University
of Pennsylvania, Philadelphia,
Pennsylvania
Sinus Rhythm Abnormalities
DEBORAH LOCKWOOD, BM, BCH, MA
Assistant Professor of Medicine, Cardiovascular Division,
Oklahoma University Health Sciences Center, Oklahoma
City, Oklahoma
Electrophysiologic Characteristics of Atrioventricular
Nodal Reentrant Tachycardia: Implications for the
Reentrant Circuits
BARRY LONDON, MD, PHD
Director, Cardiovascular Institute; Chief, Division of
Cardiology, University of Pittsburgh, Cardiovascular
Institute, Pittsburgh, Pennsylvania
Mouse Models of Cardiac Arrhythmias
FEI Lu, MD, PHD
Assistant Professor of Medicine, University of Minnesota;
Director of Clinical Cardiac Electrophysiology
Laboratory, Fairview University Medical Center,
Minneapolis, Minnesota
Head-up Tilt Table Testing
ANDREAS LUDWIG, MD
Associate Professor, Institut fin- Pharmakologie und
Toxikologie, Technical University Miinchen, Miinchen,
Germany
HCN Channels: From Genes to Function
JONATHAN c. MAKIELSKI, MD
Senior Associate Chair for Research; Professor,
Department of Medicine and Physiology, University of
Wisconsin, Madison, Wisconsin
Pharmacology of the Cardiac Sodium Channel
MAREK MALIK, MD, PHD
Department of Cardiological Sciences, St. George’s
Hospital Medical School, London, United Kingdom
Heart Rate Variability and Baroreflex Sensitivity
EDUARDO MARBAN, MD, PHD
Professor of Medicine, Physiology, and Biomedical
Engineering, Chief of Cardiology, Johns Hopkins
Hospital, Johns Hopkins University, Baltimore, Maryland
Sodium Channels
FRANCIS E. MARCHLINSKI, MD
Professor of Medicine, University of Pennsylvania School of
Medicine; Director, Cardlac Electrophysiology, University
of Pennsylvania Health System, Philadelphia, Pennsylvania
Accelerated ldioventricular Rhythm and Bidirectional
Ventricular Tachycardia
VlAS MARKIDES, MB (HoNs), BS (HONS),
MRPC (UK)
Consultant Cardiologist, St. Mary’s and Royal Brompton
& Harefield NHS Tmsts, Waller Cardiac Department,
St. Mary’s Hospital, London, United Kingdom
Mapping
STEVEN M. MARKOWITZ, MD
Associate Professor of Clinical Medicine, Cornell
University Medical Center, New York Presbyterian
Hospital, New York, New York
Ventricular Tachycardia in Patients with Structurally
Normal Hearts
BARRY J. MARON, MD
Director, Hypertrophic Cardiomyopathy Center,
Minneapolis Heart Institute Foundation, Minneapolis,
Minnesota
Ventricular Arrhythmias in Hypertrophic
Cardiomyopathy
AGUSTiN D. MART~NEZ
Research Associate, Department of Pediatrics, University
of Chicago, Chicago, Illinois
Homomeric and Heteromeric Gap Junctions
MARK A. MCGUIRE, MB, BS, PHD, FRACP
Clinical Associate Professor of Medicine, University of
Sydney; Senior Staff Cardiologist, Director of Cardiac
Arrhythmia Service, Royal Prince Alfred Hospital, New
South Wales, Australia
Electrocardiographic Manifestations of Supernormal
Conduction, Concealed Conduction, and
Exit Block
GERHARD MEISSNER, PHD
Professor, Departments of Biochemistry and Biophysics
and Cell and Molecular Physiology, School of Medicine,
University of North Carolina, Chapel
Hill, North
Carolina
Sarcoplasmic Reticulum Ion Channels
WILLIAM M. MILES, MD
Voluntary Professor of Medicine, University of Miami
School
of Medicine, Miami, Florida; Consulting
Electrophysiologist, Southwest Florida Heart Group,
Fort Myers, Florida
Assessment of the Patient with a Cardiac Arrhythmia
JOHN M. MILLER, MD
Professor of Medicine; Director, Clinical Cardiac
Electrophysiology, Krannert Institute
of Cardiology,
Indianapolis, Indiana
Differential Diagnosis of Wide QRS Complex
Tachycardia
MICHAEL A. MILLER, PHD
Assistant Research Scientist, Division of Imaging Science,
Department of Radiology, Indiana University School of
Medicine, Indianapolis, Indiana
Neurocardiac Imaging
SUNEET MITTAL, MD
Assistant Professor of Medicine, Division of Cardiology,
New York Presbyterian Hospital, Cornell University
Medical Center, New York, New York

Contributors xi
Ventricular Tachycardia in Patients with Structurally
Normal Hearts
FEDERICO MOLEIRO, MD
Full Professor (Cardiology), Experimental Cardiology
Lab, Central University
of Venezuela, Caracas, Venezuela
Parasystole
SVEN MOOSMANG, MD
Assistant Professor/Postdoc, Institut fir Pharmakologie
und Toxikologie, Technical University Miinchen,
Miinchen, Germany
HCN Channels: From Genes to Function
FRED MORADY, MD
Professor of Medicine, McKay Professor of
Cardiovascular Diseases, University of Michigan;
Director, Clinical Electrophysiology Laboratory,
University of Michigan Health System, Ann Arbor,
Michigan
Atrioventricular Reentry and Variants
ALONSO P. MORENO, PHD
Associate Professor of Medicine, Krannert Institute of
Cardiology, Indiana University School
of Medicine,
Indianapolis, Indiana
Homomeric and Heteromeric Gap Junctions
ARTHUR J. MOSS, MD
Professor of Medicine (Cardiology), Director, Heart
Research Follow-up Program, University
of Rochester
School
of Medicine and Dentistry, Rochester, New York
Long QT Syndrome-Therapeutic Considerations
ROBERT J. MYERBURG, MD
Professor of Medicine and Physiology, Director, Division
of Cardiology, University of Miami School of Medicine
D-39; Chief, Cardiology Service, Jackson Memorial
Hospital, Miami, Florida
Sudden Cardiac Death; Parasystole
HlROSHl NAKAGAWA, MD, PHD
Associate Professor of Medicine Research, University of
Oklahoma Health Sciences Center, Cardiac Arrhythmia
Research Institute, Oklahoma City, Oklahoma
Electrophysiologic Characteristics of Atrioventricular
Nodal Reentrant Tachycardia: Implications for the
Reentrant Circuits
CARL0 NAPOLITANO, MD, PHD
Adjunct Professor, School of Cardiology, University of
Pavia; Research Coordinator, Molecular Cardiology
Laboratories, IRCCS Fondazione
S. Maugeri, Pavia, Italy
Genetics of Long QT, Brugada, and Other
Channelopathies; Catecholaminergic Polymorphic
Ventricular Tachycardia and Short-coupled Torsades
de Pointes
STANLEY NATTEL, BSc, MDCM
Professor of Medicine, Paul David Chair in
Cardiovascular Electrophysiology, University of
Montreal; Director, Research Center, Montreal Heart
Institute, Montreal, Quebec, Canada
Atrial Fibrillation
JEANNE M. NERBONNE, PHD
Professor, Department of Molecular Biology and
Pharmacology, Washington University School of
Medicine, St. Louis, Missouri
Heterogeneous Expression of Potassium Channels in
the Mammalian Myocardium
VLADlMlR P. NIKOLSKI, PHD
Researcher, Department of Biomedical Engneering,
Case Western Reserve University, Cleveland, Ohio
Mechanisms of AV Nodal Excitability and Propagation
JEFFREY E. OLGlN, MD
Associate Professor of Medicine, Chief, Cardiac
Electrophysiology Service, University of California, San
Francisco, San Francisco, California
Electrophysiology of the Pulmonary Veins:
Mechanisms
of Initiation of Atrial Fibrillation
HAKAN ORAL, MD
Assistant Professor, Internal Medicine, Director,
Arrhythmia Research, University
of Michigan, Ann
Arbor, Michigan
Junctional Rhythms and Junctional Tachycardia
KENICHIRO OTOMO, MD, PHD
The University of Oklahoma Health Sciences Center,
Oklahoma City, Oklahoma
Electrophysiologic Characteristics of Atrioventricular
Nodal Reentrant Tachycardia: Implications for the
Reentrant Circuits
GAVIN Y. OUDIT, MSC, MD
Clinician Investigator Program, Internal Medicine
Resident, Faculty of Medicine, Division of Cardiology,
University Health Network, Heart
& Stroke/hchard
Lewar Centre of Excellence, University of Toronto,
Toronto, Ontario, Canada
Voltage-regulated Potassium Channels
FEIFAN OUYANG, MD
11. Medizinische Abteilung, St. Georg General Hospital,
Hamburg, Germany
Catheter Ablation of Atrioventricular Reentry
PIERRE L. PAGE, MD
Professor of Surgery, UniversitC de MontrCal, Cardiac
Surgeon, H6pital du SacrC-Coeur de MontrCal, Quebec,
Canada
Surgery for Cardiac Arrhythmias
CARLO PAPPONE, MD, PHD
Professor of Cardiology, Director, Cardiac
Electrophysiology and Pacing Unit, Department of
Cardiology, University Vita-Salute, San Raffaele
University Hospital, Milan, Italy
Pulmonary Vein Isolation for Atrial Fibrillation

xii Contributors
EUGENE PATTERSON, PHD
Associate Professor, University of Oklahoma Health
Sciences Center, Oklahoma City, Oklahoma
Electrophysiologic Characteristics of Atrioventricular
Nodal Reentrant Tachycardia: Implications
for the
Reentrant Circuits
ARKADY M. PERTSOV, PHD
Professor, Department of Pharmacology, SUNY Upstate
Medical University, Syracuse, New York
Scroll Waves in Three Dimensions
NICHOLAS s. PETERS, MD
Professor of Cardiology, Head of Cardiac
Electrophysiology, Imperial College and St. Mary’s
Hospital, London, United Kingdom; Director of
Electrophysiology Research, American Cardiovascular
Research Institute, Atlanta, Georgia
Mapping
ROBERT W. PETERS, BA, MD
Professor of Medicine, University of Maryland School of
Medicine; Chief
of Cardiology, VA Medical Center,
Baltimore, Maryland
Newer Applications of Pacemakers
SlLVlA G. PRIORI, MD, PHD
Associate Professor of Cardiology, University of Pavia;
Director
of Molecular Cardiology, Salvatore Maugeri
Foundation, Pavia, Italy
Genetics of Long QT, Brugada, and Other
Channelopathies; Catecholaminergic Polymorphic
Ventricular Tachycardia and Short-coupled Torsades
de Pointes; Long QT Syndrome-Genotype-
Phenotype Considerations
CATHERINE PROST-SQUARCIONI, MD, PHD
Laboratoire d’Histologie et de ThCrapie GCnique, UFR
LConard de Vinci, HGpital Avicenne, Bobigny, France
Ventricular Tachycardia in Arrhythmogenic Right
Ventricular Cardiomyopathies
ERIC N. PRYSTOWSKY, MD
Consulting Professor of Medicine, Duke University
Medical Center, Durham, North Carolina; Director,
Clinical Electrophysiology Laboratory, St. Vincent
Hospital, Indianapolis, Indiana
Wolff-Parkinson-White Syndrome
BONNIE 6. PUNSKE, PHD
Research Assistant Professor of Medicine and
Bioenpneering, Nora Eccles Harrison Cardiovascular
Research and Training Institute (CVRTI), University of
Utah, Salt Lake City, Utah
Body Surface Potential Mapping
ZHlLlN QU, PHD
Assistant Professor of Medicine (Cardiology), David
Geffen School of Medicine
at University of California,
Los Angeles,
Los Angeles, California
Nonlinear Dynamics of Excitation and Propagation in
Cardiac Muscle
RAFAEL J. RAMIREZ, PHD
Department of Physiology, Heart & Stroke/Richard
Lewar Centre
of Excellence, University of Toronto,
Toronto, Ontario, Canada
Voltage-regulated Potassium Channels
[LARIA RIVOLTA, PHD
Department of Molecular Cardiology, Salvatore Maugeri
Foundation, Pavia, Italy
Genetics of Long QT, Brugada, and Other
Channelopathies
RICHARD 6. ROBINSON, PHD
Professor, Department of Pharmacology, Columbia
University, New York, New York
Molecular and Cellular Bases of p-Adrenergic and
a-Adrenergic Modulation
of Cardiac Rhythm
DAN M. RODEN, MD
Professor of Medicine and Pharmacology, Director,
Division
of Clinical Pharmacology, Vanderbilt University
School
of Medicine, Nashville, Tennessee
Pharmacogenomics of Cardiac Arrhythmias and
Impact
on Drug Therapy
STEPHAN ROHR, MD
Department of Physiology, University of Bern, Bern,
Switzerland
Cardiac Tissue Architecture Determines Velocity and
Safety
of Propagation
SALVATORE ROSANIO, MD, PHD, FACC
Associate Professor of Medicine, University of Texas
Medical Branch; Director of Electrophysiology Research,
Division of Cardiology, Department
of Internal
Medicine,
John Sealy Annex Hospital, Galveston, Texas
Pulmonary Vein Isolation for Atrial Fibrillation
MICHAEL R. ROSEN, MD
Gustavus A. Pfeiffer Professor of Pharmacology,
Professor
of Pediatrics, Director, Center for Molecular
Therapeutics, Columbia University, New York, New
York
Molecular and Cellular Bases of p-Adrenergic and
a-Adrenergic Modulation
of Cardiac Rhythm
DAVID S. ROSENBAUM, MD
Associate Professor of Medicine, Biomedical
Engneering, Developmental Biology, Physiology and
Biophysics, Director, Heart and Vascular Research
Center, Case Western Reserve University
, MetroHealth
Campus, Cleveland, Ohio
Restitution, Repolarization, and Alternans as
Arrhythmogenic Substrates
LEONID v. ROSENSHTRAUKH, DSC, PHD
Professor of Physiology, Director, Department of
Physiology, Director, Laboratory of Heart
Electrophysiology, Institute of Experimental Cardiology,
Moscow, Russia
Cholinergic Atrial Fibrillation

Contributors xiii
BRADLEY J. ROTH, PHD
Associate Professor, Department of Physics, Oakland
University, Rochester, Michigan
Two-dimensional Propagation in Cardiac Muscle
YORAM RUDY, PHD
The M. Frank and Margaret C. Rudy Professor of
Cardiac Bioelectricity, Director, Cardiac Bioelectricity
Research and Training Center, Professor
of Biomedical
Engineering, Physiology and Biophysics, and Medicine,
Case Western Reserve University, Cleveland, Ohio
Ionic Mechanisms of Cardiac Electrical Activity: A
Theoretical Approach
JEREMY N. RUSKIN, BS, PHD
Associate Professor of Medicine, Harvard Medical
School; Director, Cardiac Arrhythmia Service,
Massachusetts General Hospital, Boston, Massachusetts
Ventricular Tachycardia in Patients with Dilated
Cardiomyopathy
FREDERICK SACHS, PHD
U. B. Distinguished Professor of Biophysics, Center for
Single Molecule Biophysics, Department
of Physiology
and Biophysics,
SUNY, Buffalo, New York
Heart Mechanoelectric Transduction
JEFFREY E. SAFFITZ, MD, PHD
Paul E. Lacy and Ellen Lacy Professor of Pathology,
Department
of Pathology, Washington University School
of Medicine, St. Louis, Missouri
Gap Junction Distribution and Regulation in the
Heart
PRASHANTHAN SANDERS, MBBS (HONS),
PHD, FRACP
Clinical Associate and Postdoctoral Research Fellow,
Hbpital Cardiologique du Haut-LCvCque, Bordeaux-
Pessac, France
Catheter Ablation of Atrial Fibrillation: Triggers and
Substrate
MICHAEL c. SANGUINETTI, PHD
Professor, Department of Physiology, University of Utah,
Salt Lake City, Utah
Gating of Cardiac Delayed Rectifier K+ Channels
NADIR SAOUDI, MD
Professor of Cardiology, Chef de Service, Centre
Hospitalier Princesse Grace, PrincipautC de Monaco
Parasystole
BENJAMIN J. SCHERLAG, PHD
Professor of Medicine, Helen Webster Professor of
Cardiac Arrhythmias, George Lynn Cross Research
Professor, University
of Oklahoma Health Sciences
Center, Cardiac Arrhythmia Research Institute,
Oklahoma City, Oklahoma
Electrophysiologic Characteristics of Atrioventricular
Nodal Reentrant Tachycardia: Implications for the
Reentrant Circuits
PETER J. SCHWARTZ, MD
Chairman, Cattedra Di Cardiologia, University of Pavia;
Director, School for the Board in Cardiology; Chairman,
Blood, Lung, and Heart Department, Chief, Coronary
Care Unit, IRCCS Policlinico
S. Matteo, Pavia, Italy
Long QT Syndrome-Genotype-Phenotype
Considerations; Prolonged Repolarization and
Sudden Infant Death Syndrome
DAVID SCHWARTZMAN, MD
Associate Professor of Medicine, Atrial Arrhythmia
Center, Univesity of Pittsburgh, Pittsburgh, Pennsylvania
Atrioventricular Block and Atrioventricular
Dissociation
OLIVER R. SEGAL, MRCP
Cardiology Research Fellow, St. Mary’s Hospital and
Imperial College
of Medicine, London, United
Kingdom
Mapping
DIPEN C. SHAH, MD, DNB (CARD)
Assistant Professor, Service de Cardologie, Hbpital
Cantonal Universitaire de Geneve, Geneva, Switzerland
Catheter Ablation of Atrial Fibrillation: Triggers and
Substrate
OLEG F. SHARIFOV, MD, PHD
Fellow, Department of Biomedical Engineering,
University
of Alabama at Birmingham, Birmingham,
Alabama
Cholinergic Atrial Fibrillation
KALYANAM SHIVKUMAR, MD, PHD
Director, UCLA Cardiac Arrhythmia Center and
Electrophysiology Program, David Geffen School
of
Medicine at University of California, Los Angeles, Los
Angeles, California
Implantable Cardioverter-Defibrillator: Clinical
Aspects
JEFFREY SIMMONS, MD
Assistant Professor of Clinical Medicine, Veterans
Medical Center, Miami, Florida
Sudden Cardiac Death
BRAMAH N. SINGH, MD, PHD, FRCP
University of California, Los Angeles, Cardiology
Division, VA Medical Center West Los Angeles,
Los
Angeles, California
@-Blockers and Calcium Channel Blockers as
Antiarrhythrnic Drugs
ALLAN C. SKANES, MD
Director, Electrophysiology Laboratory, London Health
Sciences Center, London, Ontario, Canada
The Use of Implantable Loop Recorders
TIMOTHY W. SMITH, DPHIL, MD
Assistant Professor of Medicine, Washington University
School
of Medicine; Staff Electrophysiologist,

xiv Contributors
Barnes-Jewish Hospital, St. Louis, Missouri
Class 111 Antiarrhythmic Drugs: Amiodarone, Ibutilide,
and Sotalol
KYOKO SOEJIMA, MD
Instructor in Medicine, Harvard Medical School;
Cardiovascular Division, Brigham and Women’s
Hospital, Boston, Massachusetts
Catheter Ablation of Ventricular Tachycardia
PAUL 1. SORGEN, PHD
Assistant Professor, Department of Biochemistry and
Molecular Biology, University of Nebraska Medical
Center, Omaha, Nebraska
Molecular Organization and Regulation of the
Cardiac Gap Junction Channel Connexin43
DAVID C. SPRAY, PHD
Professor of Neuroscience and Medicine, Department of
Neuroscience, Albert Einstein College of Medicine,
Bronx, New York
Molecular Organization and Regulation of the
Cardiac Gap Junction Channel Connexin43; Prospects
for Pharmacologic Targeting of Gap Junction
Channels
MIDUTURU SRINIVAS, PHD
Instructor in Neuroscience, Department of
Neuroscience, Albert Einstein College of Medicine,
Bronx, New York
Prospects for Pharmacologic Targeting of Gap
Junction Channels
KENNETH M. STEIN, MD
Associate Professor of Medicine, Division of Cardiology,
New York Presbyterian Hospital, Cornell University
Medical Center, New York, New York
Ventricular Tachycardia in Patients with Structurally
Normal Hearts
SUSAN F. STEINBERG, MD
Associate Professor of Pharmacology, Columbia
University, New York, New York
Molecular and Cellular Bases of P-Adrenergic and
a-Adrenergic Modulation of Cardiac
Rhythm
WILLIAM G. STEVENSON, MD
Assistant Professor, Harvard Medical School; Director,
Clinical Cardiac Electrophysiology Program, Brigham
and Women’s Hospital, Boston, Massachusetts
Catheter Ablation of Ventricular Tachycardia
JULIANE STIEBER, MD
Assistant Professor, Institut fur Pharmakologie und
Toxikologie, Technical University Munchen, Munchen,
Germany
HCN Channels: From Genes to Function
MARC0 STRAMBA-BADIALE, MD, PHD
Head, Pediatric Arrhythmias Center, IRCCS, Istituto
Auxologico Italiano, Milan, Italy
Prolonged Repolarization and Sudden Infant Death
Syndrome
S. ADAM STRICKBERGER, MD
Director, Arrhythmia Research Program, Washington
Hospital Center, Washington, D.C.
Junctional Rhythms and Junctional Tachycardia
RUEY J. SUNG, MD
Professor of Medicine, National Cheng Kung University,
School
of Medicine, Tainan, Taiwan
Exercise-induced Cardiac Arrhythmias
MICHAEL 0. SWEENEY, MD
Cardiac Arrhythmia Service, Cardiovascular Division,
Brigham and Women’s Hospital, Boston, Massachusetts
Sinus Node Dysfunction
CHARLES D. SWERDLOW, MD
Clinical Professor of Medicine, University of California,
Los Angeles, Cedars Sinai Medical Center, Los Angeles,
California
Implantable Cardioverter-Defibrillator: Clinical
Aspects
BRUNO TACCARDI, MD, PHD
Research Professor of Internal Medicine, University of
Utah School
of Medicine, Co-Director, Nora Eccles
Harrison CVRTI, Salt Lake City, Utah
Body Surface Potential Mapping
STEVEN M. TAFFET, PHD
Professor, Department of Pharmacology, SUNY Upstate
Medical University, Syracuse, New York
Molecular Organization and Regulation of the
Cardiac Gap Junction Channel Connexin43
CHING-TAI TAI, MD
Professor of Medicine, National Yang-Ming University
School of Medicine; Attending Physician, Taipei Veterans
General Hospital, Taipei, Taiwan
Catheter Ablation of Atrial Tachycardia
DANIEL THOMAS, MD
Professor, Chu PitiC Salpetriere UniversitC Paris VI;
Professor, Institut de Cardiologie, H6pital de la
Salpetriere, Paris, France
Ventricular Tachycardia in Arrhythmogenic Right
Ventricular Cardiomyopathies
GORDON F. TOMASELLI, MD
Professor, Department of Medicine, Johns Hopkins
University, Baltimore, Maryland
Sodium Channels
FERNANDO TONDATO, MD, PHD
Cardiac Electrophysiology Fellow, American
Cardiovascular Research Institute, Norcross, Georgia
Mapping

Contributors xv
JEFFREY A. TOWBIN, MD
Professor, Departments of Pediatrics (Cardiology) and
Molecular and Human Genetics, Baylor College of
Medicine; Chief, Pediatric Cardiology, Foundation Chair
in Pediatric Cardiac Research, Texas Children’s Hospital,
Houston, Texas
Human Molecular Genetics and the Heart; The
Brugada Syndrome
JOSEPH V. TRANQUILLO
Graduate Student, Department of Biomedical
Engineering, Duke University, Durham, North Carolina
Three-dimensional Propagation in Mathematical
Models
NATALIA A. TRAYANOVA, PHD
Professor, Department of Biomedical Engineering,
Tulane University, New Orleans, Louisiana
Modeling Cardiac Defibrillation
JOHN K. TRIEDMAN, MD
Associate Professor of Pediatrics, Harvard Medical
School; Senior Associate in Cardiology, Children’s
Hospital, Boston, Massachusetts
Atrial Arrhythmias in Congenital Heart Disease
MARTIN TRISTANI-FIROUZI, MD
Associate Professor, Pediatric Cardiology, University of
Utah School of Medicine, Salt Lake City, Utah
Gating of Cardiac Delayed Rectifier K+ Channels
CHIN-FENG TSAI, MD
Assistant Professor of Medicine, Division of Cardiology,
Department of Medicine, Chung Shan Medical
University Hospital, Taichung, Taiwan; Krannert
Institute of Cardiology, Indianapolis, Indiana
Catheter Ablation of Atrial Tachycardia
LESLIE TUNG, PHD
Associate Professor, Department of Biomedical
Engineering, Johns Hopkins University, School
of
Medicine, Baltimore, Maryland
Rotors and Spiral Waves in Two Dimensions
GIOIA TURITTO, MD
Associate Professor of Medicine, Director, Coronary
Care Unit and Electrophysiology Laboratory,
SUNY
Downstate Medical Center, Brooklyn, New York
Torsade de Pointes
GEORGE F. VAN HARE, MD
Associate Professor; Director, Pediatric Arrythmia
Center, Pediatric Cardiology, Stanford University, Palo
Alto, California
Ventricular Tachycardia in Patients Following Surgery
for Congenital Heart Disease
DAVID R. VAN WAGONER, BS, PHD
Associate Professor, Department of Molecular Medicine,
Cleveland Clinic Lerner College of Medicine
of Case
Western Reserve University; Associate Staff, Department
of Cardiovascular Medicine, Cleveland Clinic
Foundation, Cleveland, Ohio
Electrical Remodeling and Chronic Atrial Fibrillation
MARC A. VOS, PHD
Department of Medical Physiology, UMC Utrecht,
Utrecht, The Netherlands
Ventricular Tachycardia in Patients with Hypertrophy
and Heart Failure
GREGORY P. WALCOTT, MD
Assistant Professor of Cardiology, Department of
Medicine, University
of Alabama at Birmingham,
Birmingham, Alabama
Defibrillation Waveforms
ALBERT L. WALDO, MD
The Walter H. Pritchard Professor of Cardiology,
Professor of Medicine, and Professor of Biomedical
Engineering, Director, Clinical Cardiac
Electrophysiology Program, Case Western Reserve
University School
of Medicine, University Hospitals of
Cleveland, Cleveland, Ohio
Atrial Flutter: Mechanisms, Clinical Features, and
Management
ZULU WANG, MD
The University of Oklahoma Health Sciences Center,
Oklahoma City, Oklahoma
Electrophysiologic Characteristics of Atrioventricular
Nodal Reentrant Tachycardia: Implications for the
Reentrant Circuits
KENNETH M. WEINBERG, MD
Electrophysiology Fellow, The Feinberg School of
Medicine, Northwestern University, Chicago, Illinois
Impact of Nontraditional Antiarrhythmic Drugs on
Sudden Cardiac Death
DAVID WEINSTEIN, PHD
Technical Manager, Department of Computer Science,
Scientific and Computing Institute, University of Utah,
Salt Lake City, Utah
Three-dimensional Propagation in Mathematical
Models
MARCEL WELLNER, MD
Senior Research Scientist, Institute for Cardiovascular
Research,
SUNY Upstate Medical University, Syracuse,
New York
Theory of Reentry
BRUCE L. WILKOFF, MD
Director of Cardiac Pacing and Tachyarrhythmia
Devices, Professor
of Medicine, Cleveland Clinic Lerner
College
of Medicine, The Cleveland Clinic Foundation,
Cleveland, Ohio
implantable Cardioverter-Defibrillator: Technical
Aspects

xvi Contributors
MARK A. WOOD, MD
Associate Professor, Internal Medicine/Cardiology,
Medical College
of Virginia, Richmond, Virginia
Atrial Tachycardia
JIANYI Wu, MD
Assistant Scientist, Krannert Institute of Cardiology,
Indiana University, Indianapolis, Indiana
Mechanisms of Initiation of Ventricular
Tachyarrhythmias; Differential Diagnosis
of Wide QRS
Complex Tachycardia
JlASHlN WU, PHD
Assistant Professor Krannert Institute of Cardiology,
Indianapolis, Indiana
Mechanisms of Initiation of Ventricular
Tachyarrhythmias
D. GEORGE WYSE, MD, PHD
Professor, Faculty of Medicine, University of Calgary;
Cardiac Electrophysiologist, Calgary Health Regonhe
Libin Cardiovascular Institute
of Alberta, Calgary,
Alberta, Canada
Results of Clinical Trials on Atrial Fibrillation
KATHRYN A. YAMADA, PHD
Research Associate Professor of Medicine, Washington
University School of Medicine, St. Louis, Missouri
Gap Junction Distribution and Regulation in the
Heart
BIN YE, PHD
Department of Medicine, University of Wisconsin
School of Medicine, Madison, Wisconsin
Pharmacology of the Cardiac Sodium Channel
RAYMOND YEE, BMDSC, MD, FRCPC,
FACC
Professor of Medicine, University of Western Ontario;
Director of Arrhythmia Service, London Health Sciences
Center-University Campus, London, Ontario, Canada
The Use of Implantable Loop Recorders; Wolff-
Parkinson-White Syndrome
ALEXEY V. ZAITSEV, PHD
Research Assistant Professor, Department of
Pharmacology,
STJNY Upstate Medical University,
Syracuse, New York
Mechanisms of Ischemic Ventricular Fibrillation:
Who's the Killer?
WOJCIECH ZAREBA, MD, PHD
Associate Professor of Medicine (Cardiology), Associate
Director, Heart Research Follow-up Program, University
of Rochester School
of Medicine and Dentistry,
Rochester, New York
Long QT Syndrome-Therapeutic Considerations
GUOQIANG ZHONG, MD
Post-doctoral Fellow, Krannert Institute of Cardiology,
Indiana University, Indianapolis, Indiana
Homomeric and Heteromeric Gap Junctions
DOUGLAS P. ZiPES, MD
Distinguished Professor, Krannert Institute of
Cardiology, Indiana University School of Medicine,
Indianapolis, Indiana
Mechanisms of Initiation of Ventricular
Tachyarrhythmias; Assessment
of the Patient with a
Cardiac Arrhythmia; Neurocardiac Imaging

PREFACE
otally revised for its fourth edition, Cardiac Electro-
T physiology: From Cell to Bedside remains a cornerstone
repository
of accurate, reliable, and current cardiac elec-
trophysiology information for the bench scientist, the
academic and practicing electrophysiologist, and the cardi-
ologist interested in electrophysiology. The book includes
authors who have literally and figuratively written the
chapters in their various areas
of expertise. As such, the
book continues to live up to its subtitle of “From Cell to
Bedside” by combining information from both disciplines
between its covers. This edition maintains the tradition
established by the preceding editions of being the com-
plete reference work in the field. The first
51 chapters
cover the basic science
of cardiac electrophysiology, while
the next
69 chapters address clinical topics. Throughout
the text, the reader will have access to the latest updates
and information from
the world’s leading experts.
Examples of new basic science chapters include those
addressing the molecular and structural bases of
HCN,
stretch-activated and inward rectifier channels. In addition,
a new chapter on contraction-excitation feedback provides
the latest information on the manner in which mechanical
activity of the heart modulates electrical function.
A chapter
on nerve sprouting and arrhythmias addresses the inter-
esting problem
of how neural remodeling resulting from
the sympathetic nerve sprouting following a myocardial
infarction may serve
as a trigger for ventricular tachycardia
and fibrillation in the electrically remodeled myocardium.
Two new chapters on mechanisms
of atrial fibrillation
address the role
of the pulmonary veins as fertile ground
for the initiation
of the arrhythmia by focal activity arising
within one
of such veins, and how the maintenance of
acute atrial fibrillation depends on a localized reentrant
source(s) in the posterior left atriudpulmonary vein region,
with fibrillatory propagation toward the right atrium.
A
chapter on mechanisms of ventricular fibrillation discusses
the potential role
of the so-called strong inward rectifymg
potassium channels in determining the stability of rotors
responsible for such a lethal arrhythmia. The new chapter
on transgenic and knockout models of cardiac arrhythmias
reviews the methods for engineering mice and studying
electrical function and examines current genetic models
relevant to cardiac electrophysiology. On the other hand,
the way in which multiple common DNA variants across
the genome modulate drug responses is addressed in
a new
chapter on pharmacogenomics and cardiac arrhythmias.
New chapters on important clinical topics include Brugada
syndrome, catecholaminergic and short-coupled ventric-
ular tachycardia, as well as the use
of implantable loop
recorders. In addition, new mapping techniques are pre-
sented, and the latest on new and nontraditional antiar-
rhythmic drugs is discussed in detail, as are new results on
catheter ablation for atrial fibrillation and the role of the
pulmonary veins in atrial fibrillation.
Overall, readers will understand the molecular and
cellular bases of cardiac electrical activity, mechanisms
responsible for clinical arrhythmias, how to identify at-risk
patients, how
to evaluate them, and then how to treat with
electrical, surgical, or drug management. Clearly, the
uniqueness of this book is portrayed in its subtitle,
so a
reader can find in one place the basic and clinical issues of
all aspects of cardiac electrophysiology. This is one
of the
most important features
of Cardiac Electrophysiology: From
Cell
to Bedside.
We recognize that cardiac electrophysiology will con-
tinue to undergo dramatic changes and that future advances
may prove some, or even many, of the concepts presented
in this edition wrong. However, we believe that the ideas
presented herein will be a source of reference
to anyone
interested in cardiac electrophysiology for years to come.
As usual, the steadfast support of our wives, Joan Zipes
and Paloma Jalife, has been essential in the successful
completion of this book and is greatly appreciated. We
wish to thank also all the contributing authors for their
outstanding work and for helpingvs put together such
a
superb edition. The secretarial support of Laurie LeBouef
and Janet Hutcheson is greatly appreciated. Finally we
wish to extend our appreciation to Anne Lenehan and her
associates at Elsevier for their patience and support, and
for making
it possible to bring this text to electrophysiol-
ogws all over the world.
Douglas P. Zipes
Jose Jalife
xvii

Color Plates

COLOR PLATE 1 Ultrastructure of the Cx43 channel obtained by
electron crystallography. The resolution was
7.5 A in the membrane
plane and 21
A in the vertical direction. The left panel shows a side
view of the entire channel. The
red lines represent the lipid bilayers.
The
red asterisk indicates the point at which the pore diameter is es-
timated
to be the smallest. The right panel is a view from the cyto-
plasmic side. The channel is formed by six repeats of four identifiable
densities
(A to D), with each density corresponding to one transmem-
brane domain. (From Unger VM, Kumar NM, Gilula NB, Yeager MR:
Three-dimensional structure of a recombinant gap junction membrane
channel. Science 2831 176-1 180, 1999.)
COLOR PLATE 2
Molecular model of the Cx43 channel. The
model is based on the ultrastructure of the Cx43 channel obtained by
electron crystallography (Fig.
8-3) and attempts to assign specific
amino acids of the primary sequence to the transmembrane domains
identified by ultrastructure. A low-energy conformation solved by the
model is presented. According
to this model, the correlation between
primary sequence and the a-helical domains identified by Unger
and is as follows: domain TM4, helix
D (green rod); domain
TM1, helix
C (red rod); domain TM2, helix B' (yellow rod); domain
TM3, helix A'
(blue rod). This model, however, still needs refinement,
because specific features seem still implausible (see Fig.
&5). (From
Nunn
RS, Macke TJ, Olson AJ, Yeager M: Transmembrane alpha-
helices in the gap junction membrane channel: Systematic search of
packing models based on the pair potential function. Microsc Res Tech
521344-351,2001,)
COLOR PLATE 3
Top view of the connexon model shown in Figure
8-4. Amino acids are represented by spheres with a diameter of 10
A. Colors are assigned as follows: red, Asp Glu; blue, Arg Lys; green,
Tyr Phe Trp; yellow, Met Cys; white, Gly Ala Val Leu Ile Pro. This model
represents a low-energy conformation. However, specific features still
seem implausible, such as the fact that charged residues are in con-
tact with the lipids. (From Nunn
RS, Macke TJ, Olson AJ, Yeager M:
Transmembrane alpha-helices in the gap junction membrane channel:
Systematic search of packing models based on the pair potential func-
tion. Microsc Res Tech 52:344-351, 2001
.)

COLOR PLATE 4 Typical (slow-fast) AV node reentry induced by premature stimulation of the Crista terminalis. A, Color map of conduction
during reentry produced by a single premature impulse. Only first 120-msec interval of reentry is shown, illustrating activation of the posterior
nodal extension, the compact atrioventricular (AV) node, and the fast pathway. Map is superimposed with photograph of the preparation (see panel
6 for landmarks). Blue diamonds illustrate the position of the optical recordings shown in panel C. 6, Continuation of reentrant conduction: acti-
vation of the transitional atrionodal (AN) layer in 20 msec. The same field of view is shown. Notice significant difference in activation times be-
tween the two panels.
C, Optical action potentials recorded along the reentry pathway. Solid-line arrow illustrates conduction in the slow pathway
and fast pathway.
Dashed-line arrow illustrates rapid conduction in the superficial transitional layer. Time scale bars below show time-intervals il-
lustrated in panels A and 6 as conduction maps. D, Conventional bipolar electrograms recorded during last basic stimulus (Sl), premature stim-
ulus (S2), and reentrant beat. Electrograms were recorded from high crista terminalis (hiCrT), low crista terminalis (IoCrT), interatrial septum
(IAS), and the bundle of His (His). (From Nikolski V, Efimov
I: Fluorescent imaging of a dual-pathway atrioventricular-nodal conduction system.
Circ Res 88:E23-E30, 2001
.)

u)
E 100-
90.
80-
70-
60,
A
COLOR PLATE 6 Nerve sprouting after myocardial infarction. A,
Sympathetic nerves are distributed in perivascular areas and between
myocytes. Nerve fibers are oriented along the long axis
of myocytes
(solid arrow). B, After myocardial infarction, nerve fibers in the in-
fracted area are injured. The distal stumps undergo Wallerian degen-
eration
(solid arrows in B and C). C, The regeneration of axonal
sprouts occurs in nerve fibers proximal
to the injury (open arrow). M,
myocytes; N, nerve fiber; MI, myocardial infarction; NS, nerve sprouts.
B
+ H2-IAS ;L -c- H2-CrT
. , , , , , . , , , , ,
C
COLOR PLATE 5 Optical coherence tomography (OCT) imaging of the preparation exhibiting the dual-pathway conduction with a shift of
breakthrough point during premature stimuli at different coupling intervals associated with a “jump” in a conduction curve.
Upper left panel, Pho-
tograph of the preparation and the sites of breakthrough at different coupling intervals corresponding
to the slow- (SP) and fast-pathway (FP) con-
duction. Dual pathways were determined with fluorescent imaging.24
Lower left panel, Conduction curves during retrograde stimulation from the
bundle of
His showing the delays between the premature pacing stimulus H2 and excitations recorded with bipolar electrodes at the atrial sep-
tum
(IAS) and crista terminalis (CrT). Notice a significant jump in the curves, especially in the black one, which corresponds to His-septum con-
duction delay. Jump in the conduction curves corresponded
to switch in the breakthrough site from FP to SP? Rightpanels, Photographs show
from top
to bottom the histologic (colored) and OCT (gray) vertical sections of the preparation along the axis indicated on the photograph at the
left panel. A, atrial septum; CS, coronary sinus;
N, compact AV node; PNE, posterial nodal extension; TC, transitional cells; V, ventricular septum.
(From Gupta M, Rollins AM, lzatt JA, Efimov
IR: Imaging of the atrioventricular node using optical coherence tomography. J Cardiovasc Electro-
physiol
13:95, 2002.)

A
COLOR PLATE 7 Regional hyperinnervation after myocardial in-
farction. Nerve fibers
(arrows) are most abundant at the periphery of
infarct. In contrast, the necrotic and fibrotic zone of infarct is devoid of
nerve fibers. The denervation and nerve sprouting after myocardial in-
farct result in an inhomogeneous distribution of cardiac sympathetic
nerve.
MI, myocardial infarct; N, normal surviving myocardium. (From
Chen P-S, Chen
LS, Cao JM, et al: Sympathetic nerve sprouting, elec-
trical remodeling and the mechanisms of sudden cardiac death. Car-
diovasc Res
50:409-416, 2001 .)
pECG
Pathlength Wavelengm Excitable gap Propagation
(PL)
WL) (EG)
B
nne" - -
vv-l-
Cyde Effective Diastolic
length refractory Interval
(CL) period (DI)
(EW
COLOR PLATE 8
Reentry parameters. A, Optical maps were ob-
tained during a single cycle of reentry in a neonatal rat cell monolayer,
grown as an annulus (3-mm central obstacle, 18-mm outer diameter).
Cells were stained with RH237, and optical action potentials were
monitored at 60 recording sites marked by
white crosses. Color bar on
left
indicates relative voltage, with blue representing resting or fully re-
polarized cells, and
red representing fully depolarized cells. Numbers
indicate time in milliseconds.
First three subpanels show pathlength
(PL), wavelength (WL), and excitable gap (EG) measured at the
perimeter of the obstacle.
Last panel on right shows direction of prop-
agation of wave front
(black arrows) and wave tail (gray arrows). B, Fil-
tered action potential recorded optically from a single site in the mono-
layer during the same reentry. Cycle length (CL), effective refractory
period (ERP), and diastolic interval
(DI) are illustrated. C, Photomicro-
graph of another micropatterned culture with a 2-mm circular anatom-
ical obstacle. Cell actin was visualized by staining with fluorescein
phalloidin. (From
Y. Nabutovsky, N. Bursac, and L. Tung, unpublished
data.)
COLOR PLATE 9
Functional reentry in anisotropic confluent car-
diac monolayer. Uniformly oriented monolayer architecture is shown
using florescin phalloidis staining for actin fibers.
Frames to the right
show a single clockwise rotation of the rotor. Color bar corresponds to
normalized voltage level, as in Figure 37-1. Frames read from
leff to
right
and top to bottom. Numbers show time in milliseconds. Reentry
cycle length was 135 msec. Pseudo-electrocardiogram (pECG) shown
in
lower left is monomorphic.

pECG
1 sec
COLOR
PLATE 10 Representative initiation of single-loop reentry COLOR PLATE 11
Computer simulation of initiation and mainte-
by rapid pacing from a single point electrode. Voltage and corre- nance of two-arm spiral.
A to 0, Initiation of two-arm spiral by deliv-
sponding phase plots
(to the right of voltage plots) step through the ini- ery of a single 53 shock during an ongoing spiral wave dots. Time
tiation process.
Voltage color bar shown to the left of the first voltage between panels is 50 msec. White marks locations of phase singular-
frame is same as that
in Figure 37-3. Phase color bar shown to the ities. € to H, One complete rotation of the two-arm spiral. Time be-
left of the first phase frame is from -T (OY0) to +T (100%). Frames tween panels is 100 msec.
read
left to right and top to bottom. Numbers show time in millisec-
onds. The asterisk denotes pacing position.
Arrows denote direction of
rotation. Steady rapid pacing results in a wave break at
25 msec and
formation of transient figure-of-eight
(60, 120, and 220 msec), which
simplifies after two rotations into a single-loop reentry because
of the
drift and annihilation of one of the rotors at the monolayer boundary
(220 msec). The trajectory of the remaining rotor tip (phase singular-
ity), shown in
black, forms a longitudinally oriented arc of functional
block. pECG from the same episode shows rapid pacing from rest
(timing denoted by dashes) and resulting arrhythmia with stable
monomorphic morphology.
COLOR
PLATE 12
Phase map of complex but stable and station-
ary seven-rotor reentry.
Color bar is the same as that in Figure 37-4.
White arrows denote direction of rotation of the seven coexisting
frequency-locked and phase-locked rotors. Trajectories of tips (phase
singularities) are shown in
black during 5 seconds of activity. The
pECG is monomorphic.
pECG
1 sec

COLOR PLATE 13 Electrograms (EGs) with corresponding spectral analysis and isochrone maps from a single episode of atrial fibrillation.
A, Bipolar EG recording global activity across the two atria with its corresponding power spectrum. 6 and C, Pseudo-ECG from the left atrium
(LA) and right atrium (RA), respectively, with their corresponding power spectrum. Sequential LA (D) and RA (€) isochrone maps at a simultane-
ous timing. Timing
of isochrone maps is indicated by horizontal bars over EGs. (Modified from Skanes A, Mandapati R, Berenfeld 0, et al: Spa-
tiotemporal periodicity during atrial fibrillation in the isolated sheep heart. Circulation 98:1236-1248, 1998.)

COLOR PLATE 14 Reentrant sources of atrial fibrillation (AF). A, lsochrone map of optical activity from the free wall of the LA during sus-
tained
AF showing a clockwise reentry. 5, Optical pseudo-electrocardiogram (ECG) of the left atrium (LA) during the same episode of AF with its
corresponding power spectrum.
C, Correlation between inverse dominant frequency (DF) from pseudo-ECGs of entire movies (-3 sec long) and
rotation period of rotors found within an episode of
AF. (Modified from Mandapati R, Skanes A, Chen J, et al: Stable microreentrant sources as a
mechanism
of atrial fibrillation in the isolated sheep heart. Circulation 101 :194-199, 2000.)

COLOR PLATE 15 Phase representation of wave breakup and
reentry formation.
A, A sequence of phase maps at the indicated
times demonstrating generation of figure-of-eight reentry. At
0 msec,
two wave fronts (green/yellow) moving in opposite direction are shown
(arrows). The wave propagating downward extinguishes on refractory
tissue (red). At
16 msec, the wave propagating upward at 0 msec
breaks on refractory tissue resulting in formation of two PSs
(“f” and
‘I-” indicate their corresponding chirality). At 32 msec, two wave fronts
rotate around their PSs. At
56 msec, the wave fronts merge and begin
to propagate between the two PSs (inter-PS distance = 6.8 mm). At
80 msec, reentry completes a figure-of-eight. B, A sequence of phase
maps demonstrating a failure in generating reentry. At
0 msec, an ac-
tivated wave front (green/yellow) propagates from left
to right. At 8
msec, the wave front breaks on refractory tissue (red) resulting in for-
mation of two PSs
(“+” and “-”). At 16 msec, the two wave fronts ro-
tate around their PSs. At
24 msec, the wave fronts merge and attempt
to propagate between the two PSs (inter-PS distance = 3.3 mm). At
32 msec, reentry fails to complete. Color bar scale indicates phase
value between
--71 and 71 radians with approximated location corre-
sponding to sample action potential stages (in
A). (Modified from Chen
J, Mandapati R, Berenfeld 0, et al: Dynamics of wavelets and their role
in atrial fibrillation in the isolated sheep heart. Cardiovasc Res
48:220-232, 2000.)
COLOR PLATE 16
Propagation patterns in the
right atrium (RA) depend on pacing frequency.
A, The “breakdown frequency.” Endocardial (Endo)
and epicardial (Epi) dominant frequency
(DF) maps
of an isolated RA preparation paced at
5.0 and 7.7
Hz. Note appearance of heterogeneous DF do-
mains at
7.7 Hz. B, Response DFs versus the pac-
ing rate (n
= 5). Each symbol represents one ex-
periment. Pacing Bachmann bundle at rates less
than
-6.7 Hz results in 1:l activation. At greater
rates, the number of domains increases but the
DFs decrease. C, DF distribution is independent of
APD dispersion.
Leff, APD,, map at a pacing rate of
3.3 Hz. Right, DF map at a pacing rate of 8.3 Hz on
same preparation.
No correlations exist between
the two maps
(R2 = 0.05). APD, action potential du-
ration; CT, crista terminalis; SVC, superior vena
cava. (Modified from Berenfeld
0, Zaitsev AV,
Mironov AF, et al: Frequency-dependent break-
down of wave propagation into fibrillatory conduc-
tion across the pectinate muscle network in the iso-
lated sheep right atrium. Circ Res
90:1173-1180,
2002.)

COLOR PLATE 17 Frequency dependence of predominant propagation direction (PD). Top, Isochronal maps for 15 sequential wave fronts at
3.3 (A) and 10 Hz (13) obtained for the same location on the endocardial surface. In both panels, color scale is normalized red to blue. Bottom,
Histograms of percent recurrence of propagation in a given direction (RPD).
C, Dependence of endocardial (Endo) and epicardial (Epi) mean RPD
on pacing rate in all five experiments. Notice abrupt reduction in RPD when pacing faster than at 6.7
Hz. (Modified from Berenfeld 0, Zaitsev AV,
Mironov AF, et al: Frequency-dependent breakdown of wave propagation into fibrillatory conduction across the pectinate muscle network in the
isolated sheep right atrium. Circ Res 90:1173-1180,
2002.)

67.4 msec
II ..
115
COLOR PLATE 18 Analysis of VF dominant frequencies. A, ECG
trace.
B, Dominant frequency map with single pixel recordings (top
tracings)
and respective power spectra (bottom tracings) from RV (left)
and LV (right). LAD, left anterior descending coronary artery. (From
Samie FH, Berenfeld
0, Anumonwo J, et al: Rectification of the back-
ground potassium current: A determinant of rotor dynamics in ventric-
ular fibrillation. Circ Res
89:1216-1223, 2001 .)
37.8 msec
II
126
5
10 15 20 25 30 5 15 25 $5
5 15 25 35
Frequency (Hz) Frequency (Hz) Frequency (Hz)
B 100 msec
COLOR PLATE 19 = Core effects on wavelength and action potential duration. A, Spiral wave activity in a 2 cm x 2 cm anisotropic cardiac
sheet (ratio of longitudinal
to transverse velocity is 4:1), according to a full action potential model modified from Luo and Rudy (for further tech-
nical details see Gilmour et aP). The wave front is
red, the wave tail is green, and the resting "tissue" is blue. Note that wave front curvature in-
creases toward the center of rotation (core,
dotted line). Conduction velocity (CV) decreases as curvature increases. The wavelength (WL), de-
fined as the spatial extension of the excited state, increases from the center to the periphery. This is because the APD also increases from the
center
to the periphery (local WL = CV X APD) as a result of electrotonic interactions with the core. B, Diagrammatic representation of changes
in
APD induced by l,, during functional reentry.

COLOR PLATE 20 Increased formation of wavelets in the border
zone
(BZ) during ventricular fibrillation (VF) in a regionally ischemic
heart.
Color maps represent the spatial distribution of dominant exci-
tation frequency (DF) during VF. The DF is inverse
to the cycle length
of local activation, which correlates with local refractory period dura-
tion.IE
Circles depict the locations of wave breaks leading to formation
of wavelets during VF. In
A and B, distribution of wave breaks is su-
perimposed on the DF map during preischemic
(A) and ischemic VF
(6). Note that a sharp gradient in refractoriness across the BZ is as-
sociated with a high density of wave breaks. (From Zaitsev AV,
Sarmast F, Kolli A, et al: Wave break formation during ventricular
fibrillation in the isolated, regionally ischemic pig heart. Circ Res
92546-553, 2003.)
A B
COLOR PLATE 21
Antifibrillatory effects of global hyperkalemia
and global ischemia in the isolated, blood-petfused porcine heart.
A,
Mean dominant frequency of excitation during ventricular fibrillation
(VF) (mean dominant excitation frequency [DF]) and wave break
(We)
density as a function of the extracellular potassium (K+). With increase
in [K'],, the VF becomes more periodic and organized until it is con-
verted
to monomorphic ventricular tachycardia at [K'], equals 12.5
mM. 6, Phase singularity maps from the epicardial surface of anterior
left ventricle during VF before and
2 minutes after onset of global is-
chemia.
Arrowheads show propagating wave fronts. Circles show the
singularity points flanking individual wavelets. In the normally perfused
heart, up to 5 wavelets are present simultaneously in the mapped
area. After
2 minutes of global ischemia, only a single spiral wave is
seen in the field of view.

8.5 Vlcm -
A -60 -30 0 30 %APA B 10 2b 3'0
8.3 V/cm -
#...I
0 4.5 9 13.5 18
C 0 300 600 900 1200 1500psec D Xime (msec)
COLOR PLATE 23 Intramural virtual electrodes in porcine left ven-
tricle.
A and C, Optical recordings of intramural V, and shock field (E)
in control (black traces) and with two shocks of opposite polarities. The
numbers correspond to the photodiodes indicated in
B and D. B and
0, lsopotential maps of AV, distribution for shocks of two strengths
measured
9 msec after the shock onset. A weaker -8.8 V/cm shock
induced isolated intramural
AV, whereas a stronger -26 V/cm shock
induced globally negative intramural
AVm. €, Dependence of maximal
and minimal
AV, on the shock strength. Dashed lines separate re-
gions where Vm responses were nearly symmetric
(I), asymmetric
with isolated intramural
AV, (II), and globally negative AV, (Ill). (From
Fast VG, Sharifov OF, Cheek
ER, et al: Intramural virtual electrodes
during defibrillation shocks in left ventricular wall assessed by optical
mapping of membrane potential. Circulation
106:1007-1014, 2002.)
COLOR PLATE 22
Role of intercellular clefts in shock-induced AV,
and tissue activation. A and B, lsopotential maps of AV, induced by
shocks
of opposite polarities. White areas in the middle depict the in-
tercellular cleft. The outline corresponds
to the boundary of the photo-
diode array.
C and 0, Isochronal maps of activation spread initiated
from secondary sources during application of shocks in diastole.
Ar-
rows indicate the direction of activation spread. Activation times are
determined from the time
of earliest activation within the mapping re-
gion. (From Fast VG, Rohr
S, Gillis AM, Kleber AG: Activation of car-
diac tissue by extracellular electrical shocks: Formation of "secondary
sources" at intercellular clefts in monolayers
of cultured myocytes. Circ
Res 82:375-385,
1998.)

A
B
COLOR PLATE 24 Phase maps and scatter plots during ventricu-
lar fibrillation
(A) and at the end of 1-second shocks for (6) 12 V, 10
Hz sinusoidal;
(C) 48 V, 10 Hz sinusoidal; and (0) 36 V, 10 Hz chaotic.
Transmembrane signals from one site and the stimulus waveform are
shown below each phase map. A pair of opposite chirality-phase sin-
gularities
(+, clockwise; -, counter-clockwise) formed during the 12-
V sinusoidal shock
(6) and led to fibrillation induction. The origin in
state space
(V', V*) is represented as a Sr. Colored circle represents
the phase angle computed from Equation 1.
C
D
COLOR PLATE 25
Echocardiogram of dilated cardiomyopathy. Long axis echocardiogram demonstrating an enlarged left ventricle (LV) with
mitral regurgitation (MR), normal-size left atrium (LA) and aorta (AO), and moderate-size pericardial effusion
(PE). M-mode echocardiogram
showing dilated left ventricle with poor systolic function and pericardial effusion. IVS, interventricular septum; LVPW, left ventricular posterior wall;
S, systole;
D, diastole.

COLOR PLATE 26 = Two frames from an electroanatomical map of a focal right atrial tachycardia in a patient who had prior open heart surgery.
The atrial tachycardia was localized
to the right atrial free wall, and this map shows the temporal sequence of atrial activation.The map highlights
the centrifugal spread of atrial activation from the site of focal origin.
COLOR PLATE 27 Left atrial electroanatomic map of a
macroreentrant tachycardia. This electroanatomic map in a patient
with mitral valve
(MV) disease shows a left atrial macroreentrant
atrial tachycardia demonstrating a circuit originating from near the
left inferior pulmonary vein. This tachycardia circuit was ablated with
a series of lesions stretching from the left inferior pulmonary vein to
the mitral annulus. (Courtesy of
W. G. Stevenson.)

COLOR PLATE 28 Severe dilation of the right ventricle. Top,
Heart transplant for severe dilation of the right ventricle in a patient
with a typical form of arrhythmogenic right ventricular dysplasia
(ARVD). Myocardium seems covered by fat. The arrow indicates an
epicardial lead that was installed because of sensing failure of an au-
tomatic implantable defibrillator (ICD) endocardial lead.
Bottom, The
sensing failure is explained by the fact that the active terminal elec-
trode is no longer in contact with the endocardium, probably because
of the catheter withdrawal during the right ventricular dilation. The “au-
tomatic gain control”
of the ICD led to inappropriate shocks.
COLOR PLATE 30 Biventricular dysplasia. The same dis-
ease process, replacement of myocardium by fat and fibrosis, is
observed in this patient on the right as well as the external part
of the left ventricle. Inside this fat, there are surviving cardiomy-
ocytes and zones of fibrosis. LV, left ventricular.
COLOR PLATE 29
Typical case of Uhl’s anomaly in adults. Top,
Scissors introduced in the pulmonary artery show right ventricular wall
transparency.
Midd/e, In another patient, section of the heart has been
performed at the level of the tricuspid valve. The left ventricle is nor-
mal in both size and thickness. The right ventricle shows a large dila-
tion with an extremely thin wall, clearly seen on its paraseptal anterior
aspect.
Bottom, “Abrupt interruption of myocardium,” leading to fibro-
sis and fat without interposed myocardium.
LV Fibrosis LV Cardiomyocytes

Pericardium
COLOR PLATE 31 Biventricular spongy dysplasia. Top, The right ventricular (RV) wall has been completely replaced by fat. Two lines of fi-
brosis indicate the remnants of epicardium and endocardium. Middle, Most of the left ventricular (LV) myocardial fibers are dissociated by fat and
minor fibrosis.
~Votforn, High magnification of LV free wall.
COLOR PLATE 32
Sudden death in a 16-year-old girl with no previous symptom. A and C, The infundibular area and the adjacent zone with
trabeculations show massive replacement of the myocardium by adipocytes with surviving strands of cardiomyocytes, suggesting a localized form
of
ARVD. B, Typical pattern of increased thickness of the small coronary vessels. Epi, epicardium; Endo, endocardium.

COLOR PLATE 33 Brugada syndrome with a typical electrocardiogram pattern. The structure of the right ventricular free wall shows a layer
of adipocytes separating epicardium (Epi) and endocardium (Endo). This structure can escape identification by regular imaging techniques.
The strands of adipocytes are similar to the pattern observed in a typical patient with
ARVD who was operated on in 1977. The patient had a
sandwich-like structure
of the right ventricle at the site of origin of ventricular tachycardia. The two layers of epicardium and endocardium were
separated by a thick layer
of fat.

COLOR PLATE 34 Noncontact mapping of a premature ventricular
beat originating from the right ventricular outflow tract.
Upper panel,
The right ventricle is shown during electrical diastole. The virtual elec-
trograms corresponding
to sites 8 to 12 on the map are shown to the
right.
Lower panel, The map shows the site of earliest depolarization
(white circle) during a single premature ventricular beat that had an
identical morphology to the patient's clinical ventricular tachycardia.
Note that virtual unipolar electrogram corresponding to the site
of ori-
gin (site
8) has a QS deflection, whereas the other virtual electro-
grams distant from the earliest site have an initial R-wave.
LVOT
VT
COLOR PLATE 35
Left ventricular outflow tract (LVOT) tachycardia from the region of the aorto-mitral continuity. The panel on the leff shows
an electroanatomic map from a posterior projection during ventricular tachycardia. The aorta is denoted by the red tube and the tricuspid, and
aortic and mitral valve rings are shown. The pulmonary artery is shown in gray. Earliest activation during tachycardia is shown in red. The sites of
ablation
(dark red circles) are shown in the right panel (anterior projection) in the region of the aorto-mitral continuity valves.

COLOR PLATE 36 Left ventricular tachycardia originating from the region of the mitral valve. The panel on the left shows a left ventricular
grid constructed during sinus rhythm. The electrogram from the successful ablation site is shown in the inset. Note the large atrial and ventricu-
lar signals indicating a site contiguous to the mitral valve annulus.
The right panel shows the activation sequence during ventricular tachycardia.
Red indicates the site
of earliest activation.
COLOR PLATE 37
Sinus rhythm map of
Purkinje potentials (PPs) in a patient with
fas-
cicular ventricular tachycardia. The green
tags
identify PPs recorded from the region of
the left posterior fascicle.
The right inset
shows the electrogram recorded from this
region. The first spike represents the PP, and
the second signal is the ventricular electro-
gram.
The pink tags correspond to the area
where retrograde PPs (equivalent
to the di-
astolic potentials during ventricular tachy-
cardia) were recorded.
The left inset shows
an electrogram from this region. The first sig-
nal is a PP, followed by ventricular activation
and then a low-amplitude retrograde PP.
This site, which recorded the earliest PP
during sinus rhythm, was the site
of suc-
cessful ablation.
Retro Purkinje Potential Electrogram Purkinje Potential
Electrogram

COLOR PLATE 38 w Inversely reconstructed endocardial excitation COLOR PLATE 39 Heart with 5-day-old myocardial infarction.
time map from a normal human subject during stimulation from a Programmed stimulation induced a quasimonomorphic ventricular
catheter in the coronary sinus. Posterior left-lateral view. IVC, inferior tachycardia with a reentrant pathway, clearly visible in the measured
vena cava; LA, left atrium;
LL, lower left pulmonary vein; MA, mitral an- epicardial isochrone maps (left panel) and well-reconstructed from the
nulus; RA, right atrium;
RL, right lower pulmonary vein; RU, right up- inversely computed epicardial electrograms (right panel). (From
per pulmonary vein; SVC, superior vena cava. (From Tilg
B, Fischer G, Burnes JE, Taccardi B, Rudy Y: A noninvasive imaging modality for
Modre
R, et al: Model-based imaging of cardiac electrical excitation in cardiac arrhythmias. Circulation 102:2152-2158, 2000.)
humans.
IEEE Trans Med Imaging 21:1031-1039,2003,)
COLOR PLATE 40 Sympathetic denervation in a dog. The images
show a midventricle short axis view
of NH3 (perfusion) and metahy-
droxyephedrine
(HED) (sympathetic innervation) in a dog following re-
gional sympathetic denervation using phenol.
[N-l3]Ammonia [C-li]HED

COLOR PLATE 41 Sympathetic denervation in human subject with
coronary artery disease. The images show myocardial perfusion
(top
image) and sympathetic innervation (bottom image). The lateral wall of
the left ventricle shows a relatively large area with a mild reduction in
perfusion. The corresponding metahydroxyephedrine (HED) image
demonstrates that the function
of the sympathetic system is impaired
in the region
of the left ventricle.
COLOR PLATE 42
Activation maps of the right and left atria in an
anteroposterior orientation, in a patient with a para-Hisian focal atrial
tachycardia. The His bundle position is marked by the amber hexa-
gon. The red color denotes earliest activation and is located adjacent
to the His bundle potential, whereas the purple color represents latest
activation.

COLOR PLATE 43 Mapping and ablation of a focal right atrial tachycardia using noncontact mapping. 7, Left anterior oblique fluoroscopic im-
age showing the balloon-mounted multielectrode array (MEA) and a single mapping catheter (Map) in the right atrium.
2, Right atrial isopotential
map (right lateral projection) and corresponding unipolar virtual electrograms at sites numbered
6 to 10, as reconstructed by the noncontact map-
ping system. The isopotential map shows earliest endocardia1 activation (white, surrounded by other colors) at the site of origin of a focal right
atrial tachycardia, surrounded by nondepolarized endocardium (purple). Virtual electrograms
(right) placed over the area of the arrhythmogenic
focus on the map have a
QS morphology.
COLOR PLATE 44
Three-dimensional catheter localization during mapping of a left posterior accessory pathway in a patient with Wolff-Parkinson-
White syndrome.
7, Left anterior oblique fluoroscopic image showing a decapolar catheter in the coronary sinus (CS) and a mapping catheter
(Map) used to map around the mitral valve annulus.
2, Corresponding image from the LocaLisa mapping screen, again with mapping (Map) and
coronary sinus
(CS) catheter positions shown in a three-dimensional representation. (Courtesy Medtronic Inc., Minneapolis, Minn.)

COLOR PLATE 45 Electrogram maps of the left atrium. Top, Electroanatomic map of the left atrium (posteroanterior view) during AF with
sampling time of
45 seconds per point. Electrophysiologic information is color coded, with red representing the shortest cycle length (CL) and pur-
ple the longest CL. Note short CLs clustered around pulmonary veins.
Bottom, Local bipolar electrograms of types A, B, and C, with relative CL
histograms.

COLOR PLATE 46 Three-dimensional map of the left atrium and
pulmonary vein profile. Solid gray map of the left atrium, posteroan-
terior view. Red spheres represent radiofrequency lesions, and color
tubes represent pulmonary veins (PVs). Note the early branching of
the left superior PV and right superior PV just at their ostia and the
right lesion encircling all the veins. LI, left inferior PV; LS, left superior
PV RI, right inferior PV RS, right superior PV.
COLOR PLATE 47
Three-dimensional reconstruction of the pulmonary vein-left atrium junction. Comparison between the three-dimensional
pulmonary vein (PV)-left atrium junction reconstruction obtained by CART0
(A) and contrast magnetic resonance angiography (6). Note the high
correlation between morphology and dimension
of left atrial chamber and PVs as assessed by the two imaging techniques. LIPV, left inferior PV;
LSPV, left superior PV; RIPV, right inferion PV; RSPV, right superior PV.

COLOR PLATE 48 Three-dimensional left atrial voltage maps. Posteroanterior view (A, preablation; B, postablation), depicting peak-to-peak
bipolar electrogram amplitude. Red represents lowest voltage and purple highest voltage. Claret red spheres represent radiofrequency lesions.
Postablation, areas within and around the ablation lines, involving to some extent the posterior wall
of the left atrium, show low-amplitude (cO.1
mV) electrograms (electroanatomic remodeling). Preablation insets show pulmonary vein (PV) ostial potentials indicating the activation of mus-
cular fibers capable of conducting impulses in or out of the veins. By creation of circumferential radiofrequency lesions around each vein ostium,
PV potentials are no longer detected (postablation insets) at the same ostial points recorded before ablation (atriovenous electrical disconnec-
tion).

COLOR PLATE 49 Quantification of the low-voltage area around pulmonary vein ostia using custom-designed CART0 software. The encir-
cled low-voltage area is calculated as the surface area circumscribed by manually selected outermost points with bipolar amplitude less than
0.1
mV (A). By selecting a point outside the encircled area, the remainder of the left atrial chamber surface area is automatically calculated (6).
COLOR PLATE 50
Propagation map during left atrial tachycardia in a patient who underwent circumfential pulmonary vein ablation. Panels
7 through 7 represent freeze-frames from animated sequence (left lateral view). Shades of red on blue background represent local endocardial
activation times spanning an interval of
30 msec (red bar on time scale on right side of each panel). Note the circus movement of the activation
front around the mitral annulus. The arrhythmia was terminated by radiofrequency delivery (claret red spheres) at the isthmus between the left in-
ferior pulmonary vein (LIPV) and the mitral annulus as shown by intracardiac electrophysiologic mapping
(panel 8). CS, coronary sinus; LSPV,
left superior PV; MV, mitral valve; RIPV, right inferior PV; RSPV, right superior PV.

COLOR PLATE 51 Simulated right anterior oblique view of the in-
side of the right atrium of a human heart. The “inferior” isthmus ex-
tends from the inferior aspect of the tricuspid annulus toward the infe-
rior caval vein
(lower dashed line), and the “septal” isthmus from the
tricuspid annulus toward the coronary sinus ostium (CSO)
(upper
dashed line) and further toward the Eustachian ridge (dotted line).
Note the triangular flappy anatomy of the Eustachian valve. AV, Atri-
oventricular. (Courtesy of Yen Ho, National Heart
& Lung Institute and
Royal Brompton Hospital, London,
UK.)
TA
A1 A2
S-A1
= 50 msec
B A1-A2 = 130 msec
D-
VCI

150
COLOR PLATE 52
Verification of complete transisthmus conduction block after ablation. Top left, Double potential mapping at four sites (A to
D) along the entire isthmus after ablation from the tricuspid annulus (TA) toward the inferior caval vein (VCI) during pacing (S) from the coronary
sinus ostium (CSO).
Top right, Inferior view of the isthmus during electroanatomic mapping; three dots annotate the inferior aspect of the TA (mid-
dle dot indicates
6 o’clock position), three dots the VCI, and red (dark) dots the five ablation sites, respectively. Note, widely split double poten-
tials (A1 and A2) are recorded along the entire ablation line with the intervals separating A1 and A2 measuring uniformly 130 msec.
Bottom, In
addition
to double potential mapping, anterior ascending mapping during CSO pacing is further confirming complete isthmus block and exclud-
ing slow transisthmus conduction by demonstrating the descending wave front at the anterior free wall
(arrows) with latest atrial activation just di-
rect at the ablation line (A2 of the isthmus line electrograms). Thereafter, bidirectional conduction block is confirmed by additional pacing from an-
terior
to the ablation line (not shown).

COLOR PLATE 53 Electroanatomic remapping of the isthmus line after ablation during pacing from the coronary sinus ostium (CSO). The
gray area (dashed line) indicates fibrous nonconducting tissue in the subtricuspid region.
Leff, Double potentials were recorded along the entire
line, however, nonuniform intervals separating A1 and
A2 were recorded. These intervals measured 89 msec distally, 75 msec in the midportion
of the ablation line, and only 64 msec proximally, thereby pretending slow conduction through the isthmus close to the inferior caval vein (VCI)
(gray circle,
arrows with question mark). Right, Extending the remapping confirmed complete isthmus block (black circle close to VCI) without
additional ablation and demonstrated “lower loop” conduction across the crista terminalis (gray
arrows) and fusion with the conduction wave front
from the tricuspid annulus (TA) (white arrow). The slightly earlier conduction across the crista terminalis resulted in nonuniform intervals sepa-
rating A1 and
A2 but latest respective activation direct at the ablation line (A2 of the isthmus line electrograms), thereby confirming complete isth-
mus block.
~ ~
Basal Posterior
1200 ms
+30 mV
1400 ms
-80 mV
COLOR PLATE 57
Basal and posterior semitransparent rendering
of the postshock transmembrane potential maps on the endocardial
and epicardial surfaces of the fibrillating rabbit ventricles for two
timings, 1200 and 1400 msec, from the onset of the burst pacing. The
defibrillation shock is administered
at t =1400 msec. Images
corresponding to the activity at t
= 1400 msec also depict the scroll
wave filaments in the three-dimensional volume
of the ventricles at
COLOR PLATE 54
lsopotential map showed the earliest activation
site located near the inferior tricuspid annulus. The activation time in
the virtual
10 electrogram was earlier than the onset of P wave. CSP,
Proximal coronary sinus. that timing.

COLOR PLATE 55 lsopotential map showed a macroreentry cir-
cuit located in the low voltage zone
(LVZ) or scar in the anterior free
wall of right atrium. Color scale has been set
so that white indicates
most negative potential and blue indicates least negative potential.
The yellow
arrowhead denotes the activation direction of macroreen-
try tachycardia, and the virtual unipolar electrograms in the central
obstacle showed double potentials (number
10 to 14). Panels A to D
corresponded to the time lines (7 to 4) in the panel with virtual
electrograms.
64.21 mA
105.35 mA
106.35
mA
128.43 mA
COLOR PLATE 58 Anterior and posterior semitransparent post-
shock transmembrane potential maps on the endocardial and epicar-
dial surfaces as a function
of shock strength at postshock timing
t = 30 msec. Filaments are shown. Filament endings that are in
contact with the endocardial surface of the ventricles are shown in red,
whereas endings touching the epicardial surface are depicted in
indigo. Arrows point to filaments discussed in the text.

COLOR PLATE 56 Mapping data from a patient with prior anterior infarction. Top left, 12-Lead electrocardiograms of three different ventric-
ular tachycardias,
two of which were hemodynamically unstable. Right, A three-dimensional "voltage map" of the left ventricle. Peak-to-peak elec-
trogram amplitude is color coded with more than
1.5 mV (indicated by purple). Grey areas are electrically inexcitable scar (pacing threshold > 10
mA). Bottom left, Recording from the site indicated during sinus rhythm is low amplitude and pace-mapping captures with a
S-QRS interval of
180 msec consistent with conduction delay. The QRS resembles that of VT-1, suggesting that the stimulated wave front reaches the exit region
for VT-1. A series of radiofrequency
(RF) lesions (red circles) were constructed from the inexcitable scar, along the border of the low-amplitude
region (black dashed line
in the bottom inset). Ablation abolished all ventricular tachycardias.

PART I
STRUCTURAL AND
MOLECULAR BASES
OF ION
CHANNEL FUNCTION
CHAPTER 1
Sodium Channels
Ronald A. Li, Gordon E Tomaselli, and Eduardo Marban
CHAPTER OUTLINE I
Evolution and Genetics of Sodium Channels ......... 1
rn Design Motifs.. ........................................... .3
rn Regulation of Sodium Channel Expression
and Function
.............................................. .6
rn Conclusion.. ............................................... .8
oltage-gated sodium (Na) channels are critical sig-
V naling proteins responsible for the initial rising phase
of the action potential in excitable tissues such as heart,
muscle, and nerve cells. These complex molecules are of
particular importance in cardiac electrophysiology for sev-
eral reasons. First, they determine conduction of excita-
tion by mediating rapid transmission of depolarizing
electrical pulses throughout the myocardium; in fact, the
opening of Na channels underlies the QRS complex of the
electrocardiogram and enables synchronous ventricular
ejection. Second, Na channels are important clinically
as
the primary target of numerous therapeutic drugs such as
lidocaine and other “type
I” antiarrhythmics. Finally, gain-
and loss-of-function genetic defects in
Na channels have
been linked
to various heritable forms of the long QT syn-
drome, the Brugada syndrome, and cardiac conduction
defects.
Na channels have also played an illustrious role in
the history of physiology. Elucidation of their fundamental
properties in the squid axon by Hodgkin and Huxley’
launched modern channel theory by elegantly dissecting
the elementary processes
of gating (how channels open
and close) and permeation (how ions traverse open chan-
nels). Further,
Na channels were the first voltage-gated
ion channels to be cloned,’ ushering in the era of heterol-
ogous expression and molecular manipulation. The
cloning of the first voltage-dependent channels happily
coincided with the development of single-cell electrophys-
iology methods, notably patch clamp, which revolution-
ized the field by enabling single-channel
recording^.^
This chapter briefly reviews the general concepts of
Na channel structure and function that have emerged over
the past half century, with
a particular focus on the cardiac
channels. The reader is referred elsewhere for more com-
prehensive reviews of particular subtopics.+’
EVOLUTION AND GENETICS
OF SODIUM CHANNELS
Evolution and Phylogeny
of Sodium Channels
In human and other vertebrates, Na channels are found in
virtually all excitable tissues. These signaling molecules
were thought to have first appeared phylogenetically in jel-
lyfish, where they enable
the organism to transmit elec-
trical signals efficiently throughout a dispersed neural net,
but a much more primitive prokaryotic counterpart has
been recently identified (see Ren and associates’O and in
following). The genes encoding eukaryotic Na channels
are highly conserved, and the central selective pressure has
remained the same throughout evolution:
Na channels are
nature’s solution to the conundrum of coordination and
communication within larger organisms, particularly when
speed is of the essence. Thus, Na channels are richly con-
centrated in axons and in muscle, where they are often the
most plentiful ion channels. Mammalian heart cells, for
instance, typically express more than
100,000 Na channels
(Purkinje fiber cells being
a particularly rich source, with
more than
1 million per cell), but only 20,000 or so L-type
calcium (Ca) channels and even fewer copies of each family
of voltage-dependent potassium
(K) channels.
The cardinal molecular features of
Na channels hold
true whatever their phylogenetic origin or tissue source.
Na channels consist of various subunits (as reviewed later
in the chapter), but only the principal pore-forming
a sub-
unit is required for function. Figure
1-1A shows that the
1

2 PART I STRUCTURAL AND MOLECULAR BASES OF ION CHANNEL FUNCTION
A I II 111 IV
C
I
111
IV
D TEAi, TE43"t
Shaker
T MT TV DI Y
NaChBac Q VV T LESWAS
Cachannel
I Q C I T MEGWNS
IIQ VL T GEDWNS
Ill T V S T FEGWPQ
IVR CA
T GEAWQE
Nachannel
I R L M T QDCWEr
IIRILC GEWIET
111 Q V A T F
IVQ
IT T
FIGURE 1-1 Schematic depictions of the Na' channel cr subunit. A, Putative transmembrane topology; the charged S4 segments are
shown in white, and the reentrant S5S6 linker consisting of the
S5-P, P-loop (i.e., SS1 and SS2), and P-S6 linker in gray. 6, Schematic diagram
showing the
55 and S6 transmembrane segments, and the reentrant SSS6 linker.The S5S6 linker consists of the SSP, P-loop (i.e., SS1 and
SS2), and P-S6 linker. C, Clockwise arrangement of the four internal domains. 0, Aligned primary sequence of the P-segments in a K channel
(Shaker B), the four domains
of the cardiac L-type Ca channel, a prokaryotic Na channel (NaChBac), and the four domains of the cardiac Na
channels. Residues shown in upper case are highly conserved among mammalian voltage-dependent Na channels. The diamonds indicate the
external and internal binding sites for tetraethylammonium ion in the
K channel; the boxes outline the selectivity filters, although, in the case of
the Na channel, the residues that are most important for selectivity (circled) are outside the box.
eukaryotic Na channel a subunit is an approximately
2000-amino acid single glycoprotein consisting of four
internally homologous domains (labeled
DZ to DZV) con-
nected
by cytoplasmic linkers. Each of these domains con-
tains
six transmembrane segments (S1 to S6) and resembles
a single monomeric
a subunit of a voltage-dependent K
channel (see Chapter 3). The four homologous domains
fold together in
a clockwise orientation" to create a cen-
tral pore.
It is noteworthy that Ca" channels have a sim-
ilar overall architecture,
with important differences in
various regions (including the pore; see Chapter 2).
Because unicellular organisms express
K and Ca channels,

1 Sodium Channels 3
it is plausible that the simpler single-domain K channels
were primordial, with the subsequent evolution
of Ca
channels by gene duplication. Na channels might have
arisen in an analogous manner, or more likely, from muta-
tions in a primitive Ca channel. Consistent with the latter
possibility, a prokaryotic ion channel named NaChBac,
which consists of
a single domain with six transmembrane
segments and strong sequence homology
to voltage-gated
Ca channels (especially in the pore; see Fig. l-lq, is
voltage-dependent and Na’-selective yet sensitive to the
Ca channel blocker nifedipine.”
These evolutionary considerations serve to highlight
various themes that are general to the superfamily of
voltage-dependent cation channels: First, the architecture
is modular, consisting either of four homologous subunits
(in K channels) or of four internally homologous domains
(in mammalian Na and Ca channels). Second, as depicted
in Figure 1-1A to
C, the proteins wrap around a central
ion-conducting pore. The pore-lining regions (“P-loops”)
exhibit exquisite sequence conservation within a given
channel family of similar ionic selectivity (e.g., jellyfish,
electric eel, fruit fly, and human
Na channels have very
similar P-loops) but not among families
of different selec-
tivities (e.g., Na vs.
K channels; see Fig. 1-1D). The pore,
where numerous major functional (e.g., ionic selectivity
and conductance) and pharniacologic determinants of the
channel are fo~nd,~~~~~ is indeed analogous to the active site
of an enzyme. Third, the general strategy whereby the
channels open in response to voltage (a gating process
known
as “activation”) is highly conserved: The fourth
transmembrane segment (S4), stereotypically studded
with
a ribbon of basic residues at every third position (Fig.
1-2), lies within the membrane field and moves outward
in response to depolarization to initiate a series
of con-
formational rearrangements that culminates in channel
~pening.’.~
Genetics
The mammalian genome contains at least nine voltage-
dependent Na channel genes. Unlike the more diverse
classes
of K and Ca channels, these “isoforms” share more
than
SO% sequence identity in the transmembrane and
extracellular domains (but less
so in the cytoplasmic
linkers that connect the four domains) and exhibit rela-
tively similar functional properties. Each of the
Na
channel isoforms is expressed in a developmentally and
tissue-specific manner. The cardiac isoform, for example,
is not only the predominant
Na channel expressed in the
adult heart but is also expressed in embryonal (but not
innervated adult) skeletal muscle. Likewise, the brain
cx
subunits are found to localize in the transverse tubules of
myocytes, where they may play a role in coupling electrical
excitation to cardiac contraction.I2 The human cardiac
Na
channel hNa”1.S (formerly known as hH1; see Goldin and
coworkers6 for
Na channel nomenclature) has been
mapped to the short arm of chromosome
3 (3p2 1-24). The
genomic organization of the cardiac
Na channel gene
(SCNSA) has been described; the human gene contains 28
exons spanning
80 kb of the genome and contains a dinu-
cleotide repeat polymorphism in intron 16.
DESIGN MOTIFS
Permeation
As previously defined, the term pemeation refers to all the
pore properties of the channel. The general features of the
structural basis
of permeation have been elucidated in the
past decade. The hairpin-like SS-S6 linkers that form the
external pore vestibule and
the selectivity filter are divided
into three regions: S5-P, P-loop (whose descending and
ascending regons are termed SS1 and
SS2, respectively),
and P-S6 (see Fig. l-lB).7 Although various lines of evi-
dence have suggested that backbone pore helices similar
to
those observed in the KcsA crystal structure exist in Na
channels,I3 there are a number of notable structural and
functional differences between the Na and K channel
pores. For instance, K channels are multi-ion pores whose
permeation requires
K ions be snugly fit to several high-
affinity pore binding sites formed by backbone car-
bonyls,” but numerous previous studies suggest that the
side chains of
Na (and also Ca) channel P-loop residues are
likely
to line the pore.4 The Na channel P-S6 linkers,
which contribute to single-channel conductance by
increasing the local effective
Na’ concentration at the
external pore mouth, dip back into the membrane
to form
invaginations secondary
to the primary P-l~ops,~’ unlike
those
of K channels.” Inspection of the primary sequences
of the SS-S6 reentrant linkers in each domain (see Fig.
1-10> also reveals that each is unique. The structural basis
of permeation thus differs fundamentally from that of K
channels, in which four identical
P segments form a K+-
selective pore. Indeed, accessibility mapping studies in Na
channels have revealed marked asymmetries in the contri-
butions
of each to the permeation pathway. Two P-loops
play
a particularly prominent role in determining Na’
selectivity: 111, in which a lysine (K1418 in the cardiac
hNa”1.S sequence) is critical for discrimination for
Na+
over Ca’+, and W, in which mutations of various con-
tiguous residues (at hNa”1.5 positions 171 1 to 1714) render
the channel nonselective among monovalents.16 Although
Na and K channels appear to share certain fundamental
features, their pores differ from each other substantially
not only in their molecular architectures but also in the
mechanisms
of permeation, reflecting the additional com-
plexities that
Na+ (and probably Ca”) channels had
acquired during evolution.
It is not yet clear how particular P-loop residues
interact with the bulk solution to favor the specific flux of
Na’ by factors of 1OO:l or more over other cations, a feat
which is particularly remarkable gven the high throughput
of each individual channel (>lo7 ions/sec). Although pore
asymmetries, as discussed above, play an important role in
the permeation properties of voltage-gated mammalian
Na channels, the prokaryotic NaChBac is selective for Na’
over Ca”, suggesting that such asymmetries are not neces-
sarily required for
Na’ selectivity. Further, the presence of
four glutamates in the pore (of NaChBac), whose coordi-
nation is clearly critical for the permeation properties
of
Ca channels,” does not ensure Ca” selectivity. Early analo-
gies
to rigid structures such as the pores in ion-selective
glass membranes seem increasingly unlikely
to capture the
essence
of permeation in biologic channels. In thinking

4 PART I STRUCTURAL AND MOLECULAR BASES OF ION CHANNEL FUNCTION
about this process, it is relevant to consider that Na chan-
nels, like many enzymes, exhibit a high degree of confor-
mational flexibility. Pairs of cysteine residues engineered
into the
P segments can form internal disulfides, in specific
patterns that could not arise if there were not substantial
mobility within the m~lecule.’~*’~ The motions occur over
millisecond time scales and may span tens of
angstroms in
extreme cases. Interestingly,
an internal disulfide crosslink
renders channels less selective than those with
two reduced
sulfhydryls,” hinting that flexibility plays an important
(albeit as-yet-undetermined) role in selective ion translo-
cation. Pore motions have also been linked
to slow inacti-
vation and drug
binding."^^^
Gating: Activation and Inactivation
One of the seminal contributions of Hodgkin and Huxley’
was the notion that Na channels transit among various
conformational states in the process of opening (activa-
tion); yet another set of conformations is entered when the
channels shut during maintained depolarization (“inactiva-
tion”). The
m gates that underlie activation, and the h gate
that mediates inactivation, were postulated to have intrinsic
voltage dependence and to function independently.’
Whereas some of the implicit structural predictions of that
formulation have withstood the test of time, others have
not. The four positively charged
S4 segments are now
widely acknowledged to serve as the major voltage-sensing
apparatus. In the process of activation, several basic
residues in each
S4 segment physically traverse the mem-
brane through a water-filled crevice (“gating pore”) that is
considerably shorter than the thickness of the bilayer and
becomes narrower toward the protein interior (see Fig.
1-2).21 The contributions of each S4 segment to activation
are markedly asymmetric; some of the charged residues
play a much more prominent role than others at “homol-
ogous” positions. Furthermore, charge-altering mutations
in multiple
S4 segments do not exert simple additive
effects on gating; there is some cooperativity, the extent
of
which varies from site to site.22 Indeed, experiments using
site-directed fluorescent labeling have demonstrated that
voltage-dependent translocations of the
S4 of domain IV
occur in response to depolarization only after a lag phase
(relative
to the other domains) and have kinetics slower
than those of activation, implying that its movement may
not even be required for channel opening.23 Further, the
voltage sensors in domains
I11 and IV, but not I and 11, of
Na channels are immobilized upon fast inactivation (see
be lo^).^' Gating currents and mutagenesis studies have
additionally revealed that activation is coupled to inactiva-
tion, presumably via the domain
IV S4.2s Indeed, the time
course of current decay predominantly reflects the voltage
dependence of activation.21
If the
S4s are the sensors, where are the activation
gates? This crucial question remains unresolved. The gate
is expected to be on the internal aspect of the permeation
pathway because pore-lining residues remain accessible
to
externally applied reagents regardless of whether the chan-
nels are open, closed, or inactivated. It is possible that
S4
motions distort the S4-SS linkers, which subsequently lead
to opening or closing of the cytoplasmic pore formed by
S6s (by analogy to K channels) that serve as a gate.
A
SWDomain IV
I I1 111 IV
B
FIGURE 1-2 B Schematic representation of the Na’ channel
a-subunit illustrating the
S4 voltage sensor (A) and the Ill-IV
interdomain linker (B), which contributes to fast inactivation.
The putative receptors of the Ill-IV linker are shown by the thick lines.
Consistent with this possibility, some Na channel blockers
(such as the permanently charged lidocaine congener
QX-
314) can enter the channel from the intracellular milieu
only when the inner pore is open, or they can become
trapped in the cytoplasmic cavity when the channel is
closed. Other studies have indicated that mutations in
S6
alter Na channel gating as well as local anesthetic b10ck.~
Taken together with the finding in
K channels that S6 can
“pinch” shut the cytoplasmic pore mouth in response
to
voltage,26 S6 emerges as a leading contender for the phys-
ical activation gate.
Inactivation turns out
to be a much more arcane
process than originally envisioned by Hodgkin and
Huxley.’ Not only is there loose coupling to activation, as
previously discussed, but there are multiple inactivation
processes. These are distinguishable by their recovery
kinetics at strongly negative potentials: Repriming from
the traditional “fast” inactivation occurs over tens of mil-
liseconds, whereas recovery from “slow” and “ultra-slow”
inactivation can require tens
of seconds or longer. Fast
inactivation is
at least partly mediated by the cytoplasmic
linker between domains III and
IV, the crucial residues of
which are labeled
IFM in Figure 1-2. The 111-IV linker,
whose three-dimensional structure has been determined
by NMR spectro~copy,~’ is likely to function as a “hinge
lid” that docks onto a receptor formed by the
S4S5 cyto-
plasmic loops
of domains I11 and IV28,29 as well as residues
on the cytoplasmic end of domain
IV S6.30 This notion fits
nicely with venerable observations that fast inactivation
can be disrupted by internal proteases. Nevertheless, it is
increasingly clear that mutations scattered widely
throughout the channel affect inactivation gating, under-
mining somewhat the primacy
of the 111-IV linker. The

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writers “were not inspired to do otherwise than
to take these statements as they found them.”
Inerrancy is not freedom from misstatements,
but from error defined as “that which misleads
in any serious or important sense.” When we
compare the accounts of 1 and 2 Chronicles
with those of 1 and 2 Kings we find in the
former an exaggeration of numbers, a
suppression of material unfavorable to the
writer's purpose, and an emphasis upon that
which is favorable, that contrasts strongly with
the method of the latter. These characteristics
are so continuous that the theory of mistakes in
transcription does not seem sufficient to
account for the facts. The author's aim was to
draw out the religious lessons of the story, and
historical details are to him of comparative
unimportance.
H. P. Smith, Bib. Scholarship and Inspiration,
108—“Inspiration did not correct the
Chronicler's historical point of view, more than
it corrected his scientific point of view, which no
doubt made the earth the centre of the solar
system. It therefore left him open to receive
documents, and to use them, which idealized
the history of the past, and described David
and Solomon according to the ideas of later

times and the priestly class. David's sins are
omitted, and numbers are multiplied, to give
greater dignity to the earlier kingdom.” As
Tennyson's Idylls of the King give a nobler
picture of King Arthur, and a more definite
aspect to his history, than actual records justify,
yet the picture teaches great moral and
religious lessons, so the Chronicler seems to
have manipulated his material in the interest of
religion. Matters of arithmetic were minor
matters. “Majoribus intentus est.”
E. G. Robinson: “The numbers of the Bible are
characteristic of a semi-barbarous age. The
writers took care to guess enough. The
tendency of such an age is always to
exaggerate.” Two Formosan savages divide five
pieces between them by taking two apiece and
throwing one away. The lowest tribes can count
only with the fingers of their hands; when they
use their toes as well, it marks an advance in
civilization. To [pg 229]the modern child a
hundred is just as great a number as a million.
So the early Scriptures seem to use numbers
with a childlike ignorance as to their meaning.
Hundreds of thousands can be substituted for
tens of thousands, and the substitution seems
only a proper tribute to the dignity of the

subject. Gore, in Lux Mundi, 353—“This was
not conscious perversion, but unconscious
idealizing of history, the reading back into past
records of a ritual development which was
really later. Inspiration excludes conscious
deception, but it appears to be quite consistent
with this sort of idealizing; always supposing
that the result read back into the earlier history
does represent the real purpose of God and
only anticipates the realization.”
There are some who contend that these
historical imperfections are due to transcription
and that they did not belong to the original
documents. Watts, New Apologetic, 71, 111,
when asked what is gained by contending for
infallible original autographs if they have been
since corrupted, replies: “Just what we gain by
contending for the original perfection of human
nature, though man has since corrupted it. We
must believe God's own testimony about his
own work. God may permit others to do what,
as a holy righteous God, he cannot do himself.”
When the objector declares it a matter of little
consequence whether a pair of trousers were or
were not originally perfect, so long as they are
badly rent just now, Watts replies: “The tailor
who made them would probably prefer to have

it understood that the trousers did not leave his
shop in their present forlorn condition. God
drops no stitches and sends out no imperfect
work.” Watts however seems dominated by an
a priori theory of inspiration, which blinds him
to the actual facts of the Bible.
Evans, Bib. Scholarship and Inspiration, 40
—“Does the present error destroy the
inspiration of the Bible as we have it? No. Then
why should the original error destroy the
inspiration of the Bible, as it was first given?
There are spots on yonder sun; do they stop its
being the sun? Why, the sun is all the more a
sun for the spots. So the Bible.” Inspiration
seems to have permitted the gathering of such
material as was at hand, very much as a
modern editor might construct his account of
an army movement from the reports of a
number of observers; or as a modern historian
might combine the records of a past age with
all their imperfections of detail. In the case of
the Scripture writers, however, we maintain
that inspiration has permitted no sacrifice of
moral and religious truth in the completed
Scripture, but has woven its historical material
together into an organic whole which teaches

all the facts essential to the knowledge of Christ
and of salvation.
When we come to examine in detail what
purport to be historical narratives, we must be
neither credulous nor sceptical, but simply
candid and open-minded. With regard for
example to the great age of the Old Testament
patriarchs, we are no more warranted in
rejecting the Scripture accounts upon the
ground that life in later times is so much
shorter, than we are to reject the testimony of
botanists as to trees of the Sequoia family
between four and five hundred feet high, or the
testimony of geologists as to Saurians a
hundred feet long, upon the ground that the
trees and reptiles with which we are acquainted
are so much smaller. Every species at its
introduction seems to exhibit the maximum of
size and vitality. Weismann, Heredity, 6, 30
—“Whales live some hundreds of years;
elephants two hundred—their gestation taking
two years. Giants prove that the plan upon
which man is constructed can also be carried
out on a scale far larger than the normal one.”
E. Ray Lankester, Adv. of Science, 205-237, 286
—agrees with Weismann in his general theory.

Sir George Cornewall Lewis long denied
centenarism, but at last had to admit it.
Charles Dudley Warner, in Harper's Magazine,
Jan. 1895, gives instances of men 137, 140,
and 192 years old. The German Haller asserts
that “the ultimate limit of human life does not
exceed two centuries: to fix the exact number
of years is exceedingly difficult.” J. Norman
Lockyer, in Nature, regards the years of the
patriarchs as lunar years. In Egypt, the sun
being used, the unit of time was a year; but in
Chaldea, the unit of time was a month, for the
reason that the standard of time was the moon.
Divide the numbers by twelve, and the lives of
the patriarchs come out very much the same
length with lives at the present day. We may
ask, however, how this theory would work in
shortening the lives between Noah and Moses.
On the genealogies in Matthew and Luke, see
Lord Harvey, Genealogies of our Lord, and his
art, in Smith's Bible Dictionary; per contra, see
Andrews, Life of Christ, 55 sq. On Quirinius and
the enrollment for taxation (Luke 2:2), see
Pres. Woolsey, in New Englander, 1869. On the
general subject, see Rawlinson, Historical
Evidences, and essay in Modern Scepticism,

published by Christian Evidence Society, 1:265;
Crooker, New Bible and New Uses, 102-126.
[pg 230]
3. Errors in Morality.
(a) What are charged as such are sometimes evil
acts and words of good men—words and acts not
sanctioned by God. These are narrated by the
inspired writers as simple matter of history, and
subsequent results, or the story itself, is left to point
the moral of the tale.
Instances of this sort are Noah's drunkenness
(Gen. 9:20-27); Lot's incest (Gen. 19:30-38);
Jacob's falsehood (Gen. 27:19-24); David's
adultery (2 Sam. 11:1-4); Peter's denial (Mat.
26:69-75). See Lee, Inspiration, 265, note.
Esther's vindictiveness is not commended, nor
are the characters of the Book of Esther said to
have acted in obedience to a divine command.
Crane, Religion of To-morrow, 241—“In law and
psalm and prophecy we behold the influence of
Jehovah working as leaven among a primitive

and barbarous people. Contemplating the Old
Scriptures in this light, they become luminous
with divinity, and we are furnished with the
principle by which to discriminate between the
divine and the human in the book. Particularly
in David do we see a rugged, half-civilized,
kingly man, full of gross errors, fleshly and
impetuous, yet permeated with a divine Spirit
that lifts him, struggling, weeping, and warring,
up to some of the loftiest conceptions of Deity
which the mind of man has conceived. As an
angelic being, David is a caricature; as a man
of God, as an example of God moving upon and
raising up a most human man, he is a splendid
example. The proof that the church is of God, is
not its impeccability, but its progress.”
(b) Where evil acts appear at first sight to be
sanctioned, it is frequently some right intent or
accompanying virtue, rather than the act itself, upon
which commendation is bestowed.
As Rehab's faith, not her duplicity (Josh. 2:1-
24; cf. Heb. 11:31 and James 2:25); Jael's
patriotism, not her treachery (Judges 4:17-22;
cf. 5:24). Or did they cast in their lot with Israel

and use the common stratagems of war (see
next paragraph)? Herder: “The limitations of
the pupil are also limitations of the teacher.”
While Dean Stanley praises Solomon for
tolerating idolatry, James Martineau, Study,
2:137, remarks: “It would be a ridiculous
pedantry to apply the Protestant pleas of
private judgment to such communities as
ancient Egypt and Assyria.... It is the survival of
coercion, after conscience has been born to
supersede it, that shocks and revolts us in
persecution.”
(c) Certain commands and deeds are sanctioned as
relatively just—expressions of justice such as the age
could comprehend, and are to be judged as parts of
a progressively unfolding system of morality whose
key and culmination we have in Jesus Christ.
Ex. 20:25—“I gave them statutes that were not
good”—as Moses' permission of divorce and
retaliation (Deut. 24:1; cf. Mat. 5:31, 32; 19:7-
9; Ex. 21:24; cf. Mat. 5:38, 39). Compare
Elijah's calling down fire from heaven (2 K.
1:10-12) with Jesus' refusal to do the same,
and his intimation that the spirit of Elijah was

not the spirit of Christ (Luke 9:52-56);
cf.Mattheson, Moments on the Mount, 253-255,
on Mat. 17:8—“Jesus only”: “The strength of
Elias paled before him. To shed the blood of
enemies requires less strength than to shed
one's own blood, and to conquer by fire is
easier than to conquer by love.” Hovey: “In
divine revelation, it is first starlight, then dawn,
finally day.” George Washington once gave
directions for the transportation to the West
Indies and the sale there of a refractory negro
who had given him trouble. This was not at
variance with the best morality of his time, but
it would not suit the improved ethical standards
of today. The use of force rather than moral
suasion is sometimes needed by children and
by barbarians. We may illustrate by the Sunday
School scholar's unruliness which was cured by
his classmates during the week. “What did you
say to him?” asked the teacher. “We didn't say
nothing; we just punched his head for him.”
This was Old Testament righteousness. The
appeal in the O. T. to the hope of earthly
rewards was suitable to a stage of development
not yet instructed as to heaven and hell by the
coming and work of Christ; compare Ex. 20:12
with Mat. 5:10; 25:46. The Old Testament

aimed to fix in the mind of a selected people
the idea of the unity and holiness of God; in
order to exterminate idolatry, much other
teaching was postponed. See Peabody, [pg
231]Religion of Nature, 45; Mozley, Ruling
Ideas of Early Ages; Green, in Presb. Quar.,
April, 1877:221-252; McIlvaine, Wisdom of Holy
Scripture, 328-368; Brit. and For. Evang. Rev.,
Jan. 1878:1-32; Martineau, Study, 2:137.
When therefore we find in the inspired song of
Deborah, the prophetess (Judges 5:30), an
allusion to the common spoils of war—“a
damsel, two damsels to every man” or in Prov.
31:6, 7—“Give strong drink unto him that is
ready to perish, and wine unto the bitter in
soul. Let him drink, and forget his poverty, and
remember his misery no more”—we do not
need to maintain that these passages furnish
standards for our modern conduct. Dr. Fisher
calls the latter “the worst advice to a person in
affliction, or dispirited by the loss of property.”
They mark past stages in God's providential
leading of mankind. A higher stage indeed is
already intimated in Prov. 31:4—“it is not for
kings to drink wine, Nor for princes to say,
Where is strong drink?” We see that God could
use very imperfect instruments and could

inspire very imperfect men. Many things were
permitted for men's “hardness of heart” (Mat.
19:8). The Sermon on the Mount is a great
advance on the law of Moses (Mat. 5:21—“Ye
have heard that it was said to them of old
time”; cf. 22—“But I say unto you”).
Robert G. Ingersoll would have lost his stock in
trade if Christians had generally recognized that
revelation is gradual, and is completed only in
Christ. This gradualness of revelation is
conceded in the common phrase: “the new
dispensation.” Abraham Lincoln showed his
wisdom by never going far ahead of the
common sense of the people. God similarly
adapted his legislation to the capacities of each
successive age. The command to Abraham to
sacrifice his son (Gen. 22:1-19) was a proper
test of Abraham's faith in a day when human
sacrifice violated no common ethical standard
because the Hebrew, like the Roman, “patria
potestas” did not regard the child as having a
separate individuality, but included the child in
the parent and made the child equally
responsible for the parent's sin. But that very
command was given only as a test of faith, and
with the intent to make the intended obedience
the occasion of revealing God's provision of a

substitute and so of doing away with human
sacrifice for all future time. We may well imitate
the gradualness of divine revelation in our
treatment of dancing and of the liquor traffic.
(d) God's righteous sovereignty affords the key to
other events. He has the right to do what he will with
his own, and to punish the transgressor when and
where he will; and he may justly make men the
foretellers or executors of his purposes.
Foretellers, as in the imprecatory Psalms
(137:9; cf. Is. 13:16-18 and Jer. 50:16, 29);
executors, as in the destruction of the
Canaanites (Deut. 7:2, 16). In the former case
the Psalm was not the ebullition of personal
anger, but the expression of judicial indignation
against the enemies of God. We must
distinguish the substance from the form. The
substance was the denunciation of God's
righteous judgments; the form was taken from
the ordinary customs of war in the Psalmist's
time. See Park, in Bib. Sac., 1862:165; Cowles,
Com. on Ps. 137; Perowne on Psalms, Introd.,
61; Presb. and Ref. Rev., 1897:490-505; cf. 2
Tim. 4:14—“the Lord will render to him

according to his works”—a prophecy, not a
curse, ἀποδώσει, not ἀποδώη, as in A. V. In the
latter case, an exterminating war was only the
benevolent surgery that amputated the putrid
limb, and so saved the religious life of the
Hebrew nation and of the after-world. See Dr.
Thomas Arnold, Essay on the Right
Interpretation of Scripture; Fisher, Beginnings
of Christianity, 11-24.
Another interpretation of these events has been
proposed, which would make them illustrations
of the principle indicated in (c) above: E. G.
Robinson, Christian Theology, 45—“It was not
the imprecations of the Psalm that were
inspired of God, but his purposes and ideas of
which these were by the times the necessary
vehicle; just as the adultery of David was not
by divine command, though through it the
purpose of God as to Christ's descent was
accomplished.” John Watson (Ian Maclaren),
Cure of Souls, 143—“When the massacre of the
Canaanites and certain proceedings of David
are flung in the face of Christians, it is no
longer necessary to fall back on evasions or
special pleading. It can now be frankly admitted
that, from our standpoint in this year of grace,
such deeds were atrocious, and that they never

could have been according to the mind of God,
but that they must be judged by their date, and
considered the defects of elementary moral
processes. The Bible is vindicated, because it is,
on the whole, a steady ascent, and because it
culminates in Christ.”
Lyman Abbott, Theology of an Evolutionist, 56
—“Abraham mistook the voice of conscience,
calling on him to consecrate his only son to
God, and interpreted it as a [pg
232]command to slay his son as a burnt
offering. Israel misinterpreted his righteous
indignation at the cruel and lustful rites of the
Canaanitish religion as a divine summons to
destroy the worship by putting the worshipers
to death; a people undeveloped in moral
judgment could not distinguish between formal
regulations respecting camp-life and eternal
principles of righteousness, such as, Thou shalt
love thy neighbor as thyself, but embodied
them in the same code, and seemed to regard
them as of equal authority.”Wilkinson, Epic of
Paul, 281—“If so be such man, so placed ... did
in some part That utterance make his own,
profaning it, To be his vehicle for sense not
meant By the august supreme inspiring Will”—i.
e., putting some of his own sinful anger into

God's calm predictions of judgment. Compare
the stern last words of “Zechariah, the son of
Jehoiada, the priest” when stoned to death in
the temple court: “Jehovah look upon it and
require it”(2 Chron. 24:20-22), with the last
words of Jesus: “Father, forgive them, for they
know not what they do”(Luke 23:34) and of
Stephen: “Lord, lay not this sin to their charge”
(Acts 7:60).
(e) Other apparent immoralities are due to
unwarranted interpretations. Symbol is sometimes
taken for literal fact; the language of irony is
understood as sober affirmation; the glow and
freedom of Oriental description are judged by the
unimpassioned style of Western literature; appeal to
lower motives is taken to exclude, instead of
preparing for, the higher.
In Hosea 1:2, 3, the command to the prophet
to marry a harlot was probably received and
executed in vision, and was intended only as
symbolic: compare Jer. 25:15-18—“Take this
cup ... and cause all the nations ... to drink.”
Literal obedience would have made the prophet
contemptible to those whom he would instruct,

and would require so long a time as to weaken,
if not destroy, the designed effect; see Ann. Par.
Bible, in loco. In 2 K. 6:19, Elisha's deception,
so called, was probably only ironical and
benevolent; the enemy dared not resist,
because they were completely in his power. In
the Song of Solomon, we have, as Jewish
writers have always held, a highly-wrought
dramatic description of the union between
Jehovah and his people, which we must judge
by Eastern and not by Western literary
standards.
Francis W. Newman, in his Phases of Faith,
accused even the New Testament of presenting
low motives for human obedience. It is true
that all right motives are appealed to, and some
of these motives are of a higher sort than are
others. Hope of heaven and fear of hell are not
the highest motives, but they may be employed
as preliminary incitements to action, even
though only love for God and for holiness will
ensure salvation. Such motives are urged both
by Christ and by his apostles: Mat. 6:20—“lay
up for yourselves treasures in heaven”; 10:28
—“fear him who is able to destroy both soul
and body in hell”; Jude 23—“some save with
fear, snatching them out of the fire.” In this

respect the N. T. does not differ from the O. T.
George Adam Smith has pointed out that the
royalists got their texts, “the powers that be”
(Rom. 13:1) and “the king as supreme” (1 Pet.
2:13), from the N. T., while the O. T. furnished
texts for the defenders of liberty. While the O.
T. deals with national life, and the discharge of
social and political functions, the N. T. deals in
the main with individuals and with their
relations to God. On the whole subject, see
Hessey, Moral Difficulties of the Bible; Jellett,
Moral Difficulties of the O. T.; Faith and Free
Thought (Lect. by Christ. Ev. Soc.), 2:173;
Rogers, Eclipse of Faith; Butler, Analogy, part ii,
chap. iii; Orr, Problem of the O. T., 465-483.
4. Errors of Reasoning.
(a) What are charged as such are generally to be
explained as valid argument expressed in highly
condensed form. The appearance of error may be
due to the suppression of one or more links in the
reasoning.
In Mat. 22:32, Christ's argument for the
resurrection, drawn from the fact that God is

the God of Abraham, Isaac, and Jacob, is
perfectly and obviously valid, the moment we
put in the suppressed premise that the living
relation to God which is here implied cannot
properly be conceived as something merely
spiritual, but necessarily requires a new and
restored life of the body. If God is the God of
the living, then Abraham, Isaac, and Jacob shall
rise from the dead. See more full exposition,
under Eschatology. Some of the Scripture
arguments are enthymemes, and an
enthymeme, according to Arbuthnot and Pope,
is “a syllogism in which the major is married to
the minnor, and the marriage is kept secret.”
[pg 233]
(b) Where we cannot see the propriety of the
conclusions drawn from given premises, there is
greater reason to attribute our failure to ignorance of
divine logic on our part, than to accommodation or
ad hominem arguments on the part of the Scripture
writers.
By divine logic we mean simply a logic whose
elements and processes are correct, though not
understood by us. In Heb. 7:9, 10 (Levi's

paying tithes in Abraham), there is probably a
recognition of the organic unity of the family,
which in miniature illustrates the organic unity
of the race. In Gal. 3:20—“a mediator is not a
mediator of one; but God is one”—the law, with
its two contracting parties, is contrasted with
the promise, which proceeds from the sole fiat
of God and is therefore unchangeable. Paul's
argument here rests on Christ's divinity as its
foundation—otherwise Christ would have been
a mediator in the same sense in which Moses
was a mediator (see Lightfoot, in loco). In Gal.
4:21-31, Hagar and Ishmael on the one hand,
and Sarah and Isaac on the other, illustrate the
exclusion of the bondmen of the law from the
privileges of the spiritual seed of Abraham.
Abraham's two wives, and the two classes of
people in the two sons, represent the two
covenants (so Calvin). In John 10:34—“I said,
Ye are gods,” the implication is that Judaism
was not a system of mere monotheism, but of
theism tending to theanthropism, a real union
of God and man (Westcott, Bib. Com., in loco).
Godet well remarks that he who doubts Paul's
logic will do well first to suspect his own.

(c) The adoption of Jewish methods of reasoning,
where it could be proved, would not indicate error on
the part of the Scripture writers, but rather an
inspired sanction of the method as applied to that
particular case.
In Gal. 3:16—“He saith not, And to seeds, as of
many; but as of one, And to thy seed, which is
Christ.” Here it is intimated that the very form
of the expression in Gen. 22:18, which denotes
unity, was selected by the Holy Spirit as
significant of that one person, Christ, who was
the true seed of Abraham and in whom all
nations were to be blessed. Argument from the
form of a single word is in this case correct,
although the Rabbins often made more of
single words than the Holy Spirit ever intended.
Watts, New Apologetic, 69—“F. W. Farrar
asserts that the plural of the Hebrew or Greek
terms for ‘seed’ is never used by Hebrew or
Greek writers as a designation of human
offspring. But see Sophocles, Œdipus at
Colonus, 599, 600—γῆς ἔμῆς ἀπηλάθην πρὸς
τῶν ἐμαυτοῦ σπερμάτων—‘I was driven away
from my own country by my own offspring.’ ” In
1 Cor. 10:1-6—“and the rock was Christ”—the
Rabbinic tradition that the smitten rock followed

the Israelites in their wanderings is declared to
be only the absurd literalizing of a spiritual fact
—the continual presence of Christ, as
preëxistent Logos, with his ancient people. Per
contra, see Row, Rev. and Mod. Theories, 98-
128.
(d) If it should appear however upon further
investigation that Rabbinical methods have been
wrongly employed by the apostles in their
argumentation, we might still distinguish between
the truth they are seeking to convey and the
arguments by which they support it. Inspiration may
conceivably make known the truth, yet leave the
expression of the truth to human dialectic as well as
to human rhetoric.
Johnson, Quotations of the N. T. from the O. T.,
137, 138—“In the utter absence of all evidence
to the contrary, we ought to suppose that the
allegories of the N. T. are like the allegories of
literature in general, merely luminous
embodiments of the truth.... If these allegories
are not presented by their writers as evidences,
they are none the less precious, since they
illuminate the truth otherwise evinced, and thus

render it at once clear to the apprehension and
attractive to the taste.” If however the purpose
of the writers was to use these allegories for
proof, we may still see shining through the rifts
of their traditional logic the truth which they
were striving to set forth. Inspiration may have
put them in possession of this truth without
altering their ordinary scholastic methods of
demonstration and expression. Horton,
Inspiration, 108—“Discrepancies and illogical
reasonings were but inequalities or cracks in
the mirrors, which did not materially distort or
hide the Person” whose glory they sought to
reflect. Luther went even further than this
when he said that a certain argument in the
epistle was “good enough for the Galatians.”
[pg 234]
5. Errors in quoting or interpreting the Old
Testament.
(a) What are charged as such are commonly
interpretations of the meaning of the original
Scripture by the same Spirit who first inspired it.

In Eph. 5:14, “arise from the dead, and Christ
shall shine upon thee” is an inspired
interpretation of Is. 60:1—“Arise, shine; for thy
light is come.” Ps. 68:18—“Thou hast received
gifts among men”—is quoted in Eph. 4:8 as
“gave gifts to men.” The words in Hebrew are
probably a concise expression for “thou hast
taken spoil which thou mayest distribute as
gifts to men.” Eph. 4:8agrees exactly with the
sense, though not with the words, of the Psalm.
In Heb. 11:21, “Jacob ... worshiped, leaning
upon the top of his staff” (LXX); Gen. 47:31
has “bowed himself upon the bed's head.” The
meaning is the same, for the staff of the chief
and the spear of the warrior were set at the
bed's head. Jacob, too feeble to rise, prayed in
his bed. Here Calvin says that “the apostle does
not hesitate to accommodate to his own
purpose what was commonly received,—they
were not so scrupulous” as to details. Even
Gordon, Ministry of the Spirit, 177, speaks of “a
reshaping of his own words by the Author of
them.” We prefer, with Calvin, to see in these
quotations evidence that the sacred writers
were insistent upon the substance of the truth
rather than upon the form, the spirit rather
than the letter.

(b) Where an apparently false translation is quoted
from the Septuagint, the sanction of inspiration is
given to it, as expressing a part at least of the
fulness of meaning contained in the divine original—a
fulness of meaning which two varying translations do
not in some cases exhaust.
Ps. 4:4—Heb.: “Tremble, and sin not” (= no
longer); LXX: “Be ye angry, and sin not.” Eph.
4:26quotes the LXX. The words may originally
have been addressed to David's comrades,
exhorting them to keep their anger within
bounds. Both translations together are needed
to bring out the meaning of the original. Ps.
40:6-8—“Mine ears hast thou opened” is
translated in Heb. 10:5-7—“a body didst thou
prepare for me.” Here the Epistle quotes from
the LXX. But the Hebrew means literally: “Mine
ears hast thou bored”—an allusion to the
custom of pinning a slave to the doorpost of his
master by an awl driven through his ear, in
token of his complete subjection. The sense of
the verse is therefore given in the Epistle:
“Thou hast made me thine in body and soul—
lo, I come to do thy will.”A. C. Kendrick: “David,
just entering upon his kingdom after
persecution, is a type of Christ entering on his

earthly mission. Hence David's words are put
into the mouth of Christ. For ‘ears,’ the organs
with which we hear and obey and which David
conceived to be hollowed out for him by God,
the author of the Hebrews substitutes the word
‘body,’ as the general instrument of doing
God's will” (Com. on Heb. 10:5-7).
(c) The freedom of these inspired interpretations,
however, does not warrant us in like freedom of
interpretation in the case of other passages whose
meaning has not been authoritatively made known.
We have no reason to believe that the scarlet
thread of Rahab (Josh. 2:18) was a designed
prefiguration of the blood of Christ, nor that the
three measures of meal in which the woman
hid her leaven (Mat. 13:33) symbolized Shem,
Ham and Japheth, the three divisions of the
human race. C. H. M., in his notes on the
tabernacle in Exodus, tells us that “the loops of
blue = heavenly grace; the taches of gold = the
divine energy of Christ; the rams' skins dyed
red = Christ's consecration and devotedness;
the badgers' skins = his holy vigilance against
temptation”! The tabernacle was indeed a type

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Cardiac Electrophysiology From Cell To Bedside Douglas Zipes And Jose Jalife Auth

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Cardiac Electrophysiology From Cell To Bedside Douglas Zipes And Jose Jalife Auth

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