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Heart Physiology and Pathophysiology

Heart Physiology and Pathophysiology

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Heart Physiology and Pathophysiology

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4/5 (5 ratings)
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4,109 pages
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Released:
Oct 9, 2000
ISBN:
9780080533889
Format:
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Description

Heart Physiology and Pathophysiology, 4E, provides the foundation for the scientific understanding of heart function and dysfunction, and bridges the gap between basic cardiovascular science and clinical cardiology. This comprehensive text covers all the important aspects of the heart and vascular system. The most important and relevant disorders are presented, with emphasis on the mechanisms involved.
The first three editions of this book developed a reputation as the leading reference in cardiovascular science for researchers and academic cardiologists. This recent edition has been updated, expanded, and includes a number of new contributors. It has also been remodeled to expand its usage as a text reference for cardiology residents, practicing cardiologists, and graduate students.

Key Features
* The most comprehensive book available on this topic
* Clear, concise, and complete coverage of all important aspects of cardiovascular physiology/pathophysiology
* Completely updated version of the foremost reference on cardiovascular science, including new information on pathophysiology and electrophysiology
* Useful tool in bridging the gap between basic science, pathophysiology, and clinical cardiology
Publisher:
Released:
Oct 9, 2000
ISBN:
9780080533889
Format:
Book

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Heart Physiology and Pathophysiology - Academic Press

Table of Contents

Cover image

Title page

Copyright

Dedication

Contributors

Foreword

Preface

PART I: PUMPING ACTION AND ELECTRICAL ACTIVITY OF THE HEART

Chapter 1: Sequence of Cardiac Activation and Ventricular Mechanics

I. INTRODUCTION

II. CARDIAC MUSCLE IS SIMILAR TO OTHER MUSCLE TYPES

III. ACTIVATION OF THE HEART

IV. CONTRACTION OF THE HEART

V. SUMMARY

Chapter 2: Coronary Circulation and Hemodynamics

I. INTRODUCTION

II. BASIC CHARACTERISTICS OF THE CORONARY CIRCULATION

III. BLOOD FLOW CONTROL

IV. DYNAMICS OF CORONARY BLOOD FLOW CONTROL

V. MECHANISMS FOR CORONARY FLOW CONTROL

VI. CARDIAC CONTRACTION AND CORONARY FLOW

VII. CORONARY DIASTOLIC PRESSURE–FLOW LINES

VIII. PHYSIOLOGICAL EVALUATION OF CORONARY STENOSIS

IX. SUMMARY AND FUTURE DIRECTIONS

Chapter 3: Neurohumoral Control of Cardiac Function

I. INTRODUCTION

II. AFFERENT NEURONS

III. EFFERENT NEURONS

IV. LOCAL CIRCUIT NEURONS

V. ORGANIZATION OF THE INTRINSIC CARDIAC NERVOUS SYSTEM

VI. NEUROHUMORAL INTERACTIONS CONTRIBUTING TO CARDIAC CONTROL

VII. INTERACTIONS AMONG PERIPHERAL AUTONOMIC NEURONS

VIII. ELECTROPHYSIOLOGY OF INTRATHORACIC CARDIAC GANGLIA

IX. SYNAPTIC MECHANISMS ASSOCIATED WITH NEURONS IN INTRATHORACIC AUTONOMIC GANGLIA

X. INTERACTIONS BETWEEN CNS AND INTRATHORACIC NEURONAL NETWORKS: IMPLICATIONS FOR TREATMENT OF ANGINA PECTORIS

XI. SUMMARY

Chapter 4: Control of Cardiac Output and Its Alterations during Exercise and in Heart Failure

I. INTRODUCTION

II. THE TWO-COMPARTMENT CAPACITANCE MODEL

III. EXERCISE

IV. HEART FAILURE

V. SUMMARY

Chapter 5: Ultrastructure of Cardiac Muscle and Blood Vessels

I. INTRODUCTION AND CAUTION

II. CARDIAC MUSCLE CELLS

III. MYOCARDIAL BLOOD VESSELS

IV. SUMMARY

Chapter 6: Excitability and Impulse Propagation

I. INTRODUCTION

II. MATRICAL CONCEPT OF CARDIAC EXCITABILITY

III. INTERCELLULAR COMMUNICATION

IV. CABLE THEORY AND ELECTROTONIC POTENTIALS

V. PROPAGATION IN SPATIALLY EXTENSIVE ARRAYS OF CELLS

VI. CLINICAL IMPLICATIONS

VII. CONTROL OF ARRHYTHMIAS

VIII. SUMMARY

IX. APPENDIX

Chapter 7: Electrocardiogram and Cardiac Excitation

I. INTRODUCTION

II. ELECTRICAL SOURCES IN THE HEART

III. THE TORSO VOLUME CONDUCTOR

IV. EMERGING NEW APPROACHES TO ELECTROCARDIOGRAPHY: ECGI

V. SUMMARY

Chapter 8: Gap Junction Channels and Healing-Over of Injury

I. INTRODUCTION

II. CARDIAC GAP JUNCTION PROTEINS

III. REGULATION OF GAP JUNCTION EXPRESSION, FORMATION, AND DEGRADATION

IV. FUNCTIONAL PROPERTIES OF CARDIOVASCULAR GAP JUNCTIONS

V. SOMATIC AND GENETIC DISEASE STATES IN WHICH GAP JUNCTION EXPRESSION OR FUNCTION IS ALTERED

VI. SUMMARY

PART II: CELLULAR ELECTROPHYSIOLOGY OF HEART AND VASCULAR SMOOTH MUSCLE

Chapter 9: Electrogenesis of the Resting Potential

I. INTRODUCTION

II. PASSIVE ELECTRICAL PROPERTIES

III. DIFFUSION, PERMEABILITY, AND FLUXES

IV. ION DISTRIBUTIONS AND MAINTENANCE

V. EQUILIBRIUM POTENTIALS

VI. ELECTROCHEMICAL DRIVING FORCES AND MEMBRANE IONIC CURRENTS

VII. DETERMINATION OF RESTING POTENTIAL AND NET DIFFUSION POTENTIAL (Ediff)

VIII. ELECTROGENIC SODIUM PUMP POTENTIALS

IX. PACEMAKER POTENTIALS AND AUTOMATICITY

X. EFFECT OF RESTING POTENTIAL ON ACTION POTENTIAL

XI. SUMMARY

Chapter 10: Cardiac Action Potentials

I. INTRODUCTION

II. CURRENTS DURING PHASES OF THE ACTION POTENTIAL

III. ADDITIONAL CURRENTS CONTRIBUTING TO THE ACTION POTENTIAL

IV. REGIONAL DIFFERENCES IN ACTION POTENTIALS

V. AUTOMATICITY

VI. PATHOPHYSIOLOGY OF CARDIAC ACTION POTENTIALS

VII. SUMMARY

Chapter 11: Electrophysiology of Vascular Smooth Muscle

I. INTRODUCTION

II. MEMBRANE AND ELECTRICAL PROPERTIES OF VASCULAR SMOOTH MUSCLE

III. EXPRESSION OF ION CHANNELS

IV. REGULATION OF VASCULAR TONE BY ION CHANNELS AND MEMBRANE POTENTIAL

V. EFFECT OF PHYSIOLOGICAL FACTORS ON MEMBRANE POTENTIAL

VI. SUMMARY

Chapter 12: Sodium Channels

I. INTRODUCTION

II. MOLECULAR DETERMINATIONS OF Na+ CHANNEL FUNCTION

III. MODULATION BY PHOSPHORYLATION

IV. SODIUM CHANNELOPATHIES

V. SUMMARY

Chapter 13: Voltage-Dependent Calcium Channels

I. INTRODUCTION

II. HIGH VOLTAGE-ACTIVATED CALCIUM CHANNELS

III. REGULATION OF L-TYPE CALCIUM CHANNELS BY VOLTAGE, CALCIUM, AND CHANNEL BLOCKERS

IV. HORMONAL REGULATION OF THE CARDIAC CALCIUM CHANNEL

V. THE VASCULAR SMOOTH MUSCLE L-TYPE CALCIUM CHANNEL

VI. LOW VOLTAGE-ACTIVATED CALCIUM CHANNELS

VII. SUMMARY

Chapter 14: Voltage-Dependent K+ Channels

I. INTRODUCTION

II. OVERVIEW OF K+ CURRENTS IN CARDIAC MYOCYTES

III. VOLTAGE-DEPENDENT K CHANNEL STRUCTURE AND FUNCTION

IV. ION CHANNEL GENES

V. PHYSIOLOGY OF CARDIAC VOLTAGE-DEPENDENT K CURRENTS

VI. Kv CHANNEL GENE EXPRESSION AND THEIR RELATIONSHIP TO Kv CURRENTS IN THE HEART

VII. PHYSIOLOGY, MOLECULAR BIOLOGY, AND MUTATIONS OF K CHANNEL CLONES

VIII. SUMMARY

Chapter 15: Inwardly-Rectifying K+ Channels in the Heart

I. INTRODUCTION

II. CLASSICAL INWARDLY RECTIFYING K+ CHANNELS IN THE HEART (IK1)

III. G-PROTEIN-ACTIVATED MUSCARINIC K+ CHANNELS IN THE HEART (KACh)

IV. ATP-SENSITIVE K+ CHANNELS IN THE HEART (KATP)

V. Na+–ACTIVATED K+ CHANNELS (KNa) IN THE HEART

VI. SUMMARY

Appendix: Two-Pore K+ Channels

I. INTRODUCTION

II. STRUCTURE OF 2P/4TM K+ CHANNELS

III. ELECTROPHYSIOLOGICAL PROPERTIES

IV. REGULATION AND PHARMACOLOGY

V. TISSUE DISTRIBUTION AND PHYSIOLOGICAL ROLES OF 2P/4TM K+ CHANNELS

Chapter 16: Voltage and Calcium-Activated K+ Channels of Coronary Smooth Muscle

I. INTRODUCTION

II. KEY ROLE OF KCa CHANNELS IN THE REGULATION OF CORONARY ARTERY TONE

III. DISTRIBUTION OF KCa CHANNELS

IV. FUNCTIONAL ANATOMY OF KCa CHANNELS: ROLE OF α AND β SUBUNITS

V. MULTIPLE PATHWAYS INVOLVED IN THE REGULATION OF Kca CHANNEL ACTIVITY

VI. PHARMACOLOGY OF KCa CHANNELS

VII. PROTECTIVE EFFECTS ON CORONARY ARTERY MEDIATED TROUGH KCa CHANNELS

VIII. ROLE OF POTASSIUM CHANNELS IN AGING AND DISEASE

IX. SUMMARY

Chapter 17: Ion Channels in Vascular Smooth Muscle

I. INTRODUCTION

II. Ca2+ CHANNELS

III. Na+ CHANNELS

IV. K+ CHANNELS

V. CHLORIDE CHANNELS IN VASCULAR SMOOTH MUSCLE

VI. NONSELECTIVE CATION CHANNELS

VII. SUMMARY

Chapter 18: Cardiac Pacemaker Currents

I. INTRODUCTION

II. BACKGROUND ON THE PACEMAKER CURRENT

III. PROPERTIES OF CARDIAC If

IV. MODULATION OF PACEMAKER CHANNEL FUNCTION

V. If IN OTHER AREAS OF THE HEART

VI. PHARMACOLOGICAL BLOCKADE OF PACEMAKER CURRENTS

VII. DEVELOPMENTAL REGULATION OF PACEMAKER CURRENTS

VIII. SUBUNITS UNDERLYING THE FORMATION OF If CHANNELS

IX. SUMMARY

Chapter 19: Chloride Channels in Heart

I. INTRODUCTION

II. CHLORIDE CHANNELS IN HEART

III. SUMMARY

Chapter 20: Regulation of Cardiac Ion Channels by Phosphorylation, Ca²+, Cytoskeleton, and Stretch

I. INTRODUCTION

II. EFFECTS OF PHOSPHORYLATION

III. EFFECTS OF Ca2+

IV. EFFECTS OF CYTOSKELETON AND ITS ASSEMBLY

V. STRETCH AND OSMOTIC PRESSURE

VI. SUMMARY

PART III: PUMPS AND EXCHANGERS

Chapter 21: Cardiac Na+/K+ Pump

I. INTRODUCTION

II. MECHANISM

III. PHYSIOLOGY

IV. REGULATION OF THE Na+/K+ PUMP

V. PATHOPHYSIOLOGY

VI. SUMMARY

Chapter 22: Cardiac Na+–Ca²+ Exchanger: Pathophysiology and Pharmacology

I. INTRODUCTION

II. HISTORICAL BACKGROUND

III. BASIC CHARACTERISTICS OF THE Na+–Ca2+ EXCHANGER

IV. STRUCTURE AND LOCALIZATION

V. DEVELOPMENT AND AGING

VI. SPECIES DIFFERENCE

VII. OVEREXPRESSION AND KNOCKDOWN

VIII. DISEASES AND Na+–Ca2+ EXCHANGE

IX. PHARMACOLOGY OF Na+–Ca2+ EXCHANGE

X. SUMMARY

Chapter 23: Na+/H+ Exchanger and pH Regulation

I. INTRODUCTION

II. EXPRESSION, MOLECULAR IDENTITY, AND ROLE OF Na+/H+ EXCHANGE IN HEART PATHOPHYSIOLOGY

III. SUMMARY

Chapter 24: Transport in Nucleus

I. INTRODUCTION

II. NUCLEAR TRANSPORT

III. NUCLEAR STRUCTURE

IV. REGULATION OF NUCLEAR TRANSPORT IN CARDIAC CELLS

V. SUMMARY

Chapter 25: Sarcoplasmic Reticulum Ca²+ Transport

I. INTRODUCTION

II. STRUCTURE AND TISSUE DISTRIBUTION OF SR Ca2+-ATPase

III. REGULATION OF SR Ca2+-ATPase

IV. SR Ca2+-ATPase AND CARDIAC FUNCTION

V. SR Ca2+-ATPase IN CARDIAC DISEASES

VI. SUMMARY

Chapter 26: Calcium Release from Cardiac Sarcoplasmic Reticulum

I. INTRODUCTION

II. MECHANISMS OF EXCITATION–CONTRACTION COUPLING

III. STRUCTURE OF Ca2+ RELEASE CHANNEL/RyR

IV. REGULATION OF RyR BY ENDOGENOUS EFFECTORS

V. REGULATION OF RyR BY EXOGENOUS EFFECTORS

VI. Ca2+ RELEASE CHANNEL/RyR FUNCTION IN ISCHEMIC MYOCARDIUM

VII. S-NITROSYLATION AND OXIDATION OF Ca2+ RELEASE CHANNEL/RyR

VIII. SR Ca2+ TRANSPORT PROTEINS IN HYPERTROPHIC AND FAILING HEARTS

IX. SUMMARY

PART IV: VASCULAR ENDOTHELIUM

Chapter 27: Function of Vascular Endothelium

I. INTRODUCTION

II. NORMAL ENDOTHELIAL FUNCTION

III. PATHOPHYSIOLOGY OF THE ENDOTHELIUM

IV. ENDOTHELIAL DYSFUNCTION IN HYPERCHOLESTEROLEMIA AND POTENTIAL REVERSIBILITY

V. ENDOTHELIAL DYSFUNCTION IN DIABETES

VI. SUMMARY

Chapter 28: Ion Channels in Vascular Endothelium

I. INTRODUCTION

II. ROLE OF ION CHANNELS IN VASCULAR ENDOTHELIUM

III. Ca2+ INFLUX PATHWAYS

IV. ION CHANNELS CONTROLLING THE DRIVING FORCE FOR Ca2+ ENTRY

V. SUMMARY

PART V: EXCITATION–CONTRACTION COUPLING AND PHARMACOMECHANICAL COUPLING

Chapter 29: Electromechanical and Pharmacomechanical Coupling in Vascular Smooth Muscle Cells

I. INTRODUCTION

II. Ca2+ ENTRY MECHANISMS

III. PHARMACOMECHANICAL COUPLING

IV. SUMMARY

Chapter 30: Mechanisms Regulating Cardiac Myofilament Response to Calcium

I. INTRODUCTION

II. MYOFILAMENTS AND REGULATION OF CARDIAC OUTPUT IN EXERCISE

III. COVALENT AND NONCOVALENT MODULATION OF MYOFILAMENT RESPONSE TO Ca2+

IV. SUMMARY

Chapter 31: Vascular Smooth Muscle Contraction

I. INTRODUCTION

II. CONTRACTILE PROTEINS

III. REGULATION OF SMOOTH MUSCLE CONTRACTION

IV. REGULATORY PROTEINS

V. SUMMARY

PART VI: METABOLISM AND ENERGETICS

Chapter 32: Myocardial Energy Metabolism

I. INTRODUCTION

II. GLUCOSE

III. GLYCOGEN

IV. LACTATE AND PYRUVATE

V. FATTY ACIDS

VI. MITOCHONDRIAL ENERGY METABOLISM

VII. INTEGRATION OF MYOCARDIAL ENERGY METABOLISM

VIII. SUMMARY

Chapter 33: Metabolism and Energetics of Vascular Smooth Muscle

I. INTRODUCTION

II. MUSCLE ENERGETICS: SMOOTH MUSCLE VERSUS SKELETAL MUSCLE

III. CONTENT OF HIGH-ENERGY PHOSPHATES

IV. SUBSTRATE OXIDATION AND RESPIRATION

V. RESPIRATORY CAPACITY

VI. REGULATION OF OXIDATIVE PHOSPHORYLATION IN VSM

VII. AEROBIC GLYCOLYSIS

VIII. ORGANIZATION OF CARBOHYDRATE METABOLISM IN VSM

IX. COMPARTMENTATION OF GLYCOLYSIS

X. CHEMICAL ENERGY UTILIZATION AND CONTRACTILE ACTIVITY

XI. HOLDING ECONOMY AND ACTIVATION ENERGETICS

XII. ENERGETICS OF WORK-PRODUCING CONTRACTIONS: EFFICIENCY

XIII. ENERGETIC CONSEQUENCES AND TESTS OF LATCH MODELS

XIV. SUMMARY

PART VII: SIGNALING SYSTEMS

Chapter 34: Adrenergic Receptors in the Cardiovascular System

I. INTRODUCTION

II. MOLECULAR CHARACTERIZATION

III. ANIMAL STUDIES

IV. CLINICAL RELEVANCE OF ADRENERGIC SIGNALING IN THE CARDIOVASCULAR SYSTEM

V. SUMMARY

Chapter 35: Cardiac Action of Angiotensin II

I. INTRODUCTION

II. IMMEDIATE CARDIAC RESPONSE TO ANGIOTENSIN II

III. LONG-TERM CARDIAC RESPONSE TO ANGIOTENSIN II

IV. SUMMARY

Chapter 36: ATP and Adenosine Signal Transductions

I. INTRODUCTION

II. EXTRACELLULAR ATP AND THE CARDIOVASCULAR SYSTEM

III. EXTRACELLULAR ADENOSINE AND THE CARDIOVASCULAR SYSTEM

IV. SUMMARY

Chapter 37: Kinase Signaling in the Cardiovascular System

I. INTRODUCTION

II. INITIATION AND CONTROL OF EXTRACELLULAR STIMULI

III. INTRACELLULAR SIGNALING PATHWAYS

IV. OVERVIEW OF TYROSINE KINASE SIGNAL TRANSDUCTION

V. FLOW ACTIVATES PROTEIN TYROSINE KINASES (PTKS)

VI. FLOW ACTIVATES MAP KINASES (MAPKs)

VII. SUMMARY

Chapter 38: Calcium Signaling

I. INTRODUCTION

II. EXCITATION–CONTRACTION COUPLING

III. INFLUENCE OF CALCIUM DURING PACEMAKER ACTIVITY

IV. SUMMARY

Chapter 39: Diadenosine Polyphosphate Signaling in the Heart

I. INTRODUCTION

II. PRESENCE OF ApnA IN THE HEART

III. SYNTHESIS AND METABOLISM OF ApnA

IV. REGULATION OF ApnA LEVELS IN THE HEART

V. DOES A SPECIFIC RECEPTOR FOR ApnA EXIST IN THE HEART?

VI. CARDIAC EFFECTS OF ApnA

VII. COMPARISON OF ApnA WITH MONONUCLEOTIDES AND ADENOSINE

VIII. SUMMARY

PART VIII: DEVELOPMENTAL CHANGES AND AGING

Chapter 40: Cardiac Development and Regulation of Cardiac Transcription

I. INTRODUCTION

II. CARDIAC DEVELOPMENT

III. REGULATION OF CARDIAC GENE EXPRESSION: COMBINATORIAL MECHANISMS

IV. TRANSCRIPTION FACTORS INVOLVED IN HYPERTROPHIC CARDIAC GROWTH

V. TRANSCRIPTION FACTORS AND CONGENITAL HEART DISEASES (CHD)

VI. SUMMARY

Chapter 41: Developmental Changes of Ion Channels

I. INTRODUCTION

II. DEVELOPMENTAL CHANGES

III. SUMMARY

Chapter 42: Aging of the Cardiovascular System

I. INTRODUCTION

II. CARDIOVASCULAR STRUCTURE AND FUNCTION AT REST

III. CARDIOVASCULAR RESERVE CAPACITY

IV. CHRONIC HYPERTENSION MIMICS ACCELERATED AGING

V. ADAPTIVE RESPONSE OF THE OLDER RAT HEART TO CHRONIC STRESS

VI. HEART FAILURE IN THE AGING, SPONTANEOUSLY HYPERTENSIVE RAT (SHR)

VII. SUMMARY

Acknowledgments

Chapter 43: Changes in Autonomic Responsiveness during Development

I. INTRODUCTION

II. CELLULAR PATHWAYS MEDIATING AUTONOMIC RESPONSIVENESS

III. DEVELOPMENTAL REGULATION OF ION CHANNELS AND ITS RELATIONSHIP TO ADRENERGIC STIMULATION

IV. PARASYMPATHETIC AND OTHER NONADRENERGIC SIGNALING CASCADES

V. SUMMARY

PART IX: MECHANISM OF ACTION OF CARDIOACTIVE DRUGS

Chapter 44: Inotropic Mechanisms in Cardiac Muscle

I. INTRODUCTION

II. MAJOR CELLULAR TARGETS

III. β-ADRENERGIC AGONISTS

IV. α-ADRENERGIC ACTIVATION

V. HYPOTHERMIC INOTROPY

VI. CARDIAC GLYCOSIDES

VII. Ca OVERLOAD AND SPONTANEOUS SR Ca RELEASE

VIII. SUMMARY

Chapter 45: Mechanisms of Action of Calcium Antagonists

I. INTRODUCTION

II. CALCIUM ION CHANNELS

III. VOLTAGE AND ION EFFECTS ON CALCIUM CHANNELS

IV. CHANNEL INHIBITORS

V. L-TYPE CALCIUM CHANNELS: STRUCTURE, LIGANDS, BINDING, AND FUNCTION

VI. THERAPEUTIC ASPECTS OF CALCIUM CHANNEL LIGANDS

VII. SUMMARY

Chapter 46: Cyclic Nucleotides and Protein Phosphorylation in Vascular Smooth Muscle Relaxation

I. INTRODUCTION

II. GUANYLYL CYCLASE, CYCLIC GMP, AND CYCLIC GMP-DEPENDENT PROTEIN KINASE

III. ADENYLYL CYCLASE, CYCLIC AMP, AND CYCLIC AMP-DEPENDENT PROTEIN KINASE

IV. CYCLIC NUCLEOTIDE PHOSPHODIESTERASES

V. MECHANISMS OF VASCULAR RELAXATION

VI. SUMMARY

Chapter 47: K+ Channel Openers

I. INTRODUCTION

II. KATP CHANNELS

III. POTASSIUM CHANNEL OPENERS

IV. THERAPEUTIC POTENTIAL OF POTASSIUM CHANNEL OPENERS IN CARDIOVASCULAR MEDICINE

V. MYOCARDIAL PRESERVATION IN CARDIAC SURGERY

VI. ISCHEMIC HEART DISEASE

VII. CORONARY ARTERY SPASM

VIII. SYSTEMIC HYPERTENSION

IX. PULMONARY HYPERTENSION

X. PERIPHERAL VASCULAR DISEASE

XI. ARRHYTHMIA

XII. SUMMARY

Chapter 48: Mode of Action of Antiarrhythmic Drugs

I. INTRODUCTION

II. KINETICS OF DRUG BLOCK

III. STATE DEPENDENCE OF DRUG BLOCK

IV. ACCESS ROUTES AND SITE FOR BLOCKADE

V. MODULATION OF BLOCK

VI. CLASSIFICATION OF ANTIARRHYTHMIC DRUGS

VII. DRUGS WITH CLASS I ACTION: SODIUM CHANNEL BLOCKERS

VIII. DRUGS WITH CLASS III ACTION: POTASSIUM CHANNEL BLOCKERS

IX. DRUG WITH CLASS IV ACTION: CALCIUM CHANNEL BLOCKERS

X. OTHER ANTIARRHYTHMIC DRUGS: ADENOSINE

XI. SUMMARY

PART X: PATHOPHYSIOLOGY

Chapter 49: Cellular Mechanisms of Cardioprotection

I. INTRODUCTION

II. ACQUISITION OF CARDIOPROTECTION BEFORE THE OCCURRENCE OF ISCHEMIA

III. ACQUISITION OF CARDIOPROTECTION DURING ISCHEMIA AND REPERFUSION

IV. HOW TO MEDIATE CARDIOPROTECTION DURING ISCHEMIA AND REPERFUSION

V. TREATMENTS AFTER ACUTE MYOCARDIAL INFARCTION

VI. FUTURE DIRECTIONS OF INVESTIGATION OF CARDIOPROTECTION

VII. SUMMARY

Chapter 50: Ischemic Preconditioning: Description, Mechanism, and Significance

I. INTRODUCTION

II. NATURAL HISTORY

III. TARGETS AND TRIGGERS OF PROTECTION

IV. PROTECTION IS RECEPTOR MEDIATED

V. G-PROTEINS AND PHOSPHOLIPASES

VI. PROTEIN KINASE C

VII. MULTIPLE PKC-COUPLED RECEPTORS MAKE THE TRIGGER FOR PROTECTION REDUNDANT

VIII. BIOCHEMISTRY OF PKC

IX. 5′-NUCLEOTIDASE

X. PRECONDITIONING’S MEMORY IS NOT DEPENDENT ON PHOSPHORYLATION BY PKC

XI. TYROSINE KINASES

XII. MAP KINASES

XIII. HSP 27

XIV. KATP CHANNELS

XV. PRESERVATION OF ATP

XVI. DOES SALVAGE OF ISCHEMIC MYOCARDIUM TRANSLATE INTO IMPROVED MECHANICAL FUNCTION?

XVII. PRECONDITIONING IN HUMANS: CLINICAL ASPECTS

XVIII. SUMMARY

Chapter 51: Cardioplegia and Surgical Ischemia

I. INTRODUCTION

II. ISCHEMIC INJURY

III. BRIEF HISTORY OF THE DEVELOPMENT OF SURGICAL CARDIOPROTECTION

IV. CHARACTERISTICS OF CARDIOPLEGIC PROTECTION

V. PRINCIPLES UNDERLYING THE PROTECTION OF THE HEART DURING CARDIAC SURGERY

VI. SUMMARY

Chapter 52: Apoptosis

I. INTRODUCTION

II. APOPTOSIS: A DISTINCT TYPE OF CELL DEATH

III. TECHNIQUES TO DETECT APOPTOTIC CELL DEATH

IV. A WORM LEADS THE PATH

V. CASPASES

VI. MOLECULAR EVENTS DOWNSTREAM OF CASPASES

VII. DISPOSAL OF THE APOPTOTIC BODY

VIII. DEATH RECEPTOR PATHWAY OF CASPASE ACTIVATION

IX. MITOCHONDRIA AS INDUCERS OF APOPTOTIC CELL DEATH

X. BCL-2 FAMILY PROTEINS AND THE REGULATION OF MITOCHONDRIA-INDUCED APOPTOSIS

XI. REGULATION OF APOPTOSIS INDUCED BY DEATH RECEPTORS

XII. REGULATION OF APOPTOSIS BY INHIBITION OF DOWNSTREAM CASPASES

XIII. INTRACELLULAR SIGNALING AFFECTING APOPTOSIS

XIV. APOPTOSIS IN CARDIAC DISEASE

XV. SUMMARY

Chapter 53: Calcium Overload in Ischemia/Reperfusion Injury

I. INTRODUCTION

II. Ca2+ MOVEMENTS IN CARDIOMYOCYTES

III. REGULATION OF Ca2+ MOVEMENTS IN THE HEART

IV. Ca2+ OVERLOAD IN THE HEART

V. Ca2+ OVERLOAD AND CARDIAC DYSFUNCTION

VI. Ca2+ OVERLOAD AND ISCHEMIC HEART DISEASE

VII. MYOCARDIAL PRECONDITIONING

VIII. SUMMARY

Chapter 54: Coronary Atherosclerosis and Restenosis

I. INTRODUCTION

II. THE NORMAL ARTERY

III. PATHOLOGIC CHANGES IN THE ARTERIAL WALL IN ATHEROSCLEROSIS

IV. DISTRIBUTION OF CORONARY ATHEROSCLEROSIS AND PLAQUE COMPOSITION

V. THE VULNERABLE PLAQUE AND PLAQUE RUPTURE: THEORIES AND PATHOPHYSIOLOGY

VI. THROMBUS FORMATION

VII. LIPIDS AND ATHEROSCLEROSIS

VIII. ANTIOXIDANTS

IX. CIGARETTE SMOKING

X. HYPERTENSION AND ATHEROSCLEROSIS

XI. COMMENTS CONCERNING OTHER SIGNIFICANT RISK FACTORS

XII. RESTENOSIS AND ACCELERATED ARTERIOSCLEROSIS SYNDROMES

XIII. SUMMARY

Chapter 55: Diabetic Vascular Disease

I. INTRODUCTION

II. ROLE OF THE ENDOTHELIUM IN VASCULAR REACTIVITY

III. ENDOTHELIUM-DEPENDENT VASCULAR RESPONSES DURING DIABETES MELLITUS

IV. MECHANISMS FOR VASCULAR DYSFUNCTION DURING DIABETES MELLITUS

V. EFFECT OF DIABETES MELLITUS ON CONTRACTION OF VASCULAR SMOOTH MUSCLE

VI. EFFECT OF DIABETES MELLITUS ON VASCULAR PERMEABILITY

VII. SUMMARY

Chapter 56: Angiogenesis and Coronary Collateral Circulation

I. INTRODUCTION

II. THE HUMAN HEART: ARTERIOGENESIS OR ANGIOGENESIS?

III. MECHANISMS OF ANGIOGENESIS

IV. MECHANISMS OF ARTERIOGENESIS

V. GROWTH FACTORS INVOLVED IN ARTERIOGENESIS

VI. MORPHOLOGY OF DEVELOPING COLLATERAL VESSELS

VII. SUMMARY

Chapter 57: Molecular Pathophysiology of Cardiomyopathies

I. INTRODUCTION

II. CARDIOMYOPATHIES AS PARADIGMS OF THE CARDIAC RESPONSE TO INJURY

III. MOLECULAR PATHOPHYSIOLOGY OF HYPERTROPHIC CARDIOMYOPATHY

IV. MOLECULAR PATHOPHYSIOLOGY OF DILATED CARDIOMYOPATHY

V. SUMMARY

Chapter 58: Signal Transduction of Cardiac Myocyte Hypertrophy

I. INTRODUCTION

II. HYPERTROPHIC RESPONSE

III. MODEL OF CARDIAC HYPERTROPHY

IV. HYPERTROPHY SIGNALING

V. CARDIAC HYPERTROPHY IN GENETICALLY ALTERED ANIMALS

VI. HEART FAILURE IN GENETICALLY ALTERED ANIMALS

VII. SUMMARY

Chapter 59: Electrophysiological Changes in Hypertrophy

I. INTRODUCTION

II. ELECTROPHYSIOLOGICAL DEFECTS IN HYPERTROPHY AND HEART FAILURE

III. CONTRACTILE DEFECTS IN HYPERTROPHY AND FAILURE

IV. CALCIUM REGULATION IN CHF

V. SARCOPLASMIC RETICULUM Ca UPTAKE AND RELEASE IN CHF

VI. SARCOLEMMAL SODIUM CALCIUM EXCHANGE IN CHF

VII. WHAT CAUSES THE ABUNDANCE OF Ca REGULATORY PROTEINS TO CHANGE IN CHF?

VIII. ARE Ca REGULATORY PROTEINS GOOD TARGETS FOR GENE THERAPY?

IX. SUMMARY

Chapter 60: Molecular Basis of Inherited Long QT Syndromes and Cardiac Arrythmias

I. INTRODUCTION

II. THE LONG QT SYNDROME

III. OTHER INHERITED CARDIAC ARRHYTHMIAS

IV. SUMMARY

Chapter 61: Molecular Mechanisms of Atrial Fibrillation

I. INTRODUCTION

II. OVERVIEW

III. REMODELING IN FIBRILLATING ATRIA

IV. UNIQUE FEATURES OF MAMMALIAN ATRIA THAT MAY INFLUENCE AF

V. CELLULAR AND MOLECULAR BASIS OF ELECTROPHYSIOLOGICAL REMODELING

VI. SUMMARY

Chapter 62: Lipids Released during Ischemia and Arrhythmogenesis

I. INTRODUCTION

II. THE IMPORTANCE OF PHOSPHOLIPIDS IN CONTROLLING SARCOLEMMAL ION FLUX

III. PHOSPHOLIPID METABOLISM IN THE HEART

IV. PHOSPHOLIPID TURNOVER DURING ISCHEMIA

V. OXYGEN-DERIVED FREE RADICALS AND PHOSPHOLIPID TURNOVER

VI. ACCUMULATION OF INTERMEDIATES OF FATTY ACID OXIDATION DURING ISCHEMIA AND REPERFUSION

VII. LYSOPHOSPHOLIPID AND LONG CHAIN ACYLCARNITINE EFFECTS ON CARDIAC ELECTROPHYSIOLOGY

VIII. SUMMARY

Chapter 63: Ion Channels in the Heart

I. INTRODUCTION

II. NORMAL SPREAD OF THE IMPULSE: ROLES OF SPECIALIZED TISSUE

III. SODIUM CHANNEL CURRENT

IV. CALCIUM CHANNEL CURRENTS

V. POTASSIUM CHANNELS IN HEART: DELAYED RECTIFIERS

VI. NEUROMODULATION OF DELAYED RECTIFICATION IN THE HEART

VII. SUMMARY

Chapter 64: Cardiac Arrhythmias: Reentry and Triggered Activity

I. INTRODUCTION

II. REENTRY

III. AFTERDEPOLARIZATIONS AND TRIGGERED ACTIVITY

IV. SUMMARY

Chapter 65: Myocardial Reperfusion Injury—Role of Free Radicals and Mediators of Inflammation

I. INTRODUCTION

II. THE OXYGEN PARADOX AND THE DETRIMENTAL EFFECTS OF REACTIVE OXYGEN SPECIES

III. MYOCARDIAL REPERFUSION INJURY

IV. NEUTROPHILS AND REPERFUSION INJURY—ROLE OF ADHESION MOLECULES IN PROMOTING NEUTROPHIL-MEDIATED TISSUE DAMAGE

V. MEDIATORS OF NEUTROPHIL-INDUCED CELLULAR INJURY

VI. THE COMPLEMENT SYSTEM

VII. THE CLASSICAL COMPLEMENT PATHWAY

VIII. ACTIVATION OF THE ALTERNATIVE COMPLEMENT PATHWAY

IX. REGULATORS OF COMPLEMENT ACTIVATION (RCA)

X. ROLE OF COMPLEMENT ACTIVATION IN MYOCARDIAL ISCHEMIA/REPERFUSION INJURY

XI. COMPLEMENT ACTIVATION AND MEMBRANE SIGNALING

XII. ANAPHYLATOXINS—CORONARY ARTERY SMOOTH MUSCLE RESPONSES

XIII. INFLAMMATORY RESPONSE DURING MYOCARDIAL ISCHEMIA/REPERFUSION

XIV. ENDOGENOUS TISSUE FORMATION OF COMPLEMENT PROTEINS AND THE TERMINAL COMPLEX

XV. FREE RADICALS AND THE COMPLEMENT CASCADE

XVI. SUMMARY

Chapter 66: Cardiac Toxicology

I. INTRODUCTION

II. MAJOR CATEGORIES OF CARDIOTOXICANTS

III. SUMMARY

Chapter 67: Regulation of Gene Expression by Hypoxia

I. INTRODUCTION

II. MECHANISMS OF OXYGEN SENSING

III. SIGNAL TRANSDUCTION BY HYPOXIA

IV. HYPOXIC INDUCTION OF PHYSIOLOGICALLY RELEVANT GENES

V. SUMMARY

Chapter 68: Gene Transfer in Cardiovascular Therapy

I. INTRODUCTION

II. VECTORS FOR CARDIOVASCULAR GENE TRANSFER

III. MAJOR SHORTCOMINGS OF AVAILABLE VECTORS

IV. GENE DELIVERY TO THE VASCULATURE

V. GENE DELIVERY TO THE MYOCARDIUM

VI. CARDIOVASCULAR GENE THERAPY STRATEGIES

VII. SUMMARY

Index

Copyright

Front cover images: (Left) Three-dimensional (NMR) structure of CaM bound to a synthetic peptide corresponding to the CaM-binding domain (residues 796-815) of smooth muscle MLCK. (Right) Three-dimensional (X-ray crystallographic) structure of free CaM with four bound Ca²+ ions. For more information, see color Figure 4 in Chapter 32. (Background) Model of calcium-dependent inactivation of the L-type α1C channel. For more information, see Figure 5 in Chapter 13.

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Dedication

The fourth edition of Heart Physiology and Pathophysiology is dedicated to Planet Earth and its animal and plant inhabitants. The destruction of the environment and toxic pollution of the air, water, and soil are still occurring at an alarming rate. Our wilderness, forests, parks, and farmland are under increasing pressure. There is an urgent need for global population stabilization and global human rights. Our main salvation may be those numerous national and international nonprofit organizations that are dedicated to halting the ruthless destruction of our planet and the inhumane treatment of animals and humans. These organizations are concerned about the environment, wildlife, forests, farmland, overpopulation, animal rights and welfare, and human rights. Such deserving organizations are in desperate need of support from all of us. We urge all readers of this book to express their serious and urgent concern for the well-being of Planet Earth and all of its inhabitants, and to help educate the public and governments worldwide.

Diagram provided by courtesy of Richard S. Babb.

The Foundation of Every State is Education of its Youth.

Diogenes

Contributors

The numbers in parentheses indicate the pages on which the authors’ contributions begin.

Jun-ichi Abe(657)

Cardiovascular Research Center, University of Rochester Medical Center, Rochester, New York 14642

Hugues Abriel(1137)

Department of Pharmacology, Columbia University, New York, New York 10032

Eric A. Accili(357)

School of Kinesiology, Faculty of Applied Sciences, Simon Fraser University, Burnaby, British Columbia, Canada V5A 1S6

Daniel Acosta, Jr. (1211)

College of Pharmacy, University of Cincinnati, Cincinnati, Ohio 45267

Lee F. Allen(599)

Department of Early Clinical Research, Pfizer, Inc., Groton, Connecticut 06340

Tara J. Allen(571)

Department of Physiology, University of Missouri, Columbia, Missouri 65212

Charles Antzelevitch(1153)

Masonic Medical Research Laboratory, Utica, New York 13501

Hiroki Aoki(1065)

Cardiovascular Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215

Jeffrey L. Ardell(45)

Department of Pharmacology, James H. Quillen College of Medicine, Johnson City, Tennessee 37614

Makoto Arita(229)

Department of Physiology, Oita Medical University, Oita 879-5593, Japan

Morton F. Arnsdorf(99)

Department of Medicine, Section of Cardiology, University of Chicago, Chicago, Illinois 60637

John A. Auchampach(633)

Department of Medicine, University of Louisville, Louisville, Kentucky 40292

Shmuel Banai(967)

Department of Cardiology, Bikur Cholim Hospital, and Department of Anatomy and Cell Biology, The Hebrew University, Hadassah Medical School, Jerusalem 91120, Israel

Jacques Barhanin(1097)

Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, 06560 Valbonne, France

M. Baruscotti(357)

Department of Physiology and General Biochemistry, University of Milan, 20133 Milan, Italy

Brian M. Bennett(805)

Departments of Pharmacology and Toxicology, Faculty of Medicine, Queen’s University, Kingston, Ontario, Canada K7L 3N6

Bradford C. Berk(657)

Cardiovascular Research Center, University of Rochester Medical Center, Rochester, New York 14642

Donald M. Bers(779)

Department of Physiology, Loyola University Chicago, Maywood, Illinois 60153

Marvin Boluyt(737)

Department of Movement Science, Laboratory of Molecular Kinesiology, University of Michigan, Ann Arbor, Michigan 48109

Mulugu V. Brahmajothi(259)

Department of Physiology and Biophysics, University at Buffalo, State University of New York, Buffalo, New York 14214

Eugene Braunwald(xix)

Department of Medicine, Brigham & Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115

Alexander Burashnikov(1153)

Masonic Medical Research Laboratory, Utica, New York 13501

Donald L. Campbell(259)

Department of Physiology and Biophysics, University at Buffalo, State University of New York, Buffalo, New York 14214

D.J. Chambers(887)

Cardiac Surgical Research/Cardiothoracic Surgery, Guy’s and St. Thomas’ NHS Trust, The Rayne Institute, King’s College, St. Thomas’ Hospital, London SE1 7EH, England

Frédéric Charron(705)

Laboratory of Cardiac Growth and Differentiation, Montreal Clinical Research Institute, and Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada H2W 1R7

Vijay S. Chauhan(837)

Duke University Medical Center, Durham, North Carolina 27710

University of Western Ontario, Ontario, Canada

Guoxiang Chu(447)

Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267

Michael V. Cohen(867)

Departments of Medicine and Physiology, University of South Alabama, College of Medicine, Mobile, Alabama 36688

Humbert De Smedt(501)

Department of Physiology, Catholic University of Leuven, B-3000 Leuven, Belgium

Naranjan S. Dhalla(949)

Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, and Department of Physiology

Faculty of Medicine, University of Manitoba, Winnipeg, Canada R2H 2A6

D. DiFrancesco(357)

Department of Physiology and General Biochemistry, University of Milan, 20133 Milan, Italy

James M. Downey(3, 61, 867)

Department of Physiology, University of South Alabama, College of Medicine, Mobile, Alabama 36688

Milou D. Drici(1097)

Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, 06560 Valbonne, France

Guy Droogmans(481, 501)

Department of Physiology, Catholic University of Leuven, B-3000 Leuven, Belgium

Istvan Edes(447)

Department of Heart and Lung Diseases, University Medical School, HU-4032 Debrecen, Hungary

Masao Endoh(609)

Department of Pharmacology, Yamagata University School of Medicine, Yamagata 990-9585, Japan

Denis Escande(1097)

Physiopathologie et Pharmacologie Cellulaires et Moléculaires, Hôpital G. R. Laennec, 44035 Nantes, France

Michael S. Forbes(71)

Merry Oaks, Troy, Virginia 22974

Akikazu Fujita(281)

Department of Veterinary Pharmacology, Faculty of Agriculture, University of Osaka Prefecture, Osaka 599-8531, Japan

Tetsushi Furukawa(389)

Department of Physiology I, Akita University School of Medicine, Akita 010-8543, Japan

A. Marquis Gacy(437)

Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic and Foundation, Rochester, Minnesota 55905

Antony Galione(679)

Department of Pharmacology, Oxford University, Oxford OX1 3QT, England

S. David Gertz(967)

Department of Anatomy and Cell Biology, The Hebrew University, Hadassah Medical School, Jersualem 91120, Israel

Augustus O. Grant(837)

Duke University Medical Center, Durham, North Carolina 27710

University of Western Ontario, Ontario, Canada

Christopher D. Hardin(571)

Department of Physiology, University of Missouri, Columbia, Missouri 65212

Robert D. Harvey(373)

Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106

Armin Haunstetter(927)

Department of Cardiology, University of Heidelberg, Heidelberg, Germany

D.J. Hearse(887)

Cardiovascular Research, King’s Centre for Cardiovascular Biology and Medicine, The Rayne Institute, King’s College, St. Thomas’ Hospital, London SE1 7EH, England

Gerd Heusch(3, 61)

Department of Pathophysiology, University of Essen, 45147 Essen, Germany

Yuji Hirano(389)

Department of Cardiovascular Diseases, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan

Masayasu Hiraoka(389)

Department of Cardiovascular Diseases, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan

Franz Hofmann(247)

Institut für Pharmakologie und Toxikologie, Technische Universität München, D-80802 München, Germany

Masatsugu Hori(853)

Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita 565-0871, Japan

Steven R. Houser(1087)

Molecular and Cellular Cardiology Laboratory, Cardiovascular Research Group, Temple University School of Medicine, Philadelphia, Pennsylvania 19140

Joseph R. Hume(373)

Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada 89557

Seigo Izumo(927, 1065)

Cardiovascular Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215

Arshad Jahangir(829)

Division of Cardiovascular Diseases and Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, Minnesota 55905

Aleksandar Jovanovic(693)

Tayside Institute of Child Health, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland

Sofija Jovanovic(693)

Tayside Institute of Child Health, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland

Paul F. Kantor(543)

McMaster University, Hamilton, Canada

Gary J. Kargacin(527)

Smooth Muscle Research Group, University of Calgary Faculty of Medicine, Calgary, Alberta, Canada T2N 4N1

Robert S. Kass(1137)

Department of Pharmacology, Columbia University, New York, New York 10032

Seiko Kawano(389)

Department of Cardiovascular Diseases, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan

Junko Kimura(417)

Department of Pharmacology, Fukushima Medical University, School of Medicine, Fukushima 960-1295, Japan

Masafumi Kitakaze(853)

Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita 565-0871, Japan

Kenji Kitamura(327)

Department of Pharmacology, Fukuoka Dental College, Fukuoka 814-0193, Japan

Evangelia G. Kranias(447)

Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267

Iftikhar J. Kullo(1233)

Mayo Clinic and Foundation, Rochester, Minnesota 55905

Yoshihisa Kurachi(281)

Department of Pharmacology II, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan

Adi Kurgan(967)

Department of Surgery B, Shaare Zedek Hospital, Jerusalem 91031, Israel

Lubica Lacinová(247)

Institut für Pharmakologie und Toxikologie, Technische Universität München, D-80802 München, Germany

Edward G. Lakatta(737)

Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224

Amir Lerman(473)

Mayo Clinic and Foundation, Rochester, Minnesota 55905

Andrew P. Levy(1225)

Technion Faculty of Medicine, Bat Galim 31096, Israel

Jon W. Lomasney(599)

Department of Pathology, Northwestern University Medical School, Chicago, Illinois 60611

Gary D. Lopaschuk(543, 1125)

Cardiovascular Research Group, University of Alberta, Edmonton, Alberta, Canada T6G 2S2

Benedict R. Lucchesi(1181)

Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109

Jane A. Madden(213)

Department of Neurology, Medical College of Wisconsin, Zablocki Veterans Administration Medical Center, Milwaukee, Wisconsin 53295

Jonathan C. Makielski(99)

Departments of Medicine and Physiology, University of Wisconsin, Madison, Wisconsin 53792

Ali J. Marian(1045)

Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030

Jure Marijic(309)

Department of Anesthesiology, University of California, Los Angeles School of Medicine, Los Angeles, California 90095

Donald H. Maurice(805)

Departments of Pathology and Pharmacology and Toxicology

Faculty of Medicine, Queen’s University, Kingston, Ontario, Canada K7L 3N6

William G. Mayhan(1011)

Department of Physiology and Biophysics, University of Nebraska Medical Center, Omaha, Nebraska 68198

Gerhard Meissner(461)

Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599

Ludwig Missiaen(501)

Department of Physiology, Catholic University of Leuven, B-3000 Leuven, Belgium

Michael J. Morales(259)

Department of Physiology and Biophysics, University at Buffalo, State University of New York, Buffalo, New York 14214

A. Moroni(357)

Department of Physiology and General Biochemistry, University of Milan, 20133 Milan, Italy

Mariko Nakamura(175)

Department of Physiology I, School of Medicine, University of the Ryukyus, Okinawa 903-0125, Japan

Mona Nemer(705)

Laboratory of Cardiac Growth and Differentiation, Montreal Clinical Research Institute, and Department of Medicine, Division of Experimental Medicine, McGill University, and Department of Pharmacology, University of Montreal, Montreal, Quebec, Canada H2W 1R7

Jeanne M. Nerbonne(1107)

Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110

Thomas Netticadan(949)

Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, and Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, Canada R2H 2A6

Bernd Nilius(481, 501)

Department of Physiology, Catholic University of Leuven, B-3000 Leuven, Belgium

Katsushige Ono(229)

Department of Physiology, Oita Medical University, Oita 879-5593, Japan

Lionel H. Opie(543)

University of Cape Town, RSA 7925 Cape Town, South Africa

Jan B. Parys(501)

Department of Physiology, Catholic University of Leuven, B-3000 Leuven, Belgium

Richard J. Paul(571)

Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267

Amir Pelleg(633)

Departments of Medicine and Pharmacology, MCP Hahnemann University, Philadelphia, Pennsylvania 19102

Carmen M. Perez-Terzic(437)

Division of Cardiovascular Diseases and Department of Internal Medicine, Department of Molecular Pharmacology and Experimental Therapeutics, and Department of Physical Medicine and Rehabilitation, Mayo Clinic and Foundation, Rochester, Minnesota 55905

Valentino Piacentino, III. (1087)

Molecular and Cellular Cardiology Laboratory, Cardiovascular Research Group, Temple University School of Medicine, Philadelphia, Pennsylvania 19140

Jan J. Piek(19)

Department of Cardiology, CRIA, Academic Medical Center, University of Amsterdam, 1100 DE Amsterdam, The Netherlands

Giovanni M. Pitari(805)

Departments of Medicine and Biochemistry and Molecular Pharmacology, Division of Clinical Pharmacology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

M. Pucéat(427)

Research Center of Macromolecular Biochemistry, CNRS UPR 1086, Cedex 5, France

Stevan Rakovic(679)

Department of Pharmacology, Oxford University, Oxford OX1 3QT, England

Ilaria Rivolta(1137)

Department of Pharmacology, Columbia University, New York, New York 10032

Robert Roberts(1045)

Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030

Richard B. Robinson(761)

Departments of Pharmacology, Medicine, and Pediatrics, Columbia University, New York, New York 10032

Rosita J. Rodriguez(1211)

College of Pharmacy, Oregon State University, Corvallis, Oregon 97331

Michael R. Rosen(761)

Departments of Pharmacology, Medicine, and Pediatrics, Columbia University, New York, New York 10032

Yoram Rudy(133)

Cardiac Bioelectricity Research and Training Center, Case Western Reserve University, Cleveland, Ohio 44106

Nancy J. Rusch(213)

Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

Manjot S. Sandhu(949)

Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, and Department of Physiology

Faculty of Medicine, University of Manitoba, Winnipeg, Canada R2H 2A6

Jutta Schaper(1031)

Department of Experimental Cardiology, Max Planck Institute, D-61231 Bad Nauheim, Germany

Wolfgang Schaper(1031)

Department of Experimental Cardiology, Max Planck Institute, D-61231 Bad Nauheim, Germany

Win-Kuang Shen(829)

Division of Cardiovascular Diseases and Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, Minnesota 55905

Maria Siebes(19)

Department of Cardiology, CRIA, Academic Medical Center, University of Amsterdam, 1100 DE Amsterdam, The Netherlands

Robert D. Simari(1233)

Mayo Clinic and Foundation, Rochester, Minnesota 55905

R. John Solaro(519)

Department of Physiology and Biophysics, University of Illinois at Chicago, College of Medicine, Chicago, Illinois 60612

Jos A.E. Spaan(19)

Department of Medical Physics, CRIA, Academic Medical Center, University of Amsterdam, 1100 DE Amsterdam, The Netherlands

Nicholas Sperelakis(175)

Department of Molecular and Cellular Physiology, University of Cincinnati Medical Center, Cincinnati, Ohio 45267

David C. Spray(149)

Departments of Neuroscience and Medicine (Molecular Cardiology), Albert Einstein College of Medicine, Bronx, New York 10461

Miduturu Srinivas(149)

Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461

Susan F. Steinberg(761)

Departments of Pharmacology, Medicine, and Pediatrics, Columbia University, New York, New York 10032

Joseph R. Stimers(407)

Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205

Harold C. Strauss(259)

Department of Physiology and Biophysics, University at Buffalo, State University of New York, Buffalo, New York 14214

Sylvia O. Suadicani(149)

Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461

Universidade Sao Judas Tadeu, Sao Paulo, Brazil

Masanori Sunagawa(175)

Department of Physiology I, School of Medicine, University of the Ryukyus, Okinawa 903-0125, Japan

James Surapisitchat(657)

Cardiovascular Research Center, University of Rochester Medical Center, Rochester, New York 14642

Masayuki Tanemoto(281)

Department of Pharmacology II, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan

Rana M. Temsah(949)

Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, and Department of Physiology

Faculty of Medicine, University of Manitoba, Winnipeg, Canada R2H 2A6

Derek Terrar(679)

Department of Pharmacology, Oxford University, Oxford OX1 3QT, England

Andre Terzic(437, 693, 829)

Division of Cardiovascular Diseases and Department of Internal Medicine, and Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic and Foundation, Rochester, Minnesota 55905

Noritsuga Tohse(719)

Department of Physiology, Sapporo Medical University School of Medicine, Sapporo 060, Japan

Ligia Toro(309)

Departments of Anesthesiology and Molecular & Medical Pharmacology, University of California, Los Angeles School of Medicine, Los Angeles, California 90095

Helmut A. Tritthart(789)

Institut für Medizinische Physik und Biophysik, Karl-Franzens-Universität Graz, A-8010 Graz, Austria

David R. Van Wagoner(1107)

Department of Cardiology, The Cleveland Clinic Foundation, Cleveland, Ohio 44195

Guy Vassort(633)

INSERM U-390 Physiopathologie Cardiovasculaire, FR-34095 Montpellier, France

Monique J. Vink(149)

Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461

Gordon M. Wahler(199)

Department of Physiology, Midwestern University, Downers Grove, Illinois 60515

Scott A. Waldman(805)

Departments of Medicine and Biochemistry and Molecular Pharmacology, Division of Clinical Pharmacology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Michael P. Walsh(527)

Smooth Muscle Research Group, University of Calgary Faculty of Medicine, Calgary, Alberta, Canada T2N 4N1

Shimin Wang(259)

Department of Physiology and Biophysics, University at Buffalo, State University of New York, Buffalo, New York 14214

Stephanie H. Wilson(473)

Mayo Clinic and Foundation, Rochester, Minnesota 55905

Rui-Ping Xiao(737)

Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224

Jun Yamazaki(327)

Department of Pharmacology, Fukuoka Dental College, Fukuoka 814-0193, Japan

Chen Yan(657)

Cardiovascular Research Center, University of Rochester Medical Center, Rochester, New York 14642

Hisashi Yokoshiki(719)

Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan

Ying-Ying Zhou(737)

Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224

Foreword

When we examine the fourth edition of Heart Physiology and Pathophysiology we can be reassured that physiology’s place as the Queen of the Biological Sciences remains secure. Even more than its three illustrious predecessors, this edition provides a contemporary and comprehensive view of cardiovascular function, beginning with ultrastructure, events at the cell membrane, the processes of contraction and relaxation, the integrated function of the system, and the key mechanisms responsible for its derangement. Both the heart and the vascular system are considered, and the similarities and differences in structure and function of cardiac myocytes and vascular smooth muscle cells are clarified.

The endothelium has long been thought of as a relatively inert casing separating the blood from the vascular wall, but its important roles in vascular smooth muscle function and coagulation receive appropriate attention. The mechanisms of action of the major classes of cardiovascular drugs are also clearly presented. In the final analysis, cellular function is controlled by gene expression, and important new information on the molecular bases of cardiac and vascular injury and dysfunction is provided.

The talented editors, Drs. Sperelakis, Kurachi, Terzic, and Cohen, should be congratulated for selecting a stellar team of authors and for coordinating their efforts in preparing this important text. The fourth edition of Heart Physiology and Pathophysiology is certain to be of intense interest and immense value not only to the broad community of cardiovascular scientists and their trainees but also to cardiologists concerned with the why and wherefore of normal and abnormal cardiovascular function.

Eugene Braunwald, M.D.

Boston, Massachusetts

Preface

The first three editions of Physiology and Pathophysiology of the Heart were successful as advanced reference books for heart researchers and academic cardiologists. The books had developed a solid reputation as being the leaders in the field of cardiovascular science. The first and second editions were translated into Russian. The book was very comprehensive and authoritative. The various chapters were written by leading investigators in their respective specialty areas of cardiovascular science. Although there were some other focused books on heart function, our book was very broad based, covering an array of topics concerning heart function and malfunction.

This was the background for planning of a fourth edition. However, it was suggested that the book be remodeled to make it more of a textbook, as well as a reference book, not only for cardiovascular researchers and academic cardiologists, but also for cardiology residents, practicing cardiologists, and graduate students interested in cardiovascular science. To help in this major endeavor, three well-known cardiovascular scientists were recruited to serve as co-editors and to provide valuable input about topics that should be covered and the experts who should be invited to write chapters on those topics. The editorial work was divided among the four editors.

The editors asked each contributor to make a concise and didactic presentation of the assigned topic. Since the book would become a textbook, we requested that the contributors limit the bibliography to about 50 references, citing only key research reports, reviews, and books. We also asked that their chapter be well illustrated with clear figures.

To help achieve our goal of getting the attention of the cardiology resident and practitioner, we have placed much more emphasis on the relevant pathophysiology and mechanism of drug action. This includes coverage of cardioprotection, ischemia/reperfusion injury, ischemic preconditioning, calcium overload, atherosclerosis, diabetic vascular disease, angiogenesis, cardioplegia, heart failure, cardiomyopathies, hypertrophy, apoptosis, arrhythmias, gene expression, gene therapy, free radical damage, and toxicology. This book provides the foundation for the basic science of heart function and dysfunction, and attempts to bridge the gap between basic cardiovascular science and clinical science.

The fourth edition has been greatly reorganized, including the section headings. A number of previous chapters have been dropped, and a large number of new chapters have been added. There are now 68 chapters compared to 59 chapters in the third edition. Discussions of vascular smooth muscle, endothelial cells, and coronary circulation are integrated and presented in a logical sequence alongside discussion of cardiac muscle.

The publisher of the book is now Academic Press. We wanted to keep the price of the book in a range that students, residents, and researchers could afford. The name of the book was changed to Heart Physiology and Pathophysiology to reflect the new publisher and the new orientation toward a textbook.

The chapters were written by a distinguished group of experts and outstanding scientists from around the world. It has been our pleasure and honor to work with them in the preparation of the fourth edition. We hope that the reader will find the book useful, clear, and comprehensive.

Finally, Dr. Sperelakis wishes to acknowledge the expert technical help of Emily May and Lori Asbury in the preparation of this book.

Nicholas Sperelakis, Yoshihisa Kurachi, Andre Terzic, Michael V. Cohen

PART I

PUMPING ACTION AND ELECTRICAL ACTIVITY OF THE HEART

Sequence of Cardiac Activation and Ventricular Mechanics

JAMES M. DOWNEY

Department of Physiology, University of South Alabama, Mobile, Alabama 36688

GERD. HEUSCH

Department of Pathophysiology, University of Essen, Essen, Germany

I. INTRODUCTION

The primary function of the heart is to circulate blood through the body. It does this by acting as a mechanical pump. While on the surface this function seems simple, investigators have devoted an enormous amount of time and resources to study this pumping process. The ultimate goal is to achieve a complete understanding of how the molecular processes in the individual cells of the heart result in the gross pumping of blood. To reach that goal we must understand how the cells are activated, how tension development and shortening occur on the cellular level, and how the geometry of the fibers, which shorten in a single direction, is coupled to pressure development in the lumen and the accompanying expulsion of volume from it. Unfortunately, our understanding of each of these points remains incomplete. This book has divided the physiology of the heart into many discrete parts. Each chapter focuses on its assigned part and reviews what is known about it in detail. This chapter is designed to serve as an introduction to the basic physiology of the beating heart. The overview provided by this introductory chapter will set the stage for the following in-depth chapters.

II. CARDIAC MUSCLE IS SIMILAR TO OTHER MUSCLE TYPES

Cardiac muscle, like skeletal muscle, is a striated muscle and much of the mechanism of contraction of the two muscle types is similar. Both use the proteins actin and myosin arranged in a highly organized lattice as the basis of the force-generating apparatus. Similarly, both contract in response to an action potential on the sarcolemmal membrane. The electrophysiology of the two muscles differs dramatically, however. In skeletal muscle an action potential at the end plate of a motor neuron causes the skeletal muscle cell to depolarize through release of a transmitter substance, acetylcholine. Thus the skeletal muscle is termed neurogenic, as it contracts only in response to a neural action potential. The skeletal muscle cells are insulated from each other and are, therefore, not affected by the activation of neighboring cells. Skeletal muscle contracts in an all-or-none fashion, and the force generated for any given length will be the same for every twitch. The action potential, however, is so short in skeletal muscle that a significant amount of force can only be generated by stimulating the fiber repeatedly with a train of neural discharges (temporal summation). Cardiac muscle differs in three important respects. First, the cardiac action potential is not initiated by neural activity. Instead, specialized muscle tissue in the heart itself spontaneously initiates the action potential, making the heart’s contraction myogenic (originating within the muscle). Because of gap junctions between adjacent cardiac muscle cells, electrical activation spreads directly from muscle cell to muscle cell. Second, the duration of the cardiac action potential is much longer than that in skeletal muscle and lasts for almost a third of a second. As a result, a single action potential maintains tension development throughout systole. Neural and humoral influences have only a modulatory effect on heart rate. The third difference is that the contraction is not an all-or-none phenomenon. Skeletal muscle grades the strength of contraction through temporal and spatial summation. Because the heart’s contraction is in response to a single action potential transmitted to all fibers, the cardiac muscle cells have evolved a sophisticated system by which the force of contraction can be modulated from beat to beat.

III. ACTIVATION OF THE HEART

A. Excitation Originates within the Pacemaker

Several types of cardiac muscle fibers exist within the heart. It is often useful to classify these types broadly as either contractile or conductile. Contractile cells are the cells of the working myocardium and constitute the bulk of the muscle cells that make up the atria and the ventricles. An action potential in any one of these cells leads to vigorous force development and/or mechanical shortening. Conductile cells are specialized muscle cells that are involved with the initiation or propagation of action potentials rather than direct generation of force. The conducting cells are principally concentrated in the structures indicated in Fig. 1. Of critical importance is the sinoatrial (SA) node. The SA node lies in the right atrium near the entrance of the superior vena cava. SA nodal cells generate spontaneous action potentials and act as the normal pacemaker of the heart. An action potential in a cardiac muscle cell will, through its gap junctions, stimulate neighboring cells to generate an action potential such that each action potential originating in the SA node will be propagated over the whole heart. Because the SA node is located in the atria, action potentials will first be propagated over the atria, making them the first structures in the heart to contract.

FIGURE 1 Structure of the conduction system in the heart. See text for details.

Modified with permission from A. M. Katz, Physiology of the Heart, Raven Press, New York (1992).

Action potentials spreading across the atria eventually reach another conducting structure known as the atrioventricular (AV) node. The AV node is located in the proximal part of the interventricular septum between the origin of the coronary sinus and the septal leaflet of the tricuspid valve. The AV node serves two important functions. The first is to relay the wave of depolarization from the atria to the ventricles. A sheet of connective tissue associated with the valves separates the atria from the ventricles, and the AV node is normally the only conductive link between the atria and the ventricles. The second function of the AV node is to delay the spread of excitation from the atria to the ventricles. AV node cells are specialized to conduct very slowly from cell to cell. This delay permits the atrial contraction to fill the ventricles with blood before the latter begin to contract.

Fibers of the AV node give rise to fibers of the AV bundle (common bundle or bundle of His), which in turn divides into the left bundle branch and the right bundle branch. These branches then divide into an extensive network of Purkinje fibers. Purkinje fibers are conductile cells that conduct action potentials very rapidly. They are interwoven among the contractile cells of the ventricles and serve to quickly spread the wave of excitation throughout the ventricles. If conduction over the ventricles were slow, the heart would contract in a peristaltic wave from base to apex, which would be very inefficient at displacing blood out of the ventricles. The rapidly conducting Purkinje fibers, however, cause the ventricular cardiomyocytes to contract almost simultaneously. It is important to emphasize that all of these conducting structures (i.e., SA node, AV node, Purkinje network) are composed of specialized cardiac muscle cells (Noble, 1978).

B. Cell-to-Cell Conduction Occurs through Gap Junctions

The heart is made up of millions of individual rod-shaped cells, each arranged such that their long axes are oriented parallel to a plane tangent to the heart’s surface. The myocytes are arranged in the heart in a staggered pattern much like bricks in a wall. The region where adjacent myocytes adjoin is termed the intercalated disc and would be analogous to the mortar between the bricks (see Fig. 2). The discs run transversely or perpendicular to the cells’ long axis where the ends of two adjacent myocytes abut. The disc then turns 90° and runs longitudinally between the myocytes until another end abutment begins. The transverse aspect of the intercalated disc is filled with structures called desmosomes. The desmosomes make strong mechanical attachments between the cells, as the cardiomyocytes will shorten in the direction of their long axis. The longitudinally oriented region of the intercalated disc is rich in low-resistance connections between the cells called gap junctions. Small pores in the center of each gap junction allow ions and even small peptides to flow from one cell to another along their electrochemical gradients. An action potential in one muscle cell is propagated to adjacent muscle cells via direct electrotonic propagation across the gap junctions. Because of the gap junctions, every cell in the heart is electrically coupled to the next and, thus, the heart can behave as a single motor unit. Ventricular muscle conducts electrical impulses at about 1 m/sec. Theoretically, an ion inside an SA nodal cell could travel throughout the heart via the gap junctions. The ion could visit every cell without ever having to enter the extracellular space.

FIGURE 2 An electron micrograph of ventricular muscle. The A, I, and Z bands are clearly seen, as are mitochondria (M). The thin line that meanders through the field is an intercalated disk separating two adjacent cells. Details show gap junctions (GJ) and desmosomes (D) on the intercalated disk.

Reproduced with permission from S. R. Goodman, Medical Cell Biology, Lippincott, Philadelphia (1994).

Purkinje cells contain less contractile proteins than contractile cells and are specialized for rapid propagation. The rate of transmission of an action potential from one end of a cell to the other increases in proportion to the cell’s size. The conduction velocity is aided by the large diameter of the Purkinje cells. A Purkinje fiber also has a high density of gap junctions between its cells and it will conduct action potentials four times faster than a ventricular myocyte (4 m/sec). Because of their large size, Purkinje cells are a popular cell type to study in single cell electrophysiological investigations (Cohen et al., 1981).

Cells of the AV and SA nodes, like those in the Purkinje fibers, also have a reduced quantity of contractile proteins. Nodal cells are much smaller than either contractile cells or Purkinje cells, which results in a low propagation velocity of only 0.05 m/sec. AV nodal cells also have a reduced density of gap junctions to further depress their conduction velocity. In addition, nodal cells lack fast sodium channels, which causes the upsweep of the action potential to occur much more slowly. The reduced rate of rise of the action potential voltage also slows the rate of conduction. The low propagation velocity of AV nodal cells accounts for the delay between atrial and ventricular contraction as was noted earlier. While all of these factors act to reduce conduction velocity in the AV node, they also reduce the safety factor in this tissue. The safety factor refers to the ratio of the current actually injected into a neighboring cell to the threshold amount required to initiate an action potential. As this ratio diminishes and approaches one, the probability of conduction failure increases. As a result, conduction block in the AV node is a common clinical occurrence.

Ultrastructural features of a typical cardiac muscle cell are illustrated in Fig. 3. At first glance, the ultrastructure appears much like that in a skeletal muscle cell. Common features include the characteristic A, I, and Z bands where the actin and myosin filaments overlap, a T tubule system, and sarcoplasmic reticulum (SR). Because the pattern of banding is repetitive, it is convenient to refer to the unit from one Z band to the next as a sarcomere, the basic unit of the contractile apparatus. There are some subtle differences, however, between cardiac muscle and skeletal muscle ultrastructure. One major difference lies in the T tubules (the T stands for transverse tubules because they are transversely oriented or perpendicular to the long axis of the cell). They are centered on the Z band with only one tubule per sarcomere, unlike the case in skeletal muscle where there are two tubules per sarcomere located at A–I junctions. In addition, the SR is less developed in the cardiac muscle cell. This feature has important physiological consequences, as will be discussed later. The SR in cardiac contractile cells consists of two types of structures: (a) the sarcotubular network, making up the bulk of the SR, in close proximity to the contractile machinery; and (b) the subsarcolemmal cisternae, which abut the T tubules.

FIGURE 3 Ultrastructure of a contractile cell. A contractile cell in the heart is very similar to a skeletal muscle cell in its basic organization.

Modified with permission from A. M. Katz, Physiology of the Heart, Raven Press, New York (1992).

C. Cardiac Muscle Experiences an Action Potential

Figure 4 shows an action potential typical of what would be recorded from a contractile cell in the ventricle. The action potential causes calcium to enter the cell and to be released from the SR into the cytosol, which in turn activates the actin and myosin filaments. Note that the action potential is about 300 msec in duration, whereas an action potential in a nerve or skeletal muscle cell lasts only about 1 msec (Cranefield, 1977). The plateau phase of the action potential prolongs the active state, preventing the heart from relaxing before the ventricular contents are ejected. The rapid phase of depolarization is termed phase 0. The small initial period of positive potential is called phase 1. Phases 0 and 1 are the result of opening of fast sodium channels (Cohen et al., 1981) and the simultaneous closure of potassium channels. This causes the cell to approach the equilibrium potential for sodium. Figure 4 indicates that sodium conductance becomes high at that time. Phase 1 is followed by a long period, the plateau phase or phase 2, during which the membrane remains depolarized. Note that phase 2 is largely maintained by calcium entry through L-type calcium channels. After the plateau phase, there is a phase of repolarization, during which the membrane potential returns to its resting level. The repolarization phase, termed phase 3, results from the reopening of potassium channels. The resting potential between beats is referred to as phase 4, and at that time the cell is close to the equilibrium potential for potassium.

FIGURE 4 Simplified diagram of the time course of some of the permeability changes that contribute to the cardiac action potential.

Modified with permission from A. M. Katz, Physiology of the Heart, Raven Press, New York (1992).

D. Excitation–Contraction Coupling Is Accomplished by Calcium Ions

Cardiac muscle cells, like skeletal muscle cells, have a highly developed SR system. Excitation–contraction coupling in cardiac muscle cells is similar to that in skeletal muscle cells. Specifically, an action potential travels down the T tubules and causes the release of Ca²+ from the SR, which in turn activates the contractile machinery by attaching to troponin C-binding sites located on actin filaments. During the cardiac action potential there is a sustained increase in Ca²+ conductance, and all Ca²+ ions moving into the cell at that time contribute to mechanical activation.

Figure 5 shows a diagram of how calcium activates the cardiac muscle cell to contract. There are three pools of Ca²+ that are important to the cardiac muscle cell: the extracellular fluid, the SR, and the cytoplasm. Only Ca²+ in the latter compartment is able to bind with the troponin-binding sites and initiate contraction. During an action potential, Ca²+ entry through the sarcolemma increases the concentration of Ca²+ in the cytoplasm. Because the amount of Ca²+ entering is relatively small, however, it accounts for only a fraction of the activation of the contractile proteins. Through mechanisms that are not fully understood, it appears that this relatively small amount of Ca²+ entering the cell during the action potential triggers the release of sequestered Ca²+ within the SR. The importance of this facilitation is evidenced by the fact that heart muscle will not contract when the influx of Ca²+ across the sarcolemma is prevented, even though adequate stores of Ca²+ are still present in the SR.

FIGURE 5 A simplified model of calcium fluxes in the excitation-contraction coupling process in cardiac muscle cells.

From L. R. Johnson, Essential Medical Physiology, 2nd Ed., Lippincott-Raven, Philadelphia (1998), used with permission.

Once Ca²+ reaches the cytosol it is free to bind to troponin C located on the thin actin filaments. This binding, through a complex series of chemical actions, results in modification of the myosin molecule such that it will form crossbridges with the actin filaments and begin the contraction process.

E. Relaxation Is Accomplished by Removing Ca²+ from the Cytosol

In cardiac muscle, as in skeletal muscle, there is a Ca²+ pump in the SR, often referred to as sarcoendoplasmic reticulum calcium ATPase (SERCA). The Ca²+ pump in Fig. 5 removes Ca²+ from the cytoplasmic pool and pumps it back into the SR. When enough Ca²+ is removed from the cytosol, the muscle relaxes. The Ca²+ pump restores the concentration of Ca²+ in the intracellular pool (i.e., SR) to its preaction potential level. With each action potential some extracellular Ca²+, which is the ultimate source of SR Ca²+ stores, moves into the cell. If all of the cytosolic Ca²+ were pumped into the SR, then after only a short period of time the ability of the SR to hold all of the Ca²+ would be exceeded. Clearly, a mechanism is needed to remove Ca²+ from the cell. As shown in Fig. 5, a Na+–Ca²+ exchange system in the sarcolemma is primarily responsible for removing calcium from the cytosol. The exchanger is not a pump and can function only in concert with the membrane Na+–K+ pump, which itself is dependent on ATP as a source of energy. The exchanger will pass three Na+ ions in one direction for one Ca²+ ion in the other direction, but because of its status as an exchanger rather than a pump, it will only do so when the concentration gradients for both ions are favorable. Because the Na+–K+ pump maintains a strong transmembrane gradient for sodium, any free Ca²+ that appears in the cytosol will favorably be exchanged for three Na+ ions from the extracellular fluid. There are also true calcium pumps in the sarcolemma, which are not shown in Fig. 5; they account for only a small percentage of the calcium flux.

F. The Strength of Contraction Can Be Modulated in Cardiac Muscle

The strength of contraction generated by cardiac muscle cells is dependent on the cells’ contractility, sometimes called the inotropic state, which in turn is related to the Ca²+ fluxes described earlier. An increased contractility means that for any given length the muscle is capable of generating a greater force or shortening to a greater extent. It is important to note that the amount of Ca²+ released from the SR with each action potential is not sufficient to fully occupy all of the troponin C-binding sites. Therefore, any manipulation that leads to an enhanced cytosolic Ca²+ during systole will result in a more complete activation of the filaments and thus stronger muscle contraction. The Ca²+ fluxes can, in turn, be altered by a variety of physiological control systems, such as the sympathetic nerves working through the β adrenergic receptors. Details of these systems are discussed in detail in Chapters 3, 34, and 44.

G. Pacemaker Cells Control Heart Rate

The SA node is the normal pacemaker of the heart. Action potentials in the SA node are somewhat different from action potentials in contractile cells. The first and most obvious difference is that these action potentials lack a rapid phase 0 depolarization, as cells in the SA node lack the fast voltage-dependent Na+ channels. Another difference between contractile and nodal cells is that

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