Heart Failure. A Companion to Braunwald's Heart Disease [2 ed.] 9781416058953, 2010010218

Table of contents :
Front Cover
Title Page
Copyright Page
Dedication Page
Contributors
Foreword
Preface
In Memoriam – Helmut Drexler
Acknowledgments
Section I: Basic Mechanisms of Heart Failure
Chapter 1 - Evolving Concepts in the Pathophysiology of Heart Failure
HEART FAILURE AS A CLINICAL SYNDROME
HEART FAILURE AS A CIRCULATORY DISORDER
ALTERED ARCHITECTURE OF FAILING HEARTS
Abnormal Hemodynamics
Disordered Fluid Balance
Biochemical Abnormalities
Energy Starvation
Depressed Contractility
Neurohumoral Stimulation
MALADAPTIVE HYPERTROPHY
GENOMICS
EPIGENETICS
CONCLUSIONS AND FUTURE DIRECTIONS
REFERENCES
Chapter 2 - Molecular Basis for Heart Failure
INVESTIGATIVE TECHNIQUES AND MOLECULAR MODELING
Molecular Ontogeny is Recapitulated by Cardiac Hypertrophy
Molecular Signaling of Normal Heart Growth and Physiological Cardiac Hypertrophy
PATHOLOGICAL HYPERTROPHY: THE CARDIOMYOCYTE GROWTH/DEATH CONNECTION
Apoptosis
Autophagy (see Chapter 6)
Necrosis (see Chapter 6)
Catecholamine Cardiomyopathy: The Cardiomyocyte Contractility/Death ­Connection
Integrins Are Biomechanical Sensors for Hypertrophy
Autocrine/Paracrine Effects of Neurohormones and Growth Factors.Mechanical stretch can transduce hypertrophy via autocrine and p...
Neurohormonal Activation of Hypertrophy Signaling
Gq/Phospholipase/Protein Kinase C.Redundancy in signal transduction at the receptor level in transduction of pathological hypert...
Mitogen Activated Protein Kinases (MAPKs)
IP3-induced Ca2+-mediated Signaling.Gαq signaling causes IP3 production, which interacts with IP3 receptors to cause intracellul...
Calcineurin
Calmodulin-dependent Protein Kinase (CaMK)
HAT/HDAC-mediated Transcriptional Regulation via MEF2/CAMTA
Cross Talk Between Gαq and PI3K/Akt Hypertrophy Signaling Pathways
Non-IGF Growth Factors in Hypertrophy.Cardiac myocytes elaborate peptide growth factors in response to stress. The role of signa...
Small G Proteins
FUTURE DIRECTIONS
REFERENCES
Chapter 3 - Cellular Basis for Heart Failure
CHARACTERISTIC ELECTROMECHANICAL ABNORMALITIES OF FAILING MYOCYTES
In Vivo Cardiac Function Versus In Vitro Muscle and Myocyte ­Contractility
Calcium-Dependent Causes of Electromechanical Dysfunction in the Failing Heart
L-Type Ca2+ Channel
Ryanodine Receptor
The Sarcoplasmic Reticulum
Phospholamban
The Sodium-Calcium Exchanger
Deranged Ca2+ Metabolism may not be Due to a Change in the Abundance of Ca2+ Regulatory Proteins
Is Dysregulated Ca2+ the Cause or the Effect of Heart Failure?
The Role of Contractile Proteins in Regulating Cardiac Performance
Normal Contractile Protein Structure and Function
Length Dependence of Contractility
Heart Failure Due to Mutations of Sarcomeric Proteins
Sarcomeric Protein Isoform Switches in Failing Hearts
Phosphorylation-Dependent Regulation of Sarcomeric Proteins
PKA-mediated Phosphorylation
PKC-mediated Phosphorylation
Titin Phosphorylation and Passive Properties of Myocytes
Limited Proteolysis of Contractile Proteins
CONCLUSIONS
FUTURE DIRECTIONS
REFERENCES
Chapter 4 - Cellular Basis for Myocardial Repair and Regeneration
CELL THERAPY
The Controversy
CELL THERAPY AND MYOCARDIAL INFARCTION
Progenitor Cell Homing
Formation of Temporary Niches
Regulation of Progenitor Cell Growth
Fate of the Engrafted Cells
Mechanics of Progenitor Cells Derived ­Cardiomyocytes
CELL THERAPY AND CHRONIC INFARCT
Progenitor Cells and Fusion Events
FUTURE DIRECTIONS
REFERENCES
Chapter 5 - Myocardial Basis for Heart Failure: Role of the Cardiac Interstitium
MYOCARDIAL EXTRACELLULAR MATRIX STRUCTURE AND COMPOSITION
MYOCARDIAL EXTRACELLULAR MATRIX REMODELING IN CHRONIC HEART FAILURE
Myocardial Extracellular Matrix Remodeling in Myocardial Infarction
Myocardial Extracellular Matrix Remodeling in Left Ventricular Hypertrophy
Myocardial Extracellular Matrix Remodeling in Cardiomyopathy
EXTRACELLULAR MATRIX PROTEOLYTIC DEGRADATION: THE MATRIX METALLOPROTEINASES
Transcriptional Regulation
Matrix Metalloproteinase Gene Polymorphisms
Neurohormones, Cytokines, and Intracellular Activation
Matrix Metalloproteinase Activation
Endogenous Matrix Metalloproteinase Inhibition
Matrix Metalloproteinases and Myocardial Remodeling
Matrix Metalloproteinases and Myocardial Infarction
Matrix Metalloproteinases in Hypertrophy
Matrix Metalloproteinases and Dilated Cardiomyopathy
MODULATION OF MYOCARDIAL EXTRACELLULAR MATRIX REMODELING: DIAGNOSTIC AND THERAPEUTIC TARGETS
ACKNOWLEDGMENTS
REFERENCES
Chapter 6 - Myocardial Basis for Heart Failure: Role of Cell Death
CELL DEATH OVERVIEW
APOPTOSIS
Caspases
Extrinsic Pathway
Intrinsic Pathway
Premitochondrial/Endoplasmic Reticulum Events
Mitochondrial Events
Postmitochondrial Events
ER Stress-induced Apoptosis
Inhibitors of Apoptosis
NECROSIS
Death Receptor/RIP Pathway
Cyclophilin D/MPTP Pathway
Ca2+/Proteases
Some Unresolved Questions
AUTOPHAGIC CELL DEATH
Autophagy
Autophagic Cell Death
PUTTING CELL DEATH TOGETHER
LESSONS FROM MYOCARDIAL INFARCTION
CELL DEATH AND HEART FAILURE
Stimuli and Pathways That Mediate Cardiac Myocyte Death in Heart Failure
Stretch
Adrenergic Signaling
Renin-Angiotensin-Aldosterone System
Proinflammatory Cytokines
Heart Failure and Apoptosis
Heart Failure and Necrosis
Heart Failure and Autophagy
CELL DEATH IN HEART DISEASE: THE BIG PICTURE
TRANSLATION INTO THERAPEUTICS
SUMMARY
Acknowledgments
REFERENCES
Chapter 7 - Energetic Basis for Heart Failure
ENERGETICS OF THE NORMAL HEART
ATP Synthesis in Mitochondria
ATP Synthesis by Glycolysis
ATP Synthesis by Phosphotransfer Reactions
ATP AND THE FAILING HEART
ATP Progressively Falls in the Failing Heart
The Proximal Mechanism
The Long-Term Mechanisms
Changes in Glucose Uptake and Use
Decreased Metabolic Reserve via Glycolysis
Rescuing the failing heart by manipulating glucose metabolism
Changes in Mitochondrial ATP Synthesis
Decreased Oxidative Capacity
Changes in Substrate Selection for Oxidation Characteristic of the Heart Failure Phenotype Can Be Manipulated
Transcriptional Control of ATP Metabolism
Using Transgenesis to Define the Consequences of Decreased Capacity for ATP Synthesis
Rescuing the Heart by Regulating Gene Expression
Posttranscriptional Control of ATP Metabolism
CREATINE AND THE FAILING HEART
Cr Progressively Falls in the Failing Heart
Mechanisms for Cr Uptake
Decreased Metabolic Reserve via Creatine Kinase
Manipulating [Cr]
Loss of Cr: Adaptive or Maladaptive?
ON CAUSES AND CONSEQUENCES: ENERGETICS AND CONTRACTILE PERFORMANCE
INTERVENTIONS DESIGNED TO ALTER ENERGETICS IN THE FAILING HEART: NEW STRATEGIES FOR THERAPY
Acknowledgments
REFERENCES
Chapter 8 - Molecular and Cellular Mechanisms for Myocardial Recovery
CHANGES IN THE BIOLOGY OF THE CARDIAC MYOCYTE DURING MYOCARDIAL RECOVERY
Cardiac Myocyte Hypertrophy
Myocyte Gene Expression
β-Adrenergic Desensitization
Excitation-Contraction Coupling
Cytoskeletal Proteins
Myocytolysis
CHANGES IN THE MYOCARDIUM DURING MYOCARDIAL RECOVERY
Myocardial Fibrosis
Angiogenesis
CHANGES IN LEFT VENTRICULAR GEOMETRY DURING MYOCARDIAL RECOVERY
SUMMARY AND FUTURE DIRECTIONS
REFERENCES
Section II: Mechanisms of Disease Progression in Heart Failure
Chapter 9 - Activation of the Renin-Angiotensin System in Heart Failure
THE RENIN-ANGIOTENSIN SYSTEM
THE SYSTEMIC RAS
Angiotensinogen
Renin
Angiotensin-Converting Enzyme
THE LOCAL RAS
The Cardiac RAS
The Intracellular Cardiac RAS
NOVEL ASPECTS OF THE RAS
Ang (1-7) and ACE2
Ang III
Ang IV
Pro(renin) Receptor
ANGIOTENSIN II–MEDIATED SIGNALING PATHWAYS IN HEART FAILURE (see Chapter 45)
Angiotensin II Receptors
AT1-Mediated Intracellular Signaling
Classical G Protein–dependent Signaling Pathways.Like other seven membrane spanning domain receptor family members, agonist bind...
AT1-mediated Tyrosine Phosphorylation.Ang II induces actions through activation of tyrosine kinases, which in turn phosphorylate...
Receptor Tyrosine Kinases.In recent years, it has become apparent that transactivation of RTKs by GPCR agonists is a general phe...
Nonreceptor Tyrosine Kinases
Src Family Kinases.Studies have demonstrated that Src family kinases, such as c-Src, have an important role in regulation of gro...
FAK and PYK2 Activation.FAK and PYK2, also referred to as cell adhesion kinase, related adhesion focal tyrosine kinase, or calci...
p130Cas.p130Cas was initially characterized as a phosphotyrosine-containing protein in v-Crk- and v-Src-transformed cells,186 se...
JAK/STAT Activation.The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is involved in a wide...
Phosphoinositide 3-OH Kinase.PI3Ks are a family of lipid and protein kinases responsible for the phosphorylation of PtdIns at po...
Mitogen-activated Protein Kinases.Mitogen-activated protein kinase (MAPK) consists of a series of successively acting kinases th...
Small GTP-binding Proteins.The small GTP-binding protein (small G protein) superfamily comprises a multitude of monomeric protei...
Generation of Reactive Oxygen Species.Accumulating evidence suggests that production of ROS and activation of reduction-oxidatio...
AT2R-mediated Intracellular Signaling
G Proteins.Studies have shown that AT2R couples to intracellular signaling pathways through the pertussis toxin (PTX)-sensitive ...
Activation of Protein Phosphatases and Protein Dephosphorylation.Numerous studies have shown that activation of AT2R rapidly ind...
The Nitric Oxide–Cyclic GMP System.Recent ­studies have shown that activation of AT2R by Ang II results in a bradykinin-dependen...
Stimulation of Phospholipase A2 and Release of Arach­idonic Acid.It has been reported that AT2R activation is related to Na+ tra...
Sphingolipid-derived Ceramide.Ceramide belongs to a family of lipids known as sphingolipids, characterized by a sphingoid backbo...
SUMMARY AND FUTURE DIRECTIONS
REFERENCES
Chapter 10 - Activation of the Adrenergic Nervous System in Heart Failure
ROLE OF INCREASED ADRENERGIC DRIVE IN THE NATURAL HISTORY OF HEART FAILURE
ADRENERGIC RECEPTOR PHARMACOLOGY
ALTERED β-AR SIGNAL TRANSDUCTION IN THE FAILING HEART
MOLECULAR BASIS OF β-ADRENERGIC RECEPTOR SIGNALING
REGULATION OF β-AR GENE EXPRESSION
MYOPATHIC POTENTIAL OF INDIVIDUAL COMPONENTS OF ADRENERGIC RECEPTOR PATHWAYS
Adrenergic Receptors
G Proteins and Adenylyl Cyclase
ADRENERGIC RECEPTOR POLYMORPHISMS IN HEART FAILURE
SUMMARY
REFERENCES
Chapter 11 - Activation of Inflammatory Mediators in Heart Failure
The Biology of Proinflammatory Inflammatory Cytokines and Their Receptors
Tumor Necrosis Factor (TNF) Superfamily
Tumor Necrosis Factor.Although TNF was originally defined by its antitumor activity in vitro and in vivo, TNF is now recognized ...
The Interleukin-1 Superfamily
Interleukin-6 (IL-6)
Chemokines
Innate Immunity
Rationale for Studying Inflammatory Mediators in Heart Failure
Effects of Cytokines on Left Ventricular Function
Effects of Cytokines on Left Ventricular Structure
Effects of Proinflammatory Mediators on Endothelial Function
Clinical Trials Targeting Inflammatory Mediators in Heart Failure
Summary and Future Perspectives
REFERENCES
Chapter 12 - Oxidative and Nitrosative Stress in Heart Failure
REACTIVE OXYGEN SPECIES, ANTIOXIDANT SYSTEMS, AND OXIDATIVE STRESS
OXIDATIVE STRESS IN HUMAN HEART FAILURE
OXIDATIVE STRESS AND ANTIOXIDANT THERAPY IN ANIMAL MODELS OF HEART FAILURE
THE CELLULAR SOURCES OF OXIDATIVE STRESS IN HEART FAILURE
EFFECTS OF OXIDATIVE STRESS ON MYOCARDIAL STRUCTURE AND FUNCTION
Role of ROS in Myocardial Remodeling
Mechanisms of ROS-induced Phenotype in ­Cardiac Myocytes
ROS-induced Changes in Calcium Handling
ROS Regulation of Interstitial Matrix Turnover by Cardiac Fibroblasts
NITRIC OXIDE AND ITS INTERACTION WITH ROS
SUMMARY
REFERENCES
Chapter 13 - Alterations in Ventricular Function: Systolic Heart Failure
CELLULAR AND MOLECULAR DETERMINANTS: A VIEW FROM 30,000 FEET
MEASURING SYSTOLIC FUNCTION BY PRESSURE-VOLUME RELATIONS
BEAT-TO-BEAT REGULATION OF SYSTOLIC FUNCTION
INTEGRATIVE MEASURES OF SYSTOLIC FUNCTION
IMPACT OF PERICARDIAL LOADING ON SYSTOLIC FUNCTION
VENTRICULAR-ARTERIAL INTERACTION
TREATING SYSTOLIC DYSFUNCTION
SYSTOLIC EFFECTS OF DYSSYNCHRONY AND RESYNCHRONIZATION (see Chapter 47)
SUMMARY
REFERENCES
Chapter 14 - Alterations in Ventricular Function: Diastolic Heart Failure
DEFINITIONS
Differentiating Diastolic Dysfunction from Diastolic Heart Failure
Heart Failure with a Preserved Ejection Fraction Versus Diastolic Heart Failure
DIAGNOSIS
European Society of Cardiology Diagnostic ­Criteria
Lahey Clinic Criteria
Natriuretic Peptides (see also Chapter 37)
MEASUREMENT OF DIASTOLIC FUNCTION IN PATIENTS WITH DHF
In Vivo Quantitation of Left Ventricle Chamber Diastolic Function
Relaxation
Isovolumic Relaxation
Recoil/Suction
Auxotonic Relaxation
Stiffness
Chamber Stiffness
Myocardial Stiffness
In Vitro Quantitation of Diastolic Function
Relaxation
Viscoelastic Stiffness
MEASUREMENT OF SYSTOLIC PROPERTIES IN PATIENTS WITH DHF
STRUCTURAL CHANGES IN PATIENTS WITH DHF
MECHANISMS CAUSING DIASTOLIC DYSFUNCTION
Cardiomyocyte
Calcium Homeostasis (see also Chapter 3)
Myofilaments (see also Chapter 3)
Energetics (see also Chapter 7)
Cytoskeleton
Extracellular Matrix (see also Chapter 5)
Neurohormonal
REFERENCES
Chapter 15 - Alterations in Ventricular Structure: Role of Left Ventricular Remodeling
REMODELING CONCEPT OF HEART FAILURE
MECHANISMS OF LEFT VENTRICULAR REMODELING
Early Postinfarct Left Ventricular Remodeling
Factors Affecting the Magnitude of Remodeling after Myocardial Infarction
Late Progressive Postinfarct Left Ventricular Remodeling
ALTERATIONS IN THE MYOCYTE COMPARTMENT
Myocyte Hypertrophy
Mechanisms of Myocyte Hypertrophy and Signaling Pathways
Myocyte Death (see also Chapter 6)
Myocyte Hyperplasia (see also Chapter 4)
Alterations in Myocyte Structural Proteins (see also Chapter 5)
Contractile Proteins
Sarcomeric Skeleton Proteins
Cytoskeletal Proteins
Membrane-associated and Intercalated Disk Proteins
ALTERATIONS IN THE NONMYOCYTE COMPARTMENT
Extracellular Matrix Remodeling (see Chapter 5)
Myocardial Fibrosis
Coronary Microvasculature
CHANGES IN MYOCYTE CONTRACTILE FUNCTION (see Chapter 3)
CHANGES IN GLOBAL STRUCTURE AND FUNCTION
STRUCTURAL BASES OF HEART FAILURE
COMPENSATORY VERSUS MALADAPTIVE REMODELING
REVERSE REMODELING (see Chapter 8)
Pharmacological Approaches
Angiotensin-Converting Enzyme (ACE) Inhibitors
β-Blockers
Aldosterone Receptor Blockers
Angiotensin Receptor Blockers
Isosorbide Dinitrate/Hydralazine Combination
Cell Transplantation (see Chapter 4)
Surgical Approaches (see Chapter 55)
Cardiac Resynchronization Approach (see ­Chapter 47)
Cardiac Constraint Devices
Exercise Training Approach (see Chapter 57)
VENTRICULAR REMODELING AS A SURROGATE ENDPOINT IN HEART FAILURE
Noninvasive Assessment of Left Ventricular Remodeling (see Chapter 36)
Echocardiography
Radionuclide Ventriculography
Magnetic Resonance Imaging
CONCLUSIONS
FUTURE DIRECTIONS
REFERENCES
Chapter 16 - Alterations in the Sympathetic and Parasympathetic Nervous Systems in Heart Failure
ASSESSMENT OF SYMPATHETIC AND PARASYMPATHETIC NERVOUS SYSTEM ACTIVITY IN HUMANS
Catecholamines
Microneurography
Baroreflex–Heart Rate Sequences
Baroreflex–Sympathetic Nerve Sequences
Heart Rate Variability
Cross-Spectral Analysis
SYMPATHETIC ACTIVATION AND PARASYMPATHETIC WITHDRAWAL IN HUMAN HEART FAILURE (see also Chapters 13, 45, and 46)
Heart Failure with Impaired Systolic Function
Parasympathetic Alterations
Parasympathetic and Sympathetic Contributions to Heart Rate ­Variability
Heart Failure with Preserved Systolic Function (see Chapters 14 and 48)
CLINICAL CONSEQUENCES
Cardiac
Peripheral
Exercise
Mortality
MECHANISMS
Afferent Influences
Arterial Baroreceptor Reflexes
Cardiopulmonary Reflexes
Nonbaroreflex Mechanisms
Sleep-related Breathing Disorders (see also Chapter 32)
Myocardial Ischemia and Infarction (see also Chapter 23)
Central Integration and Interactions
Efferent Mechanisms
Ganglionic Neurotransmission
Prejunctional Mechanisms and Efferent Sympathovagal Interactions
THERAPEUTIC IMPLICATIONS
SUMMARY
FUTURE DIRECTIONS
REFERENCES
Chapter 17 - Alterations in the Peripheral Circulation in Heart Failure
CARDIOVASCULAR EFFECTS OF SUSTAINED NEUROHUMORAL ACTIVATION IN HEART FAILURE
BLOOD FLOW TO SKELETAL MUSCLE IN CHRONIC HEART FAILURE
STRUCTURAL ALTERATIONS OF PERIPHERAL ARTERIES IN CHRONIC HEART FAILURE
ALTERATION OF ENDOTHELIUM-DEPENDENT VASODILATION IN HEART FAILURE
MECHANISMS OF ENDOTHELIAL VASODILATOR DYSFUNCTION IN HEART FAILURE
Nitric Oxide Synthase in Heart Failure
Impact of Cytokines (see also Chapter 11)
Inactivation of Nitric Oxide by Superoxide Anions
Role of the Renin-Angiotensin System (see also Chapter 9)
Alterations of Vascular Signal Transduction in Heart Failure
Abnormalities of l-arginine Use in Chronic Heart Failure
Role of Physical Activity for Endothelial Function in Chronic Heart Failure (see also Chapter 57)
Abnormalities of Vascular Smooth Muscle Responsiveness in Chronic Heart Failure
POTENTIAL FUNCTIONAL IMPLICATIONS FOR PATIENTS WITH CHRONIC HEART FAILURE
PROGNOSTIC IMPLICATIONS OF ENDOTHELIAL DYSFUNCTION
REFERENCES
Chapter 18 - Alterations in Renal Function in Heart Failure
THE RENAL REGULATION OF SALT AND WATER
THE “CARDIORENAL SYNDROME”
THE CARDIORENAL AXIS AND CYCLIC GMP
THE NO-sGC-cGMP PATHWAY: A POTENT RENOVASODILATING MECHANISM
THE NATRIURETIC PEPTIDE PATHWAYS: ACTIVATORS OF RENAL PARTICULATE GUANYLYL CYCLASES
B-TYPE NATRIURETIC PEPTIDE
CHIMERIC NATRIURETIC PEPTIDES: CD-NP
PHOSPHODIESTERASE INHIBITION
OPTIMIZING sGC-pCG SIGNALING IN THE KIDNEY IN CHF
SUMMARY
REFERENCES
Chapter 19 - Alterations in Diaphragmatic and Skeletal Muscle in Heart Failure
SKELETAL MUSCLE IN HEART FAILURE
Skeletal Muscle Alterations and Stages of Heart Failure
Vascular Alterations
Skeletal Muscle Mass
Skeletal Muscle Fiber Composition
Skeletal Muscle Metabolism
Excitation Contraction Coupling
Mechanisms of Skeletal Muscle Atrophy
Mechanisms of Skeletal Muscle Inflammation
Diaphragm and Respiratory Muscle in Heart Failure
Mechanism of Dyspnea
Diaphragmatic Histochemical Changes in Heart Failure
Respiratory Muscle Function
Respiratory Muscle Perfusion
Respiratory Muscle Training
CONCLUSION
REFERENCES
Chapter 20 - Alterations in Cardiac Metabolism
PERSPECTIVES
Metabolism and Function Are Tightly Coupled
The Plasticity of Cardiac Metabolism
Energy Transfer in the Heart
METHODS FOR DETECTING DEFECTIVE SUBSTRATE METABOLISM IN THE FAILING HEART
Substrate Uptake by Arteriovenous (AV) ­Differences
NMR Spectroscopy (see Chapter 7)
Radionuclear Imaging: A Focus on Positron Emission Tomography
Transcript Analyses
Genomic Analysis
METABOLIC ADAPTATION AND MALADAPTATION OF THE HEART
Steps Leading to Metabolic Remodeling
Hypertrophy from Pressure Overload
METABOLIC REMODELING OF THE HEART IN OBESITY, INSULIN RESISTANCE, AND DIABETES
Adaptation and Maladaptation of the Heart in Obesity
Adaptation and Maladaptation of the Heart in Diabetes
CROSSTALK BETWEEN CYTOKINE SIGNALING PATHWAYS, INNATE IMMUNITY, AND METABOLISM
Nitric Oxide: Effects on Metabolism
Modulation of Myocardial Metabolism by ­Inflammatory Cytokines
Modulation of Programmed Cell Death and Cell Survival by Glucose and Fatty Acid Metabolites
Metabolism as a Target for Pharmacological ­Intervention in Heart Failure (see Chapter 50)
Trimetazidine
Ranolazine
Lipid-Lowering Agents
Propionyl-l-Carnitine
SUMMARY AND OUTLOOK
REFERENCES
Chapter 21 - Alterations in Nutrition and Body Mass in Heart Failure
BODY COMPOSITION AND HEART FAILURE FROM THE HISTORIC AND PUBLIC PERSPECTIVE: THE OBESITY PARADOX
Definition of Cardiac Cachexia
Mechanisms of Altered Body Composition in Chronic Heart Failure
Nutrition and Regulation of Feeding
Neuropeptide Y
Leptin
Melanocortins
Ghrelin
Adiponectin
Chronic Immune Activation (see Chapter 11)
Anabolic Failure
Growth Hormone (GH)
Insulin Resistance (see also Chapters 20 and 26)
MECHANISMS OF WASTING IN DIFFERENT BODY COMPARTMENTS
Muscle (see also Chapter 19)
Fat Tissue (see also Chapter 20)
Bone
THERAPEUTIC APPROACHES TO METABOLIC IMBALANCE, WEIGHT LOSS, AND CACHEXIA IN CHF
Impact of Current CHF Therapy on Body ­Composition and Metabolic Balance
β-Blockers (see also Chapter 46)
Statins (see also Chapter 24)
Nutrition
Nutritional Considerations
Pharmacotherapy of Cardiac Cachexia
Appetite Stimulants
Cannabinoids
Anabolic Steroids
Antiinflammatory Substances (see also Chapter 11)
Inhibition of Lipopolysaccharide Bioactivity
Immune Modulation by Thalidomide (see also Chapter 11)
Proteasome Inhibitors
Pentoxifylline (see also Chapter 11)
CONCLUSION AND OUTLOOK
REFERENCES
Section III: Etiological Basis for Heart Failure
Chapter 22 - Epidemiology of Heart Failure
EPIDEMIOLOGY OF HF RISK FACTORS
EPIDEMIOLOGY OF CHD IN RELATION TO HF RISK
EPIDEMIOLOGY OF HYPERTENSION IN RELATION TO HF RISK
EPIDEMIOLOGY OF OBESITY IN RELATION TO HF RISK (see Chapter 20)
STRUCTURAL AND/OR FUNCTIONAL ALTERATIONS THAT PREDISPOSE TO HEART FAILURE
LV Structural Alterations (see Chapter 15)
Asymptomatic LV Dysfunction
Screening for Ventricular Remodeling
EPIDEMIOLOGY OF CHRONIC HF
Prevalence
Incidence
Lifetime Risk
Morbidity and Mortality
EPIDEMIOLOGY OF STAGE D HF
EPIDEMIOLOGY OF ACUTE HF (see Chapter 43)
DIFFICULTIES IN INTERPRETING EVALUATIONS ADDRESSING HF EPIDEMIOLOGY
FUTURE DIRECTIONS
BIOMARKERS FOR HF RISK PREDICTION
INVESTIGATION OF HF GENOMICS
OTHER MOLECULAR APPROACHES TO HF EVALUATION
CONCLUSION
REFERENCES
Chapter 23 - Heart Failure as a Consequence of Ischemic Heart Disease
PREVALENCE OF CORONARY ARTERY DISEASE IN HEART FAILURE
PROGNOSTIC SIGNIFICANCE OF CORONARY ARTERY DISEASE IN HEART FAILURE
PATHOPHYSIOLOGY OF ACUTE HEART FAILURE IN PATIENTS WITH CAD
Underlying Coronary Artery Disease
Acute Coronary Syndromes
PATHOPHYSIOLOGY OF CHRONIC HEART FAILURE IN PATIENTS WITH CAD AND REDUCED EJECTION FRACTION
Left Ventricular Remodeling (see also Chapter 15)
Myocardial Ischemia
Hibernation/Stunning (see also Chapter 36)
Diagnosis
Clinical Implications
Endothelial Dysfunction (see Chapter 17)
Endothelial Vasodilators
Endothelial Vasoconstrictors
Clinical Manifestations
CORONARY ARTERY DISEASE AND DIASTOLIC HEART FAILURE
DIABETES, HEART FAILURE, AND CAD (see also Chapter 24)
Therapeutic Options
Immediate Management of the Hospitalized Patient
Long-term Therapies for the Heart Failure Patient with CAD
Cardiac Device and Mitral Valve Therapy
CONCLUSIONS
REFERENCES
Chapter 24 - Heart Failure as a Consequence of Dilated Cardiomyopathy
DEFINITION
EPIDEMIOLOGY OF DILATED CARDIOMYOPATHY
NATURAL HISTORY OF DILATED CARDIOMYOPATHY
Ischemic Versus Dilated Cardiomyopathy
PATHOPHYSIOLOGY
Myocardial Diseases Presenting as Dilated ­Cardiomyopathy
Idiopathic Dilated Cardiomyopathy
Familial Cardiomyopathy
Alcoholic/Toxic Cardiomyopathy
Inflammation-induced Cardiomyopathy
Inflammation-induced Cardiomyopathy: Infectious Causes
Inflammation-induced Cardiomyopathy: Noninfectious Causes
Endocrine and Metabolic Causes of Cardiomyopathy
Nutritional Causes of Cardiomyopathy
Hematological Causes of Cardiomyopathy
Physical Agents
Autoimmune Mechanisms
CLINICAL RECOGNITION
Diagnostic Evaluation
Laboratory Testing
Treatment Strategies for Dilated Cardiomyopathy
Lipid Modifying Agents
Acknowledgments
REFERENCES
Chapter 25 - Heart Failure as a Consequence of Restrictive Cardiomyopathy
DEFINITION
Diagnostic Challenges
PREVALENCE
PHENOTYPIC MANIFESTATIONS
Clinical Presentation
SCD in HCM
Morphological and functional features
Histopathological features
MOLECULAR GENETICS
Causal Genes
Modifier Genes
PATHOGENESIS
Determinants of Cardiac Phenotype in ­Hypertrophic Cardiomyopathy
Hypertrophic Cardiomyopathy Phenocopy
MANAGEMENT OF PATIENTS WITH HYPERTROPHIC CARDIOMYOPATHY
Genetic Screening
Management of Risk of Sudden Cardiac Death
Pharmacological Treatment
Surgical Myectomy (Morrow Technique) and Catheter-based Septal Ablation (Alcohol Septal Ablation)
Experimental Therapies
REFERENCES
Chapter 26 - Heart Failure as a Consequence of Diabetic Cardiomyopathy
THE EPIDEMIOLOGY OF ­DIABETES AND HEART ­FAILURE
Diabetic Cardiomyopathy: Mechanisms of Myocardial Damage
Hyperglycemia
Nonesterified Fatty Acids
Hyperinsulinemia
Diabetic Microvasculopathy
Functional and Morphological Manifestations of Diabetic Cardiomyopathy
Animal Models
Alterations in Calcium Cycling
Alterations in the Myofilament (see also Chapter 3)
Ultrastructural Changes and Passive Myocardial Stiffness in Diabetes Mellitus (see also Chapter 5)
Clinical Features of Diabetic Cardiomyopathy
Role of Diabetic Cardiomyopathy as a Mechanism of Heart Failure Symptoms
Diabetic Cardiomyopathy and Diastolic Dysfunction
Increased Left Ventricular Mass
Management of Heart Failure in Patients with Diabetes
Management of Diabetes in Patients with Heart Failure
The Question of Tight Glycemic Control
Pharmacological Therapy
Selected Future Directions
REFERENCES
Chapter 27 - Heart Failure as a Consequence of Genetic Cardiomyopathy
NORMAL CARDIAC STRUCTURE
DILATED CARDIOMYOPATHY
Clinical Genetics of Dilated Cardiomyopathy
Molecular Genetics of Dilated Cardiomyopathy
X-LINKED CARDIOMYOPATHIES
X-Linked Dilated Cardiomyopathy (XLCM)
Barth Syndrome
Autosomal Dominant Dilated Cardiomyopathy
Lamin A/C
Muscle Is Muscle: Cardiomyopathy and Skeletal Myopathy Genes Overlap
HYPERTROPHIC CARDIOMYOPATHY
Infiltrative Forms of Hypertrophic ­Cardiomyopathy
Pompe Disease (Type II Glycogen Storage Disease)
Fabry Disease
Danon Disease
AMP-Activated Protein Kinase (AMP-K)
ENERGY-DEPENDENT FORMS OF HYPERTROPHIC CARDIOMYOPATHY
Mitochondrial Cardiomyopathies
Kearns-Sayre Syndrome
MERRF Syndrome
OVERLAP DISORDERS
Left Ventricular Noncompaction
Clinical Features
Genetics
Therapy and Outcome
Restrictive Cardiomyopathy
Genetic Basis of Restrictive Cardiomyopathy
Arrhythmogenic Right Ventricular ­Cardiomyopathy
Clinical Genetics of Arrhythmogenic Right Ventricular Cardiomyopathy
Genetic Basis of Arrhythmogenic Right Ventricular Cardiomyopathy
Animal Models of Arrhythmogenic Right Ventricular Cardiomyopathy
Mechanisms of Arrhythmogenic Right Ventricular Cardiomyopathy
CONCLUSIONS AND FUTURE DIRECTIONS
REFERENCES
Chapter 28 - Heart Failure as a Consequence of Hypertension
EPIDEMIOLOGY
Pathophysiology of Hypertensive Cardiomyopathy
Mechanical Effects of Hypertension on the Left ­Ventricle.In individuals with normal blood pressure, factors that have been show...
Clinical Presentations of Hypertensive Cardiomyopathy
Hypertension and Pluricausal Cardiomyopathy
Prevention and Treatment of Hypertensive
CONCLUSION
REFERENCES
Chapter 29 - Heart Failure as a Consequence of Valvular Heart Disease
Aortic Insufficiency
Acute Aortic Insufficiency
Chronic Aortic Insufficiency
Management of Congestive Heart Failure in Aortic Insufficiency
Avoidance of CHF
Asymptomatic Left Ventricular Dysfunction
Medical Therapy
Far Advanced Left Ventricular Dysfunction
Mitral Regurgitation
Acute Mitral Regurgitation
Chronic Mitral Regurgitation
Reversal of Left Ventricular Dysfunction in Mitral Regurgitation
Secondary Mitral Regurgitation
Aortic Stenosis
Acute Aortic Stenosis
Chronic Aortic Stenosis
Treatment of Heart Failure from Aortic Stenosis
Mitral Stenosis
Therapy
Tricuspid Regurgitation
Conclusion
REFERENCES
Chapter 30 - Heart Failure as a Consequence of Congenital Heart Disease
ROLE OF CONGENITAL HEART DISEASE
Systemic Right Ventricle
L-TGA (Levo-Transposition of the Great Arteries)
D-TGA (Dextro-Transposition of the Great Arteries)
Fontan and Single Ventricle Physiology
Volume Overload Lesions
MEDICAL TREATMENT OF HEART FAILURE IN ADULTS WITH CONGENITAL HEART DISEASE
Outpatient Medical Management
Inpatient Medical Management
Surveillance
Mechanical Support (see also Chapter 56)
Surgical Therapy
Future Challenges
REFERENCES
Chapter 31 - Heart Failure as a Consequence of Viral and Nonviral Myocarditis
Cause
Pathogenesis of Postviral Cardiomyopathy
DIAGNOSIS OF CARDIOMYOPATHY DUE TO MYOCARDITIS
Typical Presentations in Heart Failure
Clinical Features
Biochemical Markers (see also Chapter 37)
Noninvasive Cardiac Testing (see also Chapter 36)
Endomyocardial Biopsy
Clinical Aspects of Nonviral Myocarditis
TREATMENT
Physical Activity (see also Chapter 57)
Antiinflammatory Agents
Antiarrhythmic Therapy
Specific Therapy
TREATMENT OF ACUTE HEART FAILURE
Neurohormonal Blockade in Myocarditis
Antiviral Therapy
Immunosuppression and Immunomodulatory Therapy
Prognosis
REFERENCES
Chapter 32 - Heart Failure as a Consequence of Sleep-Disordered Breathing
HISTORY AND REDISCOVERY OF CHEYNE-STOKES BREATHING
POLYSOMNOGRAPHY, SLEEP STAGES, AND DEFINITIONS OF SLEEP APNEA AND HYPOPNEA
EFFECTS OF SLEEP ON CARDIOPULMONARY SYSTEMS
SLEEP APNEA IN SYSTOLIC HEART FAILURE
Phenotype of Heart Failure Patients with Obstructive and Central Sleep Apnea
Gender and Sleep Apnea in Systolic Heart Failure
SLEEP APNEA IN ISOLATED DIASTOLIC HEART FAILURE
MECHANISMS OF SLEEP APNEA IN HEART FAILURE
Central Sleep Apnea
Negative Feedback Control System and Periodic Breathing
Specific Sleep Mechanisms and Genesis of Central Sleep Apnea
Obstructive Sleep Apnea
PATHOLOGICAL CONSEQUENCES OF SLEEP APNEA IN HEART FAILURE
Arterial Blood Gas Abnormalities and Their Consequences
Direct Effects of Hypoxia on Myocardium
Hypoxia and Reoxygenation, Reactive Oxygen Species, Oxidative Stress, Inflammation, and Endothelial Dysfunction
Hypoxia and Pulmonary Arteriolar Vasoconstriction
Hypocapnia
Arousals
Exaggerated Negative Intrathoracic Pressure and Its Consequences
SLEEP APNEA AUGMENTS THE HYPERADRENERGIC STATE OF HEART FAILURE
PROGNOSTIC SIGNIFICANCE OF SLEEP APNEA IN HEART FAILURE
INDICATIONS FOR POLYSOMNOGRAPHY IN HEART FAILURE
Risk Factors for Obstructive Sleep Apnea
Nocturnal Angina
Paroxysmal Nocturnal Dyspnea
Restless Sleep
Low Arterial Partial Pressure of Carbon Dioxide
Atrioventricular Arrhythmias
Progressive Left Ventricular Systolic or Diastolic Dysfunction
Pacemaker and Cardioverter Defibrillator
Awaiting Cardiac Transplantation
TREATMENT OF SLEEP APNEA IN HEART FAILURE
Obstructive Sleep Apnea
Weight Loss
Noninvasive Positive Airway Pressure Devices
Other Therapeutic Modalities
Central Sleep Apnea
Optimization of Cardiopulmonary Function
Cardiac Transplantation (see also Chapter 54)
Oxygen
Noninvasive Positive Airway Pressure Devices
CONCLUSIONS
REFERENCES
Chapter 33 - Heart Failure in Developing Countries
AFRICA
CENTRAL AND SOUTH AMERICA
ASIA
CONCLUSIONS AND FUTURE DIRECTIONS
REFERENCES
Section IV: Clinical Assessment of Heart Failure
Chapter 34 - The Prognosis of Heart Failure
PROGNOSTIC VARIABLES
Demographic Variables
Causes of Heart Failure
Comorbid Conditions that Affect Outcome of Heart Failure
Clinical Manifestation (see Chapter 35)
Ventricular Performance and Hemodynamics
Exercise Testing (see also Chapter 57)
Metabolic Parameters
Chest Radiography
Electrocardiography
Inflammatory Markers of Heart Failure (see also Chapter 11)
Neuroendocrine Activation
Endomyocardial Biopsy
PREDICTING OUTCOMES IN HEART FAILURE
THE CONVERSATION
REFERENCES
Chapter 35 - Clinical Evaluation of Heart Failure
CLINICAL EVALUATION OF PRESENTING SYMPTOMS: THE MEDICAL HISTORY
Dyspnea
Fatigue
Other Symptoms of Heart Failure
CLINICAL EVALUATION OF PRESENTING SIGNS: PHYSICAL EXAMINATION
General Inspection of the Patient
Assessment of the Volume Status of the Patient
Signs of Low Cardiac Output
Signs of Cachexia (see also Chapter 21)
LABORATORY EVALUATION OF THE PATIENT WITH HEART FAILURE
Biochemical Evaluation: Biomarker Testing (see also Chapter 37)
Electrocardiographic Evaluation: Electrocardiography
Morphological Evaluation: Chest Radiography, Echocardiography, and Magnetic Resonance Imaging (see also Chapter 36)
Ischemic Evaluation: Myocardial Viability and Coronary Anatomy (see Chapters 23 and 36)
Functional Evaluation: Cardiopulmonary Exercise Testing (see Chapter 57)
Hemodynamic Evaluation: Cardiac ­Catheterization
Histological Evaluation: Endomyocardial Biopsy
Genetic Evaluation (see Chapter 27)
FUTURE DIRECTIONS
REFERENCES
Chapter 36 - Use of Cardiac Imaging in the Evaluation of Heart Failure
ASSESSMENT OF THE LEFT VENTRICLE: VOLUMES, EJECTION FRACTION
Echocardiography
Cardiac Magnetic Resonance ­Imaging
Nuclear Imaging
Radionuclide Angiography
Echocardiography–Gated SPECT with Myocardial Perfusion Imaging
Echocardiography–Gated PET with Myocardial Perfusion Imaging
DETECTION OF MYOCARDIAL ISCHEMIA AND MYOCARDIAL INFARCTION
Echocardiography
Cardiac Magnetic Resonance Imaging
Nuclear Imaging
ASSESSMENT OF VIABILITY IN PATIENTS WITH ISCHEMIC CARDIOMYOPATHY
Echocardiography
Cardiac Magnetic Resonance Imaging
Nuclear Imaging
SPECT Imaging with Thallium-201
SPECT Imaging with Technetium 99m–Labeled Agents
PET with 2-[Fluorine-18]-Fluoro-2-Deoxy-d-Glucose
ASSESSMENT OF VALVE FUNCTION IN PATIENTS WITH HEART FAILURE
Echocardiography
Cardiac Magnetic Resonance Imaging
HEART FAILURE WITH A DEPRESSED EJECTION FRACTION (see Chapters 14 and 48)
Echocardiography
Assessment of Left Ventricular Mass and Left Atrial Size
Identification of Diastolic Dysfunction and Elevated Left Ventricular Filling Pressures
Cardiac Magnetic Resonance Imaging
Assessment of LV Mass and LA Size
Identification of Diastolic Dysfunction and Demonstration of Elevated LV Filling Pressures
Nuclear Imaging
ASSESSMENT OF RIGHT VENTRICULAR FUNCTION
Echocardiography
Cardiac Magnetic Resonance Imaging
Nuclear Imaging
ROLE OF CARDIAC IMAGING IN IMPLANTABLE CARDIAC DEVICES (see also Chapter 47)
Echocardiography
Cardiac Magnetic Resonance Imaging
Nuclear Imaging
FUTURE DIRECTIONS IN CARDIAC IMAGING
Echocardiography
-Dimensional Echocardiography
Speckle-Based Tracking Echocardiography
Cardiac Magnetic Resonance Imaging
Role of Strain and Strain Rate Imaging in Patients with Heart Failure
Nuclear Imaging
Assessment of Cardiac Sympathetic Innervation
Molecular Imaging with PET
Use of Dual Imaging Techniques in Patients with Heart Failure
REFERENCES
Chapter 37 - The Use of Biomarkers in the Evaluation of Heart Failure
BIOMARKERS IN HEART FAILURE
Markers of Myocardial Stretch
Adrenomedullin
ST2 Receptor
Markers of Inflammation
C-Reactive Protein
Markers of Myocardial Cell Death
Markers of Renal Function (see also Chapter 18)
Neutrophil Gelatinase–Associated Lipocalin
MULTIMARKER APPROACH AND FUTURE DIRECTION
CONCLUSION
REFERENCES
Chapter 38 - Measuring Quality Outcomes in Heart Failure
GENERAL PRINCIPLES OF QUALITY MEASUREMENT
Defining Quality
A Measurement Framework
The Role of the Organization of the Health Care System
The Role of Health Information Technology
THE CURRENT STATE OF QUALITY OF CARE FOR HEART FAILURE IN THE UNITED STATES
Effectiveness
Patient-Centeredness
Equity
Age
Gender
Race and Ethnicity
Geography
Uses of Quality Measures
Continuous Quality Improvement
Public Reporting
Pay for Performance
FUTURE DIRECTIONS
REFERENCES
Chapter 39 - Clinical Trial Design in Heart Failure
FUNDAMENTAL COMPONENTS OF RANDOMIZED CONTROLLED TRIALS
Hypothesis and Study Design
Patient Population
Implications of Patient Selection: Enrollment, Generalizability, and Labeling Considerations
Controls, Randomization, and Blinding
Follow-up and Adherence
Endpoints
Mortality Endpoints
Morbidity Endpoints
Symptom-Based Endpoints
Composite Measures as Heart Failure Endpoints
Surrogate Endpoints
Multiple Primary Endpoints
Secondary Endpoints
Safety Endpoints
Sample Size and Statistical Power
Data Analysis and Reporting
Intention-to-Treat Analysis
Interpretation of Endpoints
Subgroup Analysis and Other Post Hoc Testing
Publication Issues
OPERATIONAL ASPECTS OF RANDOMIZED CONTROLLED TRIALS
Study Leadership
Study Sponsor
Coordinating Center
Data and Safety Monitoring Committee
DSMC Responsibilities: Administrative Analyses and Safety Analyses
Endpoint or Clinical Events Committee
Site Investigators
Study Subjects
RANDOMIZED CONTROLLED TRIALS IN THE CONTEXT OF DRUG DEVELOPMENT: TRANSITIONAL STUDIES
Selection of Dose Range and Endpoints in ­Transitional Studies
NOVEL APPROACHES TO DESIGN OF CLINICAL TRIALS IN HEART FAILURE
RANDOMIZED CONTROLLED TRIALS IN SPECIFIC CLINICAL SETTINGS
Acute Decompensated Heart Failure
Clinical Trials with Devices and Surgery
Clinical Trials of Monitoring Tools and Strategies
NEW DIRECTIONS
REFERENCES
Section V: Therapy for Heart Failure
Chapter 40 - Development and Implementation of Practice Guidelines in Heart Failure
RATIONALE FOR GUIDELINE DEVELOPMENT
Justification
Inherent Assumptions
ROLE OF EVIDENCE-BASED MEDICINE
PROCESS OF GUIDELINE DEVELOPMENT
The Role of Experts
Overview of Guideline Development
APPROACHES TO MEDICAL EVIDENCE
Identification of Evidence
Types of Evidence
Strength of Evidence
Interpretation of Randomized Clinical Trials
Issues Specific to Statistical Analysis
Limitations of Positive Randomized Clinical Trials
Weighing the Evidence: Hierarchy of Relative Value
Expert Opinion as Evidence
EFFICACY IN BROADER CONTEXT
Endpoints Studied
Degree of Positivity or Negativity
Replication and Modification
BEYOND EFFICACY: IS TREATMENT JUSTIFIED?
DETERMINING STRENGTH OF RECOMMENDATION
Totality of Therapeutic Evidence
Scale of Strength
GUIDELINE DEVELOPMENT: PRACTICAL ASPECTS OF DRUG THERAPY
Practical Aspects of Drug Administration
IMPLICATIONS OF PRACTICE GUIDELINES FOR CARDIOVASCULAR PRACTICE
Recommend or Require?
EVOLUTION OF RECOMMENDATIONS ABOUT β-BLOCKERS
β-Blockade for Symptomatic Left Ventricular Systolic Dysfunction (see Chapter 46)
β-Blockade in Patients with Severe Heart Failure
β-Blockade for Asymptomatic Left Ventricular Dysfunction
Summary
INTEGRATION OF AVAILABLE GUIDELINES
Left Ventricular Systolic Dysfunction
Cardiac Resynchronization
Inotropic Therapy in Acute Heart Failure (see Chapter 43)
Polypharmacy
TRANSLATING CLINICAL TRIAL DATA INTO PRACTICE
Problem of Perspective
Specific Issues
Clinical Example: β-Blockade
CONCLUSION
REFERENCES
Chapter 41 - Disease Prevention in Heart Failure
DIASTOLIC AND SYSTOLIC HEART FAILURE
DISTINGUISHING FLUID RETENTION FROM ABNORMALITIES IN VENTRICULAR PERFORMANCE
Hypertension and Heart Failure
Diabetes Mellitus and Heart Failure (see Chapter 26)
Atherosclerotic Disease and Heart Failure (see Chapter 23)
Metabolic Syndrome and Heart Failure (see Chapter 20)
Obesity and Heart Failure (see Chapter 20)
Chronic Obstructive Pulmonary Disease and Heart Failure
Rheumatoid Arthritis and Heart Failure
Drug-induced Heart Failure
Cytotoxic Drugs (see Chapter 58)
Trastuzumab (see Chapter 58)
Nonsteroidal Anti-inflammatory Drugs
Thiazolidinediones
Cardiotoxic Effects of Recreational Agents (see Also Chapter 24)
FUTURE DIRECTIONS
REFERENCES
Chapter 42 - Pharmacogenomics and Pharmacogenetics in Heart Failure
RENIN-ANGIOTENSIN-ALDOSTERONE PATHWAY: THERAPEUTICS AND GENOMICS
THE ANGIOTENSIN-CONVERTING ENZYME DELETION/INSERTION POLYMORPHISM
Pharmacogenetics of the ACE D Allele: β-Blockers and Angiotensin-Converting Enzyme Inhibitors
β-Receptor Polymorphisms and β-Receptor Antagonists
α2c-Adrenergic Receptor Deletion
Aldosterone Synthase
RACE, GENOMICS, AND HEART FAILURE THERAPY
GENOME-WIDE ASSOCIATION STUDIES
FUTURE DIRECTIONS
REFERENCES
Chapter 43 - Management of Acute Decompensated Heart Failure
INITIAL CLINICAL ASSESSMENT
RECOGNIZING THE FOUR HEMODYNAMIC PROFILES
PRINCIPLES OF THERAPY GUIDED BY PROFILES
Focus on Congestion and Filling Pressures
What Is the Optimal Level of Filling Pressures?
Profile B: Wet and Warm
No Defined Role for Adjunctive Agents
Nonresponders
Cardiorenal Syndrome
“Lukewarm”
Right-Left Filling Pressure Mismatch
Very High or Very Low Systemic Vascular Resistance
Profile C: Wet and Cold
Choice of Vasoactive Agents: Vasodilator or Inotrope?
Profile L: Dry and Cold
Use of Direct Hemodynamic Monitoring
NONINVASIVE TECHNIQUES FOR MONITORING FILLING PRESSURES AND CARDIAC OUTPUT
SPECIFIC AGENTS USED DURING HOSPITALIZATION
Intravenous Vasodilators
Nitroprusside
Nitroglycerin
Nesiritide
Monitoring of Intravenous Vasodilators
Weaning from Intravenous Vasodilator Agents
Intravenous Inotropic Agents
Considerations for Use and Weaning
Specific Inotropic Agents
REEVALUATION
Escalating Support
PLANNING FOR HOSPITAL DISCHARGE
Designing the Oral Regimen
Patient Education before Discharge
Charting the Course
CONTINUUM OF CARE THROUGH THE COMMUNITY: FUTURE DIRECTIONS
REFERENCES
Chapter 44 - Management of Volume Overload in Heart Failure
TYPES OF DIURETICS
Loop Diuretics
Loop Diuretics and Hypertonic Saline
Other Diuretics
COMBINATION OF DIURETICS
EXTENT OF DIURESIS
RISKS WITH DIURESIS
DIURETIC RESISTANCE AND MANAGEMENT
REFRACTORY CONDITIONS
Inotropic Agents (see Chapter 43)
Dopaminergic Agents
Ultrafiltration and Dialysis
Natriuretic Peptides (see Chapter 18)
Adenosine Antagonists
Vasopressin Antagonists
CONCLUSION
REFERENCES
Chapter 45 - Antagonism of the Renin-Angiotensin-Aldosterone System in Heart Failure
HEMODYNAMIC EFFECTS OF INHIBITING THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM
EFFECTS OF RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM INHIBITION ON VENTRICULAR REMODELING
Experimental Observations
Clinical Studies
EFFECTS OF INHIBITING THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM ON FUNCTIONAL CAPACITY AND SYMPTOMS
Angiotensin-Converting Enzyme ­Inhibitors
Angiotensin Receptor Blockers
EFFECTS OF INHIBITING THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM ON MORBIDITY AND MORTALITY
Angiotensin-Converting Enzyme Inhibitors
Effect of Angiotensin-Converting Enzyme Inhibitors on Clinical Outcomes and Mechanisms Underlying These Effects
Angiotensin Receptor Blockers
Second Evaluation of Losartan in the Elderly (ELITE-II)
Valsartan in Heart Failure Trial (Val-HeFT)
Candesartan in Heart Failure Assessment in Reduction of Mortality (CHARM) Trial
Heart Failure Endpoint Evaluation of Angiotensin II Antagonist ­Losartan (HEAAL)
Aldosterone Receptor Blockers
Clinical Implications
PATIENT CHARACTERISTICS AND THE BENEFITS OF RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM BLOCKADE
Disease Severity and Drug Effects
Inhibition of the Renin-Angiotensin System as a Preventive Strategy
Inhibition of the Renin-Angiotensin­ System in Patients with Preserved Left ­Ventricular Ejection Fraction (see Chapter 48)
Genetic and Racial Factors Influencing the Response to Inhibition of the Renin-Angiotensin-Aldosterone System (see Chapters 42 a...
CHARACTERISTICS AND DOSING RECOMMENDATIONS FOR SPECIFIC AGENTS
POTENTIAL DRUG INTERACTIONS OF ANGIOTENSIN-CONVERTING ENZYME INHIBITORS
FUTURE DIRECTIONS
REFERENCES
Chapter 46 - Antagonism of the Sympathetic Nervous System in Heart Failure
HISTORICAL NOTES
MECHANISMS OF ACTION (see Chapter 10)
PHARMACOLOGICAL CHARACTERISTICS OF β-BLOCKING AGENTS
Lipophilic Versus Hydrophilic β-Blockers
Intrinsic Sympathomimetic Activity
Selectivity of β1-Adrenergic Receptor Blockade
β1-Receptor Density
β1-Adrenergic Receptor Binding
Inverse Agonism
Sympatholytic (Norepinephrine-Lowering) Effects
Ancillary Properties
CLINICAL RESULTS
Effects on Cardiac Function
Effects on Exercise Capacity and Symptoms
Effects on the Clinical Course: Initial Trials
Effects on the Clinical Course: Large-Scale ­Mortality Trials
PRACTICAL GUIDELINES FOR β-BLOCKER USE
β-BLOCKER THERAPY IN CLINICAL PRACTICE
β-Blocker Use
Implementation Strategies
Lack of Evidence in Specific Patients Groups: The Case of Heart Failure with Preserved ­Ejection Fraction
LIMITATIONS OF β-BLOCKER THERAPY
FUTURE DIRECTIONS
Improvement in the Clinical Pharmacology of β-Blocking Agents
Pharmacogenetic Targeting Based on Genetic Variation in Adrenergic Receptors (see Chapter 42)
REFERENCES
Chapter 47 - Device Therapy in Heart Failure
SUDDEN CARDIAC DEATH
THE BASICS OF IMPLANTABLE CARDIOVERTER-DEFIBRILLATORS (ICDs)
Antitachycardia Pacing
Device Programming
Primary Prevention of Sudden Cardiac Death
Secondary Prevention of Sudden Cardiac Death
Inappropriate Shocks from Implantable ­Cardioverter-Defibrillators
Complications of and Informed Consent for Implantable Devices
PACING AND CARDIAC RESYNCHRONIZATION
Basic Considerations
Mechanical Dyssynchrony
Candidacy for Cardiac Resynchronization ­Therapy
Special Considerations
Coronary Sinus or Left Ventricular Epicardial Lead Placement
Summary of Cardiac Resynchronization Therapy
DEVICE DIAGNOSTICS
FUTURE DIRECTIONS
REFERENCES
Chapter 48 - Treatment of Heart Failure with a Preserved Ejection Fraction
DEVELOPMENT OF TREATMENT STRATEGIES BASED ON PATHOPHYSIOLOGY OF HFPEF
Treatment of Volume Overload and Congestion
Treatment of Hypertension (see Chapter 28)
β-Blockers
Renin-Angiotensin-Aldosterone Blockade
Digoxin
Endothelin Antagonists
CURRENT RECOMMENDATIONS FOR THE MANAGEMENT OF PATIENTS WITH HFPEF
FUTURE MODALITIES OF THERAPY IN HFPEF
Selective Phosphodiesterase-Type 5 Inhibition
Advanced Glycation End Products
Lusitropic Agents
Treatment of Obstructive Sleep Apnea
Potential Device Use in HFPEF
Pacemakers
Device-Based Treatment of Resistant Hypertension
Targeting Diastolic Suction
CONCLUSIONS
REFERENCES
Chapter 49 - Heart Failure in Special Populations
RACE OR ETHNICITY AND HEART FAILURE
Clinical Features by Race or Ethnicity
Racial Differences in Response to Drug ­Treatment for Heart Failure
Angiotensin-Converting Enzyme Inhibitors
β-Blockers (see Chapter 46)
Isosorbide Dinitrate Plus Hydralazine
HEART FAILURE IN ELDERLY POPULATIONS
Clinical Features
Pathophysiology
Therapy
HEART FAILURE IN WOMEN
Clinical Features
Therapy
Angiotensin-Converting Enzyme Inhibitors (see Chapter 45)
Angiotensin Receptor Blockers (see Chapter 45)
β-Blockers (see Chapter 46)
Aldosterone Antagonists
Isosorbide Dinitrate Plus Hydralazine
Digoxin
Cardiac Resynchronization (see Chapter 47)
Implantable Cardioverter-Defibrillator (see Chapter 47)
Ventricular Assist Device (see Chapter 56)
Heart Transplantation (see Chapter 54)
REFERENCES
Chapter 50 - Emerging Strategies in the Treatment of Heart Failure
NEUROHORMONAL ANTAGONISM
Vasopressin Antagonists
Endothelin Antagonists
DIURESIS AND NATRIURESIS
Adenosine Antagonists
Ularitide
INOTROPES
Calcium Sensitizer (Levosimendan)
Cardiac Myosin Activators
Istaroxime
METABOLIC MODULATORS
Perhexiline
Trimetazidine
Ranolazine
l-Carnitine
IMMUNOMODULATORY AGENTS
Statins (see Chapters 11 and 24)
Polyunsaturated Fatty Acids (see Chapters 11 and 24)
GENE THERAPY
β-Adrenergic Signaling System (see Chapter 10)
Calcium-Handling System (see Chapter 4)
Cardiomyocyte Survival (see Chapter 6)
OTHER NOVEL THERAPIES
Sildenafil
Inhibitor of If Current in Sinoatrial Node ­(Ivabradine)
Vagal Stimulation
Testosterone
NOVEL TREATMENT STRATEGIES FOR HEART FAILURE OF SPECIFIC ETIOLOGIES
Insulin Resistance and Heart Failure (see Chapter 20)
Peripartum Cardiomyopathy
SUMMARY
REFERENCES
Chapter 51 - Cell-Based Therapies and Tissue Engineering in Heart Failure
THE CONCEPTS OF CELL THERAPY AND TISSUE ENGINEERING
POTENTIAL DONOR CELLS (see Chapter 4)
Cardiomyocytes
Cells with No Apparent Capacity for ­Cardiomyocyte Differentiation
Cardiomyocyte Progenitor Cells (see Chapter 4)
CELL TRANSPLANTATION STRATEGIES
CURRENT STATUS OF CELL THERAPY IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION AND HEART FAILURE
Randomized Trials with Unselected Bone ­Marrow Cells
Ongoing Clinical Trials in Patients with Coronary Heart Disease
Skeletal Myoblast Transplantation
Issues to Address at the Bench and the Bedside
TISSUE ENGINEERING
Basic Principles of Myocardial Tissue Engineering
Preclinical Experience with Myocardial Tissue Engineering
CHALLENGES AND FUTURE DIRECTIONS
REFERENCES
Chapter 52 - Management of Thrombosis in Heart Failure
OVERVIEW OF HEMOSTASIS AND THROMBOSIS
CHAMBERS
Endocardial Injury
Blood Stasis
Hypercoagulability
DYNAMIC FORCES OF THE CIRCULATION
Arterial Thrombosis
Thrombosis
Chronic Heart Failure
Intracardiac Thrombosis After Myocardial Infarction
Thrombosis in Left Ventricular Aneurysms in Patients with Heart Failure
Atrial Fibrillation and Left Atrial Thrombus in Patients with Heart Failure
Deep Venous Thrombosis in Patients with Heart Failure
PREVENTIVE THERAPY
Aspirin Use for the Prevention of Thromboembolism in Heart Failure
Warfarin Use for the Prevention of Thromboembolism
THE FUTURE
REFERENCES
Chapter 53 - Management of Arrhythmias in Heart Failure
ATRIAL FIBRILLATION
Hemodynamic Consequences
Rate Control
Risk Factors for Atrial Fibrillation
Relationship Between Heart Failure and Stroke Risk in Atrial Fibrillation
Relationship Between Atrial Fibrillation and ­Mortality in Heart Failure
Treatment of Atrial Fibrillation in Heart Failure
Drugs Used for Rhythm Control in Heart Failure
Radiofrequency Ablation
Drugs Used for Rate Control
Nonpharmacological Therapy for Rate Control
Rate Control Versus Rhythm Control
Recommendations
Rhythm Control
Rate Control
VENTRICULAR ARRHYTHMIAS
Causes of Ventricular Arrhythmias in Heart ­Failure
Underlying Structural Disease
Mechanical Factors
Neurohormonal Factors
Electrolyte Abnormalities
Ischemia
Drugs
Mortality from Sudden Cardiac Death in Heart Failure
Risk Assessment for Sudden Cardiac Death in Patients with Heart Failure
Left Ventricular Ejection Fraction
Ventricular Arrhythmia
Use of Left Ventricular Ejection Fraction and Nonsustained Ventricular Tachycardia as Predictors of Survival
Electrophysiological Testing
Signal-Averaged Electrocardiography
QT Dispersion
Heart Rate Variability
Repolarization (T Wave) Alternans
Prophylactic Pharmacological Therapy to Prevent Sudden Cardiac Death
Effect of Heart Failure Therapies on Arrhythmia
Pharmacological Therapy with Antiarrhythmic Agents
Prophylactic Use of an Implantable Cardioverter-Defibrillator (Primary Prevention) (see Chapter 47)
Trials in Ischemic Cardiomyopathy
Trials in Nonischemic Cardiomyopathy
Identifying the Patient at High Risk Who Is Most Likely to Benefit from a Prophylactic Implantable Cardioverter-Defibrillator
Therapy for Patients with Heart Failure Who Have Experienced a Sustained Ventricular Tachyarrhythmia (Secondary Prevention) (see...
Implantable Cardioverter-Defibrillator
AVID Trial
CIDS
CASH Trial
Meta-analysis of Secondary Prevention Trials
Long-Term Outcome
Antiarrhythmic Drug Therapy
Radiofrequency Ablation
Surgery
Transplantation
Implantable Cardioverter-Defibrillator Therapy in Hypertrophic ­Cardiomyopathy (see Chapter 25)
Recommendation for Treatment of Ventricular Tachyarrhythmias
Patients with a History of a Ventricular Tachyarrhythmia (Ventricular Tachycardia or Sudden Cardiac Death)
Prophylactic Therapy in Patients at High Risk with Cardiomyopathy
Patients with Hypertrophic Cardiomyopathy (see Chapter 25)
Patients with Unexplained Syncope
REFERENCES
Chapter 54 - Cardiac Transplantation
PATIENT POPULATION
Which Patients Need to Be Considered for Transplantation?
Evaluation of the Potential ­Recipient
Management of the Patient Waiting for Cardiac Transplantation
THE CARDIAC TRANSPLANTATION PROCEDURE
The Cardiac Donor
Surgical Considerations
EARLY POSTOPERATIVE MANAGEMENT
Cardiovascular Issues
Immunosuppression
Induction Therapy in the Perioperative Period
Maintenance Immunosuppression
Other Potential Perioperative Management Issues
CHRONIC MANAGEMENT OF THE CARDIAC TRANSPLANT RECIPIENT
Rejection
Infection
Medical Complications and Comorbid ­Conditions
Malignancy
Diabetes
Hypertension
Renal Insufficiency
Hyperlipidemia
Cardiac Allograft Vasculopathy
New Health Problems
OUTCOMES AFTER HEART TRANSPLANTATION
Survival
Functional Outcomes
FUTURE DIRECTIONS
REFERENCES
Chapter 55 - Surgical Treatment of Chronic Heart Failure
CORONARY REVASCULARIZATION FOR ISCHEMIC CARDIOMYOPATHY
Definition and Epidemiology
Pathophysiology of Ischemic Cardiomyopathy
Natural History of Ischemic Cardiomyopathy
Selection of Appropriate Candidates for ­Revascularization
Clinical Trials
Clinical Factors
Myocardial Viability
Risk of Revascularization
Benefits of Revascularization
Improvement in Symptoms of Congestive Heart Failure and in ­Functional Capacity
Improvement of Left Ventricular Function
Improvement in Survival
Summary
VALVE SURGERY FOR LEFT VENTRICULAR DYSFUNCTION (see Chapter 29)
Functional Mitral Regurgitation in Patients with Severe Left Ventricular Dysfunction
Pathophysiology
Nonsurgical Treatment Options
Mitral Valve Repair
Ischemic Mitral Regurgitation in Patients with Severe Left Ventricular Dysfunction
Pathophysiology
Mitral Valve Repair
Tricuspid Valve Surgery in Patients with Severe Left Ventricular Dysfunction
Aortic Valve Surgery in Patients with Severe Left Ventricular Dysfunction
Aortic Valve Stenosis
Aortic Valve Insufficiency
LEFT VENTRICULAR RECONSTRUCTION SURGERY
Indications for Remodeling Surgery in Ischemic Cardiomyopathy
Techniques for Remodeling Surgery in Ischemic Cardiomyopathy
Dor Procedure
Cleveland Clinic Approach
Indications for Remodeling Surgery in Dilated Cardiomyopathy
Device Therapies for Dilated Cardiomyopathy
Acorn Device
Myocor Myosplint
CONCLUSIONS
REFERENCES
Chapter 56 - Circulatory Assist Devices in Heart Failure
HISTORY
SHORT-TERM CIRCULATORY SUPPORT
Intra-aortic Balloon Pump
Abiomed Biventricular System 5000
Abiomed AB5000
Bio-Medicus Bio-Pump
Levitronix CentriMag
TandemHeart Percutaneous Transseptal ­Ventricular Assist Device
Impella Devices
BRIDGING TO TRANSPLANTATION
Thoratec Percutaneous Ventricular Assist Device System
CardioWest Total Artificial Heart
Novacor Ventricular Assist System
HeartMate XVE Left Ventricular Assist Device
HeartMate II Left Ventricular Assist Device
PERIOPERATIVE COMPLICATIONS
BRIDGING TO MYOCARDIAL IMPROVEMENT
BIOLOGICAL PROPERTIES OF VENTRICULAR UNLOADING
Morphology
Programmed Cell Death and Cell Survival (see Chapter 6)
Reversal of Dysfunctional Gene and Protein Expression (see Chapter 8)
Improved Cardiomyocyte Function
ECONOMICS AND QUALITY-OF-LIFE ISSUES
FUTURE DIRECTIONS
Jarvik 2000
MicroMed DeBakey VAD
HeartMate III
MVAD by HeartWare
Abiomed Total Artificial Heart
CONCLUSION
REFERENCES
Chapter 57 - Exercise in Heart Failure
MECHANISMS OF EXERCISE INTOLERANCE IN HEART FAILURE
Cardiovascular
Peripheral
Blood Flow
Intrinsic Skeletal Muscle Changes (see Chapter 19)
Endothelial Dysfunction (see Chapter 17)
Ergoreflex Activation (see Chapter 16)
FUNCTIONAL EXERCISE TESTING IN HEART FAILURE
-Minute Walk
Cardiopulmonary Exercise Testing
Prognostic Measures Derived from Cardiopulmonary Exercise Testing
SPECIALIZED USES OF CARDIOPULMONARY EXERCISE TESTING
Evaluation of Patients with Heart Failure for Mitral Valve Surgery
Evaluation of Chronotropic Incompetence
Adjustment of Pacemakers
Safety of Exercise Testing and Training in Patients with Heart Failure Who Have Implantable Defibrillators
THERAPEUTIC EXERCISE TRAINING FOR HEART FAILURE
Physiological Benefits of Exercise Training in Heart Failure
Cardiorespiratory Physiology and Exercise ­Tolerance
Neurohormonal Activation
Endothelial Dysfunction (see Chapter 17)
Effects on Intrinsic Skeletal Muscle ­Characteristics
Central Mechanisms: Cardiac Output
Circulating Inflammatory Factors (see Chapter 11)
Exercise Improvement with Medical or Exercise Therapy: A True Surrogate of Mortality and Morbidity?
Effects of Exercise Training on Clinical Outcomes in Heart Failure
HF-ACTION
FUTURE DIRECTIONS
REFERENCES
Chapter 58 - Management of Heart Failure Patients with Malignancy
ANTHRACYCLINES
Monitoring and Anthracycline Toxicity
ALKYLATING AGENTS
Cyclophosphamide
Ifosfamide
ANTIMICROTUBULE AGENTS
Docetaxel
Proteasome Inhibitor
TARGETED THERAPEUTIC AGENTS
Trastuzumab
Mechanism of Toxicity
Bevacizumab
Imatinib
Sunitinib
DIAGNOSIS AND MONITORING OF PATIENTS RECEIVING CARDIOTOXIC CHEMOTHERAPEUTIC AGENTS (see Chapters 36 and 37)
MANAGEMENT OF PATIENTS RECEIVING CARDIOTOXIC CHEMOTHERAPEUTIC AGENTS
Dexrazoxane
Neurohormonal Antagonists (see Chapters 45 and 46)
β-Blockers.To date, there have been four case series in which researchers have evaluated the benefit of β-blockers in the treatm...
Angiotensin-Converting Enzyme Inhibitors.There is some evidence supporting the use of ACE inhibitors in patients with anthracycl...
REVERSIBILITY OF CANCER THERAPY–INDUCED LEFT VENTRICULAR DYSFUNCTION
CONCLUSION
REFERENCES
Chapter 59 - Disease Management in Heart Failure
SIGNIFICANCE OF THE PROBLEM
Treatment Adherence
Symptom Recognition
Seeking Assistance When Needed
Changing Unhealthy Lifestyles
FAILURE OF THE TRADITIONAL HEALTH CARE DELIVERY MODEL
MANAGEMENT OF HEART FAILURE
Management of Heart Failure in Special Populations (see also Chapter 49)
PUTTING MANAGEMENT OF HEART FAILURE INTO PRACTICE
The Self-Care Paradigm
Assess Patient Factors That Interfere with Self-Care
Include Family Members and Informal Caregivers in Education
Identify and Target Patients Who Are at Risk for Rehospitalization
Components of the Management of Heart Failure That Improve ­Outcomes
Individualized, Comprehensive Patient and Family or Caregiver Education and Counseling on an Outpatient Basis.At the core of eve...
Content for Patient and Family Education and ­Counseling.Patients with heart failure must perform specific behaviors to cope wit...
Teaching and Counseling Methods.It is essential that effective behavior change strategies be given to patients and families alon...
Education and Counseling Style.Optimal patient education and counseling involve more than simply providing information. Counseli...
Timing, Setting, and Form of Education and Counseling.To be most effective, education and counseling must be provided when and w...
Health Behavior Change Strategies.In a classic article, McKenney and associates120 categorized strategies for improving adherenc...
Optimization of Medical Therapy.Another important component of the management of heart failure is optimization of drug therapy, ...
Vigilant Follow-up.Outcomes are improved when the frequency of and vigilance during follow-up appointments are increased, partic...
Increased Access to Health Care Professionals.Easy access to health care providers is a component of the management of heart fai...
Early Attention to Fluid Overload.Fluid overload is the most common cause of emergency hospitalization among patients with heart...
Coordination with Other Physicians and Agencies as Appropriate.Because many patients with heart failure are elderly with multipl...
Care Delivered by Advanced Practice Nurse–Physician Team.A final important component of optimal outpatient management of heart f...
SUMMARY
REFERENCES
Chapter 60 - Cognitive Impairment in Heart Failure
PREVALENCE
A CONCEPTUAL FRAMEWORK
MECHANISMS RESPONSIBLE FOR COGNITIVE IMPAIRMENT: STRUCTURAL AND FUNCTIONAL CHANGES WITHIN THE BRAIN
CONTRIBUTING FACTORS AND COVARIATES
Sleep-Disordered Breathing and Heart Failure (see Chapter 32)
Depression and Heart Failure
COGNITIVE FUNCTIONS RELATED TO SELF-CARE IN PATIENTS WITH HEART FAILURE
Medication Regimen
Low-Sodium Diets
Symptom Monitoring
Weight Management and Regular Exercise
ASSESSMENT OF COGNITIVE IMPAIRMENT
Cognitive Impairment Screening Tools
Mini Mental State Examination
Abbreviated Mental Test
Montreal Cognitive Assessment
Clock Drawing Test and the Mini-Cog
Cognitive Abilities Screening Instrument
Cambridge Cognitive Examination
General Practitioner Assessment of Cognition
Recommendations for Assessment of Cognitive Impairment in Patients with Heart Failure
INTERVENTION PROGRAMS FOR PATIENTS WITH HEART FAILURE AND COGNITIVE IMPAIRMENT
FUTURE DIRECTIONS
REFERENCES
Chapter 61 - Management of End-Stage Heart Failure
DEFINING LATE-STAGE HEART FAILURE
THE ROLE OF CHRONIC PARENTERAL THERAPY
CELLULAR REASONS FOR AND AGAINST CHRONIC PARENTERAL INOTROPIC THERAPY
Arguments in Support
Arguments Against
CLINICAL EVIDENCE FOR AND AGAINST CHRONIC PARENTERAL INOTROPIC THERAPY
Arguments in Support
Arguments Against
CHRONIC PARENTERAL VASODILATOR THERAPY
PHARMACOLOGICAL BRIDGING TO CARDIAC TRANSPLANTATION
STRATEGIES TO WEAN FROM CHRONIC PARENTERAL INOTROPIC THERAPY
PALLIATIVE CARE AND CHRONIC PARENTERAL THERAPY
BEYOND PARENTERAL THERAPY: THE ROLE OF PALLIATIVE CARE
CONCLUSIONS
REFERENCES
Index
A
B
C
D
E
F
G
H
I
J
K
L
M
N
O
P
Q
R
S
T
U
V
W
X
Z

Citation preview

Heart Failure A Companion to Braunwald’s Heart Disease Second Edition Douglas L. Mann, MD, FACC Lewin Professor and Chief Cardiovascular Division Washington University School of Medicine; Cardiologist-in-Chief Barnes Jewish Hospital St. Louis, Missouri

3251 Riverport Lane St. Louis, Missouri 63043

HEART FAILURE: A COMPANION TO BRAUNWALD’S HEART DISEASE, SECOND EDITION Copyright © 2011, 2004 by Saunders, an imprint of Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and ­experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

Library of Congress Cataloging-in-Publication Data   Heart failure : a companion to Braunwald’s heart disease / [edited by] Douglas L. Mann. -2nd ed.   p. ; cm   Companion v. to: Braunwald’s heart disease / edited by Peter Libby ... [et al.]. 8th ed. c2008.   Includes bibliographical references and index.   ISBN 978-1-4160-5895-3   1. Heart failure. I.  Mann, Douglas L.  II.  Braunwald’s heart disease.   [DNLM: 1. Heart Failure. WG 370 H43618 2010]   RC685.C53H426 2010   616.1’2--dc22 2010010218

Executive Publisher: Natasha Andjelkovic Developmental Editor: Brad McIlwain Publishing Services Manager: Catherine Jackson Project Manager: Janaki Srinivasan Kumar Design Direction: Steven Stave

Printed in United States of America Last digit is the print number:  9  8  7  6  5  4  3  2  1

ISBN: 978-1-4160-5895-3

To my teachers and mentors, for their enduring encouragement and support, especially Dr. James W. Covell, whom I have never thanked enough, and Dr. Andrew I. Schafer, whom I can never thank enough. Douglas L. Mann, MD, FACC

Contributors

Michael Acker, MD Professor of Surgery, Cardiothoracic Surgery Division, Department of Surgery, University of Pennsylvania School of Medicine, ­Philadelphia, Pennsylvania Kirkwood F. Adams, Jr., MD Professor of Medicine, Departments of Medicine and Radiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina Inder S. Anand, MD, FRCP, DPhil (Oxon) Professor of Medicine, Division of Cardiology, University of Minnesota Medical School; Director of Heart Failure Clinic, Veterans Affairs Medical Center, Minneapolis, Minnesota Stefan D. Anker, MD, PhD Professor of Medicine, Applied Cachexia Research, Department of Cardiology, Charité Medical School, Campus Virchow-Klinikum, Berlin, Germany; Centre for Clinical and Basic Research, IRCCS San Raffaele, Rome, Italy Piero Anversa, MD Professor of Medicine and Anesthesia, Departments of Anesthesia and Medicine, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts Catalin F. Baicu, PhD Research Assistant Professor of Medicine, The Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, South Carolina Kenneth M. Baker, MD Professor and Vice Chair, Department of Medicine, Division of Molecular Cardiology; Director, Mayborn Chair in Cardiovascular Research, Texas A&M Health Science Center, Temple, Texas Rob S. Beanlands, MD Chief, Cardiac Imaging, University of Ottawa Heart Institute, Ottawa, Ontario, Canada Kerstin Bethmann, PhD Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany Courtney L. Bickford, PharmD, BCSPS Division of Pharmacy, University of Texas M.D. Anderson Cancer Center, Houston, Texas Guido Boerrigter, MD Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Heart and Lung Research Center, Mayo Clinic and Mayo Clinic College of Medicine, Rochester, Minnesota

Julian Booker, MD Department of Cardiology, Baylor College of Medicine, Houston, Texas Biykem Bozkurt, MD, PhD Professor of Medicine, Cardiology Section, Michael E. DeBakey Veterans Affairs Medical Center, Winters Center for Heart Failure Research, Baylor College of Medicine, Houston, Texas Michael R. Bristow, MD, PhD Professor of Medicine, Deparment of Medicine, Division of Cardiology, University of Colorado Health Sciences Center, Aurora, Colorado John C. Burnett, Jr., MD Professor of Medicine, Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Heart and Lung Research Center, Mayo Clinic and Mayo Clinic College of Medicine, Rochester, Minnesota Daniel J. Cantillon, MD Professor of Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio Blase A. Carabello, MD, FACC Professor of Medicine and Vice Chairman, Department of Medicine, Baylor College of Medicine; Medical Care Line Executive, Houston Veterans Affairs Medical Center, Houston, Texas Jay N. Cohn, MD Professor of Medicine, Director, Rasmussen Center for Cardiovascular Disease Prevention, Cardiovascular Division, University of Minnesota Medical School, Minneapolis, Minnesota Wilson S. Colucci, MD Professor of Medicine, Cardiovascular Medicine Section, Department of Medicine, Boston University Medical Center, Boston, Massachusetts Leslie T. Cooper, Jr., MD Professor of Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota Lisa Costello-Boerrigter, MD, PhD Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Heart and Lung Research Center, Mayo Clinic and Mayo Clinic College of Medicine, Rochester, Minnesota Lori B. Daniels, MD Division of Cardiology, University of California, San Diego, San Diego, California

Roberta C. Bogaev, MD Cardiopulmonary Transplant Service, Texas Heart Institute, Houston, Texas

Reynolds M. Delgado III, MD Cardiopulmonary Transplant Service, Texas Heart Institute, Houston, Texas

Robert O. Bonow, MD Max and Lilly Goldberg Distinguished Professor of Cardiology, Northwestern University Feinberg School of Medicine; Co-Director, Bluhm Cardiovascular Institute, Northwestern Memorial Hospital, Chicago, Illinois

Anita Deswal, MD, MPH Associate Professor of Medicine, Section of Cardiology, Michael E. DeBakey Veterans Affairs Medical Center and Winters Center for Heart Failure Research, Baylor College of Medicine, Houston, Texas

vii

viii Abhinav Diwan, MBBS

Assistant Professor of Medicine, Center for Pharmacogenomics and Cardiovascular Division, Department of Internal Medicine, Washington University and St. Louis Veterans Affairs Medical Center, St. Louis, Missouri Wolfram Doehner, MD, PhD Professor of Medicine, Center for Stroke Research, Applied Cachexia Research, Department of Cardiology, Charité University Medical School, Campus Virchow-Klinikum, Berlin, Germany Hisham Dokainish, MD Department of Medicine, Baylor College of Medicine, Houston, Texas Gerald W. Dorn II, MD Professor of Medicine, Center for Pharmacogenomics and Cardiovascular Division, Department of Internal Medicine, Washington University, St. Louis, Missouri Helmut Drexler, MD Professor of Cardiology, Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany Arthur M. Feldman, MD, PhD Magee Professor and Chairman, Department of Medicine, Jefferson Medical College, Philadelphia, Pennsylvania G. Michael Felker, MD, MHS Associate Professor of Medicine, Division of Cardiology, Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina James D. Flaherty, MD Assistant Professor of Medicine, Interventional Cardiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois John S. Floras, MD, DPhil, FRCPC, FACC, FAHA Professor of Medicine, Mount Sinai Hospital, University Health Network, Division of Cardiology, The University of Toronto, Toronto, Ontario, Canada Viorel G. Florea, MD, PhD, DSc, FACC Assistant Professor of Medicine, University of Minnesota Medical School, Veteran’s Affairs Medical Center, Minneapolis, Minnesota Gary S. Francis, MD Professor of Medicine, Cardiovascular Division, University of Minnesota, Minneapolis, Minnesota Wayne Franklin, MD Assistant Professor of Medicine; Medical Director, Texas Adult Congenital Heart Disease Center, Baylor College of Medicine, Houston, Texas O. H. Frazier, MD Cardiopulmonary Transplant Service, Texas Heart Institute, Houston, Texas Matthias Freidrich, MD The Libin Cardiovascular Institute, Calgary, Alberta, Canada Ronald S. Freudenberger, MD Director, Center for Advanced Heart Failure, Lehigh Valley Hospital and Health Network, Allentown, Pennsylvania; Professor of Medicine, Pennsylvania State University College of Medicine, State College, Pennsylvania

Mihai Gheorghiade, MD, FACC Professor of Medicine and Surgery; Associate Chief, Division of Cardiology; Chief, Cardiology Clinical Service, Director, Telemetry Unit, Northwestern University Feinberg School of Medicine, Chicago, Illinois Thomas D. Giles, MD Professor of Medicine, Heart and Vascular Institute, Tulane University Health Sciences Center, New Orleans, Louisiana Stephen Gottlieb, MD Professor of Medicine, University of Maryland School of Medicine, Baltimore, Maryland Yusuf Hassan, MD Division of Cardiology, The University of Texas Houston Health Science Center, Houston, Texas Edward P. Havranek, MD Professor of Medicine, Denver Health Medical Center, University of Colorado Denver School of Medicine, Denver, Colorado Shunichi Homma, MD Associate Chief, Division of Cardiology; Director, Cardiovascular Ultrasound Laboratories, Professor of Medicine, Margaret Milliken Hatch Professor of Medicine, New York Presbyterian Hospital, New York, New York Burkhard Hornig, MD Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany Steven R. Houser, PhD, FAHA Professor of Phys, Cardiovascular Research Center, Molecular and Cellular Cardiology Laboratories, Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania Joanne S. Ingwall, PhD Professor of Medicine (Physiology), Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts Shahrokh Javaheri, MD Emeritus Professor of Medicine, University of Cincinnati, College of Medicine; Medical Director, Sleepcare Diagnostics, Cincinnati, Ohio John Lynn Jefferies, MD, MPH Assistant Professor of Pediatrics, Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital, Houston, Texas Mariell Jessup, MD Professor of Medicine, Cardiovascular Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Saurabh Jha, MBBS Assistant Professor of Radiology, Hospital at the University of Pennsylvania, Philadelphia, Pennsylvania Jan Kajstura, PhD Department of Anesthesia, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts David A. Kass, MD Abraham and Virginia Weiss Professor of Cardiology; Professor of Medicine; Professor of Biomedical Engineering, Institute of Molecular Cardiobiology, Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, Maryland

Arnold M. Katz, MD, DMed (Hon) Professor of Medicine Emeritus, University of Connecticut School of Medicine, Farmington, Connecticut; Visiting Professor of Medicine and Physiology, Dartmouth Medical School, Hanover, New Hampshire

Marvin A. Konstam, MD Professor of Medicine, Tufts University School of Medicine; Director, Cardiovascular Center, Tufts Medical Center, Boston, Massachusetts Varda Konstam, PhD University of Massachusetts, Boston, Massachusetts William E. Kraus, MD Professor of Medicine, Duke University School of Medicine, Durham, North Carolina Rajesh Kumar, PhD Assistant Professor, Department of Internal Medicine, Division of Molecular Cardiology, Texas A&M Health Science Center, College of Medicine, Temple, Texas Ulf Landmesser, MD Assistant Professor of Medicine, Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany Thierry H. Le Jemtel, MD Henderson Chair and Professor of Medicine; Director, Heart Failure and Cardiac Transplantation Program, Tulane University, New Orleans, Louisiana Ilana Lehmann, PhD University of Massachusetts, Boston, Massachusetts Annarosa Leri, MD Associate Professor, Department of Anesthesia, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts Martin M. LeWinter, MD Professor of Medicine and Molecular Physiology and Biophysics, University of Vermont College of Medicine, Burlington, Vermont Chang-Seng Liang, MD, PhD Professor of Medicine, Cardiovascular Medicine Section, Department of Medicine, Boston University Medical Center, Boston, Massachusetts Alan S. Maisel, MD Professor of Medicine, Division of Cardiology, University of California–San Diego, Veterans Affairs Medical Center, San Diego, California Donna M. Mancini, MD Professor of Medicine, Columbia-Presbyterian Medical Center, New York, New York Douglas L. Mann, MD, FACC Lewin Professor and Chief, Cardiovascular Division, Washington University School of Medicine; Cardiologist-inChief, Barnes Jewish Hospital, St. Louis, Missouri

Ali J. Marian, MD Professor of Molecular Medicine and Internal Medicine (Cardiology); Director, Center for Cardiovascular Genetic Research, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Texas Heart Institute at St. Luke’s Episcopal Hospital, Houston, Texas Matthew Maurer, MD Assistant Professor of Clinical Medicine, Columbia University College of Physicians and Surgeons, New York, New York Dennis M. McNamara, MD, MSc Professor of Medicine, Director, Heart Failure/Transplantation Program, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania Mandeep R. Mehra, MBBS, FACC, FACP Professor of Medicine, Herbert Berger Professor and Head of Cardiology, University of Maryland School of Medicine, Baltimore, Maryland Gustavo F. Méndez Machado, MD, MSc, FESC Consultant Cardiologist, Department of Research, IMSS Adolfo Ruiz Cortines National Medical Center, Veracruz, Mexico Marco Metra, MD Division of Cardiology, Department of Experimental and Applied Medicine, University of Brescia, Brescia, Italy Debra K. Moser, DNSc, RN, FAAN Professor and Gill Endowed Chair of Nursing, University of Kentucky, College of Nursing, Lexington, Kentucky Wilfried Mullens, MD Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio Ashleigh A. Owen, MD Medical University of South Carolina, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina Jing Pan, MD, PhD Assistant Professor, Department of Internal Medicine, Division of Molecular Cardiology, Texas A&M Health Science Center, College of Medicine, Temple, Texas Richard D. Patten, MD, FACC Assistant Professor of Medicine, Catholic Medical Center, New England Heart Institute, Manchester, New Hampshire Naveen Pereira, MD Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota Linda R. Peterson, MD, FACC, FAHA, FASE Associate Professor of Medicine and Radiology, Cardiovascular Division, Division of Geriatrics and Nutritional Sciences, Washington University School of Medicine, St. Louis, Missouri Ileana L. Piña, MD Professor of Medicine, Case Western Reserve University, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio

Contributors

Richard N. Kitsis, MD Professor of Medicine, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York

Kenneth B. Margulies, MD ix Professor of Medicine, Cardiovascular Institute, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

x Philip J. Podrid, MD

Professor of Medicine and Associate Professor of Pharmacology, Boston University School of Medicine, Boston, Massachusetts

John R. Teerlink, MD Professor of Clinical Medicine, Section of Cardiology, San Francisco Veterans Affairs Medical Center, University of California–San Francisco, San Francisco, California

J. David Port, PhD Deparment of Medicine, Division of Cardiology, Department of Pharmacology, University of Colorado Health Sciences Center, Aurora, Colorado

Veli K. Topkara, MD Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri

Kumudha Ramasubbu, MD Assistant Professor of Medicine, Winters Center for Heart Failure Research, Department of Medicine, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas

Jeffrey A. Towbin, MD Professor of Pediatrics, The Heart Institute, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio

Barbara Riegel, DNSc, RN, FAAN Professor, University of Pennsylvania, School of Nursing, Philadelphia, Pennsylvania

Patricia A. Uber, PharmD Assistant Professor of Medicine, Division of Cardiology, University of Maryland School of Medicine, Baltimore, Maryland

G E Sandler Professor of Medicine, Heart and Vascular Institute, Tulane University Health Sciences Center, New Orleans, Louisiana Douglas B. Sawyer, MD, PhD Professor of Medicine, Cardiovascular Medicine Section, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee Joel Schilling, MD, PhD Instructor in Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri Leo Slavin, MD Research Physician, Division of Cardiology, University of California–San Diego, San Diego, California Francis G. Spinale, MD, PhD Professor of Surgery, Medical University of South Carolina, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina

Peter VanBuren, MD Associate Professor of Medicine and Molecular Physiology and Biophysics, University of Vermont College of Medicine, Burlington, Vermont Ramachandran S. Vasan, MD Section Chief, Preventive Medicine, The Preventative Medicine and Cardiology Sections, Boston University School of Medicine, Boston, Massachusetts Raghava S. Velagaleti, MD The National Heart, Lung and Blood Institute’s Framingham Heart Study, Framingham, Massachusetts Stephan von Haehling, MD Applied Cachexia Research, Department of Cardiology, Charité University Medical School, Campus VirchowKlinikum, Berlin, Germany

Randall C. Starling, MD, MPH Professor of Medicine, Department of Cardiovascular Medicine, Section of Heart Failure and Cardiac Transplant Medicine, Kaufman Center for Heart Failure, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio

Bruce L. Wilkoff, MD Director of Cardiac Pacing and Tachyarrhythmia Devices, Section of Cardiac Pacemakers and Electrophysiology, Robert and Suzanne Tomsich Department of Cardiovascular Medicine, Cleveland Clinic; Professor of Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio

Lynne Warner Stevenson, MD Professor of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts

Kai C. Wollert, MD Professor of Cardiology, Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany

Carmen Sucharov, PhD Assistant Professor of Medicine, Department of Medicine, Division of Cardiology, University of Colorado Health Sciences Center, Aurora, Colorado

Edward T. H. Yeh, MD Professor of Medicine, Department of Cardiology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas

Heinrich Taegtmeyer, MD, DPhil Professor of Medicine, Department of Internal Medicine, Division of Cardiology, The University of Texas−Houston Medical School, Houston, Texas

James B. Young, MD Professor of Medicine and Executive Dean, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio

W. H. Wilson Tang, MD Professor of Medicine, Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio

Maria C. Ziadi, MD University of Ottawa Heart Institute, Ottawa, Ontario, Canada

Anne L. Taylor, MD Professor of Medicine, Columbia University College of Physicians and Surgeons, New York, New York

Michael R. Zile, MD Professor of Medicine, Division of Cardiology, Department of Medicine, Medical University of South Carolina, The Gazes Cardiac Research Institute, Charleston, South Carolina

Foreword In what seems on the surface to be a paradox, the prevalence, incidence, and mortality of heart failure are steadily climbing despite phenomenal progress in the diagnosis and treatment of all forms of cardiac disease. As we successfully manage— yet not cure—patients with heart disease, the damage to their cardiac muscles persists and sometimes progresses as adaptive compensatory mechanisms become maladaptive. With steadily increasing life spans and the growing “epidemics” of diabetes, obesity, and atrial fibrillation in the elderly, the stage is now set for a large increase in the number of heart failure cases. Thus we are facing great challenges in our quest to control cardiac disease. How are we going to win this battle? Surely not with a single magic bullet, whether it is a gene, device, or drug. We believe Douglas Mann’s excellent book, Heart Failure, details the right plan. As with any battle, we must understand the terrain on which it will be fought. The first three sections of Heart Failure do just that. Section I delves into the basic underlying mechanisms on genetic, molecular, tissue, organ, and organismal levels, whereas Section II describes the pathophysiology of disease progression. These discussions involve not only the heart but also the vascular bed, neurohormonal systems, kidneys, and lungs. The most common etiologies of heart failure are described in Section III. Section IV provides a detailed description of the clinical manifestations and laboratory features of heart failure. Finally, the current armamentaria in the treatment of heart failure—drugs, devices, and surgery—and how each of these (and their combinations) can be optimally deployed are described in Section V.

A leader in the fight against one of humankind’s most stubborn enemies, Dr. Mann should be congratulated on selecting the right topics and the best authors to write about them. His skillful editing pulled everything together, making this book much greater than simply the sum of the excellent individual chapters. This second edition builds on the first, which was warmly received. Fully one third of the chapters are new. Many chapters that appeared in the last edition have new authors and all have been updated to include the most current data and research. Special thanks are due the authors, all distinguished investigators or clinicians, for their fine contributions. This splendid second edition of Heart Failure will be enormously useful to cardiovascular specialists who care for the growing number of patients with heart failure; it will be equally useful to those who are training to deliver this care, as well as to their teachers. However, the ultimate beneficiaries of this book will be the millions of patients with heart failure worldwide. We are proud that this second edition of Heart Failure is a valued and indispensable companion to Heart Disease: A Textbook of Cardiovascular Disease. Eugene Braunwald Boston, Massachusetts Robert Bonow Chicago, Illinois Peter Libby Boston, Massachusetts Douglas P. Zipes Indianapolis, Indiana

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Preface The observation that several of the topics discussed as emerging therapies in the first edition of Heart Failure: A Companion to Braunwald’s Heart Disease have now become either the standard of care (e.g., cardiac resynchronization) or are being tested in multicenter, multinational clinical trials (e.g., stem cell therapy) could be viewed as the major justification for publishing a second edition of the Heart Failure Companion. Beyond updating the chapters covered in the first edition, the vision for the second edition was to provide an extremely broad educational platform that would serve to foster a more complete understanding and appreciation of the clinical syndrome of heart failure. To that end, the second edition contains 20 entirely new chapters that were not included in the first edition. Particular emphasis has been given to the sections on clinical assessment and treatment of heart failure (see below), which have been expanded by 75% compared to the first edition. As with the first edition, the goal in organizing this text was to provide trainees, scientists, and practicing clinicians with a resource that would present a complete bench-to-bedside overview of the field of heart failure that could be read from start to finish, or section by section. The second edition retains the same organization as the first edition and is divided into five sections that progress logically from basic molecular and cellular mechanisms that underlie heart failure (Section 1), to the mechanisms that lead to disease progression in heart failure (Section 2), to the etiologic basis for heart failure (Section 3), and finally to the clinical assessment (Section 4) and treatment of heart failure (Section 5). As with the first edition, many of the chapters were designed to parallel one another, which should allow readers to focus on the aspects of heart failure that they find most interesting. For example, the second edition features chapters

that cover the basic and clinical aspects of heart failure with a preserved ejection fraction as well as basic and clinical aspects of stem cell therapy and myocardial regeneration. The second edition also includes new chapters that reflect the overall growth in the field (e.g., biomarkers, cardiac devices, cardiac imaging, pharmacogenomics, palliative care in heart failure), as well as increased depth of understanding in the field (e.g., myocardial recovery, diabetic cardiomyopathy, heart failure as a consequence of chemotherapy, heart failure in special populations). In addition, this edition features several unique chapters that have not heretofore been covered in traditional textbooks on heart failure, including the important topic of heart failure in developing countries, the emerging issue of meaningfully measuring quality of outcomes in heart failure, and the neglected area of cognition in heart failure. The extent to which the second edition of Heart Failure: A Companion to Braunwald’s Heart Disease provides readers with a comprehensive bench-to-bedside overview of the field of heart failure reflects the extraordinary expertise and scholarship of the authors who contributed their professional time and efforts to this undertaking. It has been a great pleasure to work with them and it has been my great fortune to learn from them. Although every attempt was made to make the content of individual chapters as up-to-date as possible and include all the changes that were occurring in the field while this text was in development, we recognize the challenge of capturing all the essential elements of a field that is evolving rapidly. Accordingly, this second edition will be accessible online as well as in print, on the same Expert Consult platform that houses the parent text, Braunwald’s Heart Disease, which features regular content updates. Douglas L. Mann, MD, FACC

xiii

In Memoriam – Helmut Drexler I first met Helmut Drexler in December 1996 at a symposium at the European Heart House in Sophia Antipolis, France. Helmut was in the audience listening to a presentation that I was giving. After the presentation was finished, Helmut stood up and began asking a series of challenging and incredibly insightful questions. Although I did my best to answer his questions, he must not have been satisfied because he waited until I stepped down from the podium and continued to ask me even more challenging questions. He was absolutely relentless. Thus began my friendship with Helmut Drexler that lasted up until his untimely death on September 13, 2009. Helmut was a critical thinker who took nothing for granted. He was a classic epistemologist, who questioned everything because he wanted to understand the nature of things at their most fundamental level. His passion for understanding the basic mechanisms of heart failure was unending and his energy for translating this knowledge to the bedside was boundless. Over the span of his career he made seminal contributions to our understanding of the role of endothelial dysfunction, the renin angiotensin system, and inflammation in heart failure. He was the first to direct a randomized clinical trial of transcoronary bone marrow cell therapy for patients with acute myocardial infarction, as well as the first to highlight the shortcomings of this trial. His most significant work, which came shortly before his death, focused on the molecular mechanisms of postpartum cardiomyopathy and has paved the way for developing a potential new treatment for patients with this orphan disease. Despite all of his success Helmut’s foremost priorities were always his family and friends, as well as his faculty, many of whom have gone on to have successful independent academic careers, such as Denise HilfikerKleiner, Kai Wollert, Bernhard Schieffer, and Ulf Landmesser, among others. He is survived by his beautiful wife Krista and daughter Beatrice, who has recently completed medical school. The last time I saw Helmut we had dinner together. After updating each other on our scientific pursuits and sharing our mutual passion for family, friends, and red wine, I told him that I was thinking of moving to a different city to assume a new academic position. Helmut raised his eyes from the table and was genuinely excited for me, but then mentioned that moving was difficult because it was hard to establish strong friendships as one became older. As I learned during the years that I knew Helmut, he was generally right about most things. With his death, I have lost a good friend who cannot be replaced at any age. Douglas L. Mann, MD, FACC

Acknowledgments Any clinical reference work of the size and complexity of Heart Failure: A Companion to Braunwald’s Heart Disease does not occur in a vacuum. I would like to begin, first and foremost, by thanking Dr. Eugene Braunwald for giving me the opportunity to edit the companion volume focusing on heart failure. I would also like to thank Drs. Bonow, Libby, and Zipes, who taught me the art of editing during my apprenticeship on the eighth edition of Braunwald’s Heart Disease. The extent to which the second edition of the heart failure companion is improved over the first is attributable to what I learned from my senior co-editors. I also want to thank the incredibly supportive staff at Elsevier, who enabled me to make a m ­ yriad of improvements to the content and visual design of the text as it was being developed. In particular, I would like to thank the

following members of the Elsevier staff for their forbearance and indefatigable assistance: developmental editor Marla Sussman, project manager Janaki Srinivasan, executive publisher Natasha Andjelkovic, and her editorial assistant Brad McIlwain. I would also like to thank my administrative assistant, Ms. Mary Wingate, who remained unflappable no matter how many times I asked her to re-edit, re-format, or redo the same chapter. Lastly, I would be completely remiss if I did not thank my incredibly supportive wife, Laura, who tolerated both my presence and absence throughout the process of editing and writing for the second edition of Heart Failure: A Companion to Braunwald’s Heart Disease. Douglas L. Mann, MD, FACC

xv

LOOK FOR THESE OTHER TITLES IN THE ­BRAUNWALD’S HEART DISEASE FAMILY! Theroux: Acute Coronary Syndromes, 2nd Edition Taylor: Atlas of Cardiac Computed Tomography Kramer and Hundley: Atlas of Cardiac Magnetic Resonance Lilly: Heart Disease Review & Assessment Otto and Bonow: Valvular Heart Disease, 3rd Edition Issa: Clinical Arrhythmology and Lipidology Ballantyne: Clinical Lipidology Antman: Cardiovascular Therapeutics, 3rd Edition Black and Elliott: Hypertension Creager, Loscalzo and Dzau: Vascular Medicine Moser and Riegel: Cardiac Nursing

CHAPTER Heart Failure as a Clinical Syndrome,  1 Heart Failure as a Circulatory Disorder,  1 Altered Architecture of Failing Hearts,  2 Abnormal Hemodynamics,  3 Disordered Fluid Balance,  3 Biochemical Abnormalities,  3

1

Evolving Concepts in the Pathophysiology of Heart Failure Arnold M. Katz

We have achieved our current understanding of heart failure through a remarkable evolution of ideas that, for Western mediGenomics,  4 cine, extends back more than 2500 years.1–2 Since the fifth century bce, physicians and Epigenetics,  5 scientists have viewed this clinical synConclusions and Future drome in at least nine different ways (Table Directions,  5 1-1).3 Improved understanding of this syndrome has been made possible by an interplay between basic and clinical sciences that is narrowing the gap between bench and bedside, between basic science and clinical medicine.4 This iterative process has used new knowledge of pathophysiology to improve patient care while at the same time clinical validation of new therapeutic approaches has added to our knowledge of basic physiology. Maladaptive Hypertrophy,  4

HEART FAILURE AS A CLINICAL SYNDROME

the juice, do this for eleven days when the moon is waning because also man wanes in his abdomen.”8

HEART FAILURE AS A CIRCULATORY DISORDER Correlations between clinical manifestations and cardiac abnormalities became possible at the beginning of the sixteenth century, when physicians began to perform autopsies to identify causes of illness.9 However, there was no way to define mechanistic relationships between the clinical and autopsy findings in patients with heart failure until 1628, when William Harvey (Figure 1-2) described the circulation: “I am obliged to conclude that in animals the blood is driven round a circuit with an unceasing, circular sort of movement that this is an activity or function of the heart which it carries out by virtue of its pulsation, and that in sum it constitutes the sole reason for that heart’s pulsatile movement.”10 During the following century, physicians began to use Harvey’s discovery to understand the pathophysiology of heart failure (Figure 1-3). The first description of the hemodynamic basis of this syndrome cannot be credited to a single individual in part because medical advances in the seventeenth and eighteenth centuries were

The clinical texts attributed to Hippocrates, most of which were written between the fifth and third centuries bce, describe patients with shortness of breath, edema, and anasarca.5 However, as these are not specific, many of these patients probably suffered from conditions other than heart failure. The major reason why diagnosis is difficult, and often impossible, is that these texts lack a foundation in pathophysiology. Palpitation and shortness of breath, for example, were commonly attributed to the passage of phlegm, a cold humor generated by the brain, into the chest. During the third century bce, the center of medical science shifted to Alexandria, Egypt, where Herophilus and Erasistratus carried out human dissection and physiological experiments. Although the Alexandrian physiologists recognized that the heart contracts and understood the function of the ­semilunar valves, their efforts had no impact on understanding heart failure because they did not realize that the heart is a pump that circulates the blood. Their views did, however, have a major influence on Galen, a Greek physician who lived in the Roman Empire during the second century and whose writings were to dom TABLE 1–1   Changing Views of Heart Failure* inate western thinking for more than 1500 years. Galen also I. A clinical syndrome knew that ventricular volume decreases during systole and understood the function of the heart’s valves, but viewed II. A circulatory disorder the heart as a source of heat rather than a pump (Figure 1-1). III. Altered architecture of failing hearts Galen palpated the arterial pulse and described what almost certainly represents atrial fibrillation when he noted “comIV. Abnormal hemodynamics plete irregularity or unevenness [of the pulse], both in the V. Disordered fluid balance single beat and in the succession of beats”;6 however, he believed that the pulse is transmitted along the walls of the VI. Biochemical abnormalities arteries, rather than by pulsatile blood flow through their     Energy starvation lumens.7     Depressed contractility Failure to understand the pathophysiology of heart failure     Neurohumoral stimulation made it impossible to appreciate the causes of the signs and VII. Maladaptive hypertrophy symptoms of this syndrome and precluded any rational therapy. This provided a background for treatments of ­dyspnea VIII. Genomics and dropsy that include “take scabwort and grind and IX. Epigenetics squeeze its juice through a cloth, collect in an eggshell and * temper with honeycomb; give the patient daily a full shell of Modified from Reference 1.

1

2

Brain Animal spirits Air Pneuma (air)

Pulmonary veins

Venous a. Arterial v. Aorta

Venae cavae

Impure blood

Pneuma (air)

Lung

Bl oo d

CH 1

Pulmonary artery

Vena cava

RA

Aorta RV

Phlegm

LA LV

Vital spirits

Liver Natural spirits

FIGURE 1–1  Two views of the circulation. A, Galen’s view. Pneuma derived from air reaches the heart from the lungs via the venous artery (pulmonary artery) and arterial vein (pulmonary veins). Natural spirits that enter the heart from the liver, along with vital spirits (heat) generated in the left ventricle, are distributed throughout the body by an ebb and flow in the arteries. Animal spirits transported from the brain through nerves as phlegm contribute to the formation of pleural effusions. B, The view after Harvey. Deoxygenated blood is darkly shaded, oxygenated blood is lightly shaded. Modified from Katz AM, Konstam MA. Heart failure: pathophysiology, molecular biology, clinical management, ed 2, Philadelphia, Lippincott/Williams (2009).73

Chyla

A

B Harvey’s De Motu Cordis 1550

1700

1650

1600

1750

*

Riviere Mayow Lancisi

*

Vieussens 1550

1650 1700 1750 Year FIGURE 1–3  Time lines showing events following the publication of Harvey’s De Motu Cordis in 1628 (vertical dotted line), and the birth and death of Rivière, Mayow, Lancisi, and Vieussens (rectangles; the shaded area for Vieussens reflects uncertainty regarding the date of his birth). Dates of key publications are shown by the thick vertical rectangles; posthumous publications are indicated by asterisks. Modified from Katz AM. Raymond Vieussens and the “first” pathophysiological description of heart failure. Dialog Cardiovasc Med 2004;9:179–182.74

FIGURE 1–2  William Harvey. State portrait at the Royal College of Physicians, painted when Harvey was in his late 60s.

widely discussed among authorities and there were few publications, many of which appeared after the author’s death. Among the first to relate the clinical features of heart failure to abnormal hemodynamics were Rivière,11 Mayow,12 Lancisi,13 and Vieussens.14 The latter (Figure 1-4), in his Traité nouveau de la structure et des causes du movement naturel du coeur, published in 1715 (the year he died), integrated a

1600

superb case history, a detailed autopsy, and a surprisingly modern discussion of pathophysiology to describe the hemodynamic basis for the dyspnea and pleural effusions in a patient with rheumatic mitral stenosis.

ALTERED ARCHITECTURE OF FAILING HEARTS Efforts to understand heart failure shifted to the architecture of diseased hearts at the beginning of the eighteenth century. Lancisi, in 1707, distinguished between “dilation,” where cavity size is increased, and “hypertrophy,” where wall thickness is increased,13 and in 1759 Morgagni described the causal

Disordered Fluid Balance

FIGURE 1–4  Vieussens as a young man. Reproduced from Fishman AP, ­Richards DW. Circulation of the blood: men and ideas, New York, 1964, Oxford University Press.75

link between hemodynamic overload and cardiac hypertrophy.15 These observations were followed by more than a century of discovery that focused on architectural changes in the failing heart. Corvisart’s observation that dilation (eccentric hypertrophy) of the left ventricle has a worse prognosis than concentric hypertrophy16 led Flint to suggest that hypertrophy is an adaptive response that protects the patient from the adverse effects of dilation.17 By the end of the nineteenth century, however, it had become apparent to Osler18 and others that hypertrophy itself is deleterious.

Abnormal Hemodynamics Many nineteenth century physiologists had been aware that a physiological increase in diastolic volume leads to an increase in cardiac output,19 whereas physicians had viewed the effects of increased cavity size in terms of evidence that pathological dilation is associated with a poor prognosis (see previous discussion). Starling’s description of the Law of the Heart that bears his name, which demonstrated that physiological increases in end-diastolic volume increase cardiac output,20 was confusing to clinicians because it seemed to contradict the nineteenth century view that dilation weakens the heart. Furthermore, for the next 60 years it was commonly taught that failing hearts operate on the descending limb of the Starling curve, where increasing chamber volume decreases the heart’s ability to eject.21 This erroneous view became untenable when, in 1965, I pointed out that it is impossible for a heart operating on the descending limb of the Starling curve to function at a steady state.22 Hemodynamics remained central for understanding heart failure throughout the first half of the twentieth century, when most patients with heart disease had structural abnormalities caused by rheumatic fever, syphilis, and congenital anomalies. However, the work of Starling, Wiggers, and others who

Dyspnea and anasarca, which had dominated the clinical picture in heart failure since the time of Hippocrates, gave rise to horrible suffering that is virtually unknown today. Although fluid retention had been proposed as a cause of dropsy as early as the sixteenth century, there had been no safe way to get rid of the excess salt and water until 1920, when Saxl and Heilig accidentally observed the diuretic properties of an organic mercurial that had been given to treat syphilitic heart disease.25 Subsequent efforts to develop powerful diuretics that could be administered orally shifted the focus in heart failure research to renal physiology. This effort ended successfully in the 1950s and 1960s with the introduction of the thiazides, and subsequently of loop diuretics. Although these and other drugs can usually cause a diuresis so effective as to eliminate congestion, albeit sometimes at the expense of causing a low output state, they do little to alter the underlying causes of this syndrome. For this reason, the focus in heart failure research returned to the heart.

Biochemical Abnormalities Three areas of biochemistry began to have a major impact on cardiology during the 1950s. The first was energetics, which had influenced thinking in muscle physiology since the beginning of the nineteenth century (see Chapter 7). The second, elucidation of the mechanisms responsible for muscle contraction, relaxation, and excitation-contraction coupling, became part of cardiology when the role of changing myocardial contractility was recognized as a key to an understanding how hearts failed (see Chapter 3 and 13). The third area, the biochemistry of ligand-receptor interactions and the intracellular signal transduction pathways responsible for the neurohumoral response to reduced cardiac output, led in the 1980s to the first major advances in treating this syndrome since the introduction of mercurial diuretics (see Chapter 2). Energy Starvation Muscle thermodynamics had been studied since 1848 when Helmholtz, who described the First Law of Thermodynamics, published records of energy release by muscle as work and heat. Between the 1920s and 1950s, several groups studied the mechanical efficiency of failing hearts, but most experimental studies at that time had little pathophysiological resemblance to clinical heart failure because they used either mammalian heart-lung preparations that had deteriorated when particulates in the perfusates occluded the coronary microcirculation, or a model of heart failure caused by pulmonary stenosis and tricuspid insufficiency. More recently, NMR spectroscopy and other analytic methods demonstrated that myocardial ATP and phosphocreatine levels are significantly reduced in failing hearts,26–27 and so made it clear that energy starvation plays an important role in heart failure (see Chapter 7 and 20). Depressed Contractility In 1955, Sarnoff’s demonstration that the heart can shift from one Starling curve to another clarified the role of myocardial contractility in regulating cardiac performance.28 Although

Evolving Concepts in the Pathophysiology of Heart Failure

studied cardiac hemodynamics had little impact on patient 3 care until the early 1940s, when Cournand and Richards brought cardiac catheterization to the bedside.23 Subsequent developments in cardiac surgery24 made it possible to palliate many forms of structural heart disease, both rheumatic and congenital, but did not solve the challenges posed by heart failure because ischemic heart disease, dilated cardiomyopa- CH 1 thies, and diastolic heart failure were emerging as the major causes of this syndrome.

4 characterization of this regulatory mechanism in patients was

hampered by difficulties in measuring myocardial contractility, in the late 1960s Braunwald’s group was able to show that contractility is reduced in patients with chronic heart failure.29 This emphasis on myocardial contractility occurred at a time when muscle biochemists had found that calcium CH 1 delivery to the cytosol and its binding to troponin, a regulatory protein in the myofilaments, are major determinants of contractility.30 The widely held view that powerful inotropic agents would benefit patients with failing hearts, along with discoveries regarding mechanisms that depress contractility, stimulated efforts to develop new inotropic drugs. However, clinical trials showed that long-term inotropic therapy with β-agonists and phosphodiesterase inhibitors does more harm than good.31–32 The importance of impaired filling in the pathogenesis of heart failure was not widely recognized until the 1980s, when echocardiography and nuclear cardiology made it possible to document lusitropic abnormalities in clinical heart failure. Unfortunately, efforts to improve ventricular filling and prognosis in patients with heart failure and preserved left ventricular ejection fraction have had little success (see Chapter 48). Neurohumoral Stimulation The importance of a third type of biochemical abnormality in failing hearts was described in 1983, when Harris33 pointed out the adverse effects of the neurohumoral responses to reduced cardiac output. Although these responses, the most important of which are vasoconstriction, salt and water retention, and adrenergic stimulation, had evolved to maintain cardiac output during exercise and support the circulation when cardiac output falls after hemorrhage, they become harmful when they are sustained in chronic heart failure.34 The ability of vasoconstriction to increase cardiac energy expenditure35 and reduce cardiac output36 led Cohn and others to examine the effects of vasodilators on long-term prognosis in patients with heart failure.37–38 V-HeFT and subsequent trials made it clear that although afterload reduction causes a short-term hemodynamic improvement, not all vasodilators prolong survival and some worsen long-term prognosis.39 The dramatic benefit of angiotensin II–converting enzyme (ACE) inhibitors, which was first documented in the CONSENSUS I trial,40 suggested that beneficial effects of ACE inhibitors are due to factors other than their ability to reduce afterload (see later discussion).

MALADAPTIVE HYPERTROPHY By the late 1980s, therapy for heart failure had become so effective that it was often assumed that the judicious use of diuretics, vasodilators, and inotropes could solve most of the problems in these patients. At that time, before clinical trials had documented the poor prognosis in heart failure, many experts denied that this was a progressive syndrome. However, the view that heart failure is simply a hemodynamic disorder complicated by fluid retention was challenged when long-term trials showed that direct-acting vasodilators can worsen prognosis, and a central role for depressed contractility became untenable when inotropes were found to shorten survival in these patients (see previous discussion). Explanations for these apparently counterintuitive clinical findings began to emerge in the 1990s, when new data from the expanding fields of molecular biology rekindled interest in the deleterious effects of cardiac hypertrophy. The emphasis on cardiac hypertrophy a century earlier (see previous discussion) had not been entirely forgotten; Meerson, who in the 1950s used modern methods to study the hypertrophic response to hemodynamic overload in animals, observed, as had Osler more than 50 years earlier,18 that

overload-induced hypertrophy is both beneficial and deleterious.41 The beneficial effects of this growth response were shown clearly in the 1960s and 1970s when left ventricular hypertrophy was found to normalize wall stress in compensated aortic stenosis.42–44 These findings, which also demonstrated that deterioration of failing hearts is not simply a consequence of sustained overload, suggested that the hypertrophic response itself might play a central role in causing maladaptive hypertrophy.45 Evidence that changes in the molecular composition of failing hearts play a role in this syndrome was published in the 1950s, when the molecular weight of myosins isolated from failing hearts was reported to increase.46 However, the inability of several other groups to reproduce these findings47 provoked a fierce controversy that was resolved when the original physicochemical data were shown to have been technically flawed.48 A more durable line of evidence stemmed from early findings that changes in myosin ATPase activity represent a “tonic” mechanism that regulates myocardial contractility, which differs fundamentally from the “phasic” mechanisms mediated by changes in calcium binding to the contractile proteins (see previous discussion).49 The modern era in understanding the pathophysiology of heart failure began in 1962, when Alpert and Gordon reported that ATPase activity is reduced in myofibrils isolated from failing human hearts.50 The molecular basis for this abnormality was identified in 1976 by Hoh et al,51 who found that differences in the rate of energy release by myosin are the result of expression of different myosin isoforms. Scheuer and Penpargkul, in collaboration with my group, found that overload not only decreases energy turnover by the contractile proteins, but also slows calcium transport by the sarcoplasmic reticulum.52 Izumo, Nadal-Ginard, and others53–54 subsequently demonstrated that increased expression of the low ATPase β-myosin heavy chain isoform in failing hearts is part of a reversion to the fetal phenotype. The importance of these molecular changes was highlighted by the finding that opposite changes occur in training-induced physiological hypertrophy (the “athlete’s heart”), where increased expression of the high ATPase α-myosin heavy chain isoform increases ATPase activity and contractility.55 The practical importance of maladaptive hypertrophy became apparent in 1985 when Janis Pfeffer, Mark Pfeffer, and Braunwald reported that ACE inhibitors slow the progressive cavity enlargement, which they called remodeling, that follows experimental myocardial infarction (see Chapter 15).56 At the same time, evidence began to appear suggesting that these drugs are not only vasodilators, but also modify proliferative signaling.57 These observations, along with evidence that overload causes the heart to deteriorate (see previous discussion), indicates that the hypertrophic response can, depending on the specific signaling mechanisms that are activated, be either adaptive or maladaptive.58–62

GENOMICS Shortly after molecular biology moved to center stage in cardiology in the late 1980s,63 the Seidman laboratory described the first molecular cause of a familial cardiomyopathy, a missense mutation in the cardiac β-myosin heavy chain gene.64 This molecular abnormality was subsequently shown to represent only one of a growing number of mutations involving additional proteins that cause both hypertrophic and dilated cardiomyopathies (see Chapter 27).65 The possibility of modifying the signal pathways controlled by these mutations to activate adaptive cardiac myocyte growth and inhibit maladaptive hypertrophy represents one of today’s most promising lines of investigation.58–61

Hurst

The Heart

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Beta blockers Neurohumoral blockade Vasodilators Inotropes Digitalis Diuretics Rest

60 40 20 0

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’74 ’78 Year

’82

Braunwald

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Heart Disease

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CH 1

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’05

FIGURE 1–5  Changing management of heart failure over the past 40 years as documented by the number of pages devoted to various treatments in several editions of Hurst’s The Heart and Braunwald’s Heart Disease. (Electronic and mechanical devices and surgical therapies are not included.) From Katz AM, ­Konstam MA. Heart failure: pathophysiology, molecular biology, clinical management, ed 2, Philadelphia, Lippincott/Williams (in press).73

EPIGENETICS A newly discovered type of regulation, referred to as epigenetics,66 has recently been found to operate in heart failure. Epigenetic regulation differs from the more familiar genomic mechanisms, whose primary targets include transcription factors that interact with DNA and alternative splicing that allows synthesis of different protein isoforms by rearranging the information encoded in the exons of genomic DNA. Epigenetic mechanisms modify proliferative signaling by methylation of cytosine in genomic DNA, acetylation of histone, and inhibition of RNA translation by small RNA sequences called microRNAs. Cytosine methylation has been implicated in some familial cardiomyopathies,67–68 while histone acetylation can modify overload-induced cardiac hypertrophy.69–70 Evidence that microRNAs regulate cardiac hypertrophy71–72 is of potential therapeutic importance because short RNA segments, called small interfering (si)RNAs, can silence specific genes. The ability of (si)RNAs, which are readily synthesized commercially to block specific proliferative pathways, promise additional approaches slowing deterioration of failing hearts by inhibiting maladaptive hypertrophy.

CONCLUSIONS AND FUTURE DIRECTIONS The growing impact of the discoveries summarized in this chapter on patient care are apparent when discussions of therapy for heart failure in recent cardiology textbooks are compared (Figure 1-5). The first edition of Hurst and Logue’s Heart Disease, published in 1966, devotes almost two thirds of the discussion to cardiac glycosides and their toxicity; the remainder describes diuretics and rest. The relative lengths of the discussions of rest, diuretics, and digitalis in this text differ little from those in White’s 1931 textbook Heart Disease. Looking back even farther, to 1908, the description of therapy for heart failure in Mackenzie’s Diseases of the Heart devotes more than 11 pages to the actions and toxicity of the cardiac glycosides; a half page each to nitroglycerin and amyl nitrite, which are described as “vaso-dilators”; two pages to the appropriate level of activity; three to diet; care of the bowels and the “mental factor” receive a half page each; and there is virtually nothing about diuretics. Textbook discussions of heart failure therapy have been changing dramatically since the 1970s. The space allocated to diuretics has remained about the same, but recommendations for rest have virtually disappeared and discussions of digitalis have decreased remarkably. The latter is due in part to a decrease in the frequency of digitalis toxicity because cardiac

glycosides, once viewed as among the few effective forms of therapy, were commonly given at very high doses in severely ill patients. Discussion of nonglycoside inotropes appeared in the 1970s, as did the short-term benefits of vasodilators. Neurohumoral blockade and β-blockers received separate discussions in the 2001 edition of Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. Even more striking are recent advances in device therapy, which are not included in Figure 1-5. The evolution of our understanding of the pathophysiology and treatment of heart failure described in this chapter represents one of the major successes in biomedical research. This remarkable progress, which has been made possible by increasingly effective interactions between basic science and clinical investigation, continues a tradition that began when Harvey described the circulation. The growing impact of molecular biology, coupled with better understanding of the benefits and side effects of therapy offers considerable promise for future gains in our ability to manage patients with heart failure.

REFERENCES   1. Katz, A. M. (1997). Evolving concepts of heart failure: cooling furnace, malfunctioning pump, enlarging muscle. Part I. Heart failure as a disorder of the cardiac pump. J Cardiac Fail, 3, 319–334.   2. Katz, A. M. (1998). Evolving concepts of heart failure: cooling furnace, malfunctioning pump, enlarging muscle. Part II. Hypertrophy and dilatation of the failing heart. J Cardiac Fail, 4, 67–81.   3. Katz, A. M. (2008). The “modern” view of heart failure: how did we get here?. Circ Heart Fail, 1, 63–71.   4. Katz, A. M. (2008). The “gap” between bench and bedside: widening or narrowing. J Cardiac Fail, 14, 91–94.   5. Katz, A. M., & Katz, P. B. (1962). Diseases of the heart in the works of Hippocrates. Brit Heart J, 24, 257–264.   6. Siegel, R. E. (1968). Galen’s system of physiology and medicine. Basel, Switzerland: Karger.   7. Harris, C. R. S. (1973). The heart and vascular system in ancient Greek medicine. Oxford, UK: Oxford University Press.   8. Singer, C. (1988). The fasciculus medicinae of Johannes de Ketha. Birmingham Ala, Classics of Medicine.   9. White, P. D. (1957). The evolution of our knowledge about the heart and its diseases since 1628. Circulation, 15, 915–923. 10. Harvey, W. (1628). Exercitatio Anatomica de Moto Cordis et Sanguinis in Animalibus. Frankfurt, Germany: William Fitzer. 11. Major, R. H. (1945). Classic descriptions of disease (3rd ed.). Springfield Ill: CC Thomas. 12. Mayow, J. (1674). Tractus Quinque Medico-Physici.in Medico-Physical Works, Edinburgh, UK: The Alembic Club; 1907. 13. Lancisi, G. M. Aneurysmatibus. Opus posthumam, Rome, 1745, Palladis (Translated by W. C. Wright, New York, 1952, Macmillan). 14. Jarcho, S. (1980). The concept of heart failure. From Avicenna to Albertini. Cambridge Mass: Harvard University Press. 15. Morgagni, J. B. (1769). The seats and causes of diseases investigated by anatomy: in five books. London: Millar and Cadell (Translated by B. Alexander). 16. Corvisart, J. N. (1812). An essay on the organic diseases and lesions of the heart and great vessels. Boston: Bradford & Read (Translated by J. Gates). 17. Flint, A. (1870). Diseases of the heart (ed 2). Philadelphia: HC Lea.

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CH 1

18. Osler, W. (1892). The principles and practice of medicine. New York: Appleton. 19. Katz, A. M. (2002). Ernest Henry Starling, his predecessors, and the “law of the heart.”. Circulation, 106, 2986–2992. 20. Starling, E. H. (1918). The Linacre lecture on the law of the heart. London: Longmans Green. 21. McMichael, J. (1950). Pharmacology of the failing heart. Springfield Ill: CC Thomas. 22. Katz, A. M. (1965). The descending limb of the Starling curve and the failing heart. Circulation, 32, 871–875. 23. Cournand, A. (1975). Cardiac catheterization. Development of the technique, its contributions to experimental medicine, and its initial application in man. Acta Med Scand Suppl, 579, 3–32. 24. Comroe, J. H., Jr., & Dripps, R. D. (1974). Ben Franklin and open heart surgery. Circ Res, 35, 661–669. 25. Saxl, P., & Heilig, R. (1920). Über die diuretiche Wirkung von Novasurol und anderen Quecksilberinjektionen. Wien Klin Wochenschr, 33, 943–944. 26. Ingwall, J. S. (2002). ATP and the heart. Norwell Mass: Kluwer. 27. Neubauer, S. (2007). The failing heart - an engine out of fuel. N Engl J Med, 356, 1140–1151. 28. Sarnoff, S. J. (1955). Myocardial contractility as described by ventricle function curves: observations on Starling’s law of the heart. Physiol Rev, 35, 107–122. 29. Gault, J. H., Ross, J., Jr., & Braunwald, E. (1968). Contractile state of the left ventricle in man: instantaneous tension-velocity-length relations in patients with and without disease of the left ventricular myocardium. Circ Res, 22, 451–463. 30. Katz, A. M. (1967). Regulation of cardiac muscle contractility. J Gen Physiol, 50, 185–196. 31. Yusef, S., & Teo, K. (1990). Inotropic agents increase mortality in patients with congestive heart failure. Circulation, 82(suppl III), III-673 (abstract). 32. Felker, G. M., & O’Connor, C. M. (2001). Inotropic therapy for heart failure: an evidencebased approach. Am Heart J, 142, 393–401. 33. Harris, P. (1983). Evolution and the cardiac patient. Cardiovasc Res, 17, 313–319, 373– 378, 437–445. 34. Francis, G. S., Goldsmith, S. R., Levine, T. B., et al. (1984). The neurohumoral axis in congestive heart failure. Ann Intern Med, 101, 370–377. 35. Evans, C. L., & Matsuoka, Y. (1915). The effect of various mechanical conditions on the gaseous metabolism and efficiency of the mammalian heart. J Physiol (Lond), 49, 378–405. 36. Ross, J., Jr. (1976). Afterload mismatch and preload reserve: a conceptual framework for the analysis of ventricular function. Prog Cardiovasc Dis, 18, 255–264. 37. Cohn, J. N., & Franciosa, J. A. (1977). Vasodilator therapy of cardiac failure. N Engl J Med, 297, 27–31, 254–258. 38. Cohn, J. N., Archibald, D. G., Ziesche, S., et al. (1986). Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration cooperative study (V-HeFT). N Engl J Med, 314, 1547–1552. 39. Francis, G. S. (2001). Pathophysiology of chronic heart failure. Am J Med, 110(suppl 7A), 37S–46S. 40. CONSENSUS Trial Study Group. (1987). Effects of enalapril on mortality in severe congestive heart failure. Results of the cooperative North Scandinavian enalapril survival study. N Engl J Med, 316, 1429–1434. 41. Meerson, F. Z. (1961). On the mechanism of compensatory hyperfunction and insufficiency of the heart. Cor Vasa, 3, 161–177. 42. Sandler, H., & Dodge, H. T. (1963). Left ventricular tension and stress in man. Circ Res, 13, 91–104. 43. Hood, W. P., Jr., Rackley, C. E., & Rolett, E. L. (1968). Wall stress in the normal and hypertrophied human left ventricle. Am J Cardiol, 22, 5550–5558. 44. Grossman, W., Jones, D., & McLaurin, L. P. (1975). Wall stress and patterns of hypertrophy in the human left ventricle. J Clin Invest, 56, 56–64. 45. Katz, A. M. (1990). Cardiomyopathy of overload. A major determinant of prognosis in congestive heart failure. N Engl J Med, 322, 100–110. 46. Olson, R. E., Ellenbogen, E., & Iyengar, R. (1961). Cardiac myosin and congestive heart failure in the dog. Circulation, 24, 471–482. 47. Katz, A. M. (1970). Contractile proteins of the heart. Physiol Rev, 50, 63–158.

48. Mueller, H., Franzen, J., Rice, R. V., et al. (1964). Characterization of cardiac myosin from the dog. J Biol Chem, 239, 1447–1456. 49. Katz, A. M. (1976). Tonic and phasic mechanisms in the regulation of myocardial contractility. Basic Res Cardiol, 71, 447–455. 50. Alpert, N. R., & Gordon, M. S. (1962). Myofibrillar adenosine triphosphatase activity in congestive heart failure. Am J Physiol, 202, 940–946. 51. Hoh, J. Y., McGrath, P. A., & White, R. I. (1976). Electrophoretic analysis of multiple forms of myosin in fast-twitch and slow-twitch muscles of the chick. Biochem J, 157, 87–95. 52. Penpargkul, S., Repke, D. I., Katz, A. M., et al. (1977). Effect of physical training on calcium transport by rat cardiac sarcoplasmic reticulum. Circ Res, 40, 134–138. 53. Izumo, S., Lompré, A. M., Matsuoka, R., et al. (1987). Myosin heavy chain messenger RNA and protein isoform transitions during cardiac hypertrophy. Interaction between hemodynamic and thyroid hormone-induced signals. J Clin Invest, 79, 970–977. 54. Izumo, S., Nadal-Ginard, B., & Mahdavi, V. (1988). Protooncogene induction and reprogramming of cardiac gene expression produced by pressure overload. Proc Natl Acad Sci U S A, 85, 339–343. 55. Scheuer, j., Buttrick, P. (1985). The cardiac hypertrophic responses to pathologic and physiologic loads. Circulation, 75(part 2):1, 63–I–68. 56. Pfeffer, J. M., Pfeffer, M. A., & Braunwald, E. (1985). Influence of chronic captopril therapy on the infarcted left ventricle of the rat. Circ Res, 57, 84–95. 57. Katz, A. M. (1990). Angiotensin II: hemodynamic regulator or growth factor?. J Mol Cell Cardiol, 22, 739–747. 58. McKinsey, T. A., & Olson, E. N. (2005). Toward transcriptional therapies of the failing heart: chemical screens to modulate genes. J Clin Invest, 115, 538–546. 59. Bock, G., & Goode, J. (Eds.). (2006). Heart failure: molecules, mechanisms, and therapeutic targets Chichester, UK: Wiley. 60. Selvetella, G., Hirsch, E., Notte, A., et al. (2004). Adaptive and maladaptive hypertrophic pathways: points of convergence and divergence. Cardiovasc Res, 63, 373–380. 61. Dorn, G. W., II, & Force, T. (2005). Protein kinase cascades in the regulation of cardiac hypertrophy. J Clin Invest, 115, 527–537. 62. Hill, J. A., & Olson, E. N. (2008). Cardiac plasticity. N Engl J Med, 358, 1370–1380. 63. Katz, A. M. (1988). Molecular biology in cardiology, a paradigmatic shift. J Mol Cell Cardiol, 20, 355–366. 64. Geisterfer-Lowrance, A. A. T., Kass, S., Tanigawa, G., et al. (1990). A molecular basis for familial hypertrophic cardiomyopathy: a β-cardiac myosin heavy chain gene missense mutation. Cell, 62, 999–1006. 65. Ho, C. Y., & Seidman, C. E. (2006). A contemporary approach to hypertrophic cardiomyopathy. Circulation, 113, 858–862. 66. Goldberg, A. D., Allis, C. D., & Bernstein, W. (2007). Epigenetics: a landscape takes shape. Cell, 128, 635–638. 67. Robertson, K. D. (2005). DNA methylation and human disease. Nat Rev Genet, 6, 597–610. 68. Rodenhiser, D., & Mann, M. (2007). Epigenetics and human disease: translating basic biology into clinical applications. CMAJ, 174, 341–348. 69. Backs, J., & Olson, E. N. (2006). Control of cardiac growth by histone acetylation/deacetylation. Circ Res, 98, 15–24. 70. Trivedi, C. M., Luo, Y., Yin, Z., et al. (2007). Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3 beta activity. Nat Med, 13, 324–331. 71. Chien, K. R. (2007). MicroRNAs and the tell-tale heart. Nature, 447, 389–390. 72. van Rooij, E., & Olson, E. N. (2007). MicroRNAs: powerful new regulators of heart disease and provocative therapeutic targets. J Clin Invest, 117, 2369–2376. 73. Katz, A. M., Konstam, M. A. (2009). Heart failure: pathophysiology, molecular biology, clinical management, ed 2, Philadelphia, Lippincott/Williams. 74. Katz, A. M. (2004). Raymond Vieussens and the “first” pathophysiological description of heart failure. Dialog Cardiovasc Med, 9, 179–182. 75. Fishman, A. P., & Richards, D. W. (1964). Circulation of the blood: men and ideas. New York: Oxford University Press.

CHAPTER Investigative Techniques and Molecular Modeling,  7 Molecular Ontogeny Is Recapitulated by Cardiac Hypertrophy,  8 Molecular Signaling of Normal Heart Growth and Physiological Cardiac Hypertrophy,  9

2

Molecular Basis for Heart Failure Abhinav Diwan and Gerald W. Dorn II

Pathological Hypertrophy: The Cardiomyocyte Growth/ Death Connection,  10 Apoptosis,  11 Catecholamine Cardiomyopathy: The Cardiomyocyte Contractility/Death Connection,  13

Heart failure begins after an initial index event produces a decline in pumping capacity of the ventricle. At the cellular level, heart failure is caused by changes in the biology of the cardiac myocyte (see Chapter 3) as well as through progressive loss of Future Directions,  26 cardiac myocytes (see Chapter 6). The loss of myocytes may be focal (e.g., myocardial infarction), or diffuse (e.g., viral infection, hemodynamic overload, genetic abnormalities). Thus heart failure is the common clinical syndrome caused by any of a diverse group of injurious stimuli sufficient to produce myocardial insufficiency. The specific characteristics and clinical course of heart failure may be determined more by the myocardial response to injury and its accompanying hemodynamic overload than by the specific nature of the primary insult. With cardiac injury or hemodynamic stress, a multitude of signaling pathways are activated that may be predominantly compensatory or maladaptive. Accordingly, molecular surveys performed over the past 3 decades have defined biochemical and transcriptional signatures of failing myocardium, and reductionist experimentation has delineated responsible mechanisms of functional adaptation and decompensation. Accumulated data reveal that molecular signaling of heart failure is complex and involves activation of multiple pathways exhibiting cross-talk inhibition and potentiation, functional redundancy, and feedback or feedforward regulation. Clinically important pathophysiological linkages have been established between molecular determinants of cardiomyocyte contractility, cardiomyocyte growth, and cardiomyocyte death. Thus the themes of heart failure pathophysiology have transitioned from a primary focus on mechanical to molecular factors. As a consequence, the field has moved away from early therapeutics that stimulated neurohormone pathways in attempts to enhance pump function by increasing cardiac myocyte inotropy (catecholamines, phosphodiesterase inhibitors) or by decreasing hemodynamic loading (arterial and venous vasodilators, diuretics).1,2 The current approach for treating end-stage heart failure combines pharmacological inhibition of maladaptive molecular signaling pathways (β-adrenergic blockers, angiotensin-converting enzyme inhibitors) with “bionic” measures aimed at resting, restoring, and recovering failing myocardium (ventricular assist devices), or correcting electromechanical cardiac dysfunction (resynchronization therapy).3-5 Ongoing and future clinical trials of gene- and cell-based therapies are building upon fresh molecular insights to develop novel targets and approaches for heart failure (see Chapter 50).6

INVESTIGATIVE TECHNIQUES AND MOLECULAR MODELING The explosion of molecular information on the pathophysiology of heart failure is the result of reductionist experimentation using advanced molecular and physiological modeling in genetically manipulated systems, and a more integrated approach that takes advantage of recently developed high-throughput platforms for genetic analysis of small clinical specimens in human heart failure. The overall paradigm is that of an extrinsic biomechanical stimulus that activates molecular signaling pathways. The cardiomyocyte responds with altered gene expression that changes the protein makeup of the cell, and

ultimately the structure and function of the heart. Experimental models for dissecting out and identifying important molecular events have therefore tended to genetically and physiologically perturb a hypertrophy stimulus (e.g., transgenic overexpression of Gαq7 and induction of pressure overload by microsurgical creation of a transverse aortic constriction8). Experimental manipulation of signaling pathways has largely transitioned away from pharmacological activators and inhibitors and toward creating gain-of-function and loss-of-function mutant organisms with complementary perturbations of the candidate factor specifically in the specific cell type of interest (cardiomyocyte). To enhance appreciation of the following detailed discussion of molecular pathways for hypertrophy and heart failure, here we briefly review some general techniques and approaches used in these types of studies. Molecular investigation of cardiac hypertrophy began with development by Paul Simpson of an in vitro model system using neonatal rat cardiac myocytes.9 In contrast to adult cardiac myocytes, neonatal rat myocytes are relatively easy to prepare and can be maintained in tissue culture for weeks. Under serum-free conditions, cardiomyocytes stimulated with Gq-coupled neurohormones such as phenylephrine, angiotensin, and endothelin undergo cellular hypertrophy with many characteristics of in vivo cardiomyocyte hypertrophy: Cells enlarge, protein synthesis is accelerated, and hypertrophy-associated genes are increased in expression, including atrial natriuretic factor (ANF)10 and α-skeletal actin.11 Even when the stimulus is simple mechanical stretching, neonatal rat cardiac myocytes exhibit a characteristic hypertrophic gene program mimicking pathological hypertrophy.12 Neonatal cardiac myocytes are less useful for studies of excitationcontraction coupling due to incompletely developed sarcomeres and sarcoplasmic reticulum network. Thus techniques were developed to isolate calcium-tolerant adult cardiac myocytes from multiple vertebrate species including mice, the predominant species used for genetic manipulation.13,14 Isolated individual field-paced adult cardiac myocytes are now routinely used to

7

8 measure the effects of experimental manipulations on con-

traction, relaxation, and calcium transients. A major limitation of cultured and isolated cardiac myocyte studies is that the impact of the experiment on integrated cardiac and cardiovascular function cannot be determined. This requires perturbation and analysis in an intact organCH 2 ism with sufficient similarity to man for conclusions to have relevance to the human condition. An additional requirement is the ability to perform specific genetic manipulations in the organism, which permits specificity of molecular perturbation and tissue targeting that is typically not possible using pharmacological agents. Although important basic information has derived from studies of fruit flies and zebra fish, the genetically modified (transgenic or knockout) and physiologically modeled mouse has become the dominant experimental system for in vivo examination of the molecular event mediating cardiac hypertrophy and heart failure. Transgenic gain-of-function approaches are typically employed to evaluate whether a particular gene and its protein product are, by virtue of the protein’s functional involvement in a particular pathway, sufficient to provoke a particular outcome. Cardiomyocyte-specific expression is conventionally achieved by driving cDNA expression using cardiac-specific promoters such as Mlc2v and aMHC.15,16 These promoters drive high-level gene expression in the early embryonic heart (Mlc2v) or shortly after birth (αMHC) and thereafter. For genes with deleterious effects on fetal or postnatal cardiac development that confound the experimental interpretation or can be lethal,17 conditional expression systems permit transgene expression under temporally defined conditions by administering tetracycline or mifepristone.18-20 Loss-of-function approaches are helpful to determine whether a certain gene (or its protein product) is necessary for a given outcome. There are several ways to decrease gene function, such as transgenic expression of dominant inhibitory mutants and transgenic or adenoviral/AAV-mediated expression of specific short interfering RNAs (siRNAs). Because of specificity and stability issues with siRNAs, the potential for unanticipated effects of mutant inhibitory proteins, and the possibility that forced expression itself can induce pathology,21 targeted gene ablation is considered the gold standard for loss of function.22 Limitations of germ line gene ablation relating to noncardiac effects have been addressed by tissuespecific ablation using Cre-Lox technology and cardiomyocyte-expressed Cre.23,24 Although genetic manipulations can produce cardiac phenotypes permitting mechanistic insight, frequently the consequences of an overexpressed or ablated gene are further interrogated through surgical or pharmacological intervention. Mouse cardiac surgery was not performed when genetic manipulation of the mouse first came of age. The development of microsurgical modeling for pressure overload, volume overload, heterotopic transplantation, infarction, and ischemia-reperfusion, together with advances in microanalytical techniques for invasive hemodynamic or electrophysiological studies and sophisticated noninvasive echocardiographic and magnetic resonance imaging, has completed the investigational “tool kit” for in vivo studies of genetically and physiologically modeled mice.7,25-27

Molecular Ontogeny is Recapitulated by Cardiac Hypertrophy Cardiac hypertrophy and heart failure in the adult are characterized by reexpression of fetal cardiac genes.28-30 Here, we explore the reasons for this prototypical feature. Since cardiac failure results from loss of functioning myocardium, the optimal compensatory response to cardiac insufficiency is myocardial repair or regeneration. Indeed, the universal response

to myocardial insufficiency is cardiac hypertrophy. Hypertrophy is measured at the organ level using electrocardiographic, echocardiographic, or magnetic resonance imaging indices of myocardial mass and cardiac size, and is reflected by cardiomyocyte enlargement in the short axis (pressure overload) or long axis (volume overload).31 Although there are many similarities in gene and protein content between developing embryonic hearts and hypertrophying adult hearts, a critical difference is the inability of adult cardiac myocytes to increase in number through mitosis and cytokinesis after the early postnatal period.32,33 Accumulating evidence supports the presence of pluripotent resident and immigrant cardiac progenitor cells in the adult myocardium,34,35 but the regenerative potential of these cells is not yet known; and these cells are not currently believed to contribute in a major way to cardiomyocyte renewal and repopulation under typical circumstances. A hallmark of pathological hypertrophy in the adult heart is reexpression of embryonic cardiac genes (and the proteins they encode), often referred to as the “fetal gene program.” This is the clearest example of how the cardiac response to stress or injury recapitulates aspects of cardiac development. As might be expected for a coordinated program of expressed genes, the earliest detectable change (within hours after pressure overloading hearts or stimulating cultured cardiomyocytes to hypertrophy) is induction of regulatory transcription factors, c-fos, c-jun, jun-B, c-myc, and egr-1/nur77, and heat shock protein (HSP) 70.8 These changes are typical of cell cycle entry.36 Induction of these and other transcription factors, called “early response genes,” drives the expression of downstream genes in the fetal program (Figure 2-1). Atrial natriuretic factor (ANF) is the prototypical fetal cardiac gene, expressed early during heart development through the coordinated interactions of the Nkx2.5, GATA-4, and PTX transcription factors.37 GATA4, a zinc finger DNA binding protein, is essential for embryogenesis and formation of the linear heart tube38 and is also expressed in the adult heart. GATA4 binding sites are found on the promoters of various cardiac expressed genes as ANF, BNP, ET-1, α-skeletal actin, αMHC, βMHC, cardiac troponin c, and AT1R and regulates transcription of multiple genes in response to pressure overload and neurohormonal signaling. Forced expression of GATA4 at low levels causes mild hypertrophy with increased fibrosis, whereas ­cardiomyocyte-specific deletion of GATA4 diminished ­exercise-induced and pressure-overload hypertrophy, with no effect on normal cardiac growth.39 Antihypertrophic signaling mediated by GSK3β, a kinase downstream of the IGF1-PI3K-Akt axis that regulates normal cardiac growth (see later discussion), is transduced in part by GSK3β-induced phosphorylation and suppression of GATA4 transcriptional activity. GATA4 also complexes with other transcription factors such as Nkx2.5, MEF2, coactivator p300, SRF, and NFAT to affect cardiac gene expression (see Figure 2-1).40 SRF (serum response factor), a cardiac-enriched transcription factor, 41 was identified as a transcriptional regulator that associated with the serum response element (SRE) with characteristic recognition sequences (CArG boxes) in the c-fos gene promoter. SRF is essential for sarcomerogenesis based on its coordinated interaction with other transcription factors, such as SMAD1/3, Nkx2-5, and GATA4. Conditional cardiacspecific gene ablation of SRF resulted in embryonic lethality due to cardiac insufficiency during chamber maturation, associated with cardiomyocyte apoptosis.42 Confirmatory evidence for a critical role of SRF in normal cardiac and cardiomyocyte homeostasis came from conditional cardiomyocyte gene ablation in the adult mouse, which demonstrated progressive development of cardiomyopathy with disorganization of the sarcomeres leading to heart failure.43 Myocardin is a cardiac and smooth muscle–specific co-activator of SRF.

9

Normal growth, hypertrophic stimuli

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Its expression is induced by phenylephrine (PE) in vitro and it binds to SRF and induces ANF transcription. Accordingly, forced cardiac expression of myocardin causes pathologic in vivo hypertrophy with fetal gene expression.44 The consequences of altered cardiac gene expression on myocardial function are varied: (1) Ventricular ANF (and related brain natriuretic peptide [BNP]) expression is robust in pathological hypertrophy and heart failure, and the increase in BNP secretion from the heart forms the basis for a widely used clinical biomarker assay of heart failure.45 (2) Because of differences in ATPase activity, and therefore efficiency, it has been suggested that increased β-MHC could impair myocardial contractility,46,47 but there is little direct supportive evidence.48 (3) Downregulation of the gene encoding the sarcoplasmic reticulum Ca2+ ATPase (SERCA), the Ca2+ pump responsible for rapid reuptake of calcium into the sarcoplasmic reticulum,49 appears to be responsible for the characteristic calcium signaling abnormalities observed in experimental and human heart failure.50,51 Experimental gene therapies for heart failure are therefore targeting SERCA and its endogenous inhibitor phospholamban.52 In addition to the classic five reported fetal genes (βMHC, α-skeletal actin, ANF, BNP, and SERCA), transcriptome analysis using high-throughput microarrays in failing human and mouse hearts have identified hundreds of upregulated and downregulated genes in cardiac hypertrophy and failure53-55 (a comprehensive database of these gene expression changes is now available at cardiogenomics.org). In addition to providing mechanistic insight into heart failure, myocardial mRNA signatures may be prognostic biomarkers or therapeutic guides.56-59 An exciting new prospect is the potential for microRNAs to provide incremental information on the molecular status of the myocardium.60 MicroRNAs (miRNAs) are small (~22 nucleotide) naturally occurring RNAs that negatively regulate gene expression by promoting degradation of mRNAs and/ or inhibiting mRNA translation,61 thereby suppressing protein synthesis (Figure 2-1). Myocardial miRNA expression is altered in hypertrophic and failing myocardium,60,62,63 suggesting that stress-induced regulation of miRNA contributes to reprogramming of myocardial genes in pathological hypertrophy and heart failure.

Molecular Signaling of Normal Heart Growth and Physiological Cardiac Hypertrophy Cardiac hypertrophy is frequently classified as either “physiological” (i.e., normal postnatal growth and the cardiac enlargement that results from physical conditioning) or “pathological” (i.e., reactive hypertrophy in response to hemodynamic overload and myocardial injury).31,64,65 Descriptive terms such as “physiological” or “pathological” hypertrophy indicate the probable outcome of the hypertrophy and the nature of the inciting stimulus and signaling pathway. Physiological stimuli such as exercise and pregnancy produce physiological hypertrophy, whereas cardiac pathologies such as hemodynamic overload, myocardial infarction, or toxic and infectious myocardial damage produce pathological hypertrophy. The stimulus-response relationship was clearly defined in a recent study that used advanced microsurgical techniques to produce intermittent pressure overload, which induced quantitatively less severe hypertrophy with minimal fibrosis and fetal gene reexpression, but with the key pathological characteristics of traditional reactive pressure overload hypertrophy.66 Physiological hypertrophy of the adult heart shares important traits with normal cardiac growth that distinguish physiological from pathological hypertrophy: The extent of physiological hypertrophy in athletes and during pregnancy is typically not sufficient to impede normal cardiac mechanical function, myocardial collagen deposition is not observed, capillary density increases in proportion to the increase in myocardial mass, bioenergetic alterations enhancing fatty acid metabolism and mitochondrial biogenesis are favorable, and physiological hypertrophy regresses without permanent sequelae upon interruption of the inciting stimulus.65 A likely determinant of these favorable characteristics is the absence of the hallmark fetal gene program seen in pathological hypertrophy.67 Because of the generally beneficial effects of physiological hypertrophy, exercise68 and molecular manipulation of cardiac growth signaling pathways69 have been investigated to prevent or ameliorate the effects of pathological hypertrophy and heart failure. Both normal cardiac growth and physiological hypertrophy are mediated via the peptide growth factor, IGF-1.70

Molecular Basis for Heart Failure

FIGURE 2–1  Regulation of gene expression in normal growth and pathological hypertrophy. A common set of transcription factors determine normal cardiac growth and pathological hypertrophy, such as GATA4, Nkx2.5, SRF, MEF2, and NFATs. Hypertrophy signaling pathways result in phosphorylation of histone deacetylases (HDACs) with export out of the nucleus, permitting histone acetylation by histone acetyl transferases (HATs), with activation of gene transcription to generate messenger RNA (mRNA). mRNA is spliced to yield a mature form, which recruits the protein synthesis machinery leading to protein translation. MicroRNAs (miRNAs) inhibit mRNA translation and/or enhance mRNA degradation to negatively regulate translation. The FoxO3 family and Wnt transcription factors (not shown) negatively regulate hypertrophic growth.

10 Growth hormone released from the pituitary gland stimulates

membrane facilitates phosphorylation of membrane phosphatidylinositols at the 3¢ location, resulting in binding of Akt and its activator PDK1 via pleckstrin homology (PH) domains. Ablation of Akt1 and/or Akt2, and PDK1, reduces cardiac mass.80,81 Although IGF-1 and its downstream effectors clearly produce physiological hypertrophy, IGF-1 mediated hypertrophy evolves over time into pathological hypertrophy, with fibrosis and systolic dysfunction.82 This transitional phenotype is similar to that observed with forced expression of Akt, in which inadequate angiogenesis contributes to the transition from hypertrophy to cardiac failure.83 The hypothesis is that cardiomyocyte growth beyond a certain physical limit, whether initially physiological or pathological, exceeds the capacity for oxygen and nutrient delivery due to lack of concordant angiogenesis needed to meet the demands of the hypertrophied myocyte.84 Thus there may be pathological consequences to excessive physiological hypertrophy that could explain the relatively rare occurrences of irreversible ventricular hypertrophy and dilation in endurance sports athletes.85

IGF-1 synthesis in various tissues, primarily the liver. Likewise, development of physiological cardiac hypertrophy in response to exercise is also triggered by IGF-1, levels of which are increased in trained athletes and in cardiomyocytes in response to hemodynamic stress.71 The direct effects of IGF-1 CH 2 stimulation are beneficial, including decreased cardiomyocyte apoptosis in response to noxious stimuli in vitro and in vivo, and prevention of adverse remodeling with preservation of systolic function in vivo.72 IGF-1 does not seem to be necessary for pathological hypertrophy, however, because knockout mice lacking IGF-1 exhibit a normal hypertrophic response to pressure overload. Thus the cardiomyocyte autonomous effects of IGF-1 appear to be stimulation of normal and physiological growth. IGF-1, insulin, and other peptide growth factors activate membrane receptors with intrinsic tyrosine kinase activity (Figure 2-2). IGF-1 or transgenic expression of IGF-1 receptor causes physiological hypertrophy,73,74 whereas ablation of insulin receptors and/or IGFR1 depresses normal myocardial growth.75,76 PI3Kα is recruited to activated IGF-1 receptors (see Figure 2-2). Genomic ablation of PI3K p110α is embryonic lethal at day 9.5 of gestation,77 but dominant negative expression of p110α in the postnatal heart reduces adult heart size and prevents development of swimming-induced hypertrophy78; and forced cardiac expression of p110α stimulates physiological growth.79 PI3K p110α maintains ventricular function via membrane recruitment of protein kinase B/Akt (see Figure 2-2): IGFR-mediated translocation of the p110α subunit to the cell

PATHOLOGICAL HYPERTROPHY: THE CARDIOMYOCYTE GROWTH/DEATH CONNECTION Pathological cardiac hypertrophy is an independent risk factor for cardiac death (see Chapter 22)86 and classically exhibits progression from a compensated or nonfailing state to failing dilated cardiomyopathy.87,88 At the cellular level, massive

Growth factors, exercise: IGF-1

P

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Akt

P

P

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mTOR

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Protein synthesis Hypertrophy

FIGURE 2–2  IGF-1 signaling in physiological hypertrophy. Normal growth and exercise induce cardiac hypertrophy signaling via IGF-1 release. IGF-1 binds to the membrane-bound IGF receptor (IGFR), leading to autophosphorylation and recruitment of PI3K isoform, p110α to the cell membrane. PI3Kα phosphorylates phosphatidylinositols in the membrane at the 3’ position in the inositol ring, generating phosphatidylinositol triphosphate (PIP3). Protein kinase B (Akt) and its activator, PDK1, associate with PIP3, resulting in Akt activation, which also requires phosphorylation by PDK2 for full activity (not shown). Activated Akt phosphorylates and activated mTOR, resulting in ribosome biogenesis and stimulation of protein synthesis. Akt also phosphorylates GSK3 (both α and β isoforms), resulting in repression of its antihypertrophic signaling. The phosphatase PTEN dephosphorylates PIP3 to generate PIP2 and shut off the signaling pathway.

Apoptosis Apoptosis (see Chapter 6), derived from the Greek expression for “the deciduous autumnal falling of leaves” (apo means away from, and ptosis means falling),99 is an orderly and highly regulated energy requiring process that, in many tissues, provides for targeted removal of individual cells without provoking an immune response that could produce more extensive, collateral tissue damage.100 Geographically localized apoptosis is essential to normal development of the heart and ventricular outflow tract.101 Apoptotic indices (number of TUNEL-positive nuclei/total nuclei) are highest in the outflow tract (~50%),102 intermediate in the endocardial cushions that are sites of valve formation and left ventricular myocardium (10% to 20%),103 and lowest in the right ventricular myocardium (~0.1% at birth).104 Cardiomyocyte apoptosis parallels cardiomyocyte mitosis and therefore decreases toward the end of embryonic development, and apoptotic cardiomyocytes are extremely rare in normal adult myocardium (1 apoptotic cell per 10,000 to 100,000 cardiomyocytes).33 Abnormal persistence of apoptosis in right ventricular myocardium may contribute to the pathogenesis of arrhythmogenic right ventricular dysplasia,105 a disorder caused by mutations of the plakoglobin and desmoplakin genes and disorder of Wnt signaling, and that is characterized by right ventricular–specific apoptosis and fibrofatty replacement associated with arrhythmias and sudden death.106 The prevalence of cardiomyocyte apoptosis is markedly increased in chronic cardiomyopathies.107,108 Likewise, myocardial ischemia and reperfusion injury induce acute cardiomyocyte apoptosis in human disease109 and

experimental animal models,110 and in the subacute period 11 following the infarction, wherein it contributes to ventricular remodeling.111 Apoptotic cardiomyocyte death likely also plays a role in the transition of pressure overload hypertrophy to dilated cardiomyopathy.93,112 A powerful stimulus for cardiomyocyte apoptosis in heart failure is high levels of circulating cytokines.113 Sustained CH 2 experimental pressure overload is sufficient to induce expression of the prototypical death-promoting cytokine, TNF-α,114 and TNF signaling via the TNFR1 receptor is both negatively inotropic and stimulates cardiomyocyte hypertrophy and apoptosis.115,116 A causal role for this cytokine in heart failure is suggested by elevated TNF-α plasma levels that are correlated with the degree of cardiac cachexia,117 and by studies where TNF-α infusion or forced cardiac expression of the cytokine created myocardial hypertrophy with increased cardiomyocyte apoptosis, adverse ventricular remodeling, and systolic dysfunction in rodent models.118,119 TNF binds to the TNFR1 receptor homotrimer to trigger death receptor signaling (Figure 2-3). This results in formation of death inducing signaling complex (DISC) with recruitment of the adaptor protein FADD and activation of caspase 8, an upstream member of a family of executioner cysteine proteases (see Figure 2-3).120 Activated caspase 8 cleaves caspase 3, the effector caspase, which activates a nuclear DNAse (CAD—caspase activated DNAse), resulting in internucleosomal cleavage of DNA and chromatin condensation. Caspase 8 also cleaves Bid, a proapoptotic Bcl-2 family protein. Generation of truncated (tBid) links the extrinsic and intrinsic pathways (see Figure 2-3), leading to their simultaneous activation in TNF-induced cardiomyocyte apoptosis.119 Whereas TNF-α receptors activate cardiomyocyte death pathways113 cell survival signaling is stimulated by the IL-6 family of cytokines, including IL-6, cardiotrophin, and LIF. A shared membrane receptor for IL-6 family cytokines is glycoprotein (gp) 130 that, as with all cytokine and peptide growth factor receptors, has intrinsic tyrosine kinase activity. Binding of IL-6 or cardiotrophin induces gp130 homodimerization or oligomerization with α-subunits of other cytokine receptors, stimulating autophosphorylation on receptor cytoplasmic tails and activating intrinsic tyrosine kinase activity (Figure 2-4). Receptor tyrosine phosphorylation permits binding of adaptor proteins Grb2 and Shc to SH2 binding domains, upon which multiple signaling effectors assemble for activation of the following signaling pathways (see Figure 2-4): (1) Janus kinases (JAKs) that phosphorylate STAT transcription factors, which then migrate to the nucleus as active dimers to regulate gene expression121; (2) SH2 domain-containing cytoplasmic protein tyrosine phosphatase (SHP2), which activates the MEK/ERK pathway; and (3) the Ras/mitogen-activated protein kinase that activates MAPK and extracellular signal-regulated kinase (ERK) signaling. These signaling pathways are inhibited by SOCS family proteins,122 and transcriptional upregulation of SOCS proteins via STAT signaling providing for feedback inhibition of JAK/STAT pathways (see Figure 2-4). Consistent with important roles in cardiac development and homeostasis during periods of stress, cardiotrophin 1 and related IL-6 family member cytokines are expressed in embryonic and adult myocardium and stimulate increases in cardiomyocyte size and protein synthesis.123 Gp130 signaling is essential for embryonic cardiac development since germline deletion in mice is lethal at embryonic day 12.5 and the mice exhibit myocardial abnormalities124 (although this does not appear to be a cell-autonomous requirement125). Gp130 signaling is sufficient to provoke hypertrophy in the adult heart,126 whereas expression of dominant negative gp130 attenuates pressure overload hypertrophy.127 The gp130 signaling axis plays a critical role in cardiomyocyte survival after stress. Mice with cardiomyocytespecific deletion of gp130 develop massive cardiomyocyte Molecular Basis for Heart Failure

cardiomyocyte hypertrophy is almost always observed in dilated cardiomyopathies. Thus hypertrophy both contributes to, and is a consequence of, heart failure. The essential feature of cardiac hypertrophy is increased cardiomyocyte size/volume. Other myocardial alterations, such as fibroblast hyperplasia, deposition of extracellular matrix, and a relative decrease in vascular smooth muscle and capillary density89,90 also contribute to the progression from hypertrophy to heart failure (reviewed in Chapter 6). Conventional wisdom has long held that the primary change in ventricular geometry in reactive pressure overload hypertrophy (i.e., wall thickening)91 is helpful in postponing the inevitable functional decompensation and adverse remodeling (wall thinning and chamber dilation92) because ventricular systolic wall stress is normalized.87 This relationship is described by the Laplace equation, s = Pr/2h, where s is wall stress (force per unit of cross-sectional area), which is synonymous with afterload and is directly proportional to P (intraventricular pressure) and r (ventricular radius), and is inversely proportional to h (ventricular wall thickness). Accordingly, an increase in ventricular h to r ratio in pressure overload (concentric) hypertrophy decreases wall stress for a given intracavitary pressure. The physics of ventricular remodeling are not disputed, but there is accumulating evidence that the quantity of myocardium may be a less important determinant of left ventricular ejection performance than the quality of myocardium.88 Indeed, because of pathological upregulation of fetal cardiac genes29,30 and increased programmed cardiomyocyte death,93,94 it has been suggested that reactive hypertrophy may be entirely dispensable to functional compensation after hemodynamic overloading.95,96 Cardiomyocyte death or degeneration is a seminal feature of failing hearts, and is also detectable in pathological hypertrophy before the development of cardiomyopathy. Cardiomyocyte death may be programmed (cell suicide by necrosis, apoptosis, or autophagy) or nonelective (conventional necrosis),97 and there is evidence for all three forms of death in end-stage human cardiomyopathy.98

12

TNF TNFR1

CH 2 Mitochondria

TRADD FADD

tBid

bid

Bax Cyt c

DISC Apaf1 Caspase 9

Procaspase 8

Apoptosome DNA Cleavage Caspase 3 Apoptotic cell death Activated caspase 8 FIGURE 2–3  TNF-induced death signaling in heart failure: TNF-α binds to TNF receptor 1 (TNFR1) homotrimer, resulting in recruitment of proteins via death domains, namely TRADD and FADD; and procaspase 8 and assembly of DISC (death-inducing signaling complex). This causes cleavage activation of caspase 8, which cleaves and activates the effector caspase: caspase 3. Activated caspase 3 proteolyzes cellular substrates, causing cell death. This pathway is amplified by caspase 8-induced cleavage of Bid, a BH3 domain only Bcl-2 family protein, the truncated form of which, tBid, interacts with multidomain proapoptotic Bcl-2 proteins Bax and Bak (not shown). This results in mitochondrial outer membrane permeabilization and release of cytochrome c (cyt c), which associates with adapter protein Apaf-1, ATP, and procaspase 9, forming the apoptosome, with activation of caspase 9. Activated caspase 9 activates caspase 3. This process is opposed by Bcl-2 and Bcl-xl (not shown), and inhibitor protein XIAP. Smac/DIABLO and Omi/HtrA2 are released during mitochondrial permeabilization (not shown) and bind to XIAP, relieving its inhibitory effect. Also released are DNAses: AIF (apoptosis-inducing factor) and endoG, which cause DNA cleavage.

IL-6 family ligand CT-1

JAK STAT

-subunit

P

P

P

Sos

SHP2 P

P

JAK

JAK

STAT

P

P

Gab1/2 P p85

Shc p85

Grb2 P

STAT P

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SOCS

PI3K p110y

Akt

STAT

Ras

P Sos Grb2

Gp130

JAK

CT-1

MAPK (ERKs)

Nucleus SHP2

P

P

Cell hypertrophy survival FIGURE 2–4  Gp130-mediated survival signaling in heart failure: Ligand-induced homodimerization of Gp130, a transmembrane receptor protein, or heterodimerization with α-receptor subunits for IL-6 cytokine family members such as CT-1, LIF, or oncostatin M, causes tyrosine autophosphorylation and recruitment and activation of JAK1/2. Subsequently, two major intracellular signaling cascades are triggered: (1) Signal transducer and activator of transcription (STAT)-1/3 pathway, with STAT dimerization and translocation to the nucleus with activation of gene transcription. This pathway is opposed by induction of SOCS proteins, which bind to and prevent STAT translocation. (2) SH2-domain containing cytoplasmic protein phosphatase (SHP2)/MEK/Extracellular signal-regulated kinase (ERK) pathway. Additionally, Grb2 binding with Gab1/2 causes PI3K mediated Akt activation. These pathways signal to promote cardiomyocyte hypertrophy and survival. STAT

STAT

GENE

Autophagy (see Chapter 6) Autophagy (in Greek auto means “self” and phagein means “to eat”) is a normal cellular response to starvation and has been implicated in cell survival and cell death, depending upon the developmental stage, level of induction, and chronicity of the inciting stimulus.131 Autophagic degradation of cellular proteins plays an important role in supplying the energy needs of newborns at birth, when a state of starvation occurs between separation from placental nutrients and not feeding. Accordingly, mice deficient in the important component of autophagy, ATG5, cannot upregulate the autophagic response and are prone to death during this period.132 Foci of degenerated cardiomyocytes with autophagic vacuoles are observed in human dilated cardiomyopathy and aortic stenosis.133 Likewise, acute pressure overloading in mice causes rapid appearance of autophagic markers that persist during functional decompensation and the transition to dilated cardiomyopathy.134 In this experimental model, induction of autophagy is clearly maladaptive because suppression of autophagy prevents ventricular remodeling and cardiomyopathic decompensation. However, the role of autophagy in hypertrophy development and decompensation is unclear at this time. Decreased autophagy is observed in pressure overloaded and catecholamine challenged myocardium,135 but inhibition of autophagy that is induced in ischemic myocardium (a normal “starvation” response) increases cardiomyocyte death.136 Autophagy increases with reperfusion, but autophagy inhibition protects against reperfusion injury.136 Finally, inhibition of cardiomyocyte autophagy by conditional ATG5 ablation early in mouse cardiac development does not affect normal developmental cardiac growth or pressure overload hypertrophy, but is associated with accelerated heart failure.137 Available data suggest a multifaceted role for autophagy, which can be pathological, but may be necessary to prevent cardiomyopathic decompensation after cardiac injury or stress by eliminating misfolded or degraded proteins. Necrosis (see Chapter 6) The theme of capillary/myocardial mismatch as a causative factor in progression from hypertrophy to dilated cardiomyopathy has been advanced over the past few years as a general mechanism for decompensation of pathological hypertrophy. An adequate blood supply for growing myocardium is necessary for normal cardiac function. Accordingly, capillary density is closely coupled to myocardial growth during development.138 Cardiac hypertrophy, on the other hand, is associated with decreased capillary density and coronary flow reserve, and increased diffusion distance to myocytes.139 Capillary density is increased during the compensated phase of pathological hypertrophy, but decreases and is associated with cardiomyocyte “dropout” during decompensation.140 GATA4-mediated regulation of angiogenic VEGF and angiopoietin play an important role in hypertrophy-associated capillary/myocardial mismatch.39,83,141,142

Catecholamine Cardiomyopathy: The Cardiomyocyte Contractility/Death ­Connection

13

Activation of the sympathetic nervous system in heart failure happens early after stress to maintain cardiac function CH 2 (see Chapter 10). Persistent sympathetic activation, however, becomes progressively maladaptive over time. Catecholamines are toxic to cardiomyocytes in vitro and persistent activation of catecholamine signaling pathways causes cardiomyopathies associated with cardiomyocyte loss.143,144 These are largely β1-receptor-­mediated effects, and can be blocked by pharmacological inhibition of the L-type calcium channel. There are nine subtypes of adrenergic receptors (three each of α1, α2, and β), of which β1-receptors are the most abundant in the myocardium.145 Catecholamine signaling via cardiomyocyte β-adrenoreceptors increases myocardial contractility by stimulatory G protein (Gαs)-mediated activation of adenyl cyclase, resulting in cyclic AMP production that activates protein kinase A (Figure 2-5). β2-adrenoreceptors couple to both Gαs and the inhibitory G protein Gαi, which can inhibit adenyl cyclase and downregulate c-AMP levels. In normal myocardium, the β1receptors represent 70% to 80% of all the β-adrenoreceptors. In heart failure, preferential downregulation of β1-receptors proportionately increases inhibitory Gαi signaling.146 An important mechanism by which β1-adrenoreceptor/Gsα/ PKA signaling increases contractility is PKA-mediated phosphorylation of phospholamban (see Figure 2-5) (see Chapter 3). In its unphosphorylated state, phospholamban inhibits SERCA to decrease diastolic calcium uptake into the sarcoplasmic reticulum (SR). Phosphorylation of phospholamban relieves the inhibition of SERCA, resulting in increased SR calcium loading and larger systolic calcium transients, which augments contractility. PKA also phosphorylates L-type calcium channels to enhance calcium entry and ryanodine receptors to enhance calcium release.147 The mechanism by which catecholamines are toxic to cardiomyocytes has been addressed by genetic manipulation of signaling receptors and effectors. Forced expression of low levels of β2 (60 times normal) enhances cardiac function and rescues genetic cardiomyopathy148-150 without pathological consequences. However, forced expression of low levels of β1- or high ­levels of β2-adrenoreceptors caused a dilated and fibrotic cardiomyopathy.148,151 Likewise, transgenic expression of the β1adrenoreceptor effector Gsα causes myocardial hypertrophy that progresses to an apoptotic and fibrotic cardiomyopathy.152 Gαs-coupled β1-receptors (but not the β2-receptors) stimulate cell death via reactive oxygen species and activation of the JNK family of MAPKinases, leading to mitochondrial cytochrome c release and mitochondrial permeability transition pore formation.153 β1-adrenoreceptor signaling leads to increased SR calcium load via increased L-type calcium channel-mediated calcium influx and disinhibition of SERCA. There is increasing evidence that increased SR calcium levels may enhance contractility at the expense of increasing programmed cell death. The initial observation that intracellular calcium overload can trigger necrosis in cardiac myocytes was made more than 3 decades ago.154 Intracellular calcium overload may trigger programmed cell death via opening of the mitochondrial permeability transition pore.155 In transgenic mice with inducible cardiac expression of the β2α subunit of the L-type calcium channel, increased intracellular and SR calcium provoked widespread cardiomyocyte necrosis with cardiomyopathic decompensation,156 which could be prevented by L-type calcium channel inhibition by transgene suppression, calcium channel blockade, or ablation of cyclophilin D, a critical component of the mitochondrial permeability transition pore.157 Increased calcium influx via the L-type calcium channel in response to β1-adrenergic stimulation also activates calcium/calmodulin kinase (CaMKII), which Molecular Basis for Heart Failure

apoptosis and rapid cardiomyopathic decompensation after induction of surgical pressure overload.125 Gp130 activation is only transiently observed after pressure overload and the pathway is deactivated during the transition to failure.128 A mechanism for the transition to failure in pressure overload stress-induced hypertrophy may be interruption of gp130JAK-STAT signaling by stress-induced SOCS3 and resulting suppression of STAT3 signaling.129 Accordingly, adenoviralmediated transduction of SOCS3 prevents prohypertrophic and antiapoptotic signaling of cardiomyocyte gp130 receptors by inhibiting JAK2-STAT3/MEK1-ERK1/Akt activation. Signaling through gp130 also protects against viral myocarditis by accelerating viral clearance, whereas cardiomyocytespecific gp130 gene ablation, or expression of the gp130 inhibitor, SOCS3, accelerates the myocarditis.130

14 Ca2

CH 2

P RYR

-AR agonist

L-type Ca2 channel

Adenyl cyclase

-adrenoreceptor

Gs

G

P

Gy cAMP

SR

Gs/i

G Gy

GRK -arrestin

PLB SERCA

PLB P

Ca2(i) P

P GRK

-arrestin

Receptor endocytosis MAPK activation EGF transactivation

 PKA

P P

Calmodulin CAMK

Myofilament Necrosis via MPTP

Enhanced contractility Cell death FIGURE 2–5  β-adrenoreceptor signaling in heart failure: Catecholamine binding to the seven transmembrane myocardial β1-adrenoreceptors activates Gsα, with displacement of bound GDP by GTP. This causes cyclic AMP generation via stimulation of adenyl cyclase, which activates PKA. PKA phosphorylates the L-type calcium channel, enhancing Ca2+ entry, and phosphorylates RyR, enhancing calcium release from the SR, increasing intracellular calcium (Ca2+(i)) available for excitation contraction coupling. PKA phosphorylates phospholamban (PLB) de-repressing SERCA activity with enhanced SR Ca2+ reuptake; and phosphorylates troponin on the myofilaments, with the net effect of enhancing contractility. Termination of G protein signaling occurs with GTPase activity of Gsα, causing GTP hydrolysis and cAMP degradation by phosphodiesterases (not shown). Additionally, activated β-adrenoreceptors are phosphorylated at their cytoplasmic tails by G-protein receptor kinases (GRK), causing receptor endocytosis. Increased Ca2+(i) with chronic adrenoreceptor signaling causes necrotic cell death via calmodulin-mediated CaMK activation and mitochondrial permeability transition pore formation (MPTP) (see text). β2-adrenoreceptor activation stimulates Gαi with inhibition of adenylcyclase (not shown). A delayed phase of signaling downstream of the β1-adrenoreceptor is activated by GRK-mediated recruitment of β-arrestin with transactivation of EGF with enhanced survival signaling (see text).

phosphorylates phospholamban, thereby inhibiting its activity further and increasing the SR calcium load, and causing cardiomyocyte apoptosis in vitro.158 Inhibition of CaMKII by forced expression of a dominant negative peptide in the heart results in decreased SR calcium stores, which attenuates cardiomyocyte apoptosis159 and protects against development of catecholamine-induced cardiomyopathy.160 β2-receptors can signal both via Gs and Gi, and at physiological levels, primarily mediate cell survival in the heart.161,162 β2-adrenoreceptor signaling switches from the stimulatory Gsα pathway to the inhibitory Giα signaling upon phosphorylation of the receptor by PKA activation downstream of the Gsα subunit.163 This causes dissociation of the Gβγ subunit from Giα, resulting in activation of the PI3K-Akt survival pathway. In vitro studies employing selective expression of each β-receptor in cardiac myocytes from mice with combinatorial deletion of both β1- and β2-receptors revealed a proapoptotic effect for β1-signaling and an antiapoptotic PI3K-Akt mediated signaling cascade downstream of the β2-receptor.162 Indeed, the Giα pathway appears to protect against cell death after ischemic reperfusion injury in vivo.164 The application of insights from experimental mouse models to the human condition is supported by the clinical effects of single nucleotide polymorphisms in genes encoding adrenoreceptor signaling factors. Increased adrenergic signaling downstream of β1-receptors in individuals carrying an activating polymorphism in the β1-receptor (β1Arg389), combined with an inhibitory polymorphism in the presynaptic α2c receptor (α2CDel322-325), increases the risk of heart failure.165 Likewise, the gain-of-function polymorphism of the β1receptor may alter the response to β-blockers in heart failure.166 β-adrenoreceptor signaling is downregulated in heart failure due to receptor phosphorylation by G-protein receptor kinases (GRK) (see Figure 2-5). GRK-phosphorylated receptors attract β-arrestins 1 and 2, which terminate the receptor Gα subunit interaction. GRK2 (a.k.a. β-ARK), 5, and 6 are expressed in the myocardium. Forced cardiac expression of

GRK2 and GRK5 blunts the attenuated isoproterenol-mediated increase in contractility, whereas cardiac ablation or dominant negative inhibition enhances the contractile response, suggesting that GRK2 plays an essential role in modulating cardiac function.24,167 The consequences of GRK2-mediated β1-adrenoreceptor downregulation in heart failure are not entirely clear. Whereas a GRK2-dominant negative protein (β-ARKct) has improved some genetic and most physiological models of cardiomyopathy,168,169 cardiac-specific ablation of GRK2 worsened catecholamine-mediated cardiomyopathy24 but improved cardiac function after myocardial infarction.170 Human heart failure is characterized by sympathetic activation with increased circulating catecholamine levels associated with desensitization and downregulation of β-adrenoreceptors.146 β1-adrenoreceptors are markedly downregulated and both β1- and β2-adrenoreceptors are uncoupled, with elevated myocardial levels of GRK2. β-adrenergic blockers reverse these changes in heart failure and are associated with improved survival and reversal of adverse structural and functional remodeling parameters.171 A novel survival pathway may also be triggered downstream from β1-adrenoreceptor signaling via EGF receptor transactivation (see Figure 2-5). β-arrestin coupled with GRK5 and 6 activates a nonreceptor tyrosine kinase, Src, which activates a membrane-bound metalloproteinase, leading to cleavage of a heparin-binding EGF ligand (see later discussion under growth factors) and EGF receptor activation that is protective against catecholamine-induced cardiomyopathy by enhancing survival signaling.172 Indeed, interindividual differences in β-blocker efficacy may be due to different abilities to activate signaling through this alternate pathway (biased antagonism).173 These studies are particularly intriguing in the context of genetic studies revealing that a gain-of-function polymorphism in GRK5 is protective in heart failure.174 Whether the beneficial effects are due to enhanced β-adrenoreceptor desensitization or to increased EGF receptor transactivation is not known.

activates ILK, small GTPases, and prohypertrophic PI3K and 15 ERK-MAPKinase pathways.179 Forced expression of ILK causes compensated cardiac hypertrophy in mice, and dominant negative ILK prevents the hypertrophic response to angiotensin stimulation.179 Cardiac-specific deletion of β1-integrin or ILK causes spontaneous development of cardiomyopathy.180 Other proteins that interact with the cytoplasmic tail of inte- CH 2 grins, such as melusin and vinculin, also appear to be essential for mechanotransduction. Ablation of melusin, a striated muscle-specific protein, prevents the myocardial hypertrophic response in response to pressure overload but not neurohormonal infusion, suggesting a specific role for melusin in integrin-mediated mechanotransduction.181 Cardiac-specific ablation of vinculin, a ubiquitously expressed protein that connects the actin cytoskeleton to the cell membrane, causes progressive development of cardiomyopathy by 6 months of age in mice.182 Indeed, the β1-integrin vinculin interface may have a critical homeostatic role in cardiomyocytes as ablation of β1-integrin causes cardiac defects and periimplantation mortality, and ablation of β3-integrin causes spontaneous cardiac hypertrophy that was exacerbated with pressure overload.183 Another putative mechanical stretch sensor is at the Z-disk, wherein the small LIM-domain protein MLP (muscle LIM protein) is anchored and transduces stress stimuli via interaction with a complex of transducing proteins.184 Titin, a giant sarcomeric protein component of the thin filament that anchors the Z-disk at one end and extends to the M line at the other, is another candidate, postulated to function as a molecular spring providing passive stiffness to the cell and acting as a biomechanical sensor.185 Autocrine/Paracrine Effects of Neurohormones and Growth Factors.  Mechanical stretch can transduce hypertrophy via autocrine and paracrine release of neurohormones, and activation of respective seven-transmembrane spanning G protein-coupled receptors. Cardiomyocyte deformation induces autocrine secretion of angiotensin II, endothelin 1,

Integrins Are Biomechanical Sensors for Hypertrophy

Molecular Basis for Heart Failure

A major stimulus for hypertrophy after myocardial injury is increased load sensed by individual myocytes and surrounding myocardial fibroblasts. Attempts to isolate the biomechanical sensor of cellular load focused on mechanical deformation or “cell stretch.” Passively stretching cardiomyocytes cultured on deformable substrates provokes reactive hypertrophy with upregulation of early response and fetal genes.12 One of the mechanisms by which stretch is transduced into a biochemical signal for hypertrophy is activation of integrins, a diverse family of cell surface receptors that link the extracellular milieu to intracellular signaling scaffolds called focal adhesion complexes.175 Integrins consist of two subunits α and β in various combinations, each with an extracellular domain to interact with extracellular matrix proteins, a transmembrane part that anchors them, and a short cytoplasmic tail (Figure 2-6). Integrin cytoplasmic tails interact with the cytoskeleton at the focal adhesion complex and serve as adaptors for multiple prohypertrophic signaling proteins (see Figure 2-6): (1) Focal adhesion kinase (FAK), a tyrosine kinase; (2) Srcs, a membrane-bound SH2 domain containing tyrosine kinase; (3) Grb2-associated binder (Gab) family proteins, which are scaffolding proteins that transduce signals downstream of growth factor and cytokine receptors; (4) integrin-linked kinase (ILK), a serine-threonine kinase; and (5) adaptor proteins, such as melusin and vinculin, that link integrins to the cytoskeleton at the focal adhesion complex. Integrin signaling activated by pressure overload recruits c-Src and FAK leading to activation of ERK1/2 kinases with prohypertrophic signaling.176 Cardiomyocyte-specific ablation of FAK prevents induction of ANF in response to transverse aortic constriction, without altering the late development of fibrosis and cardiomyopathy.177 Inhibiting FAK with siRNA prevents and reverses pressure overload hypertrophy and preserves contractile function.178 The β1 subunit of integrins

Mechanical stretch

ECM

-subunit

Src -subunit

Paxillin

FAK

-actinin

P

P P

Actin

Rac/Rho

Sos

ILK

Talin

Melusin Vinculin

Gab1/2 Ras

P Grb2

Shc

Gab1/2 P p85

SHP2 PI3K p110

MAPK Activation

Cytoskeletal remodeling Akt Hypertrophy FIGURE 2–6  Integrin-mediated transduction of biomechanical stress: Integrins are heterodimeric proteins formed by the association of various combinations of single-transmembrane α and β subunits, which are attached to the extracellular matrix proteins such as laminin and fibronectin. Biomechanical stress induces change in conformation and integrin clustering, resulting in assembly of the focal adhesion complex consisting of the kinases FAK, Src, and ILK, along with adaptor proteins vinculin, paxillin, talin, α-actinin, and melusin that connect the integrins to the cytoskeletal elements (actin). Stretch-mediated phosphorylation and activation of FAK and ILK causes MAPK (ERK) activation and Akt activation via the SHP2/PI3K pathway, resulting in hypertrophic signaling. Additionally FAK activates small G proteins Rac and Rho (see later discussion), which transduce cytoskeletal reorganization in hypertrophy. Integrin signaling also activates Ras via Shc/Grb2/Gab1/2-mediated Src kinase activation, which transduces hypertrophy signaling via MAPK (ERK) activation.

16 and peptide growth factors such as FGF.186 Integrins can

also transduce hypertrophic stimuli in part via upregulation of angiotensin II.187 Interestingly, angiotensin may not be ­essential for hypertrophy transduced by stretch-induced activation of AT1R.188 Paracrine release of neurohormones, growth factors, and cytokines by nonmyocytes in the mechanically CH 2 overloaded heart also leads to cardiac fibroblast proliferation,189 acting as an amplification loop to increase neurohormonal effects on cardiomyocytes. Evidence for simultaneous involvement of multiple growth factors in stretch-induced hypertrophy is consistent with the notion that signaling pathways converge through various neurohormonal receptors.186 Neurohormonal Activation of Hypertrophy Signaling Norepinephrine, angiotensin II, and endothelin signal via heptahelical transmembrane receptors coupled to the Gq heterotrimeric G protein. G proteins consist of three polypeptide chains—α, β, and γ (Figure 2-7). The α-subunits are primarily responsible for determining activation of downstream signaling effectors and are organized into four groups: Gαs, Gαi, Gαq, and Gα12. Inactive Gα subunits bind to GDP (guanosine diphosphate) and Gβγ subunits. Upon recruitment to a ligand occupied transmembrane receptor, GTP is exchanged for GDP, resulting in dissociation of the Gα-GTP subunit from the βγ subunit and activation of downstream signaling cascades. Hydrolysis of GTP by intrinsic GTPase activity (that is augmented by regulators of G protein signaling (RGS) proteins) terminates the signal. Gαq-coupled receptors activate phospholipase C, which catalyzes the hydrolysis of phosphatidylinositol 4,5 bisphosphate (PIP2) into inositol 1,4,5 triphosphate (IP3) and diacylglycerol (DAG). DAG activates the PKC family of growth-stimulating serine-threonine kinases (see Figure 2-7) and IP3 causes intracellular Ca2+ release that can activate signaling through calcium-dependent PKCs, calcium-calmodulin dependent kinases (CaMKs), and calcineurin. Another arm of signaling is initiated by the free Gβγ

subunits, which recruit PI3Kγ to the sarcolemma and facilitate interaction with phosphoinositides. This PI3K signaling differs from the activation of the PI3Kα isoform in adaptive hypertrophic signaling, which was discussed earlier. Heart failure causes systemic and myocardial release of catecholamines, leading to Gαq activation via α1-adrenergic receptors. There are three receptor subtypes: α1A/C, α1B, and α1D, the first two of which are implicated in transducing catecholamine-induced hypertrophy signaling in the heart. In the adult human myocardium, the α1A receptor subtype predominates over α1B. Norepinephrine and phenylephrine treatment of cardiomyocytes stimulates hypertrophy in vitro with reactivation of the fetal gene program, increased cardiomyocyte size, and protein synthesis.9 Forced cardiac expression of α1B receptors provokes a cardiomyopathy and downregulated β-receptor signaling, but forced expression of α1A receptors enhances systolic function without stimulating hypertrophy.190 Gene ablation of α1A/C or α1B receptors suggests a role in blood pressure modulation without an effect on cardiac hypertrophy. Combinatorial deletion of both subtypes revealed a modest effect of α1-receptor signaling in normal cardiac growth because the double knockout hearts were approximately 13% smaller than wild types.191 In response to pressure overload, double α1-receptor knockout mice developed a cardiomyopathy, with decreased survival, increased cell death, and markedly decreased upregulation of “fetal genes,”192 likely related to the absence of prosurvival ERK signaling transduced by these receptors.193 These results indicate that α1-receptors signal in normal cardiac growth and cardiomyocyte survival in response to stress and are redundant in the transduction of pressure overload hypertrophy. Angiotensin II (Ang II), a powerful vasoconstrictor, is a potent inducer of cardiac growth via the AT1 and AT2 receptors. There are two AT1R subtypes: AT1aR and AT1bR, which are both coupled to Gαq signaling. Forced cardiac expression of AT1aR causes cardiac hypertrophy progressing to adverse

Neurohormonal agonist Cognate receptor

P

Gq

G

PLC G

Ca

P P

IP3

IP3R Sarcoplasmic reticulum

DAG

PKC

PKC

PKC

PKC

PIP2

P

2

DAG

P

Physiological hypertrophy

P PKD Ca2 -adrenergic dysfunction, heart failure

HDAC Hypertrophic gene response Nucleus

FIGURE 2–7  Neurohormonal signaling via Gαq in pathological myocardial hypertrophy. Binding of neurohormones to the cognate neurohormonal receptor causes GTP exchange and activation of the Gαq subunit, with dissociation from the Gβγ subunits and recruitment of PLCβ to the cell membrane. PLCβ causes hydrolysis of PIP2 with generation of IP3 and DAG. IP3 binds to IP3 receptors (IP3Rs) on the sarcoplasmic/endoplasmic reticulum causing Ca2+ release, which causes PKC activation along with DAG for classical PKCs (α and β). Novel PKCs (δ and ε) are activated by DAG alone. See text for details of PKC signaling in heart failure. Classical PKCs activate PKD, which phosphorylates class II HDACs (5 and 9) resulting in export from the nucleus and de-repression of hypertrophy gene transcription.

ventricular systolic function and diminished β-adrenergic 17 responsiveness and exaggerated hypertrophy and cardiomyopathic decompensation in response to isoproterenol.212 Protein kinase C (PKC) is downstream of Gαq/PLCβ and has emerged as a key mediator of altered myocardial contractility and cardiomyocyte survival in pathological hypertrophy (see Figure 2-7). The heart expresses four functionally CH 2 important PKC isoforms: PKC α and β (“conventional group,” activated by DAG with a requirement for Ca2+) and PKC δ and ε (“novel” PKCs, activated by DAG without a requirement for Ca2+).201 PKCs translocate to specific subcellular locations upon activation: PKCα to the membrane from the cytosol, PKCβ from the cytoplasm to the nucleus, PKCε from the cytoplasm and nucleus to the myofibrils, and PKCδ redistributes to the mitochondria and to a perinuclear location. PKCα is upregulated in rodent pressure overload hypertrophy7,213 and human heart failure.214 Treatment of neonatal rat ventricular myocytes with phorbol ester, a nonspecific activator of PKC signaling, causes hypertrophy resembling that of PE and Ang II. Because PKC activation requires translocation to the membrane and binding to specific anchoring proteins (RACKs), studies have interrogated specific PKC effects by transgenic expression of peptides that either facilitate or inhibit PKC translocation, conventional overexpression, or gene ablation. PKCα activation negatively regulates myocardial contractility but not hypertrophy.215,216 Indeed, inhibition of PKCα prevents contractile dysfunction in pathological hypertrophy.215,217 PKCβ overexpression is sufficient to cause myocardial hypertrophy,218 but it is not necessary since pressure overload hypertrophy is unaltered in PKCβ knockout mice.219 PKCδ appears to be a critical modifier of cell death in response to ischemic injury, without affecting myocardial hypertrophy,220 whereas PKCε is both activated in, and sufficient to cause, hypertrophy.203,221 An additional clue to the adaptive nature of PKCε-mediated hypertrophy comes from its ability to reduce Gαq-mediated pathological hyper­ trophy and decompensation when activated, and markedly worsen Gαq-mediated cardiomyopathic decompensation when inhibited.222 Ca2+-dependent, nonconventional PKCs also activate protein kinase D (PKD). Protein kinase D directly phosphorylates class II HDACs (histone deacetylases; see Figure 2-7) resulting in their export from the nucleus and de-repression of transcription. Constitutively active PKD1 causes hypertrophy progressing to cardiomyopathy and siRNA-mediated knockdown of PKD1 prevents hypertrophic cardiomyocyte growth by agonists that signal via Gαq and Rho GTPase.223 Cardiomyocyte-specific deletion of PKD1 renders the myocardium insensitive to pressure overload, angiotensin II, and isoproterenol treatment, with preserved cardiac function and prevention of remodeling,224 secondary to their role in phosphorylating class II HDACs. Molecular Basis for Heart Failure

remodeling and dysfunction194 and mice lacking AT1aR demonstrate attenuated myocardial hypertrophy in response to pressure overload with preserved systolic function.195 Angiotensin receptor antagonism attenuates hypertrophy in vitro and when given therapeutically to humans with heart failure.196 However, in vivo, there is no critical requirement for AT1R signaling in transducing pressure overload hypertrophy, likely due to angiotensin signaling via AT1bR (which is not present in humans) or redundancy in signaling with other neurohormones.197 Endothelin-1 (ET-1) is a 21–amino acid polypeptide cleaved from a larger precursor by endothelin converting enzyme. ET-1 is predominantly produced by endothelial cells, although cardiomyocytes and fibroblasts also produce small amounts. ET-1 signals via the ET1A and ET1B receptors, which are both coupled to Gα. ET-1 appears to be a part of the autoregulatory loop with Ang II because ET-1 is produced in response to Ang II stimulation, and the ET-1 receptor blockade antagonizes Ang II-mediated hypertrophy.198 Endothelin receptor blockade delays, but does not prevent, development of hypertrophy and pathological decompensation in response to pressure overload.199 Cardiomyocyte-specific deletion of ET-1A did not prevent hypertrophy due to Ang II and phenylephrine infusion in vivo,200 implying that ET-1-induced signaling is redundant in transducing pathological hypertrophy. Gq/Phospholipase/Protein Kinase C.  Redundancy in signal transduction at the receptor level in transduction of pathological hypertrophy signals led researchers to look for nodal signaling points that could be inhibited to prevent pathological hypertrophy.201 The heterotrimeric G proteins, Gαq and G11, transduce signals from angiotensin, endothelin, norepinephrine, and other neurohormones.145 Gαq/G11 signaling is essential in embryonic cardiac growth because combined ablation of Gq (gnaq) and G11 (gna11) causes embryonic lethality at day 11 with cardiac hypoplasia and failure of ventricular septation.202 In vivo, unabated Gαq signaling by forced cardiac expression was the first nodal signaling molecule shown to recapitulate pathological hypertrophy.7 Superimposed pressure overload or the hemodynamic stress of pregnancy provokes rapid cardiomyopathic decompensation caused by widespread cardiomyocyte apoptosis.203,204 Indeed, dominant negative inhibition of Gαq,205 inhibition of Gαq signaling by forced expression of inhibitory RGS4,206 or combined cardiomyocyte-specific ablation of Gαq and G11, all prevent pressure overload hypertrophy, establishing a critical role for neurohormonal activation of Gαq in transducing the pressure overload stimulus.207 Polymorphisms in the gnaq (Gαq) gene promoter that affect Gαq expression have been associated with changes in human hypertrophy and heart failure. A common single base pair change from GC to TT at position −694/−695 in the gnaq gene promoter eliminates SP-1 transcription factor binding208,209 and increases Gαq promoter activity, which is associated with increased prevalence of left ventricular hypertrophy in normal subjects209 and increased mortality in African American patients with heart failure.208 Phospholipase Cβ (PLCβ) is the downstream effector of Gαq (see Figure 2-7). Of the four isoforms, PLCβ1 and β3 are expressed in the heart. An essential role for either of these isoforms has not been evaluated for pathological cardiac hypertrophy signaling because the PLCβ1 knockout mice develop epilepsy and increased mortality beginning at 3 weeks of age,210 and PLCβ3 knockout mice demonstrate a normal life span with abnormalities in neutrophil chemotaxis and skin ulcers, but no apparent abnormalities in cardiac development.211 PLCε is another cardiac expressed phospholipase, levels of which are increased in human dilated cardiomyopathy and in response to experimental isoproterenol treatment or pressure overload.212 PLCε is downstream of Ras and regulates β-adrenergic responsiveness in cardiomyopathy. Germline ablation of PLCε is associated with reduced

Mitogen Activated Protein Kinases (MAPKs) Activated G protein-coupled receptors activate mitogen activated protein kinases (MAPKs) via the free Gβγ subunits, either directly or indirectly through cross talk with small Raslike G proteins (Figure 2-8). Multiple other signaling pathways such as receptor tyrosine kinases, receptor serine/ threonine kinases (transforming growth factor β [TGF-β]), Janus-activated kinases (JAKs via cardiotrophin-1 [gp130 receptor]), and stress stimuli, such as stretch, also activate mitogen-activated protein kinases (MAPKs) in the heart.225 MAPK pathways are activated in a cascade manner (see Figure 2-8). There are three major groups of MAPKs: extracellular signal regulated kinases (ERK), JNKs, and p38. Specific MAPKKs activate each MAPK: MAPK1/2 for ERK1/2, MAPK3/6 for p38, and MAPK4/7 for JNK. At the next tier, each MAPKKK can activate different MAPKK-MAPK pathways, providing a mechanism for integration of upstream signaling.

18

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GATA4

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The top tier of MAPK pathway consists of the MAPKKKinases (see Figure 2-8). One such MAPKKK is Mst1, forced expression of which causes an apoptotic cardiomyopathy.226 Subsequent stepwise activation of kinases (see Figure 2-8) serially culminates in the activation of the effector kinases. ERK1/2 are activated via Gαq-coupled agonists in response to hypertrophic agonists in vitro as Ang II, PE, ET-1, and stretch and in vivo by pressure overload.227 Gαq signaling in response to pressure overload is essential for ERK activation because expression of a truncated Gαq peptide blocks aortic banding-induced ERK activation.227 Available evidence suggests a role for the ERK signaling axis in promoting hypertrophy, and p38 and JNK in regulating cell survival and fibrosis. Forced expression of MEK1ERK1 causes concentric hypertrophy via activation of the ­calcineurin-NFAT pathway228 without adverse ventricular remodeling. A critical role for this pathway in hypertrophic signaling is not established because gene ablation either causes no cardiac defects (Erk1−/−);229 or has not yet been pursued in a conditional cardiac-specific manner (Erk2−/− mice are embryonic lethal with lack of trophoblast development).230 ERK 5 is related to ERK1/2 with a similar activation motif, and is activated in the heart in response to gp130 signaling (by LIF or cardiotrophin 1). Similar to ERK1/2, forced cardiac expression of MEK5 (activator of ERK5, a.k.a. big ERK) causes eccentric cardiac hypertrophy associated with the addition of sarcomeres in series within individual cardiomyocytes,231 and gene ablation of ERK5 affects embryonic survival.232 MAPKs phosphorylate multiple substrates, including enzymes and transcription factors with overlapping specificity that regulate cardiac gene expression (“immediate early response” factors), cell survival, mRNA translation (eIF4E), and mRNA stability.225 Specificity for downstream substrates is primarily determined via docking interactions. For example, p90RSKs are phosphorylated primarily by ERK1/2, whereas MAPKAPK2 is phosphorylated by p38-MAPK; and Msk1/2 may be phosphorylated by either ERK1/2 or p38MAPK. Transcription factors activated by MAPKs are nuclear localized, which suggests that MAPKs or downstream kinases translocate into the nucleus to influence gene expression. The differential effects of MAPK signaling on hypertrophy

CREB

FIGURE 2–8  Activation of MAPK signaling in pathological hypertrophy. Activated Gαq protein activates small G proteins such as Ras either directly via the released Gβγ subunits or via cross-talk with receptor tyrosine kinases (RTKs), which are activated by growth factors such as EGF, neuregulin, FGF, and IGF-1 (see discussion in text). This leads to stimulation of the mitogenactivated protein kinase (MAPK) signaling cascades. MAPKs are also activated by integrin signaling and TGF receptormediated activation of TAK1. MAPK cascades are organized into three tiers: MAPKinase kinase kinases (MAPKKKs) that activate MAPKinase kinases (MAPKKs), which subsequently activate MAPKinases. MAPKs signal redundantly via multiple transcription factors (see details in text). Gβγ subunits of the Gαq signaling complex also activate PI3Kγ, resulting in Akt activation and hypertrophy signaling.

c-jun

and/or survival responses may also be related to the timing and duration of the signal and integration with other signaling cascades that crosstalk with MAPK signaling. P38 and JNK kinases were originally discovered as “stressresponsive kinases” due to their rapid activation in response to stressful stimuli. Of the four genes encoding for p38, p38α is the most abundant in the heart, with minimal p38β detected. P38 and JNK transduce their signals by activating transcription factors c-jun, ATF2, ATF6, Elk-1, p53, and NFAT4. Activation of p38 signaling by forced expression of MKK3 and MKK6 causes early cardiac failure with ventricular fibrosis, whereas forced expression of dominant negative proteins (MKK3, MKK6, p38α, or p38β) and p38α gene ablation reveal an antihypertrophic role for p38 in cardiomyocytes.233 This antihypertrophic effect appears to be mediated via suppression of Akt and calcineurin-NFAT signaling. The effects of p38 activation on cardiomyocyte survival are unclear because nonspecific pharmacological inhibition of p38 inhibits pressure overload and ischemia–reperfusion-induced apoptotic cell death, whereas p38α ablation protects against pressureoverload-induced cardiomyocyte apoptosis.233 Similarly, JNK signaling (c-Jun N-terminal kinases) appears to be antihypertrophic because mice with either dominant negative inhibition or combined ablation of JNK1 and 2 show basal and pressure-overload-induced hypertrophy with de-repressed calcineurin-NFAT signaling.234 Pharmacological inhibition of JNK1 attenuates ischemia–reperfusion-induced cardiomyocyte apoptosis, whereas combinatorial ablation JNK1,2, and 3 increases cardiomyocyte apoptosis in response to pressure overload and ischemic reperfusion injury.233 Ask-1 is a MAPKKinase, which is upregulated in the myocardium by angiotensin stimulation via AT1R-induced oxidative stress and NF кB activation. Ask-1 ablation attenuates cardiomyocyte apoptosis and cardiomyopathic decompensation induced by angiotensin infusion235 in response to pressure overload and coronary artery ligation without an effect on hypertrophy.236 IP3-induced Ca2+-mediated Signaling.  Gαq signaling causes IP3 production, which interacts with IP3 receptors to cause intracellular release of Ca2+ (see Figures 2-7 and 2-9). In cardiac myocytes, IP3-induced Ca2+ fluxes are localized

19

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FIGURE 2–9  Neurohormonal activation of calcineurin and CaMK signaling. Gq/G11-mediated production of IP3 via PLCβ causes release of intracellular Ca2+ via the IP3Rs, leading to activation of the protein phosphatase calcineurin. Calcineurin dephosphorylates NFAT transcription factor, resulting in its nuclear translocation and activation of hypertrophy gene transcription. MCIPs are endogenous inhibitors of calcineurin activity. The increased cytoplasmic calcium concentration (Ca2+ (i)) also causes activation of CaMKs via interaction with calmodulin. CaMKs phosphorylate class II HDACs, resulting in HDAC translocation out of the nucleus and binding to 14-3-3 protein in the cytoplasm. This allows histone acetylation by HAT p300, de-repressing hypertrophic gene transcription mediated by transcription factors such as MEF2 and CAMTA.

to microdomains, in effect compartmentalizing the Ca2+induced signaling and segregating the signaling effects of local Ca2+ from the global calcium of excitation–contraction coupling. For example, β2-adrenergic receptors are associated with caveolin-3 protein within caveolar microdomains on cardiomyocytes, and this allows for the regulation of L-type calcium channel activity with β2-dependent activation, which is prevented by disruption of the caveolar architecture.237 Other examples of spatially localized IP3-induced Ca2+ release affecting signaling are calsarcin-mediated regulation of Ca2+-induced activation of prohypertrophic phosphatase calcineurin at the Z-disk and perinuclear CaMK signaling to influence gene transcription via export of HDACs.238 Calcineurin IP3-mediated release of intracellular calcium activates calcineurin and calcium/calmodulin-dependent kinase (CaMK) pathways that regulate cardiac growth (Figure 2-9).30 Calcineurin (Cn), a serine-threonine phosphatase also known as protein phosphatase (PP2B), is stimulated by Ca2+ binding to calmodulin and dephosphorylates the transcription factor Nuclear Factor of Activated T cells (NFAT) at the N-terminal serine residue, allowing its translocation to the nucleus. The functional calcineurin protein is a dimer consisting of two subunits A and B, and is encoded by five genes (CnA by α, β, and γ and CnB by CnB1 and B2), of which the mammalian heart expresses CnAα, CnAβ, and CnB1. In vitro stimulation of cardiomyocytes with hypertrophic stimuli activates calcineurin239 and calcineurin activity is increased in human compensated hypertrophy and heart failure.240 Calcineurin activity is also increased in animal models of pressure-overload-induced and exercise-induced cardiac hypertrophy. Forced expression of calcineurin causes myocardial hypertrophy that progresses to heart failure239 without inducing cardiomyocyte apoptosis.241 Studies with pharmacological inhibition of calcineurin activity with FK506 and

cyclosporine have suggested that calcineurin transduces pathological hypertrophy signaling in response to PE, Ang II, and ET-1 in vitro, and pressure-overload hypertrophy in vivo (reviewed in Heineke et al30,242). Forced expression of dominant negative calcineurin243 and gene ablation of CnAβ decrease cardiomyocyte hypertrophy in response to pressureoverload stimulus and neurohormones. Calcineurin is localized at the Z-disk in a complex with calsarcins. Ablation of calsarcin-1 increases calcineurin signaling in pressure overload, resulting in rapid progression to heart failure.244 Ablation of NFATc1245 and Nfatc2/c3/c4246 causes cardiac defects. Forced cardiac expression of constitutively active NFATc4 causes massive cardiac hypertrophy.239 Ablation of NFATc2 and NFATc3 attenuate pathological hypertrophic by transgenic calcineurin and protect against pressure-overload–and angiotensin-induced hypertrophy without affecting the development of exercise-induced adaptive hypertrophy.247,248 Calcineurin signaling is restrained by modulatory calcineurin inhibitory proteins (MCIP) (see Figure 2-9),249 which bind to calcineurin and inhibit its activity. MCIP1 gene transcription is activated in the heart by calcineurin-mediated NFAT activation, providing a negative feedback loop for calcineurin signaling, whereas MCIP2 expression is induced by thyroid hormone signaling.250 Forced expression of MCIP1 reduces unstressed heart weight (by 5% to 10%), attenuates calcineurin and swimming-induced hypertrophy, and prevents ventricular remodeling after pressure overload. MCIP1 overexpression likewise attenuates development of pathological hypertrophy, ventricular remodeling, and cardiomyo­ pathic decompensation after myocardial infarction, suggesting a beneficial effect of preventing pathological hypertrophy in the surviving myocardium.251 Thus MCIP1 appears to be antihypertrophic in many forms of cardiac growth. MCIP1 gene ablation does not result in cardiac abnormalities, indicating that MCIP1 does not regulate cardiac

Molecular Basis for Heart Failure

G

20 developmental growth.252 However, MCIP1 ablation sensitizes

the heart to calcineurin signaling, resulting in accelerated heart failure in calcineurin transgenic mice, but paradoxically reduces hypertrophy in response to pressure overload and isoproterenol.252 Indeed, a recent study suggested that MCIPs can act as facilitators of calcineurin activity, thereby CH 2 having dual functions in hypertrophy signaling.253 Calmodulin-dependent Protein Kinase (CaMK) Increased cytosolic Ca2+ activates CaMKs, a family of regulatory enzymes that phosphorylate multiple proteins that modulate myocardial contractility,254 hypertrophy, and survival signaling (see Figure 2-9). All four CaMKs, I-IV, activate MEF2mediated transcription of fetal genes255 that causes cardiomyocyte hypertrophy. Forced cardiac expression of CaMKIV causes eccentric hypertrophy with contractile impairment,255 but CaMKIV knockout mice develop pressure overload hypertrophy, suggesting that other CaMK isoforms primarily transduce pathological hypertrophy.256 Indeed, CaMKII is the predominant cardiac isoform254 and forced expression of CaMKIIδb (nuclear isoform) or CaMKIIδC (cytosolic isoform) in cardiomyocytes causes pathological hypertrophy.257,258 Expression of dominant negative CaMKIIδb blocks PE-induced cardiomyocyte hypertrophy and pathological gene expression in vitro.259 HAT/HDAC-mediated Transcriptional Regulation via MEF2/CAMTA CaMKIIδ isoforms bind to and phosphorylate HDAC4, a class II histone deactylase. The process of histone acetylationdeacetylation controls access of transcription factors, such as MEF2 and CAMTA to the chromatin machinery. Histones are nuclear proteins that constitute the nucleosome, a compact structure of chromatin genomic DNA tightly coiled around histone octamers that prevents access of transcription factors to DNA and represses gene expression. Histone acetyltransferases (HATs) acetylate conserved lysine residues in histone tails, which neutralizes the positive charge, and destabilizes histone-histone and histone-DNA interactions. Thus HATs stimulate gene expression. In contrast, histone deacetylases (HDACs) counter this effect, which promotes chromatin condensation and represses transcription (see Figure 2-9). HATs belong to five families, and p300 and CREB binding protein (CBP) are the most abundant HAT family members in the cardiac muscle.260 The HAT activity of p300 appears to play a critical role in cardiac development because targeted gene ablation is lethal between embryonic day 9.5 and 11.5, with failure to develop cardiac trabeculation and upregulate muscle-specific genes such as βMHC and α-actinin.261 P300 binds to and acts as a transcriptional coactivator of GATA4, MEF2, and SRF. Activation of p300 and CBP by ERK phosphorylation is required for expression of ANF and βMHC.262 Forced cardiac expression of these proteins stimulates hypertrophic signaling by facilitating GATA4 acetylation262 and causes adverse remodeling after myocardial infarction.263 Dominant negative p300 prevents acetylation and coactivation of GATA-4, which is associated with development of cardiomyopathy.262 Inhibition of p300 HAT activity by curcumin (a polyphenol abundant in the spice, turmeric) prevents hypertrophy and cardiomyopathic decompensation and regresses established pressure overload.264 The HDACs are classified into three categories based on the homology with the yeast HDACs. Class I HDACs primarily consist of a catalytic domain, whereas class II HDACs have phosphorylation sites that serve as targets for signaling pathways, and interact with transcription factors. Class III HDACs require NAD for activity. Class I HDACs (HDAC 1 and 2) stimulate cardiac growth. Forced cardiac expression of HDAC2 causes hypertrophy and HDAC2 null mice are resistant to hypertrophic stimuli.265 Resistance to hypertrophy in HDAC2 knockout mice is associated with increased expression of the gene encoding for inositol polyphosphate-5-phosphatase f

(Inpp5f), which activates the antihypertrophic kinase GSK3β (see later discussion). In contrast to class I HDACs, class II HDACs (HDAC4, HDAC5, HDAC7, and HDAC9) inhibit cardiac growth. Forced expression of HDAC5 and HDAC9 prevents hypertrophy in vitro in response to PE and serum, whereas HDAC5 and HDAC9 knockout hearts develop spontaneous cardiac hypertrophy266 and exaggerated hypertrophy in response to pressure overload.267 In contrast, their response to swimming-induced hypertrophy is not altered, suggesting these HDACs suppress only pathological hypertrophy. Class II HDACs are commonly associated with the MEF2 proteins in the nucleoplasm. MEF2 (myocyte enhancer factor 2) family transcription factors are essential for myogenesis and cardiac development. There are four MEF2 isoforms that bind DNA through a MADS DNA binding domain found on promoters of many cardiac expressed genes as SERCA, aMHC, and MLC2v. MEF2A and MEF2D are the predominant cardiac-expressed transcripts that regulate stress-induced gene expression.268 MEF2 activity is restrained by binding to class II histone deacetylases (HDAC4, 5, and 7), and this repression is relieved by phosphorylation of HDACs by CaMKs, which induced HDAC nuclear export (see Figure 2-9),269 and allows p300 to associate with MEF2, promoting gene transcription. By this mechanism, multiple hypertrophy signaling pathways (MAPKs, calcineurin, CaMKII, and protein kinase D) converge on MEF2 activation by class II HDAC export and relieve the transcriptional repression (see Figures 2-1, 2-7, and 2-9). MEF2D ablation prevents hypertrophy, ventricular remodeling, and gene dysregulation in response to pressure overload.270 Pharmacological inhibition of histone deacetylases inhibits hypertrophy.271 Treatment of aortic-banded mice subjected with Trichostatin A and Scriptaid (two broad spectrum HDAC inhibitors), or SK7041 (a specific class I HDAC inhibitor),272 improves survival and myocardial and cardiomyocyte hypertrophy and preserves systolic function. HDAC inhibition also regresses established cardiac hypertrophy and prevents cardiomyocyte apoptosis and myocardial fibrosis in pressureoverloaded animals, accompanied by reversion to the adult myosin gene expression pattern (αMHC predominant). Class III HDACs, such as the Sir2 family, regulate life span.273 Deacetylation by class III HDACs requires NAD+ and produces 2¢-O-acetyl-ADP-ribose (O-AADPR) and nicotinamide. Sirt1 is one of the seven Sir2 kinases or Sirtuins, and can be activated pharmacologically by resveratrol (a component of red wine, consumption of which is associated with cardiovascular benefits). Forced expression of moderate levels of Sirt1 in the heart decreases aging-associated hypertrophy, fibrosis, and diastolic function, associated with reduced oxidative stress,274 in contrast to higher levels of forced expression, which cause cardiomyopathy. CaMK signaling also activate calmodulin binding transcription activator (CAMTA) transcription factors. CAMTA2 was discovered as an essential coactivator with Nkx2.5 of ANF gene transcription in cardiomyocytes. CAMTA2 activity is normally repressed by interaction with a class II HDAC (HDAC5). Gαq-mediated activation of PKCε and PKD phosphorylates HDAC5 resulting in export from the nucleus, de-repression of CAMTA2,275 and activation of hypertrophic signaling. Forced expression of CAMTA2 provokes myocardial hypertrophy, which is enhanced by HDAC5 gene ablation. CAMTA2 knockout mice exhibit attenuated hypertrophic response to pressure overload, angiotension, and phenylephrine.276 Cross Talk Between Gαq and PI3K/Akt Hypertrophy Signaling Pathways Gαq/phospholipase C pathways cross talk with PI3K/Akt signaling axis in transducing pathological hypertrophy signals. Gαq-coupled receptors activate PI3Kγ, which is distinct from

the α-isoform activated in physiological hypertrophy signaling. Whereas PI3Kα is activated by receptor-mediated tyrosine phosphorylation, PI3Kγ binds to dissociated Gβγ, providing access to membrane phosphoinositides (see Figures 2-8 and 2-10).277 PI3Kγ (p110γ) signaling is processed through Akt, which transduces both physiological and pathological cardiac growth (see Figure 2-10), depending upon the duration of activation.278 There is transient activation of p110α by exercise, but in pressure-overload/Gαq–mediated signaling, sustained activation of PI3Kγ occurs with recruitment of additional signaling pathways in the phospholipase Cβ and calcineurin/NFAT axis. Akt signaling by Gβγ/PI3Kγ is divergent (see Figure 2-10), which may also contribute to whether the hypertrophy is adaptive or maladaptive. One pathway involves activation of mTOR (mammalian target of rapamycin) and induction of protein synthesis. mTOR exists in two complexes (mTORCs)279: mTORC1 with Raptor, which is rapamycin sensitive and is the predominant mass-regulating complex downstream of Akt signaling; and mTORC2 with Rictor and Sin, which controls the actin cytoskeleton and determines cell shape. Pharmacological inhibition of mTOR with rapamycin prevents and regresses hypertrophy.280 The mechanism by which mTOR stimulates protein synthesis is phosphorylation of S6 kinases that induce phosphorylation of ribosomal S6 protein, which recruits eukaryotic elongation factor 4E (eIF4E).281 Forced expression of S6 kinase 1 (p70/85) causes cardiac hypertrophy.282 However, combinatorial ablation of S6 kinase 1 (p70/85) and 2 (p54/56) does not alter the degree of hypertrophy in response to pressure overload, swimming, exercise, or transgenic IGFR1 expression, suggesting that activation of the S6 kinase pathway is not absolutely required for induction of protein synthesis in cardiac hypertrophy.282 A second Akt pathway leads to phosphorylation and suppression of glycogen synthase kinase (GSK3β, see Figure 2-10), and disinhibition of hypertrophy signaling. GSK3β

Molecular Basis for Heart Failure

is tonically active in the heart and its phosphorylation by 21 Akt relieves antihypertrophic signaling. In vivo, pressure overload causes rapid phosphorylation of GSK3β within 10 minutes after transverse aortic constriction is applied, suggesting early recruitment of the kinase in the hypertrophic response.181 Forced cardiac expression of GSK3β suppresses normal growth and causes cardiomyocyte dysfunction283 CH 2 and prevents isoproterenol- and pressure-overload–induced hypertrophy.284 GSK3β phosphorylates and negatively regulates the translation initiation factor e1F2B.285 GSK3β also counter-regulates the calcineurin NFAT signaling axis by phosphorylating the NFAT residues that are dephosphorylated by calcineurin (see Figure 2-10).284 GSK3β is also phosphorylated by protein kinase A (PKA) activation and G protein-PKC-ERK-p90 ribosomal S6 kinase-based signaling, de-repressing downstream hypertrophic signaling (see Figure 2-10). Like GSK3β, GSK3α signaling is also antihypertrophic, and its forced expression reduces cardiac mass, while siRNAbased knockdown prevents development of hypertrophy in response to pressure overload by inhibiting ERKs.286 Forced expression of dominant negative GSK3β increases resting heart size, enhances contractility, and prevents decompensation of pressure overload hypertrophy.287 Antihypertrophic effects of GSK3β signaling are transduced in part through the canonical Wnt signaling axis (see Figure 2-10). Wnts are extracellular proteins that signal either cell to cell as membrane-bound proteins or as secreted proteins via heptahelical frizzled receptors and single transmembrane-pass coreceptors known as low-density lipoprotein receptor-related proteins (LRPs).288 Tonic activity of GSK3β phosphorylates β-catenin, a transcription factor in the Wnt pathway, which targets it for degradation by the ubiquitinproteosome system.289 When Wnts signal via the frizzled LRP receptors, the entire complex gets recruited to the receptor with the scaffolding protein Dishevelled, resulting

Neurohormonal agonist Cognate receptor

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Hypertrophy FIGURE 2–10  Neurohormonal regulation of hypertrophy via Akt/mTOR/GSK3β signaling. Gβγ-mediated PI3Kγ activation leads to Akt activation and stimulation of protein synthesis via mTOR and suppression of antihypertrophic signaling via GSK3β. Akt also phosphorylates and causes export of FOXO transcription factors from the nucleus, suppressing ubiquitin–proteosome-mediated protein degradation. GSK3α/β exerts a tonic inhibition on multiple prohypertrophic transcription factors and its phosphorylation relieves this inhibition, resulting in hypertrophy signaling. Inhibition of GSK3 is a nodal point for convergence of hypertrophy signaling pathways and also occurs via phosphorylation by PKA (via Gsα), PKCs (via Gαq), ERK/ribosomal S6 kinases (downstream of small G protein signaling), and ILK (downstream of integrin signaling).

22 in phosphorylation of LRP and Dishevelled, which inhibits

The role of signaling downstream of two prototypical growth factors, neuregulin, and TGF-β are reviewed here in detail. Neuregulin is a member of the epidermal growth factor (EGF) signaling pathway. As with other growth factors, neuregulins cause dimerization of tyrosine kinase receptors (ErbB2, ErbB3, and ErbB4), leading to tyrosine autophosphorylation and recruitment of downstream signaling effectors296 (Figure 2-11). Neuregulin is produced in the heart primarily by the endothelial cells and therefore functions as a paracrine growth factor. All three isoforms of neuregulin are cleaved by membrane-bound metalloproteinases, producing an activated fragment that is released and associates with EGF receptor (juxtacrine signaling) (see Figure 2-11). Neuregulin-mediated EGF receptor signaling is activated by neurohormonal stimuli via β-arrestin-mediated transactivation of the β-adrenergic receptors.297 Neuregulin is induced by pressure overload paralleling the development of concentric hypertrophy298 and its levels decline along with those of ErbB2 and ErbB4 receptors during transition to dilated cardiomyopathy.299 Ablation of neuregulin 1 or ErbB2 and ErbB4 receptors causes cardiac hypoplasia and loss of trabeculation.296 Neuregulin signaling via Erb receptors primarily regulates cardiomyocyte survival and not hypertrophy as cardiomyocyte-specific ablation of ErbB2 receptor causes spontaneous development of apoptotic cardiomyopathy,300,301 which is rescued by adenoviral transduction of the antiapoptotic protein BXL-xl. Also, cardiomyocyte-specific ablation of the ErbB2 receptor markedly increases mortality after pressure overload and decreases cardiomyocyte survival with anthracycline exposure.301 Exogenously administered recombinant neuregulin improves survival, improves LV function, and retards cardiomyopathic changes in experimental cardiomyopathy.302 The importance of ErbB2 signaling in provoking cardiac pathology was unexpectedly established when an antibody against ErbB2 (a.k.a. “her2”), which is effective against metastatic breast cancer, caused a high incidence of dilated cardiomyopathy.303

GSK3β and prevents GSK3β-mediated phosphorylation of β-catenin. β-catenin therefore accumulates in the nucleus and complexes with a transcription factor TCF/LEF1 (T-cell-­ specific transcription factor/lymphoid enhancer binding factor 1) by displacing its binding protein Groucho, facilitating CH 2 gene transcription. The Wnt-β-catenin signaling pathway is antihypertrophic in the heart.290 Cardiomyocyte-specific deletion of β-catenin mildly increases cardiac mass and the cardiomyocyte cross-sectional area and upregulates hypertrophy gene expression.291 In contrast, β-catenin stabilization decreases cardiomyocyte area, upregulates the atrophyrelated protein IGFBP5, and attenuates Ang II-induced hypertrophy.291 In this instance, the attenuated hypertrophy was associated with cardiomyopathic decompensation, suggesting that the Wnt pathway suppresses adaptive hypertrophy. Akt also suppresses protein degradation via the ubiquitinproteosome system. Akt phosphorylates FoxO (O family of forkhead/winged-helix) transcription factors, which suppresses their transcriptional activity by facilitating interaction with 14-3-3 proteins, leading to export out of the nucleus and targeting for ubiquitin-proteasome degradation (see Figures 2-1 and 2-10). Akt-mediated suppression of FoxO signaling downregulates multiple atrophy-related genes or atrogins.292 Atrogin-1 is a cardiac- and skeletal musclespecific F-box protein that regulates skeletal muscle atrophy by binding to Skp1, Cul1, and Roc1, the common components of SCF ubiquitin ligase complexes.293 Since antihypertrophic FoxO-Atroxin signaling works in opposition to prohypertrophic pathways, in vivo adenoviral transduction of FoxO3 in mice reduces cardiac cell size,294 and forced cardiac expression of Atrogin-1 suppresses Akt-mediated adaptive hypertrophy signaling294 and targets calcineurin for proteasome degradation.295 Non-IGF Growth Factors in Hypertrophy.  Cardiac myocytes elaborate peptide growth factors in response to stress. Type I and II

ENDOTHELIAL CELL

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RTK

Akt, ERK

Cell survival signaling FIGURE 2–11  Neuregulin/EGF signaling in hypertrophy. Neuregulins are transmembrane proteins of the EGF family, present mainly on endothelial cells as three different types (I, II, and III). Proteolytic cleavage by ADAM (a disintegrin and metalloproteinase) family enzyme causes exposure of an EGF-like signaling domain, which interacts with erbB2 and erbB4 receptors resulting in receptor tyrosine kinase activation. EGF signaling is also activated by GRK-β-arrestin–­ mediated EGF cleavage by ligand-occupied seven-transmembrane neurohormonal receptors. Neuregulin/EGF activates Akt and ERK signaling pathways to promote cell survival in the heart.

Small G Proteins Peptide growth factors and G protein–coupled receptors also transduce neurohormone and stretch-induced hypertrophy by nonreceptor tyrosine kinases such as Src, Ras, and Raf.311 Ras, a member of the small G protein family (along with Rac, Rho, Rab, Ran, and ADP ribosylation factors) is the prototypical signaling molecule downstream of receptor tyrosine kinases (RTKs) that exist bound to GDP in the inactive state (see Figure 2-8). Upon stimulation, the GDP is exchanged for GTP and followed by a conformational change resulting in stimulation of mitogen-activated protein kinase (MAPK) cascade. Intrinsic GTPase activity then turns the signal off, returning the G protein to its basal state. GEFs are proteins that facilitate GTP exchange, and GAPs promote inactivation by activating the GTPase activity. There are four Ras proteins identified in the mammalian myocardium of which H-Ras has been the most carefully studied. Expression of constitutively active Ras promotes and dominant negative Ras inhibits cardiomyocyte hypertrophy in vitro in response to α-adrenergic agonists. Forced expression of H-Ras induces cardiomyocyte hypertrophy in vivo with preserved systolic function, myofibrillar disarray, and increased fibrosis with a unique gene expression profile consisting of ANF and BNP upregulation without upregulation of MHC or α-skeletal actin. Ras signaling also activates multiple MAPK pathways (both ERK and JNK mediated), with the combinatorial effect of its overexpression resulting in cardiomyopathic decompensation. The Rho family of kinases is constituted by at least 14 members grouped into Rho, Rac, and cdc42 subfamilies. RhoA and Rac1 are activated by Gαq signaling,312 and this in turn activates Rho kinases, ROCK1 and ROCK2. The Rho signaling pathway does not affect development of hypertrophy but has deleterious effects in pathological hypertrophic signaling. Mice with forced cardiac expression of Rho A develop fatal cardiomyopathy with conduction abnormalities and severe

atrial enlargement.313 Pharmacological Rho kinase inhibi- 23 tion prevents ventricular dilation and development of fibrosis in response to pressure overload hypertrophy in rats314 and ROCK1 deletion markedly reduces fibrosis in mice subjected to pressure overload.315 Forced expression of constitutively activated Rac1, another Rho family member, causes lethal cardiomyopathy. Rac1 interacts with gp91(phox) and p67(phox) CH 2 components of NAPDH oxidase, and its activation causes increased generation of reactive oxygen species.316 Cardiomyocyte-specific gene ablation for Rac1316 attenuates myocardial oxidative stress and hypertrophy in response to Ang II infusion. Raf kinases are a family of three serine/threoninespecific kinases (A-Raf, B-Raf, and Raf-1) ubiquitously expressed throughout embryonic development. Raf is downstream of Ras signaling and activates the MEK1ERK axis, with enhanced hypertrophic and prosurvival effects.317 Cardiac specific ablation of Raf causes apoptotic cardiomyopathy, which is rescued by inhibition of Ask-1 (apoptosis signal–regulating kinase-1),318 which physically interacts with Raf. Molecular Basis for Heart Failure

The transforming growth factor family is a large group of polypeptide growth factors divided into two groups: the TGF/activin subfamily and the bone morphogenic proteins (reviewed in Xiao304). TGF-β1 is secreted in a latent form and is tethered to the extracellular matrix, whereupon its stimulus-mediated proteolytic cleavage allows interactions with its serine-threonine kinase receptors, TGF-βRI and TGF-βRII. TGF-β is transcriptionally induced during the transition from compensated hypertrophy to failure in the spontaneously hypertensive rat model of pathological hypertrophy. Forced expression of TGF-β1 in the heart induces mild hypertrophy,305 and absence of TGF-β1 markedly attenuates hypertrophy but preserves myocardial function in response to Ang II infusion.306 TGF-β signaling activates MAPKs, such as the TAK1 (TGF-activated kinase)-MEK4-JNK1 and TAK1MEK3/6-p38 axes (see Figure 2-8), and tyrosine kinase pathways, such as Ras/extracellular signal-regulated kinase (ERK) and RhoA/p160 Rho-associated kinase (ROCK).307 Increased TAK1 activity is detected in pressure-overload hypertrophy, and forced cardiac expression of TAK1 causes cardiomyocyte hypertrophy with cardiomyopathic decompensation with increased mortality because of heart failure.308 Smad 4 is the canonical effector of TGF-β, and cardiomyocyte-specific ablation of Smad 4 causes cardiac hypertrophy with reexpression of fetal genes and the activation of the MEK1-ERK1/2 pathway.309 Thus Smad4 acts in opposition to TGF-β-induced MAPK activation. Smad 2 activation is induced by growth differentiation factor 15 (GDF15), a TGF-β family member induced by pressure overload310 and facilitates antihypertrophic signaling. Forced cardiac expression of GDF15 attenuates pressure-overload hypertrophy, without affecting the fetal gene expression program310 and GDF15 ablation exaggerates hypertrophy, leading to rapid cardiomyopathic decompensation after pressure overload.

FUTURE DIRECTIONS Much of the information described in this chapter has been generated through relatively recent techniques of molecular manipulation in cell-based and murine systems that engendered a revolution in reductionist experimentation (i.e., molecular dissection of pathophysiological processes). As a consequence, the past two decades have produced a literal encyclopedia of individual factors and their functional consequences in hypertrophy and heart failure. Yet, with all this new information, no magic bullet has been identified that prevents or cures heart failure, and a major conclusion from this work seems to be that molecular cross talk and functional redundancy between signaling factors and pathways is so prevalent that achieving a magic bullet is unlikely, if not impossible. It is interesting that two of the current foci of investigational therapeutics—targeting neurohormonal pathways166,173 and correcting calcium abnormalities156,159,319— are the same as when the senior author was a medical student approximately 30 years ago.146,320-323 Targeted gain- and loss-of-function approaches that teased out possible roles for individual components of complex biological pathways have helped us develop an essential informational framework describing molecular processes and players in the heart. Now, the reductionist revolution of experimental molecular manipulation may be waning, and the future seems to be bright for integrated molecular studies of the human condition. Aside from the critical need to apply molecular information to human disease, there have been recent technical developments that position the field for a reorientation of approach. One is the availability of experimental platforms permitting high-throughput analysis of massive numbers of endpoints using specimens obtained from individual patients. Examples of currently available and clinically applicable large-scale molecular readouts include comprehensive mRNA and microRNA signatures from cardiac tissue and detailed personal gene polymorphism profiles. Proteomic profiling and analysis of individual exomes and genomes with a resolution down to single nucleotides is within reach in the next few years. The surprising degree of interindividual variability observed in our genetic code324,325 undoubtedly contributes to observed heterogeneity in cardiac disease and response to therapy. Molecular epidemiology and a systems approach combining clinical investigation and bioinformatics, supported by basic studies, will be needed to determine how differences in gene product expression or function relate to the pathological interplay between factors and pathways.

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A second example of the need for an integrated approach to pathway analysis is the promise of regenerative cardiology (see Chapter 4). This is a very new field whose foundation is cell, developmental, and molecular biology. It is obvious that success in rebuilding myocardium from cardiac scar requires creation not just of cardiac myocytes, but also the tisCH 2 sue infrastructure that is essential for myocyte maintenance and function (i.e., cardiac interstitium, myocardial vasculature, intermyocyte physical and electrical connectivity). This is a monumental challenge, and will likely require a highly refined understanding of the interplay between myocyte and vascular growth, death, and contractile signaling. Fortunately, such an understanding is forthcoming.

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CH 2

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29

Abbreviations Used in This Chapter Abbreviation

Name

Note

Ang II

Angiotensin II

Hypertrophic agonist

AMPK

Adenosine monophosphate kinase

ANF

Atrial natriuretic factor

Early response gene

AP-1

Activator protein 1

Transcription factor

AT1aR, AT1bR

Angiotensin II receptor type Ia or Ib

Ask-1

Apoptosis signal regulating kinase 1

ATF-1

Activating transcription factor 1

β-ARK (GRK2)

β-adrenergic receptor kinase (G-protein receptor kinase 2)

BMP

Bone morphogenic proteins

BNP

Brain natriuretic peptide

CAD

Caspase associated DNAase

CaMK

Ca2+ calmodulin-dependent kinase

cAMP

Cyclic adenosine monophosphate

cAMP kinase

Cyclic 3′,5′-adenosine monophosphate kinase

CREB

cAMP response element-binding protein

cAMP responsive transcription factor

CT-1

Cardiotrophin-1

IL-6 family cytokine

DAG

Diacylglycerol

Endogenous PKC agonist

DISC

Death induced signaling complex

Signaling complex downstream of death receptor

4E-BP

4E-binding protein

EGF

Epidermal growth factor

egr-1

Early growth response gene 1

Transcription factor

eIF4F

Eukaryotic initiation factor 4F

Stimulates initiation of translation at a subset of transcripts

ErbB2-4

EGF family tyrosine kinase receptors

Receptors for neuregulins

ET-1

Endothelin 1

ETA, ETB

Endothelin receptors A, B

ECM

Extracellular matrix

EGF

Epidermal growth factor

Elk-1

TCF family transcription factor

Ets1

TCF family transcription factor

ERK

Extracellular receptor kinase

MAP kinase

FAK

Focal adhesion kinase

Nonreceptor tyrosine kinase

FGF

Fibroblast growth factor

Growth factor

c-fos

c-fos oncogene

Component of transcription factor AP-1

Gα, Gβγ

Subunits of heterotrimeric G proteins

GAP

GTPase activating proteins

GATA4

GATA binding protein 4

GDP

Guanosine diphosphate

GDF15

Growth differentiation factor 15

TGF-β family protein

GEF

Guanine exchange factor

Activators of small G proteins

gp130

Glycoprotein 130

Receptor for IL-6 family cytokines

GPCR

Heterotrimeric G protein-coupled receptor

Grb2

Growth factor receptor bound protein 2

CH 2

Gβγ dependent, phosphorylates β-adrenergic receptors

TGF-β super family ligands

Adaptor protein linking RTKs and Ras Continued

Molecular Basis for Heart Failure

MAP kinase kinase

30

Abbreviations Used in This Chapter—cont’d Abbreviation

CH 2

Name

Note

GRK

G protein receptor kinase

Inhibits G protein signaling and recruits adaptor proteins to stimulate alternate pathways

GSK3β

Glycogen synthase kinase 3β

Kinase downregulated by hypertrophic stimuli

GTP

Guanosine triphosphate

HB-EGF

Heparin-binding EGF-like growth factor

HAT

Histone acetyltransferase

Induces histone acetylation with activation of transcription

HDAC

Histone deacetylase

Represses transcription by inducing histone deacetylation

IGF-1

Insulin-like growth factor

Growth factor

IL-6

Interleukin-6

Cytokine

IP3

Inositol 1,4,5 triphosphate

ILK

Integrin linked kinase

Serine threonine kinase associated with β-integrin

JAK

Janus activating kinase

Tyrosine kinase activated by gp130

JNK

Jun N terminal kinase

MAP kinase

c-jun

jun oncogene

Component of AP-1 transcription factor

LIF

Leukemia inhibitory factor

IL-6 cytokine

MADS domain

DNA binding motif

Present in SRF and MEF2 transcription factors

MAPK

Mitogen-activated protein kinase

MAPKK

MAPK kinase

Also known as MEK or MK

MAPKKK

MAPK kinase kinase

Also known as MEKK or MKK

MEF2

Myocyte enhancer factor 2

Transcription factor

MEK-1

MAP kinase kinase 1

Activator of ERK MAPKs

MCIP

Modularity calcineurin-inhibitory proteins

Endogenous inhibitor of calcineurin

MHC

Myosin heavy chain

miRNAs

MicroRNAs

MLC

Myosin light chain

MLP

Muscle LIM protein

mTOR

Mammalian target of rapamycin

Kinase involved in regulation of protein synthesis

c-myc

myc oncogene

Transcription factor

NE

Norepinephrine

Catecholamine

NFAT

Nuclear factor of activated T cells

Transcription factor

PDK1

Phosphoinositide-dependent kinase 1

Downstream effector of PI3K

PE

Phenylephrine

α-adrenergic agonist

PI3K

Phosphoinositide 3-kinase

PIP2

Phosphatidyl inositol 4,5-bisphosphate

PIP3

Phosphatidyl inositol 3,4,5-triphosphate

PKA

Protein kinase A

PKB

Protein kinase B

PKC

Protein kinase C

PKD

Protein kinase D

PLC

Phospholipase C

PMA

Phorbol 12-myristate 13-acetate

PKC agonist

p53

Tumor suppressor gene

Transcription factor

p70S6K

Ribosomal p70 S6 kinase

Protein kinase involved in protein synthesis

Ras

Ras oncogene

Small G protein

Endogenous RNAs that inhibit mRNA translation/enhance degradation

Also known as Akt

Continued

31

Abbreviations Used in This Chapter—cont’d Abbreviation

Name

Note

RTK

Receptor tyrosine kinase

ROCK

Rho kinases

RyR

Ryanodine receptor

SERCA

Sarcoplasmic reticulum Ca2+ ATPase

Pumps Ca2+ from cytoplasm to sarcoplasmic reticulum

SH2

Src homology domain 2

Binds phosphotyrosine residues

SHP2

SH2 domain-containing cytoplasmic protein tyrosine phosphatase

siRNAs

Short interfering RNAs

Inhibit mRNA translation

SOCS

Suppressors of cytokine signaling

Endogenous repressor of STATs

c-Src

Src oncogene

Nonreceptor tyrosine kinase

SRF

Serum response factor

Transcription factor

STAT

Signal transducer and activator of transcription

Transcription factor regulated by JAKs

TCF

Ternary complex factor

Transcription factor regulated by MAPKs

TAK1

TGF-β activated kinase 1

MAPKK activated by TGF-β

TGF-β

Transforming growth factor β

Cytokine

TNF-α

Tumor necrosis factor α

Cytokine

VEGF

Vascular endothelial growth factor

Angiogenic cytokine

CH 2 Molecular Basis for Heart Failure

CHAPTER Characteristic Electromechanical Abnormalities of Failing Myocytes,  32 In Vivo Cardiac Function Versus In Vitro Muscle and Myocyte ­Contractility  32 Calcium-Dependent Causes of Electromechanical Dysfunction in the Failing Heart  33 L-Type Ca2+ Channel  33 Ryanodine Receptor  34 The Sarcoplasmic Reticulum  35 Phospholamban  35 The Sodium-Calcium Exchanger  36 Deranged Ca2+ Metabolism May not be Due to a Change in the Abundance of Ca2+ Regulatory Proteins  36 Is Dysregulated Ca2+ the Cause or the Effect of Heart Failure?  37 The Role of Contractile Proteins in Regulating Cardiac Performance  37 Normal Contractile Protein Structure and Function  38 Length Dependence of Contractility  39 Heart Failure Due to Mutations of Sarcomeric Proteins  39 Sarcomeric Protein Isoform Switches in Failing Hearts  40

3

Cellular Basis for Heart Failure Kenneth B. Margulies and Steven R. Houser

Congestive heart failure (CHF) is a syndrome characterized by deterioration of cardiac pump function. Progressive alterations in the processes that regulate contractility of single ventricular myocytes are thought to be the important contributors to this pump degeneration (see Chapter 2). Those findings that have enhanced our understanding of abnormal electrophysiology, excitationcontraction coupling, Ca2+ handling, and contractile proteins in relation to the deterioration of ventricular myocyte contractility in the failing heart are the topic of this chapter.

CHARACTERISTIC ELECTROMECHANICAL ABNORMALITIES OF FAILING MYOCYTES

Prolongation of the action potential duration, a depressed force generating capacity, Phosphorylation-Dependent and slowed contraction and relaxation rates Regulation of Sarcomeric are the hallmark functional changes of the Proteins  41 failing human heart. The action potential PKA-mediated Phosphorylation  41 abnormalities cause prolongation of the surPKC-mediated Phosphorylation  42 face electrocardiogram (acquired long QT Titin Phosphorylation and Passive syndrome),1 which renders the heart prone Properties of Myocytes  43 to arrhythmias and contributes to sudden death.2 The mechanical abnormalities of Limited Proteolysis of the failing heart contribute to its poor pump Contractile Proteins  43 performance and limit its ability to increase Conclusions  44 function during daily routine activities. The cellular and molecular bases of CHF Future Directions  44 electromechanical abnormalities have been studied both in human tissues and cells and in animal models of human disease. Animal models of human disease have been useful for those studies seeking to identify the potential causes and therapies for the cardiac dysfunction seen in hypertrophy and CHF. These animal models in large part mimic human heart disease by increasing hemodynamic loading conditions (pressure and volume overload, interrupting myocardial blood flow (infarction), and by altering the heart rate (rapid pacing or atrioventricular [AV] block). Increasingly, genetically induced deletion or overexpression of specific cardiac myocyte proteins have been used to gain novel insights into the fundamental causes and potential cures of CHF. Chamber remodeling, including increased myocardial mass and left ventricular (LV) chamber dilation, is a common feature of CHF with dilation increasing with CHF severity.3 Dilation induces increases in systolic wall stress so that muscle cells in the failing heart must develop greater than normal force to develop the pressures required to support a normal blood pressure. The consensus from most studies performed to date is that mild to moderate cardiac insults are usually followed by a compensatory response that involves hypertrophy and some LV chamber remodeling (see Chapter 15).4 In these compensatory stages, myocyte function appears to be near normal and

32

may even be increased, which would help the heart maintain pump function in the face of increased hemodynamic demands. As the cardiac insult becomes more severe, CHF with LV (LV) dilation and deterioration of pump, muscle, and myocyte performance are induced. The factors that precipitate the transition from compensated to depressed myocyte and pump function are discussed later, as are those issues that are still unresolved and deserving of additional study.

In Vivo Cardiac Function Versus In Vitro Muscle and Myocyte ­Contractility In CHF, the dilated heart has a reduced ejection fraction and ejects blood slowly. These derangements are signs of markedly increased hemodynamic loading (systolic wall stress). Under these conditions the failing heart struggles to maintain blood pressure and cardiac output. Clinical studies have documented that systolic wall stress is increased in the failing heart and is a strong predictor of heart failure severity. This parameter is also inversely related to clinical outcome.5,6 These clinical data show that the myocytes surrounding the failing ventricle must develop high force (pathologically increased systolic wall stress) to produce ejection. Persistent activation of sympathetic and renin-angiotensin signaling cascades are needed to support this contractile function.7,8 It is imperative to keep in mind that the in vitro studies performed with muscles or myocytes removed from failing hearts (human or animal models) have largely been conducted in the absence of the altered inotropic environment of the failing heart. As we discuss later, when studied under these conditions many investigators have found that the basal contractile properties of the heart are depressed.9,10 Collectively these studies show that the poor pump function of the failing heart results from two factors, excessive loading conditions (systolic wall stress) and inherent defects in myocyte contractility. Fixing these structural and functional abnormalities has been a major therapeutic challenge. CHF has many different causes and yet changes in functional characteristics of the failing heart muscle are surprisingly

CALCIUM-DEPENDENT CAUSES OF ELECTROMECHANICAL DYSFUNCTION IN THE FAILING HEART Morgan and colleagues were the first to observe alterations in the Ca2+ transient of failing human ventricular muscle.16 These early studies stimulated a large body of research on the role of deranged Ca2+ homeostasis in the mechanical abnormalities of the failing heart. Fairly consistent changes in Ca2+ handling have been observed in studies using large- and small-animal model CHF and in failing human heart muscles and myocytes, as previously reviewed in Houser et al.9,10 As mentioned previously, increasing the beating rate of normal human ventricular myocytes causes an increase in the size of the Ca2+ transient and the force of contraction (positive force-frequency relationship). In myocytes with mild to moderate hypertrophy without CHF, the peak systolic Ca2+ is normal in the basal state and only becomes depressed when conditions that increase cellular Ca2+ loading are imposed (faster pacing rates, high bath [Ca2+] or catecholamine exposure). As the severity of the inciting hypertrophic stimulus increases and ventricular function begins to change, Ca2+ transient and contractile abnormalities are found at progressively slower rates of stimulation and in normal bath [Ca2+]. When CHF is severe, such as in end-stage human heart failure, peak systolic Ca2+ and force (or shortening) are both close to normal only at very slow pacing rates. As the beating rate is increased, there is either no change or a decrease in peak systolic Ca2+ and force of contraction (negative forcefrequency relationship) in the failing heart.15,16 In addition, as CHF progresses, there is an associated increase in diastolic Ca2+ with increased heart rate.15 These results strongly support the hypothesis that changes in cellular Ca2+ handling are a final common pathway for progressive deterioration of cardiac pump function in CHF. The changes in Ca2+ handling are also likely to be critically involved in the arrhythmias,7,17

metabolic disturbances, and activation of cell death path- 33 ways18-21 and hypertrophy22 that develop during this time. This hypothesis is also strongly supported by studies in animal models that show that the transition from compensated hypertrophy to CHF coincides with the time that myocytes first lose their ability to normally maintain physiological levCH 3 els of systolic and diastolic Ca2+.23 The cellular and molecular bases of the altered Ca2+ homeostasis of the failing cardiac myocytes have been studied in some detail. Studies performed over the past decade show that changes in the abundance and regulatory state (phosphorylation, nitrosylation, etc.) of critical Ca2+ regulatory proteins are largely responsible for abnormal Ca2+ regulation.24 In normal myocytes the systolic Ca2+ transient (rise in cytosolic [Ca2+]) determines the rate and magnitude of contraction. The Ca2+ transient is derived from two sources: Ca2+ influx through L-type Ca2+ channels and Ca2+ release from the sarcoplasmic reticulum (SR). L-type Ca2+ channels in the transverse tubules are activated during the early portion of the cardiac action potential. Ca2+ enters myocytes through these channels and accumulates in diffusion limiting spaces between the T-tubules and the junctional SR. Ca2+ in this space binds to the cytoplasmic face of the Ca2+ release channel (ryanodine receptor, RyR), causing it to open. Ca2+ then moves out of the SR into the cytoplasm. Collectively these processes increase cytoplasmic Ca2+ and activate contraction. The Ca2+ transient is terminated when the Ca2+ entry and release channels close and Ca2+ efflux (Na/Ca2+ exchange) and SR reuptake by the SR Ca2+ ATPase (SERCA2) reestablish steady-state conditions. The amplitude and duration of the Ca2+ transient is regulated to modulate the rate, magnitude, and duration of contraction. SR Ca2+ release is induced and graded by Ca2+ influx through L-type Ca2+ channels.25 The magnitude of SR Ca2+ release is also determined by the amount of Ca2+ stored in the SR.26,27 Alterations in the abundance or activity (by abnormal phosphorylation) of any or all of these Ca2+ regulatory proteins have been shown to play a role in the abnormal Ca2+ transients in the failing heart (Figure 3-1). Most studies show that the amount of Ca2+ released from the SR of failing human (and most animal models) myocytes is smaller than normal and that this difference is accentuated at rapid heart rates.27,28 The molecular bases of the abnormal Ca2+ transient are discussed next. Cellular Basis for Heart Failure

consistent. Slowing of contraction and relaxation rates and prolongation of the action potential duration have consistently been the first changes observed in the early stages of CHF.11,12 Reduced force production and shortening magnitude and decreases rather than increases in contractility as the heart rate increases (positive versus negative force-­frequency relationships) are observed in more advanced CHF.13 An important finding of many in vitro studies is that nonfailing and failing human myocytes have similar contractile characteristics at low workloads (slow pacing rates, low bath Ca2+, absence of catecholamine stimulation).13 Peak developed force (or shortening) is not significantly different in nonfailing versus failing human left ventricle muscles or in myocytes paced at slow frequencies (6 cm H2O) l Alone l Plus hepatomegaly or edema Rales/crackles l Basilar crackles l More than basilar crackles Wheezing S3 gallop

1 2

2 3

1 2 — —

1 2 3 3

Alveolar pulmonary edema Alveolar fluid plus pleural fluid Interstitial pulmonary edema Interstitial edema plus pleural fluid Bilateral pleural effusion Cardiothoracic ratio >0.5 (posteroanterior projection) Upper zone flow redistribution

— 3 2 3 — — 1

4 — 3 — 3 3 2

*Diagnosis

of heart failure: two major criteria, or one major and two minor criteria, are required. criteria for diagnosis of heart failure: “definite” (score 8–12 points), “possible” (score 5–7 points), or “unlikely” (score ≤ 4 points). NHANES-1 criteria for diagnosis of heart failure: score ≥ 3 points. From Rector, T.S., Cohn, J.N. Assessment of patient outcome with the Minnesota Living with Heart Failure questionnaire: reliability and validity during a randomized, double-blind, placebo-controlled trial of pimobendan. Pimobendan Multicenter Research Group. Am Heart J, 1992;124(4):1017-25. NHANES, National Health and Nutrition Examination Survey. †Boston

made every effort to reduce sodium intake. However, careful review of their dietary habits may reveal otherwise or simply clear ignorance of salt-laden food intake. Probing into specifics often helps physicians better understand patients’ conditions and their immediate environment. Patients may also be focused on any abnormal signs and symptoms that may be attributable to heart failure or its treatment side effects. Good rapport with patients and their families is vital in eliciting information regarding adherence to medical advice and reviewing abilities to provide appropriate self-care.

Dyspnea Dyspnea is the uncomfortable awareness of breathing. When it occurs at rest or at a level of physical activity at which it is not expected, it is abnormal. Dyspnea is a nonspecific symptom that occurs with a wide variety of cardiac, pulmonary, and chest wall disorders. For example, it can also result from acute anxiety, acute coronary insufficiency, and anemia.

Patients with heart failure may manifest various types of dyspnea, including exertional dyspnea, orthopnea, paroxysmal nocturnal dyspnea, dyspnea at rest, and, with acute pulmonary edema, respiratory distress. An increase in respiratory rate (usually > 16 breaths/minute) usually accompanies dyspnea and may signal the onset of acute decompensation of stable heart failure. The mechanisms of dyspnea, fatigue, and exercise intolerance in patients with heart failure are still not well understood, inasmuch as they are not simply a result of increased pulmonary capillary wedge pressure and decreased cardiac output.10-14 There is little correlation between pulmonary capillary wedge pressure and exertional dyspnea in individual patients with heart failure, unless frank pulmonary is present.15 It is well known that in auscultation, the lungs may sound clear in a substantial proportion of patients with shortness of breath and heart failure.16 All patients with heart failure should be carefully queried regarding the threshold of dyspnea onset during exercise.

BOX 35–1 Factors That May Precipitate the Worsening of Heart Failure

Did your heart failure prevent you from living as you wanted during the last month by: 1. causing swelling in your ankles, legs, etc.? 2. making you sit or lie down to rest during the day? 3. making your walking about or climbing stairs difficult? 4. making your working around the house or yard difficult? 5. making your going places away from home difficult? 6. making your sleep at night difficult? 7. making your relating to or doing things with your friends and family difficult? 8. making your working to earn a living difficult? 9. making your recreational pastimes, sports, or hobbies ­difficult? 10. making your sexual activities difficult? 11. making you eat less of the foods you like? 12. making you short of breath? 13. making you tired, fatigued, or low on energy? 14. making you stay in a hospital? 15. costing you money for medical care? 16. giving you side effects from medicine? 17. making you feel you are a burden to your family or friends? 18. making you feel a loss of self-control in your life? 19. making you worry? 20. making it difficult for you to concentrate or remember things? 21. making you feel depressed?

TABLE 35–3   Kansas City Cardiomyopathy Questionnaire 1. Please indicate how much you are limited by heart failure (shortness of breath or fatigue) in your ability to do the following activities over the past 2 weeks? (extremely limited, quite a bit limited, moderately limited, slightly limited, not at all limited, or limited for other reasons or did not do the activity) l Dress yourself l Showering/bathing l Walking 1 block on level ground l Doing yard work, housework, or carrying groceries l Climbing a flight of stairs without stopping l Hurrying or jogging (as if to catch a bus) 2. Compared with 2 weeks ago, have your symptoms of heart failure (shortness of breath, fatigue, or ankle swelling) changed? (much worse, slightly worse, not changed, slightly better, much better, I’ve had no symptoms over the last 2 weeks) 3. Over the past 2 weeks, how much have the following signs/symptoms bothered you? (extremely, quite a bit, moderately, slightly, not at all bothersome; no such signs/symptoms) l Swelling in your feet, ankles, or legs l Fatigue l Shortness of breath 4. Over the past 2 weeks, how many times did you have swelling in your feet, ankles, or legs when you woke up in the morning? (every morning, 3 or more times a week but not every day, 1–2 times a week, less than once a week, never over the past 2 weeks) 5. Over the past 2 weeks, on average, how many times has fatigue limited your ability to do what you want? (all the time, several times/day, at least once/ day, 3 or more times/week but not every day, 1–2 times/week, less than once/week, never over the past 2 weeks) 6. Over the past 2 weeks, on average, how many times have you been forced to sleep sitting up in a chair or with at least 3 pillows to prop you up because of shortness of breath? (every night, 3 or more times/week but not every day, 1–2 times/week, less than once/week, never over the past 2 weeks) 7. Heart failure symptoms can worsen for a number of reasons. How sure are you that you know what to do, or whom to call, if your heart failure gets worse? (not at all sure, not very sure, somewhat sure, mostly sure, completely sure) 8. How well do you understand what things you are able to do to keep your heart failure symptoms from getting worse (for example, weighing yourself, eating a low salt diet, etc.)? (Do not understand at all, do not understand very well, somewhat understand, mostly understand, completely understand) 9. Over the past 2 weeks, how much has your heart failure limited your enjoyment of life? (extremely, quite a bit, moderately, slightly, not limited) 10. If you had to spend the rest of your life with your heart failure the way it is right now, how would you feel about this? (not at all satisfied, mostly dissatisfied, somewhat satisfied, mostly satisfied, completely satisfied) 11. Over the past 2 weeks, how often have you felt discouraged or down in the dumps because of your heart failure? (all the time, most of the time, occasionally, rarely, never) 12. How much does your heart failure affect your lifestyle? Please indicate how your heart failure may have limited your participation in the following activities over the past 2 weeks. (severe limited, limited quite a bit, moderately limited, slightly limited, did not limit at all, does not apply or did not do for other reasons) l Hobbies, recreational activities l Working or doing household chores l Visiting family or friends out of your home l Intimate relationships with loved ones From Green, C.P., Porter, C.B., Bresnahan, D.R., et al. Development and evaluation of the Kansas City Cardiomyopathy Questionnaire: a new health status measure for heart failure. J Am Coll Cardiol 2000; 35:1245-1255.

515

CH 35 Clinical Evaluation of Heart Failure

Myocardial ischemia or infarction Excess dietary sodium or excess fluid intake Medication noncompliance Iatrogenic volume overload Uncontrolled hypertension Arrhythmia l Atrial fibrillation or flutter l Ventricular tachyarrhythmias l Bradyarrhythmias Comorbid conditions l Fever, infections, or sepsis l Thyroid dysfunction l Anemia l Renal insufficiency l Nutritional deficiencies (such as thiamine deficiency) l Pulmonary diseases (chronic obstructive pulmonary disease, pulmonary embolism, hypoxemia) Inappropriate reduction of medications for heart failure Adverse drug effects l Alcohol l Overzealous administration of negative inotropic agents (such as β-blockers, calcium channel blockers, antiarrhythmic agents) l Nonsteroidal antiinflammatory drugs l Thiazolidinediones and other medications that can cause fluid retention l Corticosteroids

BOX 35–2 Minnesota Living With Heart Failure Questionnaire

516 Specific examples of how and when the dyspnea occurs

should be sought. The mechanism of dyspnea should be considered. Shortness of breath may be caused by concomitant pulmonary disease or respiratory muscle dysfunction.17 Increased ventilatory drive or exercise hyperventilation is believed to be a common cause of dyspnea in patients with CH 35 heart failure,18-21 but the precise mechanism of dyspnea has not been pinpointed. The mechanism of increased ventilatory drive in patients with heart failure is multifactorial and incompletely understood, but it may be related to increased peripheral chemosensitivity in the skeletal muscles and accumulation of lactic acid. Both of these may lead to exercise hyperpnea,22,23 which tires the patient out at increasingly earlier points in exercise. This concept is consistent with the “muscle hypothesis,” according to which dyspnea in patients with heart failure actually begins in the skeletal muscles.22,23 Exertional dyspnea can also occur when there is markedly elevated left ventricular filling pressure. Multiple, complex mechanisms are operative in the production of exertional dyspnea in patients with heart failure, and probably no single mechanism is dominant. Nevertheless, the augmented ventilatory response to exercise in heart failure (such as increased breathing rate in relation to the amount of exercise) is correlated with hemodynamic alterations,24 whereas peak ventilatory oxygen uptake (Vo2) is not. According to the dominant theory of increased exercise ventilatory response of heart failure, increases in carbon dioxide output in relation to peak oxygen consumption lead to bicarbonate buffering and accumulation of lactic acid.23 Lactic acid builds up at relative low levels in patients with heart failure and acts as an additional stimulus to breathing. This buildup may also contribute to the sensation of dyspnea. In some patients, there is also an increase in airway dead space because of reduced perfusion of ventilated lung tissue, which leads to inefficient gas exchange. Despite this, arterial carbon dioxide concentration is driven to low levels during peak exercise in most patients with heart failure. According to the “muscle hypothesis” of exertional dyspnea, peripheral (i.e., skeletal muscle) chemoreceptors are stimulated by higher levels of arterial oxygen and carbon dioxide concentrations in heart failure, which leads to overactivation of ergoreflexes.25 This overactivation increases both ventilatory drive and sympathetic nervous system activity through the activation of a central mechanism. Physical training in patients with heart failure may reduce exaggerated ergoreflex activity and thereby improve the response to exercise.26 Clearly, exertional dyspnea in patients with heart failure is complex, multifactorial, and not simply a result of increased filling pressures. Reflex control mechanisms involving the heart, lungs, brain, and skeletal muscles and a buildup of lactic acid in the working muscles are probably involved; they would lead to an increased ventilatory response to exercise.

Fatigue As with dyspnea, the mechanism of fatigue in patients with heart failure is uncertain. Cardiac fatigue was widely assumed to be simply a result of low cardiac output, but since 2000, it has become clear that abnormalities of skeletal muscles and other noncardiac comorbid conditions such as anemia may contribute to fatigue. Abnormalities of high-energy phosphates in the skeletal muscles of patients with heart failure are well documented (see also Chapter 19),27-31 even in the presence of normal regional blood flow.29 Muscle fatigue is related to abnormal phosphocreatinine depletion, acidosis, or both in the working muscle. The anaerobic regeneration of adenosine triphosphate (ATP) is impaired in the skeletal muscles of patients with heart failure. There is also a shift in fiber distribution: The percentage of the fast-twitch, glycolytic, easily fatigable type IIb fibers is increased.27 Patients with heart

failure have major histological alterations in skeletal muscle and biochemical alterations,32 including the development of skeletal muscle atrophy.33 Significant ultrastructural abnormalities34 lead to diminished oxidative capacity of working muscle.35,36 Chronic fatigue begets further inactivity, which leads to further deconditioning and a greater extent of disability. In the late stages of heart failure, low cardiac output and anemia related to chronic disease probably also contribute to fatigue. Patients who are ambulatory with heart failure should be encouraged to stay physically active,37,38 and participation in a structured exercise training program can improve exercise tolerance.39-41

Other Symptoms of Heart Failure An occasional patient with heart failure presents with palpitations, lightheadedness, or even frank syncope. In the authors’ experience, this is unusual. However, heart block, arrhythmias with circulatory collapse, or even atrial fibrillation or premature beats may be a presenting feature of heart failure, which is especially common in specific conditions such as acute myocarditis, sarcoid cardiomyopathy, or Chagas’ disease. Right upper quadrant pain caused by acute liver congestion or early satiety may be another presenting symptom. Additional presenting symptoms might include nocturnal angina, weight loss (weight gain is more common), and cough. Other signs and symptoms of heart failure are usually present. Sometimes symptoms of heart failure are more subtle and are often mistakenly misdiagnosed as “bronchitis” (dry productive cough), “asthma” (wheezing due to cardiac asthma), or “insomnia” (Hunter-Cheyne-Stokes respiration). Many endocrine abnormalities can be associated with heart failure and may be treatable. In asymptomatic people it is not uncommon for cardiomegaly to be diagnosed on a routine chest radiograph or for left bundle branch block or arrhythmia to be detected on an electrocardiogram; both situations are forerunners to the development of heart failure and cardiac dysfunction.

CLINICAL EVALUATION OF PRESENTING SIGNS: PHYSICAL EXAMINATION A careful physical examination is always warranted in the evaluation of patients with heart failure. The purpose of the examination is to help determine the cause and severity of the heart failure. Obtaining additional information about the hemodynamic profile, documenting the response to therapy, and determining the prognosis are important additional goals of the physical examination.

General Inspection of the Patient The diagnosis of heart failure is relatively straightforward by simple medical history and physical examination. It is not unusual for an experienced physician to sense the severity of the heart failure syndrome within the first few minutes of walking into the examination room, meeting the patient, and observing the patient carefully. Hospitalized patients often have labored or uncomfortable breathing. They may not be able to finish a sentence because of shortness of breath. Lying down may be difficult because of orthopnea. Altered respiratory signs such as coughing, Hunter-Cheyne-Stokes respiration, and cyanosis are sometimes observed. Peripheral cyanosis, which is limited to exposed skin, usually indicates inadequate perfusion or low cardiac output. In contrast, central cyanosis is uncommon, but when it occurs, it is found predominantly in the tongue, uvula, and buccal mucosa; its presence indicates intracardiac or intrapulmonary shunting. Some patients demonstrate cachexia, a particularly poor

Assessment of the Volume Status of the Patient Pertinent features of the cardiac physical examination, such as jugular venous distention and tissue congestion, are especially important in the accurate assessment of the patient with heart failure. It can be useful to dichotomize the signs of heart failure as those of volume overload and those of low cardiac output (see Figure 35-3).42 Signs of volume overload include increased jugular venous distention, prominent V waves, gallop heart rhythm (or third heart sound [S3]), rales and pleural effusion, anasarca, ascites, and peripheral edema. On occasion, specific organomegaly is present; examples include enlarged and sometimes tender liver, enlarged spleen (rare), and cardiomegaly. According to the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial,43 the presence of orthopnea and increased jugular venous distention may be useful for detecting increased intracardiac filling pressures, whereas a global assessment of inadequate perfusion (“cold profile”) may be useful for detecting reduced cardiac index. Despite the historical use of the term congestive heart failure, it is not unusual for patients with advanced heart failure to consistently demonstrate no evidence of volume overload.16 For reasons that are unclear, such patients do not

NO Low perfusion at rest Yes

NO

Yes

A

B

seem to retain significant amounts of salt and water; hence, 517 they are subject to overdiuresis, which leads in some cases to prerenal azotemia. Patients should be examined while they are lying down, with the head tilted at 45 degrees. The physician should examine a patient from the patient’s right side (oslerian tradition). The most important assessment of volume status is careful examination of the jugular venous CH 35 pressure; unfortunately, this is somewhat of a lost art.16,44,45 It is important to understand that jugular venous pressure often reflects left- and right-sided filling pressures but that a substantial number of patients with heart failure have relatively normal intracardiac filling pressures and no distended neck veins. In patients with mild heart failure, the jugular venous pressure may be normal when the patient is lying with the head tilted at 45 degrees, but it rises to abnormal levels with compression to the right upper quadrant. This is referred to as hepatojugular reflux. To elicit this sign, the right upper quadrant should be compressed firmly, gradually, and continuously for 1 minute while the neck veins are observed. The presence of hepatojugular reflux that very slowly dissipates on release of hand pressure is a sign that intracardiac filling pressures are abnormally increased.46 Despite the common lack of abdominal complaints, some patients do accumulate fluid in the form of ascites or visceral edema. Examination of the abdomen should be performed to determine the presence of ascites, hepatosplenomegaly, or pulsatile, tender liver. Splenomegaly is rare in heart failure. However, hepatomegaly is common, and acute congestion can lead to rather severe right upper quadrant tenderness that mimics cholecystitis. On occasion, patients with acute decompensation and severe right upper quadrant pain may even go to the operating room for cholecystectomy with the suspicion of acute cholecystitis, where the actual problem is found to be acute hepatic congestion. Liver transaminase levels are often elevated during acute passive congestion, and in severe right-sided heart failure, levels of clotting factors and total bilirubin may be increased. Raised intra-abdominal pressures have been recognized in patients with congestion and decompensated heart failure, which further illustrates the evidence and hemodynamic impact of abdominal congestion.47 Normal, hyperdynamic, or sustained precordial pulsations may be present. Cardiomegaly tends to displace the point of maximal impulse, which is also sustained in cases of severe left ventricular hypertrophy. Physical examination of the precordial pulsation, however, is inadequate for assessing

Warm and dry

Warm and wet

(Low Profile)

(Complex)

L

C

Cold and dry

Cold and wet

Clinical Evaluation of Heart Failure

prognostic sign. The presence of severe peripheral edema and ascites are obvious in visual inspection. Examination of the arterial pulse is very important. The absence of pulses should be noted, as should the character of the pulse detected. Pulsus alternans (a strong beat alternating with a weak beat), although unusual, is virtually diagnostic for severe advanced heart failure. Pulsus paradoxus (a substantial diminishment in the amplitude of the arterial pulse during inspiration) is found in pericardial tamponade. It is usually confirmed by measuring blood pressure carefully during the phases of inspiration and expiration. Pulsus paradoxus is also seen in an occasional patient with severe asthma, pulmonary embolism, pregnancy, or marked obesity and in patients with superior vena cava syndrome. Patients with aortic stenosis may have diminished upstroke of the carotid pulse, whereas patients with severe, chronic aortic regurgitation manifest accentuated pulses and a series of findings related to a large stroke volume. Peripheral pulses may be absent in patients with coarctation of the aorta. Therefore, a thorough assessment of the pulses is always warranted.

Signs/Symptoms of Congestion: Orthopnea/PND Jugular venous distension Hepatomegaly Edema Rales (rare in chronic heart failure) Elevated est. PAsys Valsalva square wave Abdominal-jugular reflux

Possible Evidence of Low Perfusion: Narrow pulse pressure Cool extremities Sleepy/obtunded Hypotension with ACE inhibitor Low serum sodium Renal dysfunction FIGURE 35–3  Clinical presentation of acute heart failure syndrome based on congestion and perfusion. (From Nohria, A., Lewis E., Stevenson, L. W. (2002). Medical management of advanced heart failure. JAMA, 287, 628-640.)

518 the degree of left ventricular dysfunction. In some patients, a

third heart sound is audible and palpable at the apex. Patients with enlarged or hypertrophied right ventricles may have a sustained and prolonged left parasternal impulse that extends throughout systole. A third heart sound (or gallop rhythm) is most commonly CH 35 present in patients with volume overload who have tachycardia and tachypnea. It may be absent in many patients with advanced heart failure, but the presence of a third heart sound can signify severe hemodynamic compromise.48 The murmurs of mitral and tricuspid regurgitation are frequently present in patients with advanced heart failure, although severe regurgitation is frequently present in the absence of an audible murmur. The presence of jugular venous distention and a third heart sound imply a poor prognosis49 and disease progression50 and should always be sought and recorded in the notes. Of interest is that signs of pulmonary congestion (such as rales, pulmonary edema, and elevated jugular venous pressure) are frequently absent even in patients with raised pulmonary capillary wedge pressure.16 Similar to patients with long-standing mitral stenosis, patients with chronic, severe heart failure tend to have robust lymphatic drainage of the pulmonary interstitial spaces. The absence of rales does not preclude impending pulmonary edema, and direct hemodynamic measurements may sometimes be necessary. Instead, tachypnea (and in some extreme cases, hypoxia) is often associated with significant pulmonary congestion. An increase in circulating volume is often associated with evidence of excessive adrenergic activity. This evidence includes diaphoresis, tachycardia, pallor, and coldness of the extremities. The adrenergic nervous system is similarly activated during low cardiac output. Relief of congestion is always an important primary goal in the management of patients with chronic heart failure; thus, the identification of the volume overload state is a critical step in the physical examination.51

Signs of Low Cardiac Output Patients in a low-output state may exhibit a wide variety of clinical signs (from cool, dry skin, pallor, or peripheral cyanosis to normal color, warmth, and appearance). In some cases, pulses may be diminished and blood pressure may be low with a narrow pulse pressure. Some patients demonstrate virtually no signs of inadequate blood flow despite a low cardiac output. They may be alert and cognitively responsive despite extreme diminishment in cardiac index (i.e., 4 fb)

15

93

78

39

2.13

1.09

Hepatojugular reflux

83

27

65

49

1.13

1.54

JVP ≥ 12 mm Hg

65

64

75

52

1.79

1.82

81

28

33

0.23

0.85

JVP < 8 mm Hg

4.3

From Drazner MH, Hellkamp AS, Leier CV, et al. Value of clinician assessment of hemodynamics in advanced heart failure: the ESCAPE trial. Circ Heart Fail 2008;1:170-177. fb, fingerbreadths; JVP, jugular venous pressure.

520

BNP

1.0 0.9

Sensitivity

CH 35

0.6

Sensitivity (true positives)

0.7 0.5 0.4

Area under the receiver-operating-characteristic curve, 0.91 (95% confidence interval, 0.90-0.93)

0.3 0.2

NT-proBNP, 300 pg/mL NT-proBNP, 450 pg/mL NT-proBNP, 600 pg/mL NT-proBNP, 900 pg/mL NT-proBNP, 1000 pg/mL

0.9

BNP, 50 pg/mL BNP, 80 pg/mL BNP, 100 pg/mL BNP, 125 pg/mL BNP, 150 pg/mL

0.8

NT-proBNP

1.0

0.1

0.8 0.7 0.6 0.5 0.4

Area under the curve = 0.94

0.3

P < 0.0001

0.2 0.1

0.0

0.0 0.0 BNP

pg/mL 50 80 100 125 150

0.2

0.4 0.6 1-Specificity

Sensitivity Specificity

0.8

PPV

NPV

Accuracy

71 (68-74) 77 (75-80) 79 (76-81) 80 (78-83) 83 (80-85)

96 (94-97) 92 (89-94) 89 (87-91) 87 (84-89) 85 (83-88)

79 83 83 83 84

(95 percent confidence interval)

97 (96-98) 93 (91-95) 90 (88-92) 87 (85-90) 85 (82-88)

62 (59-66) 74 (70-77) 76 (73-79) 79 (76-82) 83 (80-85)

1.0

Note: PPV = positive predictive value, NPV = negative predictive value.

0.0 Cutoff, pg/mL 300 450 600 900 1000

0.2

Sensitivity, % 99 98 96 90 87

0.8 0.4 0.6 1-Specificity (false positives) Specificity, % 68 76 81 85 86

1.0

PPV, %

NPV, %

Accuracy, %

62 68 73 76 78

99 99 97 94 91

79 83 86 87 87

Note: PPV = positive predictive value, NPV = negative predictive value.

FIGURE 35–4  Receiver operator characteristic curves for diagnostic accuracies for B-type natriuretic peptide (BNP) (left) and amino-terminal pro–B-type natri­ uretic peptide (NT-proBNP) (right). CHF, congestive heart failure; Ve, ventilation; Vco2, carbon dioxide production. (Left, From Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002;347:161-167. Right, From Januzzi JL Jr, Camargo CA, Anwaruddin S, et al. The N-terminal Pro-BNP Investigation of Dyspnea in the Emergency Department (PRIDE) study. Am J Cardiol 2005;95:948-954.) Copyright © (2011) American Medical Association. All rights reserved.

FIGURE 35–5  Appropriate lead placement (arrows) for cardiac resynchronization therapy in chest radiography.

resonance sequences enable the study of cardiac motion (myocardial tagging, blood flow velocity (phase contrast method), and myocardial scarring (late enhancement technique), and specific patterns may indicate the presence of infiltrative diseases (such as amyloidosis, sarcoidosis, hemachromatosis) or myocarditis (see also Chapter 36).

Ischemic Evaluation: Myocardial Viability and Coronary Anatomy (see Chapters 23 and 36) Coronary artery disease is the cause of heart failure in about two thirds of patients with left ventricular systolic dysfunction, and up to one third of patients with nonischemic cardio-

myopathy experience chest pain that mimics angina (see also Chapter 23).56,60 Researchers have also pointed out that underdiagnosis or misdiagnosis of ischemic heart disease among patients with heart failure is common if angiographic evaluation was not undertaken as part of the heart failure workup.61,62 Patients with systolic heart failure and severe coronary artery disease have, by definition, ischemic cardiomyopathy, and in some cases this reduction in myocardial function may be improved with percutaneous coronary intervention (PCI) or surgical revascularization. Most patients with heart failure should be considered candidates for diagnostic coronary angiography to determine whether significant coronary artery disease is present, especially in patients for

521

CH 35 Clinical Evaluation of Heart Failure FIGURE 35–6  Cardiac magnetic resonance imaging (MRI) assessment of myocardial viability with cine-imaging (top left), myocardial tagging imaging (top right), TurboFlash perfusion imaging with gadolinium (bottom left), and delay-enhanced imaging with gadolinium (bottom right).

whom revascularization is often very beneficial. This clearly remains highly controversial because such an invasive procedure may not be needed in most patients with a good clinical history and in whom clinical suspicion of heart failure is low because of the lack of cardiovascular risk factors. However, coronary artery disease may not be easily predicted from the medical history, physical examination findings, and echocardiogram.63 For a patient who has angina pectoris and heart failure, an even more compelling argument can be made for performing diagnostic coronary angiography. On the other hand, severe coronary artery disease and reduced left ventricular function are present but anginal symptoms are minimal, demonstration of myocardial viability is of paramount importance (and is discussed in Chapter 37). Also, diagnostic evaluation for coronary artery disease provides only a “snapshot” at the time of evaluation, and atherosclerotic diseases may progress over time, leading to progressive ischemia. In the case of cardiac MRI, assessment of myocardial viability is of utmost importance to detect ischemic but viable myocardium for potential therapeutic interventions. In patients with heart failure, of whom 60% to 70% suffer from coronary artery disease, these techniques are helpful for therapeutic and prognostic stratification. Late-enhancement MRI has become a tool for determining lesion size in patients with myocardial infarction. The spatial and temporal relationship measured through differential uptake and release of contrast material in the viable tissue versus scar tissue can provide the location as well as extent of the scar.

Functional Evaluation: Cardiopulmonary Exercise Testing (see Chapter 57) For many activities of daily living, a fundamental requirement is the ability to perform aerobic work. Functional capacity is usually measured in metabolic equivalents (METs) where 1 MET represents 3.5 mL of O2/kg/min. Exercise testing is a valuable tool in the diagnosis and assessment of patients with heart failure38 (Table 35-6). It has long been recognized that the simple history and physical examination, as well as various subjective functional classification systems, can be too nonspecific and relatively insensitive. Therefore, exercise

testing can add substantial precision in the initial evaluation of the patient with heart failure. This is particularly true when heart transplantation is a consideration or when quantitative information on assessing an individual patient’s disability is necessary. The primary goal of metabolic exercise testing is to determine the functional status and prognosis of the patient objectively (see also Chapter 57). Exercise testing in patients with heart failure was first widely applied in the late 1970s to test the response of patients to various drug therapies.13 Although it has become apparent that response of exercise to short-term drug therapy is not predictive of long-term drug efficacy,64 useful information regarding how to gauge the degree of disability more precisely has emerged from these studies. More recently, exercise testing has been used to assess the severity of heart failure and to help determine the prognosis for individual patients. In retrospect, it has become clear that measurements of the peak Vo2 and the slope of the ratio of ventilation (Ve) to carbon dioxide production (Vco2) (Ve/Vco2) are powerful predictors of prognosis. Serial improvement in peak Vo2, either in response to therapy or occurring spontaneously, has also been demonstrated to have prognostic value.65 However, the Ve/Vco2 slope remains the strongest predictor of prognosis, better even than peak Vo2.66 The usefulness of cardiac output estimation during standard metabolic exercise testing is under intense investigation.67 Metabolic exercise testing is of value in determining whether the heart or lungs are causing the dyspnea. Increased ventilation (Ve) with regard to carbon dioxide production is a hallmark finding of patients with heart failure66,68 (Figure 35-7). The slope of the Ve/Vco2 ratio offers important prognostic information, perhaps even more than Vo2.68,69 However, the increase in Ve/Vco2 slope observed in patients with heart failure is nonspecific70; it can also be abnormally steep in patients with primary lung disease.71 Assessment of functional capacity is typically performed on a motorized treadmill or a stationary bicycle ergometer. The functional capacity can be estimated or measured directly by gas exchange methods (Vo2) from the highest work level achieved. Estimates of functional capacity such as exercise duration are less reliable than direct measurements of gas exchange. Peak Vo2 and anaerobic ventilatory threshold are

522 TABLE 35–6   Weber Classification of Functional

140

Impairment in Aerobic Capacity and Anaerobic Threshold as Measured during Incremental Exercise Testing

100

Class

Degree of Impairment

Vo2 Max (mL/min/kg)

A

None to mild

>20

> 14

B

Mild to moderate

16–20

11–14

C

Moderate to severe

10–16

8–11

D

Severe

6–10

5–8

20

E

Very severe

4.0 cm) is present, or if the LVEF exceeds 60%.65 However, if the LV is severely dysfunctional (LVEF < 30%) or if the mitral valve regurgitation is secondary to LV dilation, the results of surgical mitral valve correction are often suboptimal, and medical management may be more appropriate.65 Severe and chronic aortic valve disease (stenosis or regurgitation) can result in significant LV systolic dysfunction. Twodimensional echocardiography can readily reveal the cause of aortic valve disease (degenerative, rheumatic, congenital or bicuspid, or secondary to aortic root disease), and Doppler imaging can accurately reflect the severity of aortic valve disease.65-67 In general, in the setting of significant aortic valve stenosis or regurgitation (more than moderately severe), if a patient is symptomatic or has signs of LV dilation or systolic dysfunction, surgery is warranted.65 In asymptomatic severe aortic valve stenosis or regurgitation, echocardiography can be helpful for determining surgical timing.65-67 For patients with low-gradient aortic stenosis (moderate stenosis with LVEF < 35%), low-dose dobutamine stress echocardiography can be helpful for distinguishing true, severe aortic stenosis from “pseudo”–aortic stenosis and for demonstrating the presence of LV contractile reserve.65,68,69 In general, patients

Cardiac Magnetic Resonance Imaging Although echocardiography typically provides comprehensive information for diagnostic and therapeutic decision CH 36 making in valvular disease, CMR imaging may be a useful alternative in patients with limited image quality in ultrasound studies. CMR imaging may also be helpful by providing a “third opinion” in patients with conflicting or inconclusive findings. Sometimes, additional information such as tissue characteristics may help physicians make informed therapeutic decisions. Whereas regurgitant and stenotic jets may be readily apparent in cine images, the assessment of valvular disease requires a quantitative evaluation of flow or flow velocity data, or both. The accuracy of flow quantification by CMR imaging has been previously validated.70,71 In regurgitant valvular heart disease, regurgitant volume and fraction can be measured by comparing left ventricular stroke volume with systolic aortic flow. CMR imaging allows for measuring effective cardiac output and can therefore provide an important objective parameter of heart failure related to low output. In stenotic valvular disease, flow quantification can be used to identify increased transvalvular flow velocity and calculate pressure gradients.72 A planimetric quantification of the aortic valve area provides reliable results and avoids the limitations introduced by irregularly turbulent jets and varying pressure gradients.73-75 This may be of special importance in patients with associated heart failure, inasmuch as the pressure gradient is often unreliable in low-output states. Use of Cardiac Imaging in the Evaluation of Heart Failure

Mortality rate (%)

16

with true stenosis or contractile reserve respond favorably to 535 aortic valve replacement.65,68,69

HEART FAILURE WITH A DEPRESSED EJECTION FRACTION (see Chapters 14 and 48) Echocardiography Assessment of Left Ventricular Mass and Left Atrial Size In diastolic heart failure, also referred to as heart failure with a preserved ejection fraction (LV > 46% to 50%), elevated left atrial pressures (which reflect LV filling pressures in the absence of obstructive mitral valve disease) lead to increased pulmonary venous pressures and dyspnea at rest or during exertion.76-80 In order for left atrial (LA) pressures to be elevated in the absence of significantly depressed LVEF, LV relaxation and compliance generally are impaired (see Chapter 14).76,77,80 Therefore, increased LV mass (≥90 g/m2 for women and ≥115 g/m2 for men; i.e., LV hypertrophy) is common in patients with diastolic heart failure.5,76,80 Because LA pressures are elevated in this scenario, LA enlargement (≥30 mL/m2) is usually observed.76-81 In previous studies, increasing degrees of LV mass have been correlated with increasing LV diastolic dysfunction and filling pressures.82 Similarly, increasing LA size is correlated with increasing LV filling pressures and worse outcome in patients with diastolic heart failure.81,83 In cases of ischemic or infiltrative heart disease, significant LV hypertrophy may be absent, and yet LA volumes are often enlarged.77,84 Identification of Diastolic Dysfunction and Elevated Left Ventricular Filling Pressures Clinically, diastolic dysfunction secondary to impaired LV relaxation and increased LV stiffness is usually demonstrated by Doppler echocardiography.76-81 The best correlate of symptoms and survival in diastolic heart failure is elevation of left atrial (or left ventricular filling) pressure, readily estimated through comprehensive echocardiography with Doppler measurement.76,77 Pulsed Doppler interrogation of transmitral and

536 Normal diastolic function

Velocity (m/s)

Mitral inflow at peak valsalva maneuver*

Velocity (m/s)

2.0

Doppler tissue imaging of mitral annular motion

Mitral inflow

Pulmonary venous flow

Velocity (m/s)

2.0

Velocity (m/s)

CH 36

0.75 65-76(?) years?

yes

Consider permanent mechanical support

no

End-of-life considerations or investigational therapy

yes

Consider permanent mechanical support

no

End-of-life considerations or investigational therapy

Consider permanent mechanical support, unlikely candidate

no

End-of-life considerations or investigational therapy

no Active or recent malignancy? no Diabetes with severe end-organ damage?

yes

no FEV/FVC < 40%?

Consider heart-lung transplantation

no

yes

Nutritional modification

BMI > 35-40

yes

Consider heart-lung transplantation

yes

End-of-life considerations or investigational therapy

FIGURE 54–1  Flowchart depicting evaluation of a patient for cardiac transplantation. BMI, body mass index; FEV, forced expiratory volume; FVC, forced vital capacity; HIV, human immunodeficiency virus; VAD, ventricular assist device.

no BMI < 20 or BMI > 35-40?

Consider permanent mechanical support (VAD) to weight loss

no Irreversible pulmonary hypertension?

no

End-of-life considerations or investigational therapy

no Other comorbid conditions present? (cirrhosis, vascular disease, addiction, hepatitis C, HIV, social or psychiatric disorders)

yes

Individual transplant term decisions

no Determine transplant status and immunological status

acceptable

List for transplant

at risk for a poor outcome without transplantation; however, they often manifest signs and symptoms of end-organ failure of the pulmonary, hepatic, and renal systems, which may signal an ominous prognosis even with a transplant procedure. Each patient must then undergo an extensive medical and psychosocial evaluation by the transplantation team to detect contraindications to transplantation and to further determine prognosis, the urgency of transplantation, and immunological status. There are a number of relative contraindications to heart transplantation; one of the most debated and variable among centers is the upper age limit for consideration. In general, patients older than 65 years are ineligible; more often, such patients undergo high-risk reparative surgery, implantation of permanent cardiac assist devices, or investigational therapies, such as cell transplantation, or they may receive hearts from an alternative list of less-than-optimal donors.16 However, one heart transplantation guideline indicated that the maximum age for eligibility could be as high as 70 years;

therefore, individual centers must determine their own age cutoff.17,18 The presence of an active or recent malignancy or of diabetes with severe end-organ damage limits life expectancy after transplantation, and these are common reasons why potential recipients are ineligible. Significant lung disease complicates postoperative management and precludes the possibility of normal physical functioning; extremes of weight, as measured by body mass index, have also been shown to worsen posttransplantation prognosis.4 Patients with advanced heart failure and renal dysfunction are generally ineligible for heart transplantation because abnormal renal function increases morbidity after transplantation. Thus, it is important to clearly distinguish patients with potentially reversible renal failure from patients in whom renal dysfunction is associated with advanced, irreversible end-stage renal disease. At many transplantation centers, combined heart-kidney transplantation procedures are performed in selected patients.19,20

Management of the Patient Waiting for Cardiac Transplantation In the United States, solid organ transplantation is regulated, audited, and facilitated by the government. The United Network for Organ Sharing (UNOS) is the national organization

that maintains organ transplant waiting lists and allocates 789 identified donor organs; it is organized by regions throughout the country and integrated closely with local organ procurement organizations. Donor hearts are assigned to recipients according to a priority status that is standardized nationally. The priority status is based on the recipient’s level of medical urgency, blood type, body size, and duration of time at a par- CH 54 ticular status level. Patients awaiting heart transplantation are assigned a risk status according to the level of medical support they require. Patients who can be maintained safely and successfully outside the hospital are assigned the status of lowest priority, status 2. Intermediate priority is given to patients who require hospitalization and some continuous inotropic support or who require ongoing VAD therapy (status 1B). The highest priority (status 1A) is assigned to patients who require high-dose, continuous, inotropic infusions or mechanical support, such as an intra-aortic balloon pump (IABP), ventilator, or VAD therapy. Such critically ill patients must be located in an intensive care unit and undergoing continuous hemodynamic monitoring with SwanGanz catheters. Patients with VADs in place who are waiting for transplantation are given an automatic 30-day status 1A listing, with the timing at the discretion of the center. Thereafter, if the function of the VAD is normal, the patient is reassigned to status 1B. Donor hearts are offered geographically (by the location of the donor) and sequentially (to patients with the highest priority and the appropriate blood type). This process has been facilitated by a computerized system that requires transplantation teams to have online access at all times. Nevertheless, speed and timing are critical aspects of optimal donor allocation, because potential donors often exist in an unstable hemodynamic environment that may affect the viability of the donor heart. In addition, transportation of donor hearts is generally limited by a “cold ischemic” time (the duration of organ viability between harvest and implantation) of approximately 4 hours. Pretransplantation waiting times in the 11 UNOS donor regions vary considerably, as do the challenges to individual transplantation teams in managing waiting recipients throughout the United States. The ability of potential recipients to be listed for and receive an organ transplant is influenced by a number of different factors, including candidate gender, size and blood group, presensitization status, source of health insurance or lack thereof, type of cardiac disease, proximity to a transplantation center, and even the number of other transplantation centers in the region. Information about these and many other parameters of the United States transplantation program are available to the public on a variety of websites, including the official UNOS website (http://www. unos.org/), on which site-specific data may also be compared nationally or by city or region. Since about 2000, an increasing number of heart transplant recipients have been listed and undergone transplantation as status 1A or 1B, in comparison with the less urgent status of years past.26 This fact probably reflects the increasing use of VADs as a bridging method in desperately ill patients before transplantation; earlier, similar patients would have died. Mechanical support devices often allow patients to be managed successfully as outpatients while they await transplantation, but the implantation of the device qualifies the recipient to at least a status 1B or more urgent. There is considerable debate about the outcome of patients with VADs, in comparison with patients who undergo transplantation without a prior VAD, with strong arguments on both sides.27 Nevertheless, the available data from the Organ Procurement and Transplantation Network (OPTN) and from the Scientific Registry of Transplant Recipients (SRTR) website (www.ustransplant.org) suggest that overall survival is no different for patients who undergo transplantation as status 1A, 1B, or 2, as illustrated in Figure 54-2. Cardiac Transplantation

Pulmonary arterial hypertension—whether accompanied by a pulmonary vascular resistance of greater than 6 Wood units that cannot be reduced by medical therapy or occurring after the placement of a ventricular assist device (VAD)—is considered an absolute contraindication to cardiac transplantation. In the setting of fixed pulmonary hypertension, the donor right ventricle often fails, which in many cases leads to early postoperative mortality.21 In some centers, individual patients with irreversible pulmonary pressures may be considered for a combined heart-lung transplantation procedure. Other comorbid conditions may negatively affect a transplantation team’s decision to further consider a potential recipient; these conditions include hepatitis C or cirrhosis, peripheral or cerebral vascular disease, advanced neuropathy, human immunodeficiency virus (HIV) status, addictions to alcohol or illicit drugs, and social or psychiatric disorders. Appropriate counseling of the patient who is ineligible for heart transplantation should include end-of-life preparation and discussions about possible investigational approaches.22 Each patient undergoes immunological evaluation, which is increasingly sophisticated, to determine ABO blood type; antibody screening; testing for panel reactive antibody (PRA); and human leukocyte antigen (HLA) typing. The presence and levels of anti-HLA antibodies is determined by cytotoxic testing in which the recipient’s serum is incubated with lymphocytes from 30 to 60 individuals that represent a wide range of HLA antigens. The PRA value is expressed as a percentage of cell panel members that undergo cytolysis and is considered positive if more than 10% of the cell panel members undergo cytolysis. The PRA test can identify the presence of circulating anti-HLA antibody but not the specificity or strength of antibody. Enzyme-linked immunosorbent assay (ELISA) and flow cytometry can also determine PRA and are more sensitive than the cytotoxic test.23 The most common cause of sensitization, or elevated PRA levels, is pregnancy; however, sensitization can also occur with transfusions, prior transplantation, or insertion of a VAD. Patients with a PRA exceeding 10% usually must undergo prospective crossmatching in order to identify a prospective donor. This involves testing the recipient’s serum with donor cells, in the presence of complement, to see whether cytotoxicity occurs. Cell destruction portends an unacceptably increased potential for either acute rejection or more chronic, recurrent rejections. Highly sensitized patients—those with high circulating levels of preformed antibodies—often have to wait long periods before a suitable donor can be found. Newer and more sensitive immunological techniques have further quantified the type and number of circulating antibodies in patients waiting for transplantation and have challenged transplantation teams in knowing which potential donors are acceptable. Moreover, prospective crossmatching techniques can be done only for donors and recipients in a single geographical region, and teams must increasingly travel outside a region for donors; this makes it difficult to obtain donor organs for their sensitized waiting patients. Virtual crossmatching methods are now being used with some success, in which flow cytometry–based, single-antigen bead assays enable the clear identification of antibody specificities. Prospective donors with these antigens can be avoided, and a compatible donor can be selected without the need for prospective crossmatching. This increases the number of donor matches outside the geographical area of the local organ procurement organization.24,25

790 100 90 80

CH 54

70 60 50 40 30 20 10 0

Status 1A

Status 1B 1 year

3 year

Status 2 5 year

FIGURE 54–2  Percentages of patients surviving 1, 3, and 5 years after heart transplantation, in the United States, according to listing status. (Adapted from the information on the Scientific Registry of Transplant Recipients website, National Transplant Statistics [http://www.ustransplant.org]; accessed March 14, 2010.)

Patients waiting for transplantation must be regularly reevaluated for the possibility of worsening status, which would necessitate a change in priority; the development of a new comorbid condition that would preclude transplantation; or significant clinical improvement that would warrant a reconsideration of the listing. An analysis of the OPTN/ SRTR data suggests that the overall death rate among patients waiting for heart transplantation has fallen from 220 to 142 patients per 1000 patient-years at risk.26 In addition, all transplantation teams acknowledge that some patients are removed from the waiting list each year because of marked clinical improvement, despite the great care in patient selection.28

THE CARDIAC TRANSPLANTATION PROCEDURE The Cardiac Donor In view of increasing organ demand, efficacious donor management and meticulous selection are crucial in maintaining excellent transplantation outcomes. Organ procurement representatives have become highly skilled in the rapid but thorough evaluation of potential donors, often screening for multiple organ harvests from a single donor. Obviously, any medical history about the donor is crucial, including any relevant cardiovascular disorders before brain death. All donors are screened for communicable diseases, including viral disorders such as hepatitis and HIV infection. In contrast to blood bank donation, donors with behavioral risk factors are not barred from contributing to the organ supply. Accordingly, clinicians have increasingly debated the risk associated with transplantation and how much of the donor-associated risk should be conveyed to the potential recipient.29 Specific information that is relevant for the assessment of cardiac donor suitability also includes the presence or absence of thoracic trauma, donor hemodynamic stability, pressor and inotropic requirements, duration of cardiac arrest, the need for cardiopulmonary resuscitation, and number of hypotensive episodes and the method by which hypotension was managed. Echocardiography is an invaluable screening method to evaluate potential donors. Some potential donors undergo hemodynamic deterioration caused by brain death, which

necessitates inotropic or pressor infusions and substantial fluid administration, with subsequent derangements in electrolytes and hemoglobin concentration. The resultant cardiovascular instability leads to suboptimal condition of some donor hearts and has compounded the problem of donor shortage. To increase the donor yield, recommendations have been published to improve the evaluation and successful use of potential cardiac donors.6,30 The acceptable “cold ischemia” time for cardiac transplantation is approximately 4 hours. Prolonged ischemic time has been shown to be a significant risk factor for mortality after cardiac transplantation, especially when coupled with other risk factors, such as older donor age. In the first two decades of heart transplantation, the upper limit of donor age was 35 years, but older donors are now used frequently; an age up to 60 years is considered safe by most centers.31 It has become quite standard to perform cardiac catheterization on the older donor to further clarify the integrity of the coronary circulation. The final decision to accept a heart for transplantation is made at the time of harvesting, after direct examination of the heart for myocardial infarction, trauma, coronary calcification, left ventricular hypertrophy, or dilatation. The harvesting team communicates the decision to the recipient hospital’s transplantation team, so that the recipient may be prepared for surgery. One of the main problems thought to be responsible for early graft failure after transplantation is inadequate myocardial protection during prolonged ischemic transport.1,32,33 Current myocardial preservation techniques allow interventions to be made during five different phases of the transplantation procedure: donor cardiovascular management; protection during explantation; protection during transportation to the recipient center; protection during implantation; and protection during the immediate reperfusion period.34,35 Optimal protection of donor hearts will, it is hoped, ultimately expand the potential donor pool and enhance early graft function. Moreover, endothelial injury that occurs during organ procurement, preservation, and reperfusion, as well as ongoing injury during the life span of the cardiac allograft, results in endothelial activation.36 If protection strategies can successfully reduce ischemia-reperfusion damage, long-term heart transplantation outcomes may be improved by the protective effects on endothelial cells, which would reduce the subsequent development of cardiac allograft vasculopathy (CAV). This goal has spurred the development of new devices that are designed to further protect the harvested heart during transportation by continuous bloodless circulation or autologous blood-perfused systems.32

Surgical Considerations The two most common surgical approaches for the implantation of the donor heart are the biatrial and bicaval anastomoses (Figure 54-3). The biatrial anastomosis technique has long had a reputation for being simple, safe, and reproducible; four suture lines are made in the left atrium, pulmonary artery, aorta, and right atrium. The bicaval anastomosis technique was introduced in the early 1990s with the intentions to reduce right atrial size, to minimize distortion of the recipient heart, to preserve atrial conduction pathways, and to decrease tricuspid regurgitation. This alternative procedure entails five anastomoses: left atrium, pulmonary artery, aorta, inferior vena cava, and superior vena cava. Although there has been no prospective trial to establish the superiority of either technique, the bicaval technique is now performed more often in the United States, primarily because it appears to decrease the need for permanent pacemakers in transplant recipients.37-39 Some surgeons have become increasingly interested in techniques to minimize subsequent tricuspid regurgitation and have described tricuspid annuloplasty performed simultaneously with the transplantation surgery.40

791

FIGURE 54–3  Surgical techniques for cardiac transplantation. A, Standard Shumway (biatrial) technique of orthotopic heart transplantation. B, Bicaval technique of orthotopic heart transplantation. (Modified from Al Khaldi A, Robbins RC. New directions in cardiac transplantation. Annu Rev Med 2006;57:455)

CH 54

Many transplantation candidates have had pacemaker or cardiac defibrillator devices implanted during the years leading up to their need for transplantation. These devices are typically removed surgically at the end of the transplantation operation, after the chest has been closed. Likewise, previous heart surgery—most commonly, coronary artery bypass graft procedures—lengthens the time it takes to prepare the recipient to receive the donor heart and increases the risk of bleeding during and after surgery. Just as the age at the time of transplantation has increased since 2000, so too has the number of patients who have undergone previous heart surgery. Of most importance is that the number of patients about to undergo transplantation with VADs in place has steadily increased, and so transplantation procedures are riskier and result in more bleeding.41-46 The most common reason for failure to wean a heart transplant recipient from cardiopulmonary bypass is right-sided heart failure, evidenced by a low cardiac output despite a rising central venous pressure. In the surgical field, the right heart chambers can be observed to dilate and contract poorly. Intraoperative transesophageal echocardiography (TEE) displays a dilated, poorly contracting right ventricle and an underfilled, vigorously contracting left ventricle. Right ventricular function may be enhanced with inotropic agents and pulmonary vasodilators, but the prognostic importance of preoperative pulmonary vascular resistance becomes obvious in these first few hours after surgery.47,48

EARLY POSTOPERATIVE MANAGEMENT Cardiovascular Issues In general, the management of the heart transplant recipient early after surgery does not differ substantially from that after other open-heart procedures, although the transplant recipient is generally debilitated after suffering severe heart failure for weeks or months before surgery. Cardiac transplant recipients often go into surgery with profoundly disturbed hemodynamics and significant renal insufficiency. Postoperative management has to be undertaken with close scrutiny of the urine output and renal function, because a rising creatinine level may necessitate a change in the immunosuppressive regimen. The resultant fluid overload may serve to further overdistend a struggling right ventricle. Many patients manifest generalized edema within the first week after surgery; however, it generally responds to intravenous diuretics. Vasomotor alterations of the peripheral vasculature that result in tissue edema contribute to this occurrence. Because the donor heart is denervated after surgical implantation, bradycardia is a frequent problem, and a direct-acting β-agonist drug should be available. Temporary pacing leads

B are necessary for all recipients, because most are dependent on external pacemakers for a number of days after surgery; as many as 10% to 15% of transplant recipients require a permanent pacemaker.46 Cardiac transplant recipients typically need chronotropic and inotropic support for a few days in the intensive care unit, after which time the infusions are weaned as tolerated. Many centers use isoproterenol for this purpose because of its lack of vasoconstrictive effects on the pulmonary vasculature. Inhaled agents have been used to achieve selective pulmonary vasodilation in cardiac transplant recipients, especially those with preoperative pulmonary hypertension. Inhaled nitric oxide is a potent vasodilator that has a selective effect on the pulmonary vasculature because of its rapid breakdown in the lung.47 Administration of nitric oxide in heart transplant recipients with pulmonary hypertension has been shown to reduce pulmonary vascular resistance and improve right ventricular function. Iloprost, a carbacyclin analogue of prostaglandin I2, can be aerosolized and has been administered in an inhaled form to treat severe pulmonary hypertension. The inhaled agents, delivered via the ventilator, are initiated in the operating room and continued until right ventricular function has stabilized.

Immunosuppression Cardiac transplantation centers throughout the world have individual approaches to the management of immunomodulation for transplant recipients so that the donor heart is not rejected. All centers adhere to the principle that no patient undergoing heart transplantation is at low risk for rejection. Instead, it is more appropriate to stratify patients as those at average risk and those at high risk for subsequent rejection. Before transplantation surgery, patients at high risk for rejection include those with preformed antibodies (e.g., sensitized patients), usually secondary to previous surgery that necessitated transfusions; pregnant patients; patients waiting on mechanical circulatory assist devices; and, possibly, African American patients.43 In addition, it is useful to characterize patients as being at higher risk of developing important comorbid conditions after transplantation, including infection, acute renal failure, or worsening diabetes, because an immunosuppressive regimen may have to be modified accordingly. After transplantation, a risk profile may be additionally tailored according to the retrospective crossmatch information and cytomegalovirus status of the donor and recipient. An immunosuppression strategy is thus developed for each patient on the basis of their risk for rejection and their risk for developing important complications of the immunosuppressive drug therapy.1,49-52 Nevertheless, most immunosuppressive regimens begin with the simultaneous use of three classes of drugs: glucocorticoids, calcineurin inhibitors, and antiproliferative agents. In a subset of patients, transplantation teams

Cardiac Transplantation

A

792 administer a variety of drugs for induction therapy, with the idea to rapidly enhance immune tolerance. Induction Therapy in the Perioperative Period Induction therapy is a heterogeneous application of perioperative antibody drugs used in combination with a foundational CH 54 immunosuppressive regimen in solid-organ transplantation. The ultimate aim of induction is to inhibit only the T cells that respond to donor antigen. The aim of induction treatment is for the recipient to achieve immunological unresponsiveness to the transplant in the presence of a fully functioning immune system (donor-specific tolerance). Both polyclonal and monoclonal antibodies have been used for this form of therapy; their use depends on the institution and the country. Induction therapy is currently used in approximately 40% of heart transplant recipients.53-55 Theoretically, induction agents should reduce the overall rate of rejection, but their primary benefit currently seems to be the delay of cellular rejection in the first 4 to 8 weeks of the early postoperative period, when renal dysfunction is most worrisome. Induction therapy may allow the less aggressive use of the calcineurin inhibitors, which would spare renal function initially, during the most vulnerable period. Drugs used for induction include antithymocyte globulins (polyclonal antibodies) and the anti-CD3 antibody OKT3 and the interleukin-2 receptor antagonists daclizumab and basiliximab (monoclonal agents). OKT3 was widely used as induction in the past, but it has virtually vanished as an option because of the subsequent increased rejection rates and occurrence of lymphomas.56 The antithymocyte globulins are currently used more commonly for the first 3 to 7 or even 14 days after transplantation, despite a paucity of efficacy data for the population of heart transplant recipients. The use of basiliximab has been explored in three trials: one in which the drug was compared with OKT3 induction57 and two in which basiliximab was compared with placebo in a randomized design.58,59 Although basiliximab was less toxic than OKT3, it did not alter outcome with regard to rejection, infection, or survival. In comparison with placebo, a significant delay in rejection occurred with basiliximab, but rates of late rejection may have increased. Basiliximab was found to be noninferior to rabbit antithymocyte globulin for the prevention of acute rejection in a trial of 35 patients.60 Da­clizumab, in comparison with no induction, reduced rejection without an attendant increase in mortality.61 Thus, there may be some rationale for administering the induction agents to patients at high risk (e.g., those with preformed antibodies, renal dysfunction, or a worrisome retrospective crossmatch), but there are no compelling data as yet in the population of heart transplant recipients, and they are the subjects of considerable controversy.53,62,63 Maintenance Immunosuppression As mentioned previously, immunosuppressive regimens begin with the simultaneous use of three classes of drugs: glucocorticoids, calcineurin inhibitors, and antiproliferative agents. In the immediate postoperative period, they are given parenterally, with a quick transition to oral formulations. Corticosteroids are nonspecific anti-inflammatory agents that work primarily by lymphocyte depletion. Patients receive high doses of initially intravenous and then oral steroids that are gradually tapered over the next 6 months; the goal is often to withdraw steroid therapy completely. At many centers, steroids are given several hours before the transplantation surgery. Side effects include cushingoid appearance, hypertension, dyslipidemia, weight gain with central obesity, peptic ulcer formation and gastrointestinal bleeding, pancreatitis, personality changes, cataract formation, hyperglycemia progressing to steroid-induced diabetes, and osteoporosis with avascular necrosis of bone. The well-appreciated adverse

profile of the corticosteroids has prompted the development of a number of innovative strategies to eliminate them as early as possible after the transplantation surgery. Corticosteroids are also usually the drug of first choice to treat acute rejection.64,65 There are two calcineurin inhibitors: cyclosporine and tacrolimus. Their main mechanism of action involves binding to specific proteins to form complexes that block the action of calcineurin, a key participant in T-cell activation. The calcineurin inhibitors serve to block the signal transduction pathways responsible for T- and B-cell activation and therefore act specifically on the immune system and do not affect other rapidly proliferating cells. Critical and often limiting adverse effects include nephrotoxicity, in as many as 40% to 70% of patients, and hypertension with the development of left ventricular hypertrophy; both drugs cause approximately equivalent incidences of these untoward events.64,66 Hirsutism, gingival hyperplasia, and hyperlipidemia are more frequent with cyclosporine, and diabetes and neuropathy are more frequent with tacrolimus.60 The incidences of deep venous thrombosis, tremor, headache, convulsions, and paresthesias of the limbs are also increased with both drugs.64,65 There are target therapeutic levels for both drugs; these goals are also adjusted over the subsequent months and years after transplantation. Therapeutic levels have been typically calculated with trough blood samples, but it has been shown that cyclosporine concentration 2 hours after administration (C2) is a more accurate predictor of total cyclosporine exposure.67 It remains to be demonstrated whether the short- or long-term efficacy of cyclosporine in heart transplant will be further improved by monitoring the 2-hour cyclosporine concentration. In the United States, tacrolimus is now available in generic formulations; therefore, this drug tends to be the calcineurin inhibitor of choice in most centers.68,69 As discussed later, progressive renal insufficiency is a major limitation of the calcineurin inhibitors, and investigators continue to explore methods to minimize their use or withdraw it altogether.62,66 Antiproliferative agents either directly or indirectly inhibit the expansion of alloactivated T- and B-cell clones. In this class, azathioprine was the earliest agent used, and it served as the mainstay of immunosuppression even before the routine use of cyclosporine. In the 2000s, mycophenolate mofetil has replaced azathioprine as the first-line antiproliferative drug; several randomized trials have demonstrated its ­superiority to azathioprine.70-73 Mycophenolate mofetil is hydrolyzed to mycophenolic acid, which inhibits de novo purine syntheses. The major adverse effect of both azathioprine and mycophenolate mofetil is leukopenia; the use of mycophenolate mofetil can be limited by debilitating diarrhea or nausea. It is likely that the combination of myco­phenolate mofetil and tacrolimus potentiates their individual adverse effects. Sirolimus (often called rapamycin) and everolimus are two newer agents that block activation of T cells after autocrine stimulation by interleukin-2. They also are known to inhibit proliferation of endothelial cells and fibroblasts. Their action complements that of calcineurin inhibitors, and both sirolimus and everolimus have been used as maintenance immunosuppressive agents, as alternatives to standard immunosuppressive agents, and as rescue drugs for rejection. Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been shown to slow the progression of CAV with established disease,74-76 and everolimus has been demonstrated to reduce both acute rejection and CAV.77 In one randomized trial, sirolimus, in comparison with azathioprine, when added to cyclosporine and steroids, decreased by half the number of patients with acute rejection, which resulted in less subsequent development of CAV.72,73 Because the drugs inhibit the proliferation of fibroblasts, they may cause

Other Potential Perioperative Management Issues In addition to the common postoperative problems encountered after heart surgery, the transplant recipient is frequently debilitated and may be malnourished, particularly if he or she has not been supported by a VAD. Issues concerning exercise rehabilitation and nutrition can be time consuming for the transplantation team and challenging for the patient and family. Depression in patients with chronic heart failure is a regular occurrence and is not immediately alleviated by the transplantation procedure.81-83 In addition, marked emotional lability is common in recipients and is aggravated by the high-dose steroids used. As a result, successful heart transplantation teams must focus on more than the physical needs of the new transplant recipient. On occasion, the stress of the wait for transplantation often depletes the family of financial resources and emotional resiliency. On the other hand, patients are often rehabilitated much faster if they were allowed time to recover from the heart failure syndrome by the use of VAD support before receiving the transplant. It is critical that a transplantation center have dedicated physical therapists, nutritionists, and social workers or psychologists who can act in concert to address these noncardiovascular issues.

CHRONIC MANAGEMENT OF THE CARDIAC TRANSPLANT RECIPIENT Rejection Rejection involves cell- or antibody-mediated cardiac injury that results from the recognition of the cardiac allograft as nonself. This process is categorized into three major types of rejection, according to histological and immunological criteria: hyperacute, acute, and chronic.49,84-87 Hyperacute rejection results when an abrupt loss of allograft function occurs within minutes to hours after circulation is reestablished in the donor heart; it is rare in modern-day transplantation. The phenomenon is mediated by preexisting antibodies to allogeneic antigens on the vascular endothelial cells of the donor organ, which is now avoided with current HLA typing techniques. These antibodies fix complement that promotes

intravascular thrombosis. Subsequently, the graft vasculature 793 is occluded rapidly, and swift and overwhelming failure of the cardiac graft occurs. Acute cellular rejection or cell-mediated rejection is a mononuclear inflammatory response, predominantly lymphocytic, that is directed against the donor heart, most commonly occurs from the first week to several years after CH 54 transplantation, and occurs in up to 40% of patients during the first year after surgery. The key event in both the initiation and the coordination of the rejection response is T-cell activation, moderated by interleukin-2, a cytokine. Interleukin-2 is produced by CD4 cells and, to a lesser extent, by CD8 cells and exerts both an autocrine and a paracrine response. Unlike renal and liver transplants, cardiac transplants have no reliable serological markers for rejection. Therefore, the endomyocardial biopsy remains the “gold standard” for the diagnosis of acute rejection. Biopsy is performed via a transjugular approach weekly and then every other week for several months; monthly biopsy continues for 6 to 12 months in many programs and for years thereafter in some. Cell-mediated rejection is graded according to a universally agreed-upon system that is periodically reviewed (Table 54-1).88 Risk factors for early rejection include younger recipient age, female gender, female donor, cytomegalovirus-positive serological status, prior infections, African American recipient race, and number of HLA mismatches.43,89 Of most importance is that patients who fail to take or tolerate their immunosuppressant drugs, especially early in the postoperative course, are at very high risk for severe or recurrent cellular rejection. The occurrence of one or more episodes of treated rejections during the first year is a risk factor for both 5-year mortality and development of transplant coronary disease.90 Likewise, treatment for acute rejection in the first 6 months after transplantation contributes to a slower overall rehabilitation of the patient. The aggressiveness of treatment for cell-mediated rejection depends on the biopsy grade, clinical correlation, patient risk factors, rejection history, length of time after transplantation, and whether target levels of the immunosuppressant drugs are achieved. For example, an asymptomatic, early moderate rejection in a patient soon after transplantation who has achieved at least target levels of immunosuppressants or who has one or more risk factors for early rejection would be treated more aggressively than a patient at low risk for rejection with no history of cell-mediated rejection. Another form of acute rejection is acute humoral rejection, or antibody-mediated rejection (AMR), which occurs days to weeks after transplantation and is initiated by antibodies rather than by T cells. The alloantibodies are directed against donor HLA or endothelial cell antigens. AMR is a serious complication after heart transplantation and manifests as graft dysfunction or hemodynamic abnormalities in the absence of the appearance of cellular rejection on biopsy samples. AMR is now recognized as a distinct clinical entity, and strict histopathological and immunological criteria for its diagnosis have been established (Table 54-2).88,91 Further testing, including immunofluorescent staining of specially prepared myocardial tissue, is often necessary to elucidate the presence of AMR and is an important consideration in the evaluation of the transplant recipient with left ventricular dysfunction. The pathological markers of AMR identifiable in endomyocardial biopsy tissue include deposits of immunoglobulin M, immunoglobulin G, or complement in the microvasculature or myocytes. Antibodies with specificity for non-HLA antigens on the graft may also be present in the circulation, and their presence should support the diagnosis of AMR. Patients at greatest risk for AMR are women, patients with a high PRA screen value, and patients with a positive crossmatch. It is estimated that significant AMR occurs in Cardiac Transplantation

significant difficulties with wound healing, and most centers do not use them as initial therapy immediately after the transplantation surgery. The drugs have also been associated with the development of significant pericardial effusions. Sirolimus has been increasingly utilized to replace the calcineurin inhibitors as a strategy to improve renal dysfunction or to reverse left ventricular hypertrophy.66,78,79 The long-standing use of the maintenance combination of cyclosporine, azathioprine, and steroids has been challenged in a number of trials. Tacrolimus plus mycophenolate mofetil and tacrolimus plus sirolimus were compared with cyclosporine plus mycophenolate mofetil in a multicenter trial.71 The overall rate of 1-year survival did not differ among the three regimens, but there was statistically less significant rejection with or without hemodynamic compromise with tacrolimus plus mycophenolate mofetil than with cyclosporine plus mycophenolate mofetil. Overall, patients taking tacrolimus plus mycophenolate mofetil had better renal function and triglyceride levels at 1 year. This trial has been pivotal in promoting tacrolimus as the primary calcineurin inhibitor in use worldwide. Researchers in later studies explored the use of converting a calcineurin inhibitor to sirolimus or everolimus for a renal-sparing effect.80 Unfortunately, many of these newer approaches are being implemented without the benefit of rigorous, controlled trials.

794 TABLE 54–1   Current and Previous Grading Systems for Cell-Mediated Rejection in Heart Transplantation 2004

CH 54

1990

Grade 0 R

No rejection

Grade 0

Grade 1 R, mild

Interstitial and/or perivascular infiltrate with up to one focus of myocyte damage

Grade 1, mild l A: Focal l

B: Diffuse

Grade 2 R, moderate

Two or more foci of infiltrate with associated ­ yocyte damage m

Grade 2, moderate (focal)

Grade 3 R, severe

Diffuse infiltrate with multifocal myocyte damage ± edema ± hemorrhage ± vasculitis

Grade 3, moderate l A: Focal l B: Diffuse Grade 4, severe

No rejection Focal perivascular and/or interstitial infiltrate without myocyte damage Diffuse infiltrate without myocyte damage One focus of infiltrate with associated myocyte ­ amage d Multifocal infiltrate with myocyte damage Diffuse infiltrate with myocyte damage Diffuse, polymorphous infiltrate with extensive ­myocyte damage ± hemorrhage + vasculitis

From Stewart S, Winters GL, Fishbein MC, et al. Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant 2005;24:1710-1720.

TABLE 54–2   Diagnostic Criteria for Antibody-Mediated Rejection Criteria

Finding

Comment

Clinical

Graft dysfunction

Histological

Capillary endothelial changes: swelling, denudation, congestion Macrophages in capillaries Neutrophils in capillaries Interstitial changes: edema and/or hemorrhage

Required Required More severe cases More severe cases

Immunopathological

Immunoglobulin (G,M, and/or A) plus C3d and/or C4d or C1q staining (2 to 2+) in capillaries by immunofluorescence CD68 positivity for macrophages in capillaries and/or C4D staining of ­capillaries with 2 to 3+ intensity by paraffin immunohistochemistry Fibrin in vessels

One of the first two immunopathological criteria is required

Serological

Evidence of anti–human leukocyte antigen class I and/or class II ­antibodies or other anti–donor antibody at time of biopsy

Supports other findings

More severe cases

Adapted from Stewart S, Winters GL, Fishbein MC, et al. Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant 2005;24:1710-1720.

about 7% of patients, but that number may be as high as 20%. Because antibody assays are becoming more precise, AMR will probably be recognized more often, with a correlating need for newer treatment algorithms.84,92,93 Chronic rejection, or late graft failure, is an irreversible, gradual deterioration of graft function that occurs in many allografts months to years after transplantation. Current concepts suggest that donor heart dysfunction in the chronic stages of maintenance immunosuppression is related to chronic rejection, is mediated by antibodies, or is a result of progressive graft loss from ischemia. The last process is characterized by intimal thickening and fibrosis that lead to luminal occlusion of the graft vasculature; it is often referred to as “CAV”, or transplant coronary artery disease. An approach to managing nonspecific graft dysfunction (Figure 54-4) is focused primarily on the diagnosis of AMR, as opposed to the presence of CAV.94 Attention has also focused on noninvasive methods to detect rejection. Gene expression assays have been developed by identifying a number of candidate gene markers from a pool of more than 25,000 genes of interest through the use of gene-chip array technology. Subsequently, realtime polymerase chain reaction (PCR) technologies are used in the peripheral blood to identify a pattern of gene activation that may be correlated with allograft rejection. One such assay is available for clinical use, but it is not yet clear how

the information obtained can be best used in a wide range of transplant recipients.95

Infection Despite the advances in immunosuppressive management, a major untoward consequence remains the occurrence of lifethreatening infections. Infections cause approximately 20% of deaths within the first year after transplantation and continue to be a common cause of morbidity and mortality throughout the recipient’s life. The most common infections in the first month after surgery are nosocomial, bacterial, and fungal infections related to mechanical ventilation, catheters, and the surgical site. Mortality rates are highest for fungal infections, followed by those for protozoal, bacterial, and viral infections. Aspergillus and Candida species account for the most common fungal infections after heart transplantation. In addition, a higher number of infections of any type during the first month after transplantation increases the risk of a subsequent fatal cytomegalovirus infection, a rejection (because immunosuppression frequently has to be decreased in order to treat the infection), or a prolonged hospital stay. Viral infections, especially cytomegalovirus, can enhance immunosuppression, which results in additional opportunistic infections. Accordingly, each heart transplantation team must develop a prophylactic regimen against cytomegalovirus, Pneumocystis

TABLE 54–3   Usual Care and Individual Decisions in

Nonspecific graft dysfunction

Histological features: Lymphocyte infiltration

Absent

Positive CMR

Negative CMR

ISHLT Grade

Consider TCAD

the Management of Patients After Heart ­Transplantation

Histological features: Endothelial and capillary abnormalities Absent

Negative AMR 0

Present

Further testing: Immunoglobulin, complement, CD68, C4d

Treatment

FIGURE 54–4  Diagnostic algorithm for nonspecific graft dysfunction. AMR, antibody-mediated rejection; CMR, cell-mediated rejection; ISHLT, International Society of Heart and Lung Transplantation; TCAD, transplant coronary artery disease. (From Jessup M, Brozena S. State-of-the-art strategies for immunosuppression. Curr Opin Organ Transplant 2007;12:536-42.)

carinii, herpes simplex virus, and species causing oral candidiasis that is to be used during the first 6 to 12 months after transplantation. Prophylactic intravenous ganciclovir or oral valganciclovir is generally given for variable amounts of time in the cytomegalovirus-seronegative recipient of a heart from a cytomegalovirus-seropositive donor. Optimal prophylaxis regimens and timing have not been completely standardized, and some of the decisions to be made about prophylaxis are outlined in Table 54-3.96 The necessity of routine prophylaxis, however, has withstood the test of time. The regimen increases substantially the number of medications taken and potential drug interactions the recipient may experience. Some of the important drug interactions are listed in Table 54-4.64,65,97

Medical Complications and Comorbid ­Conditions The complications after heart transplantation reflect, in part, the premorbid status of the majority of transplant recipients who have vascular disease and other significant medical conditions. After 5 years, more than 90% of recipients have hypertension, at least 80% have hyperlipidemia, and more than 30% of patients have diabetes (Table 54-5).7 Each year after transplantation, a larger number of patients develop clinically significant CAV, which is the major limitation of survival after transplantation. Almost 30% of recipients have CAV by 5 years, and at least half do so at 10 years. Likewise, progressive renal insufficiency is an insidious problem that has been addressed only since about 2007 by substitution protocols to limit the administration of calcineurin inhibitors.78,98 Malignancy The magnitude of overimmunosuppression in many transplant recipients is illustrated by the prediction of a 30% to 40% incidence of neoplasia in transplant recipients since 1980. The risk of fatal malignancy increases progressively in the years after transplantation, and there is a substantially higher risk in immunosuppressed patients than in the normal population. Posttransplantation lymphoproliferative disease and lung cancer are the most common fatal malignancies (Table 54-6).7 Risk factors for malignancy are multifactorial and include impaired immunoregulation, a synergistic effect with other carcinogens such as nicotine or ultraviolet light exposure, and oncogenic causes such as the Epstein-Barr virus and

Individual Decisions

Maintenance Immunosuppression l Corticosteroids l Calcineurin inhibitors l Antiproliferative agents

Wean from prednisone completely? Cyclosporine or tacrolimus? Azathioprine or mycophenolate mofetil? Induction of immunosuppression? l Polyclonal antibodies: ­antithymocyte globulins l Monoclonal antibodies: OKT3, basiliximab, daclizumab

Viral prophylaxis Ganciclovir, acyclovir, ­valacyclovir

Duration of prophylaxis? Drug choice for risk profile?

Fungal prophylaxis l Fluconazole l Trimethoprim/sulfamethoxazole, dapsone, pentamidine

Duration of prophylaxis? Reinstitution during intensified immunosuppression?

Vascular protection Pravastatin, simvastatin

Efficacy of other statins? Role of aspirin? Role of rapamycin and everolimus? Target lipid levels?

Antihypertension therapy l Goal: optimal blood pressure control

First-line drug or drugs of choice?

Surveillance for rejection Endomyocardial biopsy

Role of echocardiography or other noninvasive tools? Role of biomarkers or gene expression assays? How long and how often to perform biopsy? Role of humoral rejection and methods to detect it?

Surveillance for vasculopathy of transplanted heart l Coronary arteriography

Role of noninvasive testing? Role of intravascular ultrasonography? Role of computed tomographic angiography?

Surveillance for malignancy l Annual examination l Chest radiography l Colonoscopy, mammography, other imaging tests* l Dermatological examinations

Role of primary care team versus transplantation team?

l

Positive AMR 1 Treatment

Usual Care

l

l

*Recommended

adult immunization schedule: United States, 2010*. Ann Intern Med. 152:36-39. Screening for breast cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2009;151:716-726. Clinical guideline: screening for ovarian cancer: Recommendations and rationale. Ann Intern Med. 1994;121:141142. Clinical guideline: Part I: Suggested technique for fecal occult blood testing and interpretation in colorectal cancer screening. Ann Intern Med. 1997;126:808-810. Clinical guideline: Part III: Screening for prostate cancer. Ann Intern Med. 997;126:480-484.

papillomavirus. The cumulative amount of immunosuppression is positively correlated with risk of malignancy. The incidences of lymphoproliferative disease, skin and lip cancers, and Kaposi’s sarcoma are particularly high. Malignancies account for 24% of deaths after 5 years. Accordingly, as illustrated in Table 54-4, transplantation teams must ensure that the transplant recipient is adequately screened on a regular basis for the development of cancer.99,100 Diabetes Patients who develop new-onset diabetes mellitus after transplantation are at increased risk for morbidity and mortality. Accumulating evidence suggests that long-term outcomes,

CH 54 Cardiac Transplantation

Present

795

796 TABLE 54–4   Commonly Used Drugs and Potential Drug Interactions with Immunosuppressants

Drug

Potential Interaction

Acyclovir

Increased nephrotoxicity with calcineurin inhibitors

Allopurinol

Increased bone marrow suppression with azathioprine

Amlodipine or felodipine

Increased levels of calcineurin inhibitor

Antacids

Decreased levels of mycophenolate mofetil

Antidepressants

Increased levels of calcineurin inhibitor

Cimetidine

Increased levels of calcineurin inhibitor

Calcineurin inhibitors

Increased levels of mycophenolate mofetil

Clotrimazole

Increased levels of calcineurin inhibitor

Colchicine

Increased toxicity of colchicine

Diltiazem

Increased level of calcineurin inhibitor; increased neurotoxicity

Erythromycin or ­clarithromycin

Increased level of calcineurin inhibitor; ­prolonged QT intervals

Ganciclovir or ­valganciclovir

Increased nephrotoxicity with calcineurin inhibitors; leukopenia

Iron

Decreased levels of mycophenolate mofetil

Ketoconazole

Increased levels of calcineurin inhibitor

Phenobarbital

Decreased levels of calcineurin inhibitor

Phenytoin

Decreased levels of calcineurin inhibitor, increased levels of phenytoin

Primidone

Decreased levels of calcineurin inhibitor

Rifampin

Decreased levels of calcineurin inhibitor

Statin drugs

Increased risk for myopathy/rhabdomyolysis

St. John’s wort

Decreased levels of calcineurin inhibitor levels

Target of rapamycin inhibitors

Increased nephrotoxicity with calcineurin inhibitors

Trimethoprim-­ sulfamethoxazole

Increased nephrotoxicity with calcineurin inhibitors

Verapamil

Increased levels of calcineurin inhibitor

CH 54

including patient survival and graft survival, may be adversely affected. New-onset diabetes is characterized by decreased B-cell insulin secretion and increased insulin resistance secondary to the effects of immunosuppression. Many cases of new-onset diabetes are attributed to the high-dose steroids used early after transplantation surgery, but it is now appreciated that the calcineurin inhibitors play an important role as well. Impaired B-cell function appears to be the primary mechanism underlying the induction of diabetes by calcineurin inhibitors.101,102 The risk factors for the development of diabetes after transplantation include obesity, increased age, family history of diabetes, abnormal glucose tolerance, and African American or Hispanic descent. Changing trends in the demographics of transplant recipients, such as increased age and increased body mass index, suggest that current patients may be at greater risk of new-onset diabetes than were earlier patients. In one study, transplant recipients older than 45 years were 2.9 times more likely to become diabetic after transplantation.102 Higher body mass index increases risk of insulin resistance, and steroids can cause glucose intolerance, insulin resistance,

and frank hyperglycemia. African American patients are more likely to develop new-onset diabetes mellitus regardless of the immunosuppression used, but they are particularly susceptible after treatment with tacrolimus.64,97 Unfortunately, there are very poor data about specific drugs to be used in the management of patients with new-onset diabetes after cardiac transplantation. Hypertension The excess risk of hypertension is related primarily to the use of calcineurin inhibitors, both because of direct effects of the drugs on the kidney and because of the associated renal insufficiency that is also highly prevalent. The incidence of hypertension may be lower with tacrolimus than with cyclosporine.103 Blood pressure elevation in this population is characterized by a disturbed circadian rhythm without the normal nocturnal fall in blood pressure and with a greater 24-hour hypertensive burden. Posttransplantation hypertension is difficult to control and often necessitates a combination of several antihypertensive agents. Renal Insufficiency In a large registry of almost 70,000 recipients of nonrenal solid organ transplants, the risk of developing chronic renal failure was 16% at 10 years.104 Various causes have been postulated for early renal insufficiency associated with calcineurin inhibitors, including renal arteriolar vasoconstriction directly mediated by calcineurin inhibitors, increased levels of endothelin-1 (a potent vasoconstrictor), and decreased nitric oxide production and alterations in the kidney’s ability to adjust to changes in serum tonicity. Until the early 2000s, renal insufficiency, once present, progressed inexorably to renal failure. A number of new trials are in progress to evaluate the effects of substituting an mTOR inhibitor (sirolimus or everolimus) for a calcineurin inhibitor on renal function and on rejection episodes.78,98 Hyperlipidemia Hyperlipidemia occurs as commonly in transplant recipients as in the general population. The concern has been that in many studies, hyperlipidemia has been associated with the development of CAV, cerebrovascular, and peripheral vascular disease, and the attendant morbidity and mortality of these vascular disorders. Typically, total cholesterol, lowdensity lipoprotein (LDL) cholesterol, and triglyceride levels increase by 3 months after transplantation and then generally fall somewhat after the first year. A number of drugs commonly used after transplantation contribute to the hyperlipidemia observed. Corticosteroids may lead to insulin resistance, increased synthesis of free fatty acids, and increased production of very low density lipoprotein. Cyclosporine increases serum LDL cholesterol and binds to the LDL receptor, which decreases its availability to absorb cholesterol from the bloodstream; tacrolimus probably causes less hyperlipidemia. Sirolimus and mycophenolate mofetil also have unfavorable effects on lipid levels. Sirolimus in escalating doses has been shown to result in prominent elevation in triglyceride levels.64,97 Lipid-lowering therapy with any statin or with 3-hydroxy3-methylglutaryl–coenzyme A (HMG-CoA) reductase inhibitor was strongly associated with a marked improvement in 1-year survival in the Heart Transplant Lipid registry.105 In heart transplant recipients, pravastatin and simvastatin have been associated with outcome benefits in survival, severity of rejection, and CAV,43,106 whereas studies in kidney transplantation have not supported this finding. However, no long-term trials or data in this population have demonstrated improved outcomes with lowering LDL cholesterol levels to a specific target with more potent or higher dose statin therapy. Statins are metabolized differently, some by the cytochrome

797

TABLE 54–5   Morbidity After Heart Transplantation for Adults* Within 5 Years

Outcome

Percentage with Known Response

Within 10 Years

Total N with Known Response

Percentage with Known Response

Total N with Known Response

Hypertension

93.8%

8266

98.5%

1586

CH 54

Renal dysfunction

32.6%

8859

38.7%

1829

Cardiac Transplantation

l

Abnormal creatinine level ( 2.5 mg/dL

8.4%

8.2%

l

Chronic dialysis

2.5%

4.9%

Renal transplantation

0.5%

1.2%

Hyperlipidemia

87.1%

9237

93.3%

1890

Diabetes

34.8%

8219

36.7%

1601

Cardiac allograft vasculopathy

31.5%

5944

52.7%

896

*Cumulative prevalence in survivors 5 and 10 years after transplantation (follow-up assessments: April 1994 to June 2006). Modified from Hertz MI, Aurora P, Christie JD, et al. Registry of the International Society for Heart and Lung Transplantation: a quarter century of thoracic transplantation. J Heart Lung Transplant 2008;27:937-942.

TABLE 54–6   Malignancy After Heart Transplantation in Adults Malignancy/Type

1-Year Survivors

5-Year Survivors

10-Year Survivors

No malignancy

20,442 (97.1%)

7780 (84.9%)

1264 (68.1%)

Malignancy (all types combined)

612 (2.9%)

1389 (15.1%)

592 (31.9%)

282 142 132 56

937 127 359 39

360 38 108 126

l l l l

Skin Lymph Other Type not reported

Cumulative prevalence in survivors (follow-up assessments: April 1994 to Jane 2006). From Hertz MI, Aurora P, Christie JD, et al. Registry of the International Society for Heart and Lung Transplantation: a quarter century of thoracic transplantation. J Heart Lung Transplant 2008;27:937-942.

cyproheptadine (CYP) 3A4 and some by CYP2C9, and others are metabolized by a non-CYP mechanism in the liver. Thus, caution must be used in administration of statin drugs beyond the doses used in the randomized trials of simvastatin and pravastatin.97 Transplantation teams must develop a coherent strategy about the goal and target doses of statins in their transplant recipients. Cardiac Allograft Vasculopathy The development of CAV remains the most disheartening long-term complication of heart transplantation; the annual incidence rate is 5% to 10%. The prognosis of heart transplant recipients is largely determined by the occurrence of CAV; after the first postoperative year, CAV becomes increasingly prevalent as a cause of death. CAV can develop as early as 3 months after transplantation and is detected angiographically in 20% of grafts at 1 year and in 40% to 50% at 5 years.107,108 In contrast to eccentric lesions seen in atheromatous disease, CAV results from neointimal proliferation of vascular smooth muscle cells, so that it is a generalized process. Typically, the condition is characterized by concentric narrowing that affects the entire length of the coronary tree, from the epicardial to intramyocardial segments, which leads to rapid tapering, pruning, and obliteration of third-order branch vessels. The majority of affected patients do not experience anginal symptoms because of denervation of coronary arteries. The first clinical manifestation of CAV may include myocardial ischemia and infarction, heart failure, ventricular arrhythmia, or sudden cardiac death.

The causes of CAV are multifactorial. The risk of CAV increases as the number of HLA mismatches and the number and duration of rejection episodes increase. Various nonimmunological factors have been associated with development of CAV, including cytomegalovirus infection of the recipient, donor or recipient factors (e.g., age, gender, pretransplantation diagnosis), and factors related to surgery (ischemiareperfusion injury). Classic risk factors for vascular disease such as smoking, obesity, diabetes, dyslipidemia, and hypertension also increase the risk for CAV. In an effort to detect the development of CAV, transplantation teams must devise an approach to screen for the disease and, when it is found, control its progression. The usefulness of coronary angiography is limited by the fact that CAV produces concentric lesions that affect the distal and small vessels, often before becoming apparent in the main epicardial vessels. Intravascular ultrasonography is currently the most sensitive imaging technique for studying early CAV. Intravascular ultrasonography provides quantitative information about vessel wall structure and lumen dimensions. An increase in intimal thickness of at least 0.5 mm in the first year after transplantation is a reliable indicator of both CAV development and 5-year mortality.109,110 However, the increased invasiveness and cost of intravascular ultrasonography preclude its widespread application. Dobutamine stress echocardiography has high sensitivity (83-95%) and specificity (between 53% and 91%) in comparison with angiographic CAV and even greater specificity than intravascular ultrasonography in

798 detecting disease.111 Most transplantation centers perform

one of these screening tests on an annual basis to assess the risk of new CAV. The only definitive treatment of CAV is a second heart transplantation procedure. Other approaches, such as implantation of coronary stents and angioplasty, may CH 54 have high restenosis rates and are unlikely to be effective because of the diffuse nature of the process.112,113 Another approach to the prevention of CAV is the use of pravastatin and simvastatin. These drugs effectively repress the induction of major histocompatibility complex class II (MHC-II) expression by interferon-γ and thereby inhibit T-cell proliferation. In addition, statins have a direct influence on the expression of genes for growth factors that are essential for the proliferation of smooth muscle cells. Randomized controlled trials have shown that both drugs result in significantly lower cholesterol levels, significantly improved survival rates, significantly fewer severe rejections, and a significantly lower incidence of CAV.110,114 It is not clear whether other statin drugs have the same benefit in this population. Researchers have increasingly examined the efficacy of sirolimus and of everolimus in preventing the development or progression of CAV in heart transplant recipients. The precise role of the two drugs in maintenance immunosuppression has not yet been determined, but they are frequently used and hold the promise of reducing coronary intimal thickening once CAV has been detected.107 New Health Problems Patients waiting for a heart transplant should have an updated review of immunizations, and yearly influenza vaccines should be encouraged thereafter, along with the periodic pneumococcal vaccine.115 Vaccines with live viral particles must be avoided by immunocompromised transplant recipients. In general, a comprehensive visit is scheduled at the anniversary of the transplantation procedure so that annual issues may be reviewed, beyond the typical cardiovascular problems addressed so frequently in the first year. These include thorough skin and eye examinations and recommended screening examinations such as mammography, colonoscopy, and rectal and pelvic examinations, according to guidelines. This is the opportune time to reinforce the necessity of regular physical exercise, maintenance of ideal body weight, abstinence from tobacco, and moderation with alcohol. The annual examination is also the occasion when many transplantation teams look more carefully for the presence of CAV. In many centers, recipients are prescribed daily aspirin to prevent further vascular disease, but no randomized trials have evaluated the benefits of antiplatelet therapy in heart transplant recipients. Likewise, most recipients are given vitamins, stool softeners, iron supplements, and proton pump inhibitors early after surgery, primarily on the basis of empirical findings. These are part of the decisions that must be made on a programmatic basis for the transplant recipient (see Table 54-4). The development of osteoporosis is a major problem in the population of transplant recipients, and vertebral fractures are common and result in marked debilitation; prophylaxis with calcium and vitamin D is usually initiated. At least 50% of patients before transplantation have evidence of osteopenia, and osteoporosis is common among patients with advanced heart failure.116 Glucocorticoids given after transplantation surgery are a major contributor to additional bone loss; most bone loss occurs in the first 6 to 12 months. Depression, a common finding in patients with heart failure, occurs in up to 25% of transplant recipients and can interfere remarkably with a satisfactory recovery. A number of antidepressants may be prescribed, but the potential for adverse drug interactions must be considered (see Table 54-5).

The management of gout may also be difficult because of drug interactions. Colchicine may increase the risk of myoneuropathy, and nonsteroidal anti-inflammatory drugs often cause worsening renal insufficiency and hyperkalemia. Allopurinol and azathioprine administered together can cause life-threatening neutropenia. Thus, transplant recipients must be instructed to discuss any new medicines prescribed to them with the transplantation team before they take these medicines.64,97,117 Physicians outside the transplantation center may be reluctant to care for the heart transplant recipient, which complicates the comprehensive management of these patients. Ideally, primary care physicians could provide a very important and early intervention that might be life-saving. The most common errors made by referring physicians who are unaware of normal transplantation procedures are the prescriptions of new drugs that result in adverse drug interactions (see Table 54-5). Both calcineurin inhibitors are metabolized in the liver by the cytochrome P-450 enzyme system. The activity of this system is influenced by hepatic dysfunction. Inducers of CYP3A4 include amiodarone, rifampin, and phenytoin; these drugs have the potential to lower the levels of calcineurin inhibitors. Agents that inhibit CYP3A4, and also raise levels of the immunosuppression regimen, include antifungals, macrolide antibacterials, calcium channel antagonists, and grapefruit juice.117 Physicians must use a higher index of suspicion when evaluating the possibility of infection in a transplant recipient, who must always be considered an immunocompromised host. Physicians unaccustomed to caring for infection-prone transplant recipients may inadvertently miss an important manifestation of an infectious disease, especially early in the posttransplantation course. Again, communication with the transplantation team should be fostered as a strategy to prevent these and countless other problems.

OUTCOMES AFTER HEART TRANSPLANTATION Survival Figure 54-5 depicts the latest data from the International Society for Heart and Lung Transplantation regarding overall transplantation survival.7 During the first year after transplantation, early causes of death are graft failure, infection, and rejection, with an overall 1-year survival rate of 87%. Interestingly, although worldwide approaches to the management of cardiac transplant recipients are substantially different from center to center, the outcomes are surprisingly similar. The 5-, 10-, and 15-year rates of survival after heart transplantation were very comparable in two centers: one in Nantes, France,100 and one in Utrecht, The Netherlands ­(Figure 54-6).118 Indeed, this phenomenon of similar outcomes despite marked differences in programmatic management may be regarded as a testament to the overall antirejection strategy. Nonspecific graft failure accounted for 41% of deaths during the first 30 days after transplantation, whereas noncytomegalovirus infection was the primary cause of death during the first year. After 5 years, CAV and late graft failure (31% together), malignancy (24%), and noncytomegalovirus infection (10%) were the most prominent causes of death.18,44,119

Functional Outcomes By the first year after transplantation surgery, 90% of surviving patients report no functional limitations, and approximately 35% return to work.120 These statistics may change

HEART TRANSPLANTATION Kaplan-Meier survival (1/1982-6/2006) 100

Half-life = 10.0 years Conditional half-life = 13.0 years

80 Survival (%)

CH 54 60 N=74,267 40 20

N at risk at 22 years: 70

0 0

1

HEART TRANSPLANT SURVIVAL 80 70

2

3

4

5

6

7

8

9 10 11 12 13 14 15 16 17 18 19 20 21 22 Years

the resting heart rate of a recipient is typically 90 to 115 beats per minute. Likewise, β-blockers may further impair exercise response in transplant recipients and should not be first-line therapy for hypertension in this population.

60

FUTURE DIRECTIONS

50 40 30 20 10 0

5 year

10 year Nantes

15 year

Utrecht

FIGURE 54–6  Overall rates of survival 5, 10, and 15 years after heart transplantation in Nantes, France, and Utrecht, The Netherlands. Note that the outcomes in the two countries are similar. (Data from Roussel JC, Baron O, Perigaud C, et al. Outcome of heart transplants 15 to 20 years ago: graft survival, post-transplant morbidity, and risk factors for mortality. J Heart Lung Transplant 2008;27:486-493; and Tjang YS, van der Heijden GJ, Tenderich G, et al. Survival analysis in heart transplantation: results from an analysis of 1290 cases in a single center. Eur J Cardiothorac Surg 2008;33:856-861.)

as the demographics of cardiac transplant recipients evolve. There are numerous challenges for optimal functional outcomes, not the least of which are nonreimbursement for cardiac rehabilitation programs by many third-party payers in the United States and the reluctance of many U.S. employers to hire transplantation survivors. Adapting to life after transplantation involves a variety of pretransplantation factors, including the patient’s duration of illness, personality, intelligence, social support, and financial well-being. The heart transplantation procedure markedly reduces cardiac filling pressures observed in the recipient before transplantation and augments cardiac output. During exercise, maximal cardiac output may be abnormal, as a result of denervation, limited atrial function, decreased myocardial compliance from rejection or ischemic injury, and donorrecipient size mismatch.121 Much of this hemodynamic abnormality may be normalized with regular exercise.122,123 Immediately after surgery, a restrictive hemodynamic pattern is frequently observed that gradually improves over a few days to weeks. Approximately 10% to 15% of recipients develop a chronic restrictive-type response during exercise that may produce fatigue and breathlessness. In the absence of parasympathetic innervation that normally lowers the heart rate,

Heart transplantation is one of multiple competing therapeutic options for treating advanced heart failure, including “destination” or permanent mechanical circulatory support (see Chapter 56). As newer therapies, such as cell transplantation (see Chapter 51) and better permanent mechanical devices, become available, the role of heart transplantation will need to be redefined as the therapy of choice. Moreover, the cost effectiveness of the transplantation procedure will decrease if 40% to 50% of patients require a VAD preoperatively. Organ allocation may need to be reconsidered in this era of rapid HLA typing and virtual crossmatching. An ideal immunosuppressive regimen for cardiac transplantation will prevent cellular rejection, retard the development of CAV, have no nephrotoxicity, and produce negligible morbidity with regard to lymphoproliferative disease and opportunistic infections. The development of renal-sparing strategies in transplant recipients is one of the most significant therapeutic challenges. This and other modifications of the standard regimen must be explored in future trials. Trial networks to investigate some of these newer ideas or therapies must be established to facilitate research in this fragile population. In the United States, there is now an acknowledged secondary subspecialty in medicine specifically for cardiologists who want to acquire expertise in the care of the heart transplant recipient.124 Surgical training has allowed for the increased skill required to manage the wide array of mechanical circulatory support devices used to sustain the patient with advanced heart failure. Mechanisms to fund the prolonged training of these transplantation specialists, and other transplantation personnel, must be found in an increasingly impoverished health care system.

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FIGURE 54–5  Overall survival after heart transplantation among 74,267 first-time recipients; the 10-year survival rate was at least 50%. (From Hertz MI, Aurora P, Christie JD, et al. Registry of the International Society for Heart and Lung Transplantation: a quarter century of thoracic transplantation. J Heart Lung Transplant 2008;27:937-942.)

799

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CH 54

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Tacrolimus versus cyclosporine microemulsion for heart transplant recipients: a meta-analysis. J Heart Lung Transplant, 28, 58–66. 104. Lonze, B. E., Warren, D. S., Stewart, Z. A., et al. (2009). Kidney transplantation in previous heart or lung recipients. Am J Transplant, 9, 578–585. 105. Wu, A. H., Ballantyne, C. M., Short, B. C., et al. (2005). Statin use and risks of death or fatal rejection in the Heart Transplant Lipid Registry. Am J Cardiol, 95, 367–372. 106. Bilchick, K. C., Henrikson, C. A., Skojec, D., et al. (2004). Treatment of hyperlipidemia in cardiac transplant recipients. Am Heart J, 148, 200–210. 107. Delgado, J. F., Manito, N., Segovia, J., et al. (2009). The use of proliferation signal inhibitors in the prevention and treatment of allograft vasculopathy in heart transplantation. Transplant Rev, 23, 69–79. 108. Schmauss, D., Weis, M., Schmauss, D., et al. (2008). Cardiac allograft vasculopathy: recent developments. Circulation, 117, 2131–2141. 109. Tuzcu, E. M., Kapadia, S. R., Sachar, R., et al. (2005). Intravascular ultrasound evidence of angiographically silent progression in coronary atherosclerosis predicts long-term morbidity and mortality after cardiac transplantation. J Am Coll Cardiol, 45, 1538– 1542. 110. Kobashigawa, J. A., Tobis, J. M., Starling, R. C., et al. (2005). Multicenter intravascular ultrasound validation study among heart transplant recipients: outcomes after five years. J Am Coll Cardiol, 45, 1532–1537. 111. Bacal, F., Moreira, L., Souza, G., et al. (2004). Dobutamine stress echocardiography predicts cardiac events or death in asymptomatic patients long-term after heart transplantation: 4-year prospective evaluation. J Heart Lung Transplant, 23, 1238–1244. 112. Bhama, J. K., Nguyen, D. Q., Scolieri, S., et al. (2009). Surgical revascularization for cardiac allograft vasculopathy: is it still an option? J Thorac Cardiovasc Surg, 137, 1488–1492. 113. Gupta, A., Mancini, D., Kirtane, A. J., et al. (2009). Value of drug-eluting stents in cardiac transplant recipients. Am J Cardiol, 103, 659–662. 114. Kobashigawa, J. A. (2006). Cardiac allograft vasculopathy in heart transplant patients: pathologic and clinical aspects for angioplasty/stenting. J Am Coll Cardiol, 48, 462–463. 115. Magnani, G., Falchetti, E., Pollini, G., et al. (2005). Safety and efficacy of two types of influenza vaccination in heart transplant recipients: a prospective randomised controlled study. J Heart Lung Transplant, 24, 588–592. 116. Ebeling, P. R. (2009). Approach to the patient with transplantation-related bone loss. J Clin Endocrinol Metab, 94, 1483–1490. 117. Page, R. L., II, Miller, G. G., & Lindenfeld, J. (2005). Drug therapy in the heart transplant recipient: part IV: drug-drug interactions. Circulation, 111, 230–239. 118. Tjang, Y. S., van der Heijden, G. J., Tenderich, G., et al. (2008). Survival analysis in heart transplantation: results from an analysis of 1290 cases in a single center. Eur J Cardiothorac Surg, 33, 856–861. 119. Vaseghi, M., Lellouche, N., Ritter, H., et al. (2009). Mode and mechanisms of death after orthotopic heart transplantation. Heart Rhythm, 6, 503–509. 120. Grady, K. L., Naftel, D. C., Young, J. B., et al. (2007). Patterns and predictors of physical functional disability at 5 to 10 years after heart transplantation. J Heart Lung Transplant, 26, 1182–1191. 121. Scott, J. M., Esch, B. T., Haykowsky, M. J., et al. (2009). Cardiovascular responses to incremental and sustained submaximal exercise in heart transplant recipients. Am J Physiol Heart Circ Physiol, 296, H350–H358. 122. Roten, L., Schmid, J. P., Merz, F., et al. (2009). Diastolic dysfunction of the cardiac allograft and maximal exercise capacity. J Heart Lung Transplant, 28, 434–439. 123. Haykowsky, M., Taylor, D., Kim, D., et al. (2009). Exercise training improves aerobic capacity and skeletal muscle function in heart transplant recipients. Am J Transplant, 9, 734–739. 124. Konstam, M. A., Jessup, M., Francis, G. S., et al. (2009). Advanced heart failure and transplant cardiology: a subspecialty is born. J Am Coll Cardiol, 53, 834–836.

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CH 54 Cardiac Transplantation

  73. Eisen, H. J., Kobashigawa, J., Keogh, A., et al. (2005). Three-year results of a randomized, double-blind, controlled trial of mycophenolate mofetil versus azathioprine in cardiac transplant recipients. J Heart Lung Transplant, 24, 517–525.   74. Raichlin, E., Chandrasekaran, K., Kremers, W. K., et al. (2008). Sirolimus as primary immunosuppressant reduces left ventricular mass and improves diastolic function of the cardiac allograft. Transplantation, 86, 1395–1400.   75. Mudge, G. H., Jr. (2007). Sirolimus and cardiac transplantation: is it the “magic bullet”?Circulation, 116, 2666–2668.   76. Raichlin, E., Bae, J. H., Khalpey, Z., et al. (2007). Conversion to sirolimus as primary immunosuppression attenuates the progression of allograft vasculopathy after cardiac transplantation. Circulation, 116, 2726–2733.   77. Sánchez-Fructuoso, A. I. (2008). Everolimus: an update on the mechanism of action, pharmacokinetics and recent clinical trials. Expert Opin Drug Metab Toxicol, 4, 807–819.   78. Groetzner, J., Kaczmarek, I., Schulz, U., et al. (2009). Mycophenolate and sirolimus as calcineurin inhibitor-free immunosuppression improves renal function better than calcineurin inhibitor-reduction in late cardiac transplant recipients with chronic renal failure. Transplantation, 87, 726–733.   79. Kushwaha, S. S., Raichlin, E., Sheinin, Y., et al. (2008). Sirolimus affects cardiomyocytes to reduce left ventricular mass in heart transplant recipients. Eur Heart J, 29, 2742–2750.   80. Rothenburger, M., Zuckermann, A., Bara, C., et al. (2007). Recommendations for the use of everolimus (Certican) in heart transplantation: results from the second GermanAustrian Certican Consensus Conference. J Heart Lung Transplant, 26, 305–311.   81. Dobbels, F., Vanhaecke, J., Dupont, L., et al. (2009). Pretransplant predictors of posttransplant adherence and clinical outcome: an evidence base for pretransplant psychosocial screening. Transplantation, 87, 1497–1504.   82. Saeed, I., Rogers, C., Murday, A., et al. (2008). Health-related quality of life after cardiac transplantation: results of a UK national survey with norm-based comparisons. J Heart Lung Transplant, 27, 675–681.   83. Fusar-Poli, P., Picchioni, M., Martinelli, V., et al. (2006). Anti-depressive therapies after heart transplantation. J Heart Lung Transplant, 25, 785–793.   84. Singh, N., Pirsch, J., & Samaniego, M. (2009). Antibody-mediated rejection: treatment alternatives and outcomes. Transplant Rev, 23, 34–46.   85. Fedson, S. E., Daniel, S. S., & Husain, A. N. (2008). Immunohistochemistry staining of C4d to diagnose antibody-mediated rejection in cardiac transplantation. J Heart Lung Transplant, 27, 372–379.   86. Tan, C. D., Baldwin, W. M., III, & Rodriguez, E. R. (2007). Update on cardiac transplantation pathology. Arch Pathol Lab Med, 131, 1169–1191.   87. Patel, J. K., & Kobashigawa, J. A. (2006). Should we be doing routine biopsy after heart transplantation in a new era of anti-rejection? Curr Opin Cardiol, 21, 127–131.   88. Stewart, S., Winters, G. L., Fishbein, M. C., et al. (2005). Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant, 24, 1710–1720.   89. Jarcho, J., Naftel, D. C., Shroyer, T. W., et al. (1994). Influence of HLA mismatch on rejection after heart transplantation: a multiinstitutional study. The Cardiac Transplant Research Database Group. J Heart Lung Transplant, 13, 583–595.   90. Taylor, D. O., Edwards, L. B., Boucek, M. M., et al. (2005). Registry of the International Society for Heart and Lung Transplantation: twenty-second official adult heart transplant report—2005. J Heart Lung Transplant, 24, 945–955.   91. Reed, E. F., Demetris, A. J., Hammond, E., et al. (2006). Acute antibody-mediated rejection of cardiac transplants. J Heart Lung Transplant, 25, 153–159.   92. Kfoury, A. G., Hammond, M. E., Snow, G. L., et al. (2009). Cardiovascular mortality among heart transplant recipients with asymptomatic antibody-mediated or stable mixed cellular and antibody-mediated rejection. J Heart Lung Transplant, 28, 781–784.   93. Turgeon, N. A., Kirk, A. D., Iwakoshi, N. N., et al. (2009). Differential effects of donorspecific alloantibody. Transplant Rev, 23, 25–33.   94. Jessup, M., & Brozena, S. (2007). State-of-the-art strategies for immunosuppression. Curr Opin Organ Transplant, 12, 536–542.   95. Deng, M. C., Eisen, H. J., Mehra, M. R., et al. (2006). Noninvasive discrimination of rejection in cardiac allograft recipients using gene expression profiling. Am J Transplant, 6, 150–160.   96. Potena, L., Grigioni, F., Magnani, G., et al. (2009). Prophylaxis versus preemptive anticytomegalovirus approach for prevention of allograft vasculopathy in heart transplant recipients. J Heart Lung Transplant, 28, 461–467.   97. Lindenfeld, J., Page, R. L., II, Zolty, R., et al. (2005). Drug therapy in the heart transplant recipient: part III: common medical problems. Circulation, 111, 113–117.   98. Gonzalez-Vilchez, F., de Prada, J. A., Exposito, V., et al. (2008). Avoidance of calcineurin inhibitors with use of proliferation signal inhibitors in de novo heart transplantation with renal failure. J Heart Lung Transplant, 27, 1135–1141.

CHAPTER Coronary Revascularization for Ischemic Cardiomyopathy,  802 Definition and Epidemiology,  802 Pathophysiology of Ischemic Cardiomyopathy,  803 Selection of Appropriate Candidates for ­Revascularization,  803 Risk of Revascularization,  805 Benefits of Revascularization,  806 Summary,  807

55

Surgical Treatment of Chronic Heart Failure Wilfried Mullens and Randall C. Starling

Cardiac surgical interventions have been performed for decades on patients with Valve Surgery for Left congestive heart failure; these procedures Ventricular Dysfunction,  807 initially carried high rates of perioperative Functional Mitral Regurgitation morbidity and mortality, as observed in the in Patients with Severe Left 1970s and 1980s. Accordingly, the role of Ventricular Dysfunction,  807 surgery was limited to cases of failed mediIschemic Mitral Regurgitation cal management and desperation. Fortuin Patients with Severe Left nately, a real resurgence of interest into the Ventricular Dysfunction,  809 surgical options of heart failure has emerged Tricuspid Valve Surgery in Patients as a result of evolving surgical techniques with Severe Left Ventricular and devices that treat both ischemic and Dysfunction,  809 nonischemic heart failure. Aortic Valve Surgery in Patients Because of the aging of the population, with Severe Left Ventricular the significant increase in the prevalence, Dysfunction,  810 morbidity, and mortality from heart failure is a compelling problem. Advances in the Left Ventricular Reconstruction treatment of acute myocardial infarction Surgery,  811 and nonischemic cardiomyopathy have led Indications for Remodeling Surgery in to increased survival of patients. However, Ischemic Cardiomyopathy,  811 this has resulted in a continuous increase in Techniques for Remodeling Surgery in the number of patients ultimately presenting Ischemic Cardiomyopathy,  812 with heart failure. Although cardiac transIndications for Remodeling Surgery in plantation remains a valuable therapeutic Dilated Cardiomyopathy,  813 option for advanced end-stage heart failure Device Therapies for Dilated (see Chapter 54), the field of transplantation Cardiomyopathy,  813 continues to be plagued by a finite number Conclusions,  814 of organ donors. Mechanical devices, such as implantable left ventricular assist devices (LVADs), are expensive, have a high incidence of adverse events, and therefore have not yet achieved their goal as a readily available alternative to transplantation for advanced heart failure (see Chapter 56). However, the advent of axial flow LVADs as bridges to transplantation has markedly improved outcomes for transplant recipients. Ongoing trials with new-generation LVADs for chronic or “destination therapy” are expected to demonstrate improved outcomes and result in more widespread use (see Chapter 56). As the numbers of patients suffering from advanced heart failure continue to grow and the availability and feasibility of cardiac transplantation and assist devices may not meet that growing demand, a substantial number of patients with heart failure will probably become candidates for and derive benefit from heart failure surgery. Because heart failure is a continuous disease process with ongoing detrimental reverse remodeling of the ventricles, insights into its pathophysiological features have led to major advances in surgical therapies (see Chapter 15). Contemporary surgical techniques and devices are attempts to restore the geometry of the failing ventricle and thereby arrest or reverse the adverse remodeling processes. As a result, cardiac function and subsequent outcomes have improved. Major advances in pharmacotherapy and imaging modalities have helped the surgical team select patients who will benefit most from surgical treatment of advanced heart failure. The management of chronic heart failure yields the best results through a combined medical and surgical approach, both of which are possible with a multidisciplinary team. In this chapter, current and evolving surgical strategies for treating congestive heart failure are reviewed, with a focus on three major areas: revascularization

802

for ischemic heart disease, operations for valvular lesions, and ventricular remodeling surgery. Of course, patients’ needs in these three areas often overlap; for example, a patient with ischemic cardiomyopathy may undergo coronary artery bypass, mitral valve repair, and left ventricular (LV) reconstruction of scarred dyskinetic anterior infarcted segments.

CORONARY REVASCULARIZATION FOR ISCHEMIC CARDIOMYOPATHY Definition and Epidemiology Ischemic cardiomyopathy is currently defined as significantly impaired (LV) dysfunction (left ventricular ejection fraction [LVEF] ≤ 35% to 40%) that results from coronary artery disease.1 Ischemic cardiomyopathy is considered to be the most common cause of heart failure; it currently affects 2.5 million people in the United States, the annual incidence is 40,000 new cases, and the annual mortality rate is 200,000 (see Chapter 22).2 Because of aging and increased cardiovascular risk profiles of the population in the United States, the population-attributable risk has been estimated to be as high as 68% among men and 56% among women.3 In addition, according to a review of almost 2000 patients with symptomatic heart failure and LVEF lower than 40%, patients with ischemic cardiomyopathy had significantly worse outcomes than those with nonischemic cardiomyopathy.1 In contrast, patients with single-vessel disease who had no history of myocardial infarction or revascularization had a prognosis similar to that in patients with nonischemic cardiomyopathy. Older data from the Framingham Heart Study suggested that the prevalence of heart failure after a myocardial infarction is 14% at 5 years and 22% at 10 years.4 However, more recent data showed this prevalence to be much higher, ranging from 10% at 2 years to more than 40% at 6.5 years after myocardial infarction.5,6 Improved early revascularization, intensive care strategies, and heart failure therapies (medications and

Pathophysiology of Ischemic Cardiomyopathy The mechanism most commonly involved in myocardial dysfunction secondary to ischemic cardiomyopathy is the loss of myocytes, which eventually leads to progressive reverse remodeling of the heart (see also Chapters 6 and 23).9 The LV remodeling process after myocardial infarction is complex, involving myocyte stretch and slippage, a phenomenon that also occurs in the adjacent remote viable myocardium.10 Ischemia-induced cellular changes include loss of myofibrils and disorganization of the structural proteins within the myocyte. In addition, extracellular changes, including fibrosis and alterations in the fiber orientation, cause changes in the geometrical shape of the heart.11 Eventually, these processes lead to a progressive dilation of the ventricles with a subsequent increase in wall tension and impairment of systolic and diastolic function. Thus, the progressive loss of viable myocardium over time after the myocardial infarction is a continuous process that ultimately might be accompanied by the clinical heart failure syndrome.12 However, restoration of myocardial blood flow in addition to surgical restoration of LV chamber geometry (section on left ventricular reconstruction surgery ) might reverse this detrimental process. Insights into the myocardial ischemia-induced changes on a cellular level help physicians to better determine which patients will benefit most from revascularization strategies (see also Chapter 23). Although transient ischemia can lead to a period of prolonged dysfunction even after the restoration of flow (“stunning”), persistent but asymptomatic ischemia might induce LV dysfunction (“hibernation”) that can mimic nonischemic causes of heart failure. Stunned myocardium is used to describe a condition in which a short-term, total or near-total reduction of coronary blood flow produces an abnormality in regional LV wall motion of limited duration (hours or days) after reperfusion.13-15 In contrast, hibernating myocardium is a state of persistently impaired myocardial and LV function at rest as a result of chronically reduced coronary blood flow that can be partially or completely restored to normal either by improving blood flow or by reducing oxygen demand.13-16 If the hibernating myocardium is not treated in a timely manner, however, it may be associated with progressive cellular damage, recurrent myocardial ischemia, myocardial infarction, heart failure, and death.17 Positron emission tomography (PET) has proved to be an excellent imaging modality for guiding selection of patients for revascularization strategies because it has shown that regions with abnormal wall motion may still be metabolically active and might therefore improve after revascularization.18 Such regions are likely to appear hypokinetic, rather than akinetic or dyskinetic, during routine echocardiographic examination. In addition, the reduction in resting coronary blood flow in hibernating segments and the improvement after coronary intervention can be demonstrated by cardiovascular magnetic

resonance imaging (MRI).19 Although in the clinical setting 803 stunned myocardium is often superimposed on hibernation, or irreversible contractile dysfunction, earlier identification of hibernating myocardial regions with prompt myocardial revascularization is crucial in preventing and reversing the ongoing reverse remodeling process of the heart. CH 55 Natural History of Ischemic Cardiomyopathy The prognosis of patients after myocardial infarction depends on the extent of LV damage.20 According to the Coronary Artery Surgery Study (CASS) registry, the 12-year survival rate among medically treated patients with LVEF lower than 35% was 21%, in comparison with 54% among patients with LVEF between 35% and 50%.21 With current interventional techniques, survival rates have improved, especially with the addition of angiotensin-converting enzyme (ACE) inhibitors, β-blockers, statins, implantable CRT devices, and defibrillators to the armamentarium of heart failure therapy. However, one study demonstrated that after a mean follow-up period of 4.4 years, of the patients who had developed ischemic cardiomyopathy, 34% had died and 4.6% had undergone cardiac transplantation.22 In those patients, outcomes were worse than in patients with an idiopathic or peripartum cardiomyopathy but considerably better than in patients with infiltrative, chemotherapy-induced, or human immunodeficiency virus (HIV)–induced cardiomyopathy (Figure 55-1).

Selection of Appropriate Candidates for ­Revascularization Clinical Trials No randomized clinical trial has been performed to evaluate the outcome of coronary artery bypass graft (CABG) surgery in patients with advanced ischemic cardiomyopathy (see also Chapter 23). However, in January 2002, a randomized, multicenter, international clinical trial, Surgical Treatment of Ischemic Heart Failure (STICH), was initiated to compare contemporary medical therapy plus CABG, medical therapy alone, and CABG with or without surgical ventricular restoration for patients with congestive heart failure and coronary heart disease. The STICH trial is sponsored by the National Heart, Lung, and Blood Institute as well as industry sponsors and has recruited 2212 patients with heart failure, LVEF lower than 35%, and coronary artery disease amenable to CABG at 127 clinical sites. The Hypothesis 1 group consists of 1212 patients, of whom 602 were randomly assigned to receive medical therapy alone and 610 were randomly assigned to receive medical therapies plus CABG. Follow-up assessment is ongoing, and the results have not yet been reported. The other 1000 patients in the STICH trial had dominant anterior dyskinesia or akinesia of the left ventricle and had been assigned to receive surgery; they were further randomly assigned to undergo CABG surgery alone or CABG plus surgical ventricular restoration. These patients represent the Hypothesis 2 group.23 Surgical ventricular reconstruction (SVR) reduced the end-systolic volume index by 19%, in comparison with a reduction of 6% with bypass surgery alone. New York Heart Association (NYHA) class of heart failure and 6-minute walk distance improved from baseline to a similar degree in the two groups in Hypothesis 2. However, no significant difference was observed in the primary outcome (death from any cause or hospitalization for cardiac causes), which occurred in 59% who were assigned to undergo CABG alone and in 58% who were assigned to undergo CABG with SVR (P = .90). The addition of SVR to CABG reduced the LV volume, in comparison with CABG alone, but the seemingly beneficial ventricular remodeling was not associated with a greater improvement in symptoms or exercise tolerance or with a reduction in the rate of death or hospitalization for

Surgical Treatment of Chronic Heart Failure

devices, such as cardiac resynchronization therapy [CRT] and implantable cardioverter-defibrillator [ICD]) have increased survival of patients admitted with extensive myocardial infarcts; as a result, the number of late presentations of congestive heart failure has increased. The development of heart failure late after myocardial infarction is related to a variety of factors, including the size and location of the infarct, the presence of ischemic mitral regurgitation (IMR), and perhaps inflammatory status, as assessed by serum C-reactive protein level.5-7 In addition, the risk of developing heart failure is also increased two to three times in patients with continuous angina, which suggests that myocardial ischemia contributes to the progressive LV dysfunction.8 Therefore, strategies must be in place to detect and treat heart failure and ongoing, potentially reversible ischemia in patients who might benefit from coronary revascularization.

804

100

CH 55 FIGURE 55–1  Outcomes of patients with cardiomyopathy, stratified by cause. HIV, human immunodeficiency virus. (From Felker GM, Thompson RE, Hare JM, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 2000;342:1077-1084.)

Proportion of patients surviving

Peripartum

75 Idiopathic 50

Doxorubicin

Ischemic heart disease

Infiltrative myocardial disease 25 HIV infection 0

0

5

10

15

Years

cardiac causes (see Figure 23-11). A disappointing finding was that the surgical strategies to reduce ventricular volume that have been examined in clinical trials (STICH, trials with the Acorn support device, trials with partial left ventriculectomy) have failed to provide the beneficial clinical outcomes that were anticipated. The three major randomized clinical investigations of CABG versus medical management—the Veterans Administration Cooperative Study,24 the European Coronary Surgery Study,25 and CASS26—have excluded patients with heart failure or severe LV dysfunction. Such patients have been traditionally considered too “high risk” because of the severe LV dysfunction, and their conditions were deemed inoperable. This category of patients with end-stage ischemic cardiomyopathy accounts for 40% to 50% of heart transplantations performed.27 Even with contemporary heart-failure treatment, a significant amount of these patients die while awaiting heart transplantation, and because of existing comorbid conditions, organ shortage, or both, others are too fragile to undergo transplantation.28 In addition, survival of patients with viable ischemic myocardium is reduced when revascularization is not undertaken.29 Therefore, each patient with ischemic cardiomyopathy must be carefully evaluated to determine the suitability for revascularization. Clinical Factors In the selection of candidates for revascularization, several clinical factors might play a role, including the presence of angina, suitability of target vessels for bypass grafting, heart failure symptoms, LV dimension, and the severity of hemodynamic compromise.30 The absence of angina should not preclude consideration for surgical revascularization; however, there is little information about the percentage of patients with heart failure who have silent ischemia that might be ameliorated by revascularization. Myocardial Viability Patients with ischemic cardiomyopathy are heterogeneous with regard to adequacy of target vessels for revascularization, ischemic jeopardy, and myocardial viability (see also Chapters 36 and 23). Therefore, clinicians should use utmost care in preoperatively selecting patients who will benefit most from revascularization. Most researchers have found that revascularization of hibernating myocardium in patients with ischemic cardiomyopathy improves both survival and LV function in comparison with medical therapy alone, regardless of the

preoperative degree of LV dysfunction.18,31-36 However, in many of these studies, the presence of angina was also a criterion for enrollment, which may have served as a clinical indicator of the extent of viability. Moreover, these types of studies have important limitations, including bias in selecting patients who undergo CABG, a lesser likelihood that negative findings will be published, and—because contemporary standard medical therapies (e.g., statins) are not used and internal mammary artery grafts are underused—uncertainty of applicability to current practice. Nevertheless, revascularization should be considered, because augmentation of coronary flow to viable ischemic or hibernating myocardium will improve LV function and survival. Several noninvasive imaging modalities may identify patients who have ischemic or hibernating myocardium amenable to revascularization surgery if adequate target vessels exist. The information concerning the myocardial viability that these modalities can provide differs because the different techniques depend on the inotropic reserve (dobutamine stress echocardiography [DSE]), demonstration of cell membrane integrity (thallium-201 imaging), preserved myocardial metabolism (PET with 2-[fluorine-18]-fluoro-2deoxy-d-glucose [18FDG]), or the absence of scar tissue (gadolinium-enhanced MRI) in areas of dysfunctional myocardium. DSE has been useful in the preoperative prediction of viable myocardium; it has an overall specificity of 91% and sensitivity of 68% for prediction of segmental recovery (see also Chapter 36).37 DSE is used to examine the inotropic reserve of dysfunctional but viable myocardium. Viable myocardium exhibits improved regional contractile function (inotropic reserve), as assessed by simultaneous transthoracic echocardiography, in response to dobutamine. Segmental wall motion is monitored during infusion of increasing doses of dobutamine. Augmentation of segmental wall motion beginning at a low dose and continuing during higher doses of dobutamine (uniphasic response) is suggestive of myocardial stunning. However, augmentation at low doses followed by a reduction in function at higher doses (biphasic response) is indicative of ischemia and hibernation. Of importance is that the prevalence of contractile reserve among patients with ischemic cardiomyopathy is independent of the angiographic extent and severity of coronary disease.38 A contractile response to dobutamine appears to require at least 50% viable myocytes in a given segment and is correlated inversely with the extent of interstitial fibrosis observed on myocardial biopsy samples.39 In single photon emission computed tomography (SPECT) with thallium-201 scintigraphy, thallium-201 is used as a

acid (Gd-DTPA) are areas of myocardial necrosis and irrevers- 805 ible injury; regions that fail to hyperenhance are viable. In addition, quantitative perfusion assessment can document the reduction in resting coronary blood flow in hibernating segments. The degree and transmural extent of enhancement with contrast-enhanced CMR imaging are inversely related to the potential of recovery of LV function after CH 55 revascularization.48,49 Magnetic resonance myocardial tagging is another CMR method that quantifies local myocardial segment shortening throughout the LV myocardium and across the LV wall thickness. This method can be combined with low-dose dobutamine infusion to quantify the amount of myocardial viability, on the basis of end-diastolic wall thickness combined with dobutamine-induced systolic wall thickening; together, these methods may provide a better prediction of LV functional recovery. For example, end-diastolic wall thickness of more than 10 mm preoperatively, in combination with dobutamine-induced systolic wall thickening of 2 mm or more in 50% or more of dysfunctional segments, is well correlated with postoperative improvement in function; however, only 4% of the segments with an end-diastolic wall thickness of less than 6 mm will improve.50 In comparison with DSE, dobutamine CMR has higher sensitivity (86% vs. 74%) and specificity (86% vs. 70%), but it is more labor intensive and more technically challenging.51 Unlike nuclear scintigraphy and DSE, which appear to have limited predictive accuracy if more severe systolic dysfunction is present, contrast-enhanced CMR imaging has greater accuracy in segments with the most severe dysfunction, which represents another advantage of this technique.52 At the Cleveland Clinic, CMR imaging has an established role in detecting the extent of viable myocardium and areas of scarring that might be amenable to reperfusion or other operative strategies that necessitate cardiopulmonary bypass. Surgical Treatment of Chronic Heart Failure

perfusion tracer because it has a high (80%) first-pass myocardial extraction fraction across physiological ranges of myocardial blood flow (see also Chapter 36). The myocardial uptake is a process requiring cell membrane integrity, and this fraction is therefore indicative of regional perfusion, as well as myocardial viability. Several approaches have been used to optimize the information obtained from thallium-201 scintigraphy, mostly involving a baseline stress image and one or two delayed images (4-hour redistribution and 24-hour late-delayed imaging). Regional thallium-201 redistribution activity represents the extent of regional myocardial viability; therefore, thallium-201 scintigraphy after a single stress injection has become the standard imaging technique for determining such viability. The demonstration of reversible ischemia by the conventional 4-hour stress-redistribution protocol implies the presence of viable myocardium. However, up to 50% of segments that have fixed defects at 4 hours might nonetheless recover either perfusion or function after revascularization.40,41 Therefore, several modifications of the 4-hour stress-redistribution protocol were developed to improve the accuracy of viability detection. Late (24-hour) redistribution or immediate reinjection of a second, smaller dose of thallium-201 after the redistribution images often enables visualization of segments in a significant number of perfusion defects that had been deemed fixed by imaging at only 4 hours. In comparison with DSE, myocardial perfusion scintigraphy can identify segments with fewer viable myocytes. In one series, for example, DSE and thallium-201 scintigraphy showed equivalent sensitivity among segments with more than 75% viable myocytes (78% vs. 87%), but DSE was much less sensitive among segments with 25% to 50% viable myocytes (15% vs. 82%).42 However, in comparison with thallium-201 scintigraphy, DSE was found to have greater specificity and positive predictive value in forecasting functional recovery after revascularization.43 PET is often considered the gold standard for evaluating myocardial perfusion and viability (see also Chapter 36).44 Its advantage is that it enables clinicians to assess perfusion and metabolism simultaneously. PET requires the use of positron-emitting radionuclides, which are incorporated into physiologically active molecules. Ischemia shifts myocyte metabolism from fatty acids to glucose. Thus, uptake of a glucose analogue, 18FDG, by myocytes in an area of dysfunctional myocardium indicates metabolic activity and, thus, viability. Regional perfusion can be assessed simultaneously with an agent that remains in the vascular space, thereby demonstrating blood flow (such as nitrogen-13 ammonia or rubidium-82). As a result, PET has the potential to differentiate between normal, stunned, hibernating, and necrotic myocardium. The presence of enhanced 18FDG uptake in regions of decreased blood flow (known as “PET mismatch”) is diagnostic for hibernating myocardium, and a concordant reduction in both metabolism and flow (“PET match”) is thought to represent predominantly necrotic myocardium. Regional dysfunction in the presence of normal perfusion is indicative of stunning. Of importance is that myocardial segments with significant reductions in both blood flow and 18FDG uptake have only a 20% chance of functional improvement after revascularization, whereas dysfunctional hibernating territories have approximately an 85% chance of functional improvement after revascularization.18,45-47 The greater the number of viable myocardial segments, the greater the likelihood that revascularization will improve global LV function and consequently improve heart failure symptoms and survival. Contrast medium–enhanced cardiac magnetic resonance (CMR) imaging can be used to establish the presence of hibernating myocardium (see also Chapter 36). Regions of myocardium that exhibit late (or delayed) enhancement 10 minutes after the injection of gadolinium–diethylenetriaminepenta-acetic

Risk of Revascularization The most effective way of stratifying operative risk for cardiac surgical patients is to use a risk prediction algorithm that incorporates multiple variables to derive a risk score. Two of the algorithms most widely used for this purpose in the United States are the one developed by the Society of Thoracic Surgeons and the European System for Cardiac Operative Risk Evaluation (EuroSCORE); http://www.euroscore.org/calculator).53-57 Both algorithms incorporate patient age, sex, comorbid conditions, and the severity and acuity of cardiac disease, and both can accurately predict 30-day mortality. One limitation of such risk prediction algorithms is their dependence on the patient data from which they were derived; as the patient population changes, and as surgical technique changes, risk analyses may soon become outdated.58 The presence of LV dysfunction and heart failure remains one of the most important independent predictors of operative mortality and other major adverse events after CABG (Figure 55-2).59 In a prospective observational study of more than 8600 patients undergoing CABG between 1992 and 1997, the rate of operative mortality varied: less than 2% of patients with LVEF higher than 40%, 4% of those with LVEF of 20% to 40%, and 8% of those with LVEF lower than 20%.60 However, the Cleveland Clinic reported lower in-hospital mortality rates for patients with normal (1.5%), moderately impaired (2.5%), or severely impaired (3.2%) LV function when they reviewed more than 14,000 cases of patients who underwent isolated CABG between 1990 and 1999. In addition, the Cleveland Clinic also reported that the numbers of patients at high risk had increased, but the surgical morbidity rate, adjusted for preoperative risk score, had fallen significantly from 14.5% (in 1986) to 8.8% (in 1994; P < .001).61

806

Improvement in Symptoms of Congestive Heart Failure and in ­Functional Capacity

20 Observed Expected

18 16 14 Percent

CH 55

12 10 8 6 4 2 0

A

1

2

3

4

5

6

7

8

9

10

Decile of risk

Correlate Pre-CABG creatinine 3.0 mg/dL (265 mol/L) Age 80 yrs Cardiogenic shock Emergent operation Age 70 to 79 yrs Prior CABG Left ventricular section fraction 150/100 mm Hg). Both heart failure and LV dysfunction generally recover when sunitinib therapy is withheld and appropriate institution of medical management is initiated (see later discussion). Sunitinib caused mitochondrial injury and cardiomyocyte apoptosis in mice and in cultured rat cardiomyocytes.54 Hypertension induced by sunitinib may play an important

role in causing heart failure, inasmuch as sunitinib may inhibit a receptor tyrosine kinase that aids in regulating the response of cardiomyocytes in the setting of hypertensive stress.55 In addition, sunitinib may cause cardiotoxicity through inhibition of ribosomal S6 kinase, leading to the activation of the intrinsic apoptotic pathway and adenosine triphosphate depletion.56

DIAGNOSIS AND MONITORING OF PATIENTS RECEIVING CARDIOTOXIC CHEMOTHERAPEUTIC AGENTS (see Chapters 36 and 37) In order to detect cardiac dysfunction in patients treated with chemotherapy, heart function must be monitored regularly during treatment. A baseline evaluation of LVEF must be obtained for comparison, and it is recommended that the same method be used for comparing serial measurements. Serial assessment of LVEF was first shown to be useful in clinical practice by Alexander and associates.57 On the basis of their experiences, algorithms have been developed for serial monitoring of LVEF during anthracycline-based therapy.58,59 Measurement of systolic function through evaluation of the LVEF with either multiple-gated angiography (MUGA) or echocardiography is one of the most commonly used methods of monitoring and diagnosing chemotherapy-induced cardiomyopathy. Radionuclide imaging of LV function appears to yield results comparable with those of 2-dimensional echocardiography with regard to monitoring changes in LV function.60,61 However, it is not sensitive for early detection of preclinical (subclinical) cardiac disease, and it is influenced

MANAGEMENT OF PATIENTS RECEIVING CARDIOTOXIC CHEMOTHERAPEUTIC AGENTS At present, the guidelines of the Heart Failure Society of America and the American College of Cardiology/American Heart Association (ACC/AHA) do not contain specific recommendations for treatment of patients with what is presumed to be chemotherapy-induced heart failure. However, it is probably most reasonable at this time to treat the patient like any patient with newly diagnosed heart failure, as discussed in Chapters 45 and 46. In this regard, it is critical to rule out other potential causes of heart failure (see Table 35-2) before chemotherapy is assumed to have been the cause. Medical management of patients with stage A disease should focus on risk-factor reduction by controlling hypertension, diabetes, and hyperlipidemia, with the goal of preventing ventricular remodeling. Treatment of stages B, C, and D disease is aimed at improving survival, slowing disease progression, and alleviating symptoms. Patients with end-stage heart failure with refractory symptoms at rest despite maximal medical therapy and without evidence of cancer recurrence could be considered for synchronized pacing, placement of a ventricular assist device, or cardiac transplantation.65 The effects of several agents discussed previously (including trastuzumab, imatinib, and sunitinib) appear to be reversible to some degree, and such reversal may be promoted by aggressive treatment with ACE inhibitors and β-blockers. Treatment with specific agents is discussed as follows.

Dexrazoxane 851 Dexrazoxane (Zinecard) is a free-radical scavenger that is used to protect the heart from the cardiotoxic side effects of anthracyclines. Several randomized control trials have been conducted to examine the effects of dexrazoxane in combination with anthracyclines, and all of these studies revealed that dexrazoxane is a highly effective cardioprotective agent CH 58 that allows higher cumulative doses of doxorubicin.16 However, one trial demonstrated that dexrazoxane might interfere with the antitumor activity of doxorubicin,17 but this has not been a consistent finding in other studies. In the metaanalysis conducted by Van Dalen and colleagues,68 a statistically significant benefit was found in favor of dexrazoxane for the occurrence of heart failure (relative risk, 0.29; 95% confidence interval, 0.20 to 0.41). No evidence was found for differences in response rate or survival between the subjects taking dexrazoxane and the control group. In children with acute lymphoblastic leukemia, Lipshultz and associates7 found that dexrazoxane prevented cardiac injury (as reflected by elevations in troponin T levels) related to doxorubicin therapy, without compromising the antitumor efficacy of doxorubicin. In this study, children treated with doxorubicin alone were more likely to have elevated troponin T levels (50% vs. 21%; P < .001) and extremely elevated troponin T levels (32% vs. 10%; P < .001) than were those who received dexrazoxane and doxorubicin. The rate of event-free survival at 2.5 years was 83% in both groups (P = .87 by the log-rank test).7 Data for children confirm the protective role of dexrazoxane in patients receiving anthracyclines. At present, however, the American Society of Clinical Oncology guidelines69 recommend that dexrazoxane be considered for patients with metastatic breast cancer who have received more than 300 mg/m2 of doxorubicin and who may benefit from continued doxorubicin-containing therapy. The use of dexrazoxane can also be considered in adult patients with other malignancies who have received more than 300 mg/m2 of doxorubicin-based therapy; however, caution should be exercised in the use of dexrazoxane in settings in which doxorubicin-based therapy has been shown to improve survival. Management of Heart Failure patients with Malignancy

by contractility and preload/afterload effects that lead to transient changes. Therefore, other measurements of systolic function (e.g., fraction shortening) and diastolic function (e.g., ratio of early to late diastolic filling) have been used to detect early cardiotoxicity in addition to LVEF.60 Abnormalities on exercise echocardiograms may be a better predictor of impending heart failure.25 Biomarkers may also provide useful clues about patients at risk for developing heart failure, as well as the progression of heart failure. Measurements of brain natriuretic peptide (BNP) are helpful in differentiating symptoms of heart failure from those of noncardiac causes when patients present to the emergency room.62 The test is, however, limited because it is relatively nonspecific and because of a large range of “normal” values.63 An elevated BNP level in patients undergoing chemotherapy appears to be more closely associated with impairment of LV diastolic function than with impairment of LV systolic function.64 As noted in the “Monitoring and Anthracycline Toxicity” section, cardiac troponin measurement is a very sensitive way of diagnosing myocardial injury and damage. Not surprisingly, their persistent elevation is predictive of poor outcome and development of heart failure in cancer patients receiving chemotherapy.27 Endomyocardial biopsy is the most sensitive method of detecting anthracycline cardiotoxicity; light microscopy reveals marked myofibril loss and vacuolar degeneration, and electron microscopy reveals extensive loss of myofilaments.65,66 However, abnormalities detected on electron microscopy have not been shown to be correlated highly with risk of development of heart failure, and these abnormalities are often present in patients at cumulative doses well below those associated with an increased risk of heart failure. Because of the technical nature of the procedure and the inherent risks, this is not a practical way to detect or monitor patients with anthracycline cardiotoxicity; serial determination of LV function, although insensitive, is the currently accepted method. Moreover, not every form of drug-induced cardiomyopathy can be detected reliably with endomyocardial biopsy, inasmuch as cardiac damage may be scattered.67

Neurohormonal Antagonists (see Chapters 45 and 46) β-Blockers.  To date, there have been four case series in which researchers have evaluated the benefit of β-blockers in the treatment of anthracycline-induced cardiomyopathy.4,70-73 In one study, beta blockers improved left ventricular ejection fraction in patients with anthracyline-induced cardiomyopathy. This improvement in myocardial function was comparable if not greater than the beneficial effects seen with beta blocker use in idiopathic dilated cardiomyopathy (Figure 58-3).72 Of the β-blockers, carvedilol may have therapeutic advantages over the others in anthracycline-induced cardiomyopathy, inasmuch as it has been shown to possess antioxidant properties.4 Moreover, in a single-blind, placebocontrolled trial in which the primary outcome was change in LVEF within 6 months of treatment, treatment with carvedilol prevented a decline in LVEF and prevented LV diastolic dysfunction.24 Angiotensin-Converting Enzyme Inhibitors.  There is some evidence supporting the use of ACE inhibitors in patients with anthracycline-induced cardiomyopathy.25,75,76 In a randomized, double-blind, controlled clinical trial in which enalapril was compared with placebo in 135 long-term survivors of pediatric cancer who had at least one cardiac abnormality identified at any time after anthracycline exposure, enalapril was shown to prevent a decline in LVEF in these long-term survivors. Although there was no difference in the primary outcome variable of maximal cardiac index, as determined by cycle ergometry, the rate of decline in LV end-systolic wall stress was greater in the subjects who took enalapril than in

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failure is identified, these patients should be treated aggressively with heart failure medications, which often lead to reversal of heart failure. Future studies will address the identification of genetic profiles of patients at risk for developing cancer therapy–induced heart failure, the optimal treatment strategies, and whether therapy for heart failure can be discontinued safely.

30

REFERENCES

70

Pre-treatment EF

Post-treatment EF

60

CH 58

LVEF (%)

50

P = .015

P = .041

20 10 0 IDC

ACM

FIGURE 58–3  β-Blockade in left ventricular dysfunction induced by doxorubicin (Adriamycin). Affected patients were treated with β-blockers (metoprolol, carvedilol, and propranolol). The control group consisted of 16 consecutively chosen age- and sex-matched patients with idiopathic dilated cardiomyopathy (IDC) that was treated with β-blockers. The mean left ventricular ejection fraction (LVEF) improved from 28% to 41% (P = .041) in patients with doxorubicin-induced left ventricular dysfunction, whereas the LVEF improved from 26% to 32% (P =.015) in the patients with IDC. ACM, Adriamycin-induced cardiomyopathy; EF, ejection fraction. (From Noori A, Lindenfeld J, Wolfel E, et al. Beta-blockade in Adriamycin-induced cardiomyopathy. J Card Fail 2000;6:115-119.)

those who took the placebo (−8.59 vs. 1.85 g/cm2; P = .033); the reduction was 9% by year 5 of the study.25 However, in an observational study of 18 children treated with enalapril for LV dysfunction or heart failure, the beneficial effects of enalapril diminished after 6 to 10 years as a result of progressive LV wall thinning.76 Thus, the clinical effects of ACE inhibitors in chemotherapy-induced heart failure are variable. Patients already taking β-blockers and ACE inhibitors before receiving chemotherapy should continue taking these medications, because withdrawal from these drugs can lead to deterioration of LV systolic function.

REVERSIBILITY OF CANCER THERAPY– INDUCED LEFT VENTRICULAR DYSFUNCTION In contrast to that caused by anthracyclines, the LV dysfunction that occurs with several of the tyrosine kinase inhibitors, including trastuzumab, imatinib, and sunitinib, appears to have some degree of reversibility.77 Discontinuation of trastuzumab is generally recommended when clinically significant heart failure occurs. However, patients who experience cardiotoxicity while receiving trastuzumab generally recover cardiac function when trastuzumab is discontinued over a mean time period of 1.5 months.77 Patients who have experienced benefit with trastuzumab therapy and who have improved cardiac function while on a standard heart regimen may restart trastuzumab therapy while receiving protective heart failure medications and close cardiac monitoring.77 In addition, Memorial-Sloan-Kettering Cancer Center has proposed guidelines for the management of patients treated with trastuzumab on the basis of physical status and LVEF.78

CONCLUSION Cancer therapy–induced heart failure is a common problem observed by cardiologists and oncologists. Recognition and early detection of heart failure is critical for optimal management of patients undergoing cancer therapy. Once heart

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Br J Haematol, 131, 561–578. 17. Swain, S. M., Whaley, F. S., Gerber, M. C., et al. (1997). Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol, 15, 1318–1332. 18. Von Hoff, D. D., Layard, M. W., Basa, P., et al. (1979). Risk factors for doxorubicininduced congestive heart failure. Ann Intern Med, 91, 710–717. 19. Pai, V. B., & Nahata, M. C. (2000). Cardiotoxicity of chemotherapeutic agents: incidence, treatment and prevention. Drug Saf, 22, 263–302. 20. Gharib, M. I., & Burnett, A. K. (2002). Chemotherapy-induced cardiotoxicity: current practice and prospects of prophylaxis. Eur J Heart Fail, 4, 235–242. 21. Grenier, M. A., & Lipshultz, S. E. (1998). Epidemiology of anthracycline cardiotoxicity in children and adults. Semin Oncol, 25, 72–85. 22. Lipshultz, S. E., Alvarez, J. A., & Scully, R. E. (2008). Anthracycline associated cardiotoxicity in survivors of childhood cancer. Heart, 94, 525–533. 23. Swain, S. M., Whaley, F. S., & Ewer, M. S. (2003). Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer, 97, 2869–2879. 24. Kalay, N., Basar, E., Ozdogru, I., et al. (2006). Protective effects of carvedilol against anthracycline-induced cardiomyopathy. J Am Coll Cardiol, 48, 2258–2262. 25. Silber, J. H., Cnaan, A., Clark, B. J., et al. (2004). Enalapril to prevent cardiac function decline in long-term survivors of pediatric cancer exposed to anthracyclines. J Clin Oncol, 22, 820–828. 26. Iarussi, D., Indolfi, P., Casale, F., et al. (2005). Anthracycline-induced cardiotoxicity in children with cancer: strategies for prevention and management. Paediatr Drugs, 7, 67–76. 27. Cardinale, D., Sandri, M. T., Colombo, A., et al. (2004). Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. Circulation, 109, 2749–2754. 28. Braverman, A. C., Antin, J. H., Plappert, M. T., et al. (1991). Cyclophosphamide cardiotoxicity in bone marrow transplantation: a prospective evaluation of new dosing regimens. J Clin Oncol, 9, 1215–1223. 29. Goldberg, M. A., Antin, J. H., Guinan, E. C., et al. (1986). Cyclophosphamide cardiotoxicity: an analysis of dosing as a risk factor. Blood, 68, 1114–1118. 30. Gottdiener, J. S., Appelbaum, F. R., Ferrans, V. J., et al. (1981). Cardiotoxicity associated with high-dose cyclophosphamide therapy. Arch Intern Med, 141, 758–763. 31. Morandi, P., Ru fini, P. A., Benvenuto, G. M., et al. (2005). Cardiac toxicity of high-dose chemotherapy. Bone Marrow Transplant, 35, 323–334. 32. Quezado, Z. M., Wilson, W. H., Cunnion, R. E., et al. (1993). High-dose ifosfamide is associated with severe, reversible cardiac dysfunction. Ann Intern Med, 118, 31–36.

57. Alexander, J., Dainiak, N., Berger, H. J., et al. (1979). Serial assessment of doxorubicin cardiotoxicity with quantitative radionuclide angiocardiography. N Engl J Med, 300, 278–283. 58. Schwartz, R. G., McKenzie, W. B., Alexander, J., et al. (1987). Congestive heart failure and left ventricular dysfunction complicating doxorubicin therapy. Seven-year experience using serial radionuclide angiocardiography. Am J Med, 82, 1109–1118. 59. Steinherz, L. J., Graham, T., Hurwitz, R., et al. (1992). Guidelines for cardiac monitoring of children during and after anthracycline therapy: report of the Cardiology Committee of the Children’s Cancer Study Group. Pediatrics, 89, 942–949. 60. Ganz, W. I., Sridhar, K. S., Ganz, S. S., et al. (1996). Review of tests for monitoring doxorubicin-induced cardiomyopathy. Oncology, 53, 461–470. 61. Ritchie, J. L., Singer, J. W., Thorning, D., et al. (1980). Anthracycline cardiotoxicity: clinical and pathologic outcomes assessed by radionuclide ejection fraction. Cancer, 46, 1109–1116. 62. Mueller, C., Scholer, A., Laule-Kilian, K., et al. (2004). Use of B-type natriuretic peptide in the evaluation and management of acute dyspnea. N Engl J Med, 350, 647–654. 63. Hassan, Y., Shapira, A. R., & Hassan, S. (2002). B-type natriuretic peptide in heart failure. N Engl J Med, 347, 1976–1978. 64. Nousiainen, T., Vanninen, E., Jantunen, E., et al. (2002). Natriuretic peptides during the development of doxorubicin-induced left ventricular diastolic dysfunction. J Intern Med, 251, 228–234. 65. Friedman, M. A., Bozdech, M. J., Billingham, M. E., et al. (1978). Doxorubicin cardiotoxicity. Serial endomyocardial biopsies and systolic time intervals. JAMA, 240, 1603–1606. 66. Mason, J. W., Bristow, M. R., Billingham, M. E., et al. (1978). Invasive and noninvasive methods of assessing Adriamycin cardiotoxic effects in man: superiority of histopathologic assessment using endomyocardial biopsy. Cancer Treat Rep, 62, 857–864. 67. Yusuf, S. W., Razeghi, P., & Yeh, E. T. (2008). The diagnosis and management of cardiovascular disease in cancer patients. Curr Probl Cardiol, 33, 163–196. 68. van Dalen, E. C., Caron, H. N., Dickinson, H. O., et al. (2008). Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database Syst Rev (2), CD003917. 69. Hensley, M. L., Hagerty, K. L., Kewalramani, T., et al. (2009). American Society of Clinical Oncology 2008 clinical practice guideline update: use of chemotherapy and radiation therapy protectants. J Clin Oncol, 27, 127–145. 70. Fazio, S., Palmieri, E. A., Ferravante, B., et al. (1998). Doxorubicin-induced cardiomyopathy treated with carvedilol. Clin Cardiol, 21, 777–779. 71. Mukai, Y., Yoshida, T., Nakaike, R., et al. (2004). Five cases of anthracycline-induced cardiomyopathy effectively treated with carvedilol. Intern Med, 43, 1087–1088. 72. Noori, A., Lindenfeld, J., Wolfel, E., et al. (2000). Beta-blockade in Adriamycin-induced cardiomyopathy. J Card Fail, 6, 115–119. 73. Shaddy, R. E., Olsen, S. L., Bristow, M. R., et al. (1995). Efficacy and safety of metoprolol in the treatment of doxorubicin-induced cardiomyopathy in pediatric patients. Am Heart J, 129, 197–199. 74. Oliveira, P. J., Bjork, J. A., Santos, M. S., et al. (2004). Carvedilol-mediated antioxidant protection against doxorubicin-induced cardiac mitochondrial toxicity. Toxicol Appl Pharmacol, 200, 159–168. 75. Cardinale, D., Colombo, A., Sandri, M. T., et al. (2006). Prevention of high-dose ­chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation, 114, 2474–2481. 76. Lipshultz, S. E., Lipsitz, S. R., Sallan, S. E., et al. (2002). Long-term enalapril therapy for left ventricular dysfunction in doxorubicin-treated survivors of childhood cancer. J Clin Oncol, 20, 4517–4522. 77. Ewer, M. S., & Lippman, S. M. (2005). Type II chemotherapy-related cardiac dysfunction: time to recognize a new entity. J Clin Oncol, 23, 2900–2902. 78. Keefe, D. L. (2002). Trastuzumab-associated cardiotoxicity. Cancer, 95, 1592–1600.

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33. Martin, M., Pienkowski, T., Mackey, J., et al. (2005). Adjuvant docetaxel for node-positive breast cancer. N Engl J Med, 352, 2302–2313. 34. Marty, M., Cognetti, F., Maraninchi, D., et al. (2005). Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2–positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol, 23, 4265–4274. 35. Richardson, P. G., Sonneveld, P., Schuster, M. W., et al. (2005). Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med, 352, 2487–2498. 36. Voortman, J., & Giaccone, G. (2006). Severe reversible cardiac failure after bortezomib treatment combined with chemotherapy in a non–small cell lung cancer patient: a case report. BMC Cancer, 6, 129. 37. Krause, D. S., & Van Etten, R. A. (2005). Tyrosine kinases as targets for cancer therapy. N Engl J Med, 353, 172–187. 38. Chen, M. H., Kerkela, R., & Force, T. (2008). Mechanisms of cardiac dysfunction associated with tyrosine kinase inhibitor cancer therapeutics. Circulation, 118, 84–95. 39. Cohen, P. (2002). Protein kinases—the major drug targets of the twenty-first century? Nat Rev Drug Discov, 1, 309–315. 40. Blume-Jensen, P., & Hunter, T. (2001). Oncogenic kinase signalling. Nature, 411, 355–365. 41. Feldman, A. M., Lorell, B. H., & Reis, S. E. (2000). Trastuzumab in the treatment of metastatic breast cancer: anticancer therapy versus cardiotoxicity. Circulation, 102, 272–274. 42. Seidman, A., Hudis, C., Pierri, M. K., et al. (2002). Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol, 20, 1215–1221. 43. Ewer, M. S., Gibbs, H. R., Swafford, J., & Benjamin, R. S. (1999). Cardiotoxicity in patients receiving trastuzumab (Herceptin): primary toxicity, synergistic or sequential stress, or surveillance artifact? Semin Oncol, 26, 96–101. 44. Bird, B. R., & Swain, S. M. (2008). Cardiac toxicity in breast cancer survivors: review of potential cardiac problems. Clin Cancer Res, 14, 14–24. 45. Crone, S. A., Zhao, Y. Y., Fan, L., et al. (2002). ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat Med, 8, 459–465. 46. Lee, K. F., Simon, H., Chen, H., et al. (1995). Requirement for neuregulin receptor ErbB2 in neural and cardiac development. Nature, 378, 394–398. 47. Meyer, D., & Birchmeier, C. (1995). Multiple essential functions of neuregulin in development. Nature, 378, 386–390. 48. Ferrara, N., Hillan, K. J., Gerber, H. P., & Novotny, W. (2004). Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov, 3, 391–400. 49. Miller, K., Wang, M., Gralow, J., et al. (2007). Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med, 357, 2666–2676. 50. Miller, K. D., Chap, L. I., Holmes, F. A., et al. (2005). Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol, 23, 792–799. 51. Kerkela, R., Grazette, L., Yacobi, R., et al. (2006). Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med, 12, 908–916. 52. Demetri, G. D. (2007). Structural reengineering of imatinib to decrease cardiac risk in cancer therapy. J Clin Invest, 117, 3650–3653. 53. Patyna, S., Arrigoni, C., Terron, A., et al. (2008). Nonclinical safety evaluation of sunitinib: a potent inhibitor of VEGF, PDGF, KIT, FLT3, and RET receptors. Toxicol Pathol, 36, 905–916. 54. Chu, T. F., Rupnick, M. A., Kerkela, R., et al. (2007). Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet, 370, 2011–2019. 55. Khakoo, A. Y., Kassiotis, C. M., Tannir, N., et al. (2008). Heart failure associated with sunitinib malate: a multitargeted receptor tyrosine kinase inhibitor. Cancer, 112, 2500–2508. 56. Force, T., Krause, D. S., & Van Etten, R. A. (2007). Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer, 7, 332–344.

CHAPTER Significance of the Problem,  854 Treatment Adherence,  854 Symptom Recognition,  855 Seeking Assistance When Needed,  855 Changing Unhealthy Lifestyles,  856

59

Disease Management in Heart Failure Debra K. Moser and Barbara Riegel

Despite considerable scientific advances in the pharmacological and surgical management of patients with heart failure, one of Management of Heart the greatest challenges still facing clinicians Failure,  856 is how to provide effective, efficient outManagement of Heart Failure in patient management for these patients that Special Populations,  857 results in good clinical outcomes. Patients with heart failure consume a disproportionPutting Management of Heart ately high percentage of health care costs Failure into Practice,  857 because of repeated bouts of decompenThe Self-Care Paradigm,  857 sation that necessitate hospitalization or Summary,  864 emergency intervention.1,2 This problem is expected to increase as the incidence and prevalence of heart failure continue to escalate.3,4 Most hospitalizations are thought to be preventable because they are precipitated by factors that are modifiable and could be better addressed during outpatient management. The major reasons for preventable hospitalizations are patients’ lack of adherence to prescribed regimens and failure to seek early treatment for worsening symptoms.5,6 According to the traditional view of the relationship between the patient and health care provider, the physician or advanced practice nurse prescribes a regimen, and the patient follows it.7 In this view, failure of the regimen to produce the desired outcome usually is blamed on the patient’s failure to follow the regimen. Indeed, even the best therapeutic plan will fail if patients do not follow it. However, reasons for patient nonadherence are complex. By simply blaming the patient for not following the prescribed plan, clinicians ignore these complexities and overlook contributing factors that could be remedied with intervention. Many factors that contribute to failure to implement the treatment plan have been identified. These factors are related to the patient, provider, and health care system. Patient-related factors can often be overcome or compensated for by changes in the health care provider’s approach or by changing the health care delivery system.8 Inadequacies in the delivery of advice and recommendations by clinicians contribute significantly to treatment noncompliance and poor outcomes.9-12 Other common reasons for rehospitalization are poor discharge planning, inadequate follow-up after discharge, and health care providers’ failure to attend to patient characteristics (e.g., depression, cognitive impairment, lack of a social support system, inability to pay for expensive medications) that render patients prone to repeated hospitalizations.13-15 Thus, to understand why therapeutic regimens fail, it is more helpful to address issues involving the patient, provider, and health care system.16 Optimal outpatient management of patients with heart failure depends on a thorough understanding of all three factors that contribute to nonadherence and how to address them (Table 59-1). Knowing what to recommend and prescribe for patients is important in outpatient management, but understanding how to convey this information to patients and how to structure the system to support treatment adherence is even more important. Thus, the focus of this chapter is on application of effective models of care for outpatient management. Failure of the Traditional Health Care Delivery Model,  856

SIGNIFICANCE OF THE PROBLEM Treatment Adherence In a report on adherence to long-term therapies, the World Health Organization estimated that rates of such adherence are about 50% in developed countries and even lower in developing countries.8 The consequences of poor

854

adherence include adverse health outcomes, poor quality of life, and increased health care costs.8 As Haynes emphasized in a Cochrane Database report on medication adherence, “Increasing the effectiveness of adherence interventions may have a far greater impact on the health of the population than any improvement in specific medical treatments.”17 Treatment adherence among patients with heart failure is poor.18 Medication nonadherence is a significant contributor to rehospitalization. In one study, of 231 patients with heart failure who were hospitalized with sodium retention, 20% had not adhered to the drug regimen.19 In another study of 94 patients with heart failure, 13% admitted to not taking their medications as prescribed.20 These statistics, obtained through patient self-reports, are probably underestimates of the true prevalence of nonadherence. Objective indicators of adherence reveal far greater levels of nonadherence. In a study of more than 7000 elderly patients prescribed digoxin, only 10% of the sample refilled their prescription often enough to have taken the appropriate amount of medication for 1 year; 19% of patients refilled the prescription only one time.21 Electronic event monitoring of angiotensin-converting enzyme (ACE) inhibitor therapy revealed that 19% of patients took less than 70% of the prescribed doses and that adherence declined markedly among patients who were prescribed formulations that required dosing more than once per day.22 Lack of medication adherence is clearly linked to increased risk for rehospitalization and mortality in patients with heart failure.23 Adherence to a low-sodium diet is important for patients with heart failure, according to heart failure guidelines. Adherence to dietary recommendations of sodium restriction is even lower than adherence to medication regimens. Fewer than half of patients consistently follow a low-sodium diet.19 Even after a 6-month education intervention, only 35% of patients studied routinely avoided salty foods, which demonstrates the need to take into account factors involving patients, providers, and the health care system.24 One reason for poor adherence to dietary sodium restrictions may be failure

TABLE 59–1   Actions to Increase Compliance with Prevention and Treatment Recommendations Specific Strategies

Patients must engage in essential prevention and treatment behaviors. l Decide to control risk factors. l Negotiate goals with provider. l Develop skills for adopting and maintaining recommended behaviors. l Monitor progress toward goals. l Resolve problems that block achievement of goals. Patients must communicate with providers about prevention and treatment services.

Understand rationale, importance of commitment. Develop communication skills. Use reminder systems. Use self-monitoring skills. Develop problem-solving skills; use social support networks. Define own needs on basis of experience. Validate rationale for continuing to follow recommendations.

Actions by Providers

Specific Strategies

Providers must foster effective communication with patients. Provide clear, direct messages about importance of a behavior or therapy.

l

l

Include patients in decisions about prevention and treatment goals and related strategies.

Incorporate behavioral strategies into counseling. Providers must document and respond to patients’ progress toward goals. l Create an evidence-based practice. l Assess patients’ compliance at each visit. l Develop reminder systems to ensure identification and follow-up of patient status. l

Actions by Health Care Organizations Health care organizations must develop an environment that supports ­prevention and treatment interventions.

l l

Provide tracking and reporting systems. Provide education and training for providers.

Provide adequate reimbursement for allocation of time for all health care professionals. Health care organizations must adopt systems to rapidly and efficiently incorporate innovations into medical practice.

l

Provide verbal and written instruction, including rationale for treatments. Develop skills in communication/counseling. Use tailoring and contracting strategies. Negotiate goals and a plan. Anticipate barriers to compliance and discuss solutions. Use active listening. Develop multicomponent strategies (i.e., cognitive and behavioral). Determine methods of evaluating outcomes. Use self-report or electronic data. Use telephone follow-up.

Specific Strategies Develop training in behavioral science, office set-up for all personnel. Use preappointment reminders. Use telephone follow-up. Schedule evening/weekend office hours. Provide group/individual counseling for patients and families. Develop computer-based systems (electronic medical records). Require continuing education courses in communication, behavioral counseling. Develop incentives tied to desired patient and provider outcomes. Incorporate nursing case management. Implement pharmacy patient profile and recall review systems. Use electronic transmission storage of patient’s self-monitored data. Obtain patient data on lifestyle behavior before visit. Provide continuous quality improvement training.

Reproduced with permission from Miller NH, Hill M, Kottke T, et al. The multilevel compliance challenge: recommendations for a call to action. A statement for healthcare ­professionals. Circulation 1997;95:1085-1090, Table 1. Copyright © American Heart Association.

of providers to stress the importance of a sodium-restricted diet. Although heart failure guidelines consistently emphasize the importance of sodium restriction, one study revealed that fewer than 22% of patients admitted for an exacerbation of heart failure were prescribed a sodium-restricted diet at discharge.19 Another reason may be failure of clinicians to assess patients’ skill in choosing a diet low in sodium. Only one study was located in which clinicians assessed patient skill in the ability to sort foods into those containing high and low sodium content.25 The authors found that only 14% of patients were aware of the sodium restriction guideline and only 58% was able to read the label’s sodium content. Clearly, the current approaches to educating patients about this important aspect of therapy are lacking in some manner.

Symptom Recognition According to the self-care model described in “The Self-Care Paradigm” section, patients must be able to recognize symptoms if they are to manage their heart failure successfully. Patients with heart failure who are able to recognize their symptoms are more successful in subsequent steps of the self-care process.26 However, symptom recognition has been found to be poor in most patients with heart failure.13,27 In careful studies of patients’ recognition of symptoms, fewer

than 50% of patients were able to recognize the common symptoms of worsening heart failure, including weight gain, edema, difficulty sleeping because of shortness of breath, and fatigue, and 40% of patients were unable to recognize escalating shortness of breath.26 Difficulty in recognizing symptoms may stem, in part, from failure of health care providers to teach this important aspect of care. Few patients are instructed, even during a hospitalization for exacerbation of heart failure, to weigh themselves to monitor fluid status; most patients do not appreciate the importance of daily weighing, and as a consequence, most do not weigh themselves daily.24,28,29 Bennett and colleagues30 noted that self-monitoring was reported only by patients who attended a heart failure clinic. Self-monitoring (e.g., daily weighings, edema assessment) was apparently not emphasized to patients receiving care in other settings.

Seeking Assistance When Needed Knowing when to seek assistance from a health care provider and doing so are important self-care behaviors for patients with heart failure. Failure to seek care in a timely manner— before symptoms have escalated to the point where hospitalization is necessary to control them—is common among patients with heart failure. However, care-seeking behavior

CH 59 Disease Management in Heart Failure

Actions by Patients

855

856 among patients with heart failure is an understudied area.

Frontiero and associates20 found that only about half of patients reported talking to their physician whenever they needed guidance. Many patients wait days with worsening symptoms, even shortness of breath, before seeking care.31

CH 59

Changing Unhealthy Lifestyles Exercise, limiting alcohol consumption, and smoking cessation would benefit many patients with heart failure, but adherence with these recommendations is poor. In one study, 67% of patients reported not exercising regularly.20 Ni and colleagues32 reported that 30% of patients had stopped exercising after heart failure was diagnosed. One fourth of patients failed to appreciate the risk of drinking excess alcohol, 12% were current smokers, and 21% engaged in physical exercise less than once a month or never. It has been noted in other patient populations that physicians often fail to recommend changing unhealthy lifestyle behaviors.33

FAILURE OF THE TRADITIONAL HEALTH CARE DELIVERY MODEL It is really no surprise that adherence to treatment is poor; many patients with heart failure are unable to recognize their early symptoms, and unhealthy lifestyle behaviors are common, in view of the traditional health care delivery model. In most cases, patients with heart failure are treated by clinicians who use usual practices typical of traditional health care delivery models. Management in traditional models is characterized by episodic, brief encounters with health care providers and punctuated by hospitalizations for acute exacerbations of heart failure. Several aspects of this typical care model actually contribute to increased rates of rehospitalization.10 Despite the opportunity to closely assess patients, modify therapy under observation, and provide intensive education during a hospitalization for an acute exacerbation, the preponderance of evidence suggests that management during hospitalization is inadequate.10 Approximately 20% of unplanned hospital readmissions for heart failure have been attributed to substandard inpatient care.10 The areas of substandard care thought to contribute most to readmissions are lack of patient and family education and failure to organize follow-up care. In-hospital patient education is limited; many patients receive inadequate education and counseling.9,34 Follow-up after hospital discharge usually consists of a few short visits with physicians in which there is little time to address the multiple and complex medical, behavioral, psychosocial, environmental, and financial issues that complicate the care of patients with heart failure. Failure to prescribe appropriate drug therapy also contributes substantially to the high rate of rehospitalizations for heart failure. Multiple guidelines35-38 describe standards for heart failure medical therapy that are based on results of large controlled clinical trials; nonetheless, as many as 50% to 72% of patients still do not receive prescriptions for ACE inhibitors and other drugs demonstrated to be effective in heart failure, do not receive them in adequate doses, or receive prescriptions for drugs such as calcium channel blockers that may have deleterious effects in heart failure.12,39-41 Thus, although there have been some improvements in prescription patterns for patients with heart failure, the use of appropriate medications for heart failure is not yet widespread. Because these issues must be addressed in order to improve heart failure outcomes, and because of the increasing incidence, prevalence, and economic costs of heart failure, many authorities have recommended that the current treatment patterns of fragmented care, in which acute in-patient episodes are common, be changed to comprehensive, integrated expert

multidisciplinary care patterns.2,42 By changing the outpatient health care delivery model for patients with chronic heart failure to incorporate evidence-based components shown to improve outcomes, many patient, provider, and system factors that contribute to nonadherence will be addressed.

MANAGEMENT OF HEART FAILURE Most patients with heart failure seek the attention of health care providers because they experience worrisome symptoms. The most common symptoms of heart failure are manifestations of volume overload, including shortness of breath, fatigue, peripheral edema, and difficulty sleeping, which greatly impair patients’ quality of life.43 These symptoms are particularly burdensome because patients with heart failure are usually elderly and often have multiple comorbid conditions, multiple drug prescriptions, psychosocial concerns, financial constraints, and physical limitations.13 In addition, many of these patients are socially isolated, cognitively impaired, and depressed.13,44-48 The symptoms of heart failure, although burdensome, are often subtle initially and may be confused with signs of normal aging or drug side effects.49 Because of the subtlety of early symptoms, patients need access to experts with whom they can discuss their questions and concerns. Sorting out the various symptoms and managing the complex medication regimen require a specialized knowledge base that general practitioners may not have mastered.50 The complexities of heart failure care are suited to disease management, which, by definition, involves practice redesign with increased availability of experts, use of evidencebased guidelines, improved education and counseling, and use of monitored outcomes to improve care processes. Disease management has been shown to (1) improve knowledge about heart failure; (2) facilitate health behavior change that improves self-care, including adherence to treatment and management of symptoms; and (3) improve clinical outcomes, such as lower rehospitalization rates, lower hospitalization costs, and lower rates of mortality.51-60 Since the 1980s, when the first program of management for heart failure was tested, more than 50 published studies have been conducted to test the effects of heart failure specialty care delivered in a disease management model. Although each program is different, all programs include care that reflects a significant departure from traditional episodic care delivery. These programs can be categorized broadly into two types: (1) heart failure clinics and (2) heart failure care delivered in or to the home. In addition, there are other heart failure–specific programs that do not meet criteria of disease management programs. Although these approaches are not disease management in the true sense, some authors have referred to them as disease management, and some have been effective in improving outcomes in patients with heart failure.61-63 Heart failure clinics are disease management programs in which service is provided primarily in an outpatient clinic setting; patients come to the clinic to receive care from practitioners with expertise in heart failure. Programs providing heart failure care in or to the home include a variety of disease management approaches, all of which entail heart failure–specific care that is delivered primarily in the patient’s home; care may be delivered by telephone, in person, or by both means. Many of these programs take a case management approach. Included in this group of studies are examples of true multidisciplinary care in which experts from three or more disciplines work collaboratively to deliver heart failure specialty care.64 Other programs involve only mailed educational materials,63 only a home telemonitoring system,61 or increased access only to primary care.62

Management of Heart Failure in Special Populations (see also Chapter 49) Surprisingly few investigators have tested disease management approaches in vulnerable patient populations such as minority, immigrant, or poor populations or populations of color. In one systematic review of cardiovascular disease interventions, only seven studies in vulnerable populations with heart failure were identified. This lack of research is surprising, inasmuch as significantly more African Americans than white patients are hospitalized for heart failure.65 Prevalence and incidence of heart failure appear to be lower among Hispanic populations than among African American and white populations, but hospitalization rates may be higher. Alexander and colleagues66 found that the percentage of patients rehospitalized for heart failure or other causes, total hospital days, and total hospital charges were all significantly higher for Hispanic patients than for non-Hispanic white patients; Hispanic patients were more likely to be rehospitalized multiple times. Little to nothing is known about Native American and Asian Pacific Islander residents in the United States. The studies included in a systematic review65 were a subset of some of the major disease management studies, chosen if they included a significant proportion of African American patients. Artinian and associates67 enrolled 18 patients, 65% of whom were African American. Benatar and associates68 enrolled 216 patients, of whom 186 (86%) were African American. DeWalt and coworkers69 enrolled 25 patients, of whom 15 (60%) were African American with poor literacy. Naylor and colleagues70 enrolled 239 patients, of whom 86 (36%) were African American. Rich and associates71 enrolled 282 patients, of whom 155 (55%) were African American. Sisk and coworkers72 enrolled 406 patients, of whom 187 (46%) were African American and 134 (33%) were Hispanic. Finally, O’Connell and associates73 enrolled 35 indigent patients, of whom 18 (51%) were Hispanic, into a pretest/ posttest assessment of case management for heart failure. After Davis and coworkers65 completed their review, Riegel and colleagues74 published the report of a randomized, controlled trial testing a telephone-based disease management approach, previously shown to be effective in the general population, in a sample of Hispanic patients. Patients selfidentified as Hispanic who were hospitalized with chronic heart failure were enrolled and randomly assigned to receive either telephone calls from bilingual/bicultural nurse case managers for 6 months (n = 69) or usual care (n = 65). Surprisingly, the intervention had no effect on hospitalization rate, quality of life, or depression in this sample. In comparison with the results of Sisk and coworkers72—the only other randomized controlled trial with a significant proportion of Hispanic patients—Riegel and colleagues’ method effectively lowered the rehospitalization rate (143 hospitalizations among patients receiving telephone calls vs. 180 hospitalizations among the patients receiving usual care at 12 months). However, only 33% of Sisk and coworkers’ population were Hispanic, and results were not analyzed by race or ethnicity. Riegel and colleagues suggested that a different approach may be needed in culturally diverse, elderly, functionally

compromised, poorly educated, or unacculturated groups. 857 This is clearly an area in which further research is needed.

PUTTING MANAGEMENT OF HEART FAILURE INTO PRACTICE Despite the superiority of outpatient management of heart failure, only a minority of patients with heart failure receive care through these care delivery models. Assuming that nonadherence is the result of factors related to the patient, provider, and health care system, a concerted effort to influence each of these components will have the best chance of improving outcomes in this challenging patient population. Programs of management for heart failure address each of these three areas. Patient factors are assessed and addressed, providers work from a knowledge base and framework that ensures appropriate care, and the system for care delivery has been modified to produce optimal outcomes. Thus, appropriate patients should be referred to these management programs when possible. However, these management programs are not available to the majority of patients and providers. In such cases, it is possible for providers to use the principles of management of heart failure in their practice (Box 59-1). An individual provider will have difficulty using disease management principles alone; therefore, a physician–advanced practice nurse team is suggested and described further later in the “Care Delivered by Advanced Practice Nurse–Physician Team” section. A vital first step in implementing management of heart failure is to understand and promote patient self-care.

The Self-Care Paradigm Clinicians long ago accepted the idea of self-care for patients with diabetes mellitus. They have been much slower to accept it for patients with other types of chronic illnesses, despite compelling evidence that promotion of patients’ selfcare abilities results in improved outcomes.75-77 Self-care is the process in which patients, often with the help of their families or another caregiver, participate in their own care­ (Figure 59-1). Self-care is the foundation upon which successful management of heart failure is built. The terms selfcare, self-management, adherence, and knowledge frequently are used interchangeably, but each has a distinct meaning.78 Investigators have often measured regimen adherence or knowledge and call these “self-care”.24 In other studies, knowledge is assumed to be sufficient for self-care by authors who overlook the fact that knowledge is necessary but not sufficient for self-care.79 Thus, it is important that clinicians understand the process of self-care so that they can assist patients to participate effectively in it. The self-care process includes both maintenance and management components.80 An assumption of self-care is that for patients with heart failure to be successful at self-care, they must engage in the behaviors that will help them to stay physiologically stable (e.g., eating a low-sodium diet) and they must adhere to the prescribed regimen, which is selfcare maintenance. They also must make decisions about how to address signs and symptoms when they occur (e.g., take extra diuretic if weight increases 3 pounds [1.4 kg] in 1 week), which is self-care management. The process of self-care consists of the stages illustrated in Figure 59-1. A major factor that influences patients’ skill at self-care management activities is self-efficacy, or confidence in one’s ability to perform self-care.80 Stage 1 of the self-care process, maintenance, involves symptom monitoring and treatment adherence. Self-care maintenance involves following the advice of health care providers to follow the treatment plan, make healthy lifestyle choices, and monitor for symptom changes. Patients who

CH 59 Disease Management in Heart Failure

Although a few studies have demonstrated a neutral or negative effect of management programs for heart failure, most such programs, regardless of type, have yielded positive outcomes.51-60 Meta-analyses have confirmed that in most studies, patients who are cared for in these programs experience fewer rehospitalizations, incur lower health care costs, and, in many cases, have longer survival (Table 59-2).51,54,57 Many patients demonstrate improved functional and symptom status and enjoy better quality of life than they did before the intervention and in comparison with patients treated with usual care.54,56,57

858 TABLE 59–2   Meta-analyses of Management Programs for Heart Failure Number of Studies Characteristics Reference Reviewed of Studies

CH 59

Number of Patients Included in Studies Reviewed

Results

Conclusions

Clark et al (2007)57

13 Trials (9 studies of structured telephone support, 3 studies of telemonitoring, 1 study of both)

All-cause mortality (14 studies): All randomized, 4264 Patients; controlled trials mean age of study l 20% reduction, 95% CI = 0.08-0.31 l Telemonitoring (RR = 0.62; 95% CI = 0.45-0.85) was participants: more beneficial than the structured telephone support 57-75 years; (RR = 0.85; 95% CI = 0.72-1.01) NYHA classes II-IV; LVEF < 40% All-cause admissions (8 studies): l No benefit from telemonitoring (RR = 0.98; 95% CI = 0.84-1.15) or structured telephone support (RR = 0.94; 95% CI = 0.87-1.02) Admissions for heart failure (9 studies): l No benefit from telemonitoring (RR = 0.86; 95% CI = 0.57-1.28) or structured telephone support (RR = 0.78; 95% CI = 0.68-0.89). QOL, cost, and acceptability: l Significant improvement in QOL in 3 of 6 studies l Lower health care costs in 3 of 4 studies of structured telephone support interventions l Acceptable to patients in 3 of 4 studies

Gohler et al (2006)8

36 Trials (16 in the United States): DMPs consisted of patient education (on average, three educational components) and discharge plan (scheduled clinic visits, home visits, or nurse-initiated telephone contacts);

All randomized, 8341 Patients; All-cause admissions (32 studies): l Pooled difference on the first all-cause rehospitalization: controlled trials 37%-99% men; mean age of study 8% favoring DMPs (P < .0001, 95% CI = 0.05-0.11; participants: NNT = 13, 95% CI = 0.09-0.20) l Pooled difference on the subsequent all-cause rehospital56-79 years; 33%-100% NYHA ization: 19% favoring DMPs (P < .0001, 95% CI = classes II-IV 0.02-0.35; NNT = 5, 95% CI = 0.03-0.50) l Personal contact was more effective than telephone ­contact (risk difference, −10.5% vs. −3.6%) All-cause mortality (30 studies): l Pooled mortality difference: 3% favoring DMPs (P 50% men in failure DMP): l Clinical follow-up with supervision by cardiology 16 studies; age ­department, home visitation, and telephone follow-up are of majority of effective in decreasing hospitalization participants ≥ 70 years; LVEF < 40% l Clinical follow-up with PCP supervision (RR = 1.17; 95% CI = 0.90-1.51) did not decrease hospitalization in most participants; comorbid Quality of life, medication use, and mortality: l Improved quality of life conditions: diabetes mellitus l No difference in mortality (19%-52%), hyper- l Modest increased use of ACE inhibitors l Significantly increased medication adherence in one study tension (29%76%), COPD (19%-36%)

DMPs are an effective intervention in decreasing hospitalizations of patients with heart failure but not mortality

4445 patients; >50% men in 16 studies; mean age of study participants: 73.3; 61.0 ± 20.5% of patients with NYHA classes III and IV

All randomized, 238 Patients; controlled trials 37%-62% men; mean age of study participants: 71-83.3 years

Hospital readmission rates (8 studies: RR = 0.79; 95% CI = 0.68-0.91) Mortality (6 studies: RR = 0.98; 95% CI = 0.72-1.34) Quality of life (4 studies) l In 3 studies, disease-specific instruments were used: significant improvement noted only in 2 of the 3 studies

Peridischarge programs decrease number of hospital readmissions, but not mortality rates

All randomized, 5039 Patients controlled trials of multidisciplinary management programs in an outpatient setting

Admissions for heart failure (27% of reduction; NNT = 11): l Reduced in DMPs with follow-up by a specialized multidisciplinary team (RR = 0.74; 95% CI = 0.63-0.87), in DMPs focused on self-care activities (RR = 0.66; 95% CI = 0.52-0.83), and in DMPs with telephone contact with instructions to see PCP if condition was deteriorating (RR = 0.75; 95% CI = 0.57-0.99) All-cause admissions: l Reduced in DMPs with follow-up by a specialized multidisciplinary team (RR = 0.81; 95% CI = 0.71-0.92; NNT = 10; 20% reduction) and in DMPs focused on self-care activities (RR = 0.73; 95% CI = 0.57-0.93) but not in DMPs with telephone contact (RR = 0.98; 95% CI = 0.80-1.20) Mortality: l Reduced in DMPs with follow-up by a specialized multidisciplinary team (RR = 0.75; 95% CI = 0.59-0.96; NNT = 17; 25% reduction) but not in DMPs focused on self-care activities (RR = 1.14; 95% CI = 0.67-1.94) or in DMPs with telephone contact (RR = 0.91; 95% CI = 0.67-1.29)

Multidisciplinary approaches reduce rates of hospitalization for heart failure; in particular, programs involving specialized follow-up by a multidisciplinary team decrease all-cause hospitalizations and mortality The benefits and cost effectiveness of these multidisciplinary programs compare favorably with those of established drug treatments for heart failure Continued

CH 59 Disease Management in Heart Failure

Yu et al (2006)60

Number of Patients Included in Studies Reviewed

860 TABLE 59–2    Meta-analyses of Management Programs for Heart Failure—cont’d Number of Studies Characteristics Reference Reviewed of Studies

CH 59

Phillips et al (2004)54

Number of Patients Included in Studies Reviewed

Results

Conclusions

Medication, QOL or functional status, and cost: l Higher use of proven efficacious medications in intervention recipients (6 studies) l Higher adherence to medication and dietary regimens (5 studies) l Improved QOL and functional status in intervention recipients (9 studies) l Cost savings with intervention (15 studies) Readmission (8 studies): 14 Trials (10 in the All randomized, 3304 Patients; l Fewer intervention recipients were readmitted: NNT = 12, United States): 3 controlled trials 62% men, 14% RR = 0.75, 95% CI = 0.64-0.88 studies of a single nonwhite; mean l CHF- or CVD-specific readmission: RR = 0.65; 95% CI = home visit; 6 studage of study 0.54-0.79 ies of a home visit participants: 70 l Combined endpoint of death or readmission: RR = 0.73; with or without years or older in 95% CI = 0.62-0.87 frequent telephone 16 studies and Mortality (14 studies): contacts; 4 studies younger than 70 of frequent clinic years in 2 studies; l Trend toward lower rates of all-cause mortality (RR = 0.87; 95% CI = 0.73-1.03) visit and teleLVEF < 40% in 8 phone follow-up studies and LVEF Length of stay, QOL, and medical costs: or a home visit, > 40% in 2 studies l Difference of length of stay between intervention and control groups was not significant or both; 1 study l Significant improvement in QOL in intervention recipients of a day hospital l Cost effectiveness (cost difference: −$359, 95% CI = with an available −$763-$45, for non-U.S. trials and −$536, 95% CI = specialized heart −$956-$115, for U.S. trials) failure unit

Comprehensive discharge planning with postdischarge support for older adults with heart failure significantly reduced readmission rates and may improve survival and QOL without increasing costs

ACE, angiotensin-converting enzyme; CHF, congestive heart failure; CI, confidence interval; COPD, chronic obstructive pulmonary disease; CVD, cardiovascular disease; DMP, ­disease management program; LVEF, left ventricular ejection fraction; NNT, number needed to treat; NYHA, New York Heart Association; PCP, primary care provider; QOL, q ­ uality of life; RR, relative risk.

BOX 59–1 Putting Principles of Management of Heart Failure into Practice 1. Understand and promote patient self-care 2. Assess and address patient factors that affect adherence to regimens and ability to engage in self-care 3. Teach skills preferentially over knowledge 4. Include family members and informal caregivers in education 5. Identify and target patients who are at high risk for rehospitalization 6. Employ components of management programs for heart failure that improve outcomes l Individualized, comprehensive patient and family or caregiver education and counseling on an outpatient basis l Optimization of medical therapy l Vigilant follow-up l Increased access to health care professionals l Early attention to fluid overload l Coordination with other agencies as appropriate l Either physician-directed care with assistance from nurse coordinators or nurse-managed care by experienced ad­vanced practice cardiovascular nurses with access to a cardiologist 7. Use behavioral strategies to increase adherence to regimen

routinely monitor themselves are more likely to seek treatment at the early stages of exacerbation. Heart failure is notable for the subtlety of early symptoms, and so symptom monitoring is an essential component of self-care maintenance. Subsequent stages of the self-care process reflect management, which is an active, iterative, deliberate decision-­ making process undertaken in response to symptoms.80 Symptom management is essential for patients with heart failure if they are to control what may be a precarious balance

between relative health and symptomatic heart failure. In self-care management, once the patient recognizes changes in signs and symptoms, the patient must make decisions about how to respond. Stage 2, symptom recognition, involves recognition that a change in signs or symptoms has occurred and that the change is related to heart failure. If patients recognize a symptom as related to their heart disease, they are more likely to appropriately evaluate its urgency and respond more quickly.81 Stage 3, symptom evaluation, is the process by which patients attempt to distinguish between important and unimportant symptom changes. If a symptom is judged to be important, it is more likely that the patient will decide that he or she needs to take action.80 Patients may proceed through these stages and not take action because they lack knowledge about what to do, judge that the costs of the action outweigh the benefits, fail to understand the importance of the symptom change, or believe that no effective strategy is available. Health care providers can intervene at this point and increase patients’ knowledge about important signs and symptoms and education them about the appropriate actions to take when changes occur. Stage 4, treatment implementation, involves action in response to the prior stages. Some actions are intuitive and require little thought (e.g., rest). Some actions can be performed independent of others (e.g., diet adjustments), and some actions are interdependent or require some guidance from a health care provider (e.g., adjusting diuretic dose). Stage 5, treatment evaluation, concerns the effectiveness (e.g., in symptom relief) of selected treatments. If a treatment is effective, it may be attempted again. Research has shown that this ability is learned through experience.20 However, other ways of increasing this expertise must be found if patients with newly diagnosed heart failure are to avoid rehospitalization during the first few months after their initial hospitalization. Outpatient management with a disease

861

SELF-CARE OF HEART FAILURE MODEL Self-care maintenance

Symptom recognition

Symptom evaluation

Treatment implementation

Treatment evaluation

FIGURE 59–1  Self-care encompasses two processes: maintenance and management. Selfcare maintenance involves engagement in making healthy life style choices and being adherent CH 59 to the prescribed regimen. Self-care management is the process of decision making when symptoms or signs change.

Self-care confidence

management approach to heart failure is one such way, but it is important to determine first what patient factors exist that could interfere with the patient’s ability to optimally engage in self-care. Assess Patient Factors That Interfere with Self-Care Numerous issues can interfere with patients’ self-care abilities.15 Advancing age, low education level, and low health literacy can affect patients’ ability to learn and comply with treatment recommendations.20 Inability to communicate with the provider because of language-, age- and culture-related beliefs has also been demonstrated to be a major factor interfering with adherence to treatment regimens. Cognitive dysfunction is increasingly recognized as a common problem among patients with heart failure44,82 that can contribute to poor self-care.83 Simple measures such as a clock-drawing test are available for routine screening of cognitive abilities.44 Personal factors such as lack of motivation, low self-efficacy, emotional distress (especially depression), poor health habits such as smoking, and lack of perceived control also contribute to difficulties practicing self-care and changing health behaviors.28,84,85 Situational factors such as social isolation, lack of support,28 and the challenges of implementing a complex treatment regimen under limited economic resources13 complicate matters further. Illness factors such as length of experience with the diagnosis, symptom severity, physical limitations, and presence of multiple comorbid conditions can contribute to poor compliance and poor selfcare.28,86 As the importance of these factors to self-care and outcomes becomes increasingly obvious, health care providers must be educated about assessing and managing them. Include Family Members and Informal Caregivers in Education Family members and friends are the unobserved and often neglected informal caregivers who provide substantial support for many patients with heart failure.87 Failure to include informal caregivers in disease management approaches can contribute to poor outcomes. In particular, patients who have any of the factors above that can adversely affect self-care may need the support of informal caregivers.88-90 Whenever possible, it is essential to identify these caregivers and include them in education and counseling sessions.91 Identify and Target Patients Who Are at Risk for Rehospitalization Existing evidence suggests that approaches to the management of heart failure are most effective when used for patients who are at risk for rehospitalizations.92-94 Because a patient’s heart failure status can change over time, it is necessary to reassess risk status often. A number of risk factors for rehospitalization have been identified and confirmed in multiple studies. Older age, particularly older than 75 years, is a major risk factor.95 A previous hospital admission for heart failure within the previous 30 days to 1 year92,96,97 is another important risk factor, as are multiple hospitalizations for any reason within the previous 5 years.71,98 The presence of comorbid illnesses,

particularly multiple active conditions, is another major risk factor.96,97 Three specific comorbid conditions increase risk: (1) history of chronic obstructive pulmonary disease; (2) diabetes; and (3) renal insufficiency as reflected by creatinine level of 2.5 mg/dL or higher or by higher level of blood urea nitrogen.92,96,97 Patients with depression or anxiety,99-101 those with inadequate support systems or who live alone,102 those with cognitive impairment,103 and those with functional impairment98 are also at increased risk for rehospitalization. Components of the Management of Heart Failure That Improve ­Outcomes Clinicians who do not have access to management programs for heart failure can, nonetheless, make great strides in improving heart failure patient outcomes by incorporating effective aspects of these programs in their practice. There have been no comparisons of the individual components used in management programs for heart failure, but examination of studies with neutral or negative findings and of recent studies where some components have been omitted provides sufficient information to make recommendations about the components that are likely to improve outcomes (see Box 59-1). Each of these components is described below. Individualized, Comprehensive Patient and Family or Caregiver Education and Counseling on an Outpatient Basis.  At the core of every successful management program for heart failure is individualized, comprehensive education and counseling, the goal of which is to improve adherence to the prescribed regimen.24,104-106 The addition of comprehensive education and counseling alone to the regimen improves clinical outcomes as long as they include behavioral strategies to increase adherence.107 Outpatient education and counseling must always supplement inpatient education. Inpatient education alone is inadequate, and patients are not able to retain most of what they are taught in the hospital.32 Regardless of the quality of inpatient education, patients are ill, anxious, distracted, and thus in poor condition to learn and retain material. In addition, there is little time in the hospital to impart all of the needed information. Patients and their families and informal caregivers must perform the majority of heart failure care at home. If a patient does not know what is required and why, does not have the motivation or skills to accomplish it, or does not appreciate the importance of the activities, the patient cannot participate effectively in care. Therefore, the goals of education and counseling are to help patients and their informal caregivers acquire the knowledge, skills, and motivation they need to adhere to the treatment plan and participate effectively in self-care. To help patients do this, health care providers not only need to impart necessary knowledge but also must impart it in a manner that promotes retention and application of what is learned. Content for Patient and Family Education and ­Counseling.  Patients with heart failure must perform specific behaviors to cope with the illness. They must limit dietary sodium to 2 to 3 g per day, take medications as prescribed routinely, and get periodic flu and pneumococcal immuniza-

Disease Management in Heart Failure

Symptom monitoring and treatment adherence

Self-care management

862 tions (comply with treatment). They need to be taught to weigh

themselves daily and how to monitor for common symptoms of decompensation such as shortness of breath, fatigue, peripheral swelling, waking at night with coughing or shortness of breath, dizziness, and swelling (monitor signs and symptoms).108 They need to be taught when to report abnormalities CH 59 to their health care provider (seek assistance when necessary). Finally, many patients with heart failure should be encouraged to exercise, stop smoking, limit or halt their alcohol intake, and control other comorbid conditions such as diabetes, hypertension, or hyperlipidemia (change unhealthy lifestyles).108 Specific education and counseling to support patients successfully engage in these behaviors are described in Box 59-2. Teaching and Counseling Methods.  It is essential that effective behavior change strategies be given to patients and families along with provision of information. Behavior change researchers have long demonstrated that knowledge alone is insufficient for changing behavior,109 and even now patients report frustration at being told what to do without being given the skills to make the expected behavior change.28 In addition, a number of factors that contribute to nonadherence and rehospitalization also contribute to difficulties in putting information into action. Thus, clinicians need to understand factors that influence patients’ ability to make recommended health behavior changes and must become familiar with effective behavior change strategies that they can teach. In addition to the conditions described in the “Assess Patient Factors That Interfere with Self-Care” section, the following conditions are barriers to adherence. It is important to assess and address these barriers if they are present. Impediments inherent in recommended treatments themselves can limit adherence considerably. The number of medications, treatment complexities, drug side effects, cost of medications, cost of transportation to the pharmacy and to physicians’ offices, and unsafe location of the neighborhood pharmacy all can contribute to medication nonadherence.13,28 Other barriers to medication adherence included medication unpleasantness; difficulty remembering to take medication; having to take too many medications each day; the action of diuretics, which makes it difficult to leave home; and nighttime awakenings to urinate. It may be difficult to follow recommendations for dietary sodium restriction because of time, cost, taste, difficulty understanding diet requirements, inability to socialize when food is involved, limitations on eating out, and limitations on eating prepackaged and canned foods.28 Education and Counseling Style.  Optimal patient education and counseling involve more than simply providing information. Counseling emphasizes individualized delivery of important information, taking into account the factors discussed previously that interfere with successful participation in care (e.g., language, cognitive function, mood), as well as a patient’s readiness to change. Prochaska and colleagues110,111 proposed a model of change that acknowledges that many people are not ready to engage in the behaviors that health care providers advocate. According to their model, patients in the precontemplation phase of change are not considering change; those in the contemplation phase are thinking about change but have yet to commit to change; and those in the preparation phase are planning to make changes in the future and may have already engaged in some early steps of change. Most patients are in one of these three early phases when a provider advocates a new behavior. Few patients are in the action phase (in which change has occurred) or maintenance phase (change has been maintained for 6 months or more), even when the need for behavioral change was recognized before it was addressed by a provider (e.g., smoking cessation). Correction of patients’ misperceptions regarding their condition and treatment is another important aspect of education and counseling. It is helpful to assess patients’ current

BOX 59–2 Education and Counseling for Patient and Family or Informal Caregiver General Topics 1. Explanation of heart failure l Include explanation of symptoms 2. Psychological responses l Possibility of increased depression and anxiety l Necessity of treatment if anxiety or depression persists 3. Immunizations needed l Flu and pneumococcal vaccines 4. Prognosis 5. Advanced directives Examples of Skills Needed to Manage Heart Failure ­Successfully 1. How to read nutrition labels 2. How to assess for ankle swelling, other edema, fatigue, and dyspnea 3. How to compensate for missing a medication 4. How to prepare for an office visit with the provider Symptom Monitoring and Recognition 1. Symptoms to be expected versus symptoms of worsening heart failure, and how to monitor 2. Self-monitoring with daily weighings 3. What to do in case of increased symptoms Dietary Recommendations 1. Diet with no more than 2 to 3 g of sodium 2. Fluid management l Fluid restriction unnecessary except for patients with hyponatremia, but moderation in fluid intake (