Index. A Action potential duration, increased, by decreases in sodium current,

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1 Heart Failure Clin 1 (2005) Index Note: Page numbers of article titles are in boldface type. A Action potential duration, increased, by decreases in sodium current, Adenylyl cyclase, overexpression of, 230 Amyloid, toxic aggregates and, Amyloidosis, Amyloidotic cardiomyopathies, 247 Animal models, of heart failure, Apoptosis, Bcl-2 family proteins in, 253 cardiac myocyte, 276 cardiomyocyte, in advanced heart failure, 256 cardiomyocyte resistance to, gene therapy to augment, caspases in, 252 definition of, 251 effects of nitric oxide synthases on, in heart failure, 277 extrinsic and intrinsic pathways of, 252 in etiology and progression of heart failure, in experimental models of heart failure, 257 in heart failure, therapeutic implications of, mechanisms of, 252 mitochondria in, mitochondrial pathway of, 252 molecular regulation of, of cardiac myocytes, á 1 -adrenergic receptor and, 188 promotion of, by nitric oxide, 277 Apoptosis proteins, control of, 254 inhibitor of, 254 Arrhymogenic events, I Na -induced, in ventricular myocytes, Arrhythmia(s), cellular, classes of, 174 in acute myocardial infarction, 193 in heart failure, 193 in long QT syndrome, 193 likelihood of, in failing cardiomyocyte, 174 mechanisms of, during reductions in sodium current, á 1 -Adrenergic receptor, and apoptosis of cardiac myocytes, 188 á-adrenergic receptor kinase, gene therapy to inhibit, 290 in heart function, 226 á-adrenergic receptor kinase-c-terminus expression, rescue of muscle lim protein knockout by, 231 á-adrenergic receptor(s), density of, gene therapy to restore, 290 in heart failure, overexpression of, pharmacogenomics of, á-adrenergic signaling, dysregulation of, in heart failure, gene therapy to manipulate, 289 á-adrenergic signaling system, in human heart, á-adrenoceptor, in control of calcium handling in cardiac myocyte, 172 reduced responses of, in failing cardiomyocyte, response in phenotype, of failing cardiomyocyte, B á-blockers, differences between, in heart therapy, Bcl-2 family proteins, end-stage cardiomyopathy of and, 254 in apoptosis, 253 proapoptotic, two groups of, 254 Bisoprolol, /05/$ see front matter D 2005 Elsevier Inc. All rights reserved. doi: /s (05) heartfailure.theclinics.com

2 314 INDEX Bone marrow-derived stem cells, , , 307, 308 Bucindolol, 186 C Ca 2+ homeostasis, endoplasmic reticulum chaperone function and, 242 Caenorhabditis elegans, 251 Calcineurin, 266 active, overexpression of, Calcineurin 1, regulator of, 163 Calcineurin inhibitors, prevention of hypertrophic response by, 226 Calcium channel overexpression, L-type, 225 Calcium concentration, intracellular, in cardiac hypertrophy, 268 Calcium handling, in cardiac myocyte, á-adrenoceptor control of, 172 Calcium influx, effects of rate of depolarization and membrane potential on, Calmodulin kinase, constitutively active, overexpression of, 227 Calsequestrin-overexpressing mice, rescue of, with phospholamban knockout mice, 230 Calsequestrin overexpression, 223 Calsequestrin overexpression hypertrophy, and Na+ and -Ca 2+ exchanger overexpression, 230 camp-dependent protein kinase, phosphorylation and, 175, 176 camp-dependent protein kinase substrates, for excitation-contraction coupling, 175 camp response element-binding protein overexpression, 225 Cardiac action potential, reduced sodium currents and, 194, 195 Cardiac function, phospholamban in, Cardiac hypertrophy, cytokines in, 266 definition of, 263 growth factors in, 266 in mechanical overload, intracellular signaling in, mechanisms of, neurohumeral stimuli and, two forms of, 264 Cardiac jelly, valve formation and, 162, 163 Cardiac myocyte(s), apoptosis of, á 1 -adrenergic receptor and, 188 calcium handling in, á-adrenoceptor control of, 172 Cardiac myocyte hypertrophy, 276 Cardiac myocyte programmed cell death. See Apoptosis. Cardiac precursors, bilateral, migration of, Cardiac remodeling, after myocardial infarction, NOS3 in, description of, etiologies of, 276 fibrosis in, fibroblasts in, nitric acid and, NOS2 in, studies in mice, 280 NOS3 in, 282 studies in mice, 282 Cardiogenesis, and regulation of cardiac-specific gene expression, Cardiomyocyte(s), apoptotic pathways in, 252 failing, arrhythmias in, likelihood of, 174 characteristics of, 207 impaired relaxation in, diastolic dysfunction and, reduced á-adrenoceptor responses of, in failing cardiomyocyte, reduced contraction in, role of á-adrenoceptor response in phenotype of, 177 removal of phospholamban and, residual, reinduction to mitotic cycle, in cell therapy, 291 resistance to apoptosis, gene therapy to augment, Cardiomyocyte apoptosis, in advanced heart failure, 256 Cardiomyocyte hypertrophy, and interstitial fibrosis, in mice, 187 Cardiomyopathy(ies), amyloidotic, 247 end-stage, Bcl-2 family of proteins and, 254 familial hypertrophic, 221 myosin-binding protein-c mutation models of, sarcomere protein gene mutation models of, 221

3 INDEX 315 idiopathic dilated, 171 depressed contraction in, 172 protein unfolding in, transthyretin, 246 Cardiomyoplasty, cellular. See Cell therapy, in heart failure. Carvedilol, 186 Caspases, in apoptosis, 252 Catecholamines, adrenergic receptors and, 183 Cell death, programmed. See Apoptosis. Cell growth, patterns of clonal cell organization and, 161 Cell therapy, autologous, clinical trials using, 307, 308 bone marrow-derived stem cells in, 308 in heart failure, , by injection of exgenous contractile cells into scar, 292 by naturally contractile cells, by noncontracting cell transplantation, 292 by potentially contractile cells, by reinduction of residual cardiomyocytes fo mitotic cycle, 291 by transformation of in-scar fibroblasts into contractile cells, cell delivery in, survival/functional effect of, delivery systems for, 295 skeletal myoblasts in, 308 Cell transplantation, noncontracting, in cell therapy, 292 Cells, genes and, targeting of, in progression to heart failure, Chromatin, compaction and aggregation of, in apoptosis, 251 Conduction system, development of, Congestive heart failure, renin-angiotensin system and, 265 Constitutive gp130, gp130 receptor knockout and, Contractile cells, exogenous, injection into scar, in cell therapy, 292 natural, in cell therapy, potential, in cell therapy, Contraction, reduced, in failing cardiomyocyte, Cyclosporine, 266 Cytokines, growth factors, and receptors, in cardiac hypertrophy, 266 Cytosol, degradation of proteins in, 243 Cytosolic molecular chaperone families, nomenclature of, 238 D Depolarization, rate of, and membrane potential, changes in, effects on calcium influx, and membrane voltage, effects on I Ca, 195, 196 reduced sodium currents and, 194, 195 Diastolic dysfunction, impaired relaxation in failing cardiomyocyte and, DiGeorge syndrome, 162 Diseases, human, misfolding proteins in, Down syndrome, 163 Drosophila melanogaster, formation of heart of, DSCR1 gene, 163 E Endoplasmic reticulum, misfolded proteins in, Endoplasmic reticulum-associated protein degradation, 243 Endoplasmic reticulum chaperone function, and Ca 2+ homeostasis, 242 Endoplasmic reticulum folding machinery, 240 Endoplasmic reticulum lectin chaperone complex, 241 Endoplasmic reticulum stress response, 243, 244, 247 Endoplasmic reticulum unfolding response, transgenic mice models of, 247 Endothelial progenitor cells, 305 Excitation-contraction coupling, changes in phase 0 of action potential on, sarcoplasmic reticulum in, 207, 208

4 316 F Fabry s disease, 247 Fibroblasts, in-scar, transformation into contractile cells, in cell therapy, G G protein à subunit, cardiac stimulatory, overexpression of, 229 G-protein-coupled receptor kinases, in heart failure, 185 G-proteins, in cardiac hypertrophy, 267 Gàq and G11 double knockout, 232 Gàq and Gsà, overexpression of, 229 Gene expression, cardiac-specific, regulation of, cardiogenesis and, Gene therapy, in heart failure, delivery systems for, 295 to augment cardiomyocyte resistance to apoptosis, to inhibit á-adrenergic receptor kinase, 290 to manipulate á-adrenergic receptor signaling, 289 to modulate calcium homeostasis, 288 to reduce phospholamban protein levels, 289 to restore á-adrenergic receptor density, 290 to restore sarcoplasmic reticulum Ca 2+ -ATPase activity, transduction efficiency/functional effect of gene product in, Genes, and cells, targeting of, in progression to heart failure, Growth factors, cytokines, and receptors, in cardiac hypertrophy, 266 Grp78/Grp94 complex, Gsà, overexpression of, synergistic effects of, on familial hypertrophic cardiomyopathy, 232 H Heart, early morphogenesis of, sarcoplasmic reticulum in, Heart defects, congenital, incidence of, 272 Heart disease, molecular models of, transgenic models of heart failure and, INDEX Heart failure, animal models of, 219 criteria for selection of, reasons for, 219 apoptosis in, arrhythmias in, 193 as complex syndrome, 268, 306 á-adrenergic receptors in, cardiac troponin knockout in, causes of, 171 cell therapy in, , congestive, renin-angiotensin system and, 265 decreased sodium current during, 201 dysregulation of á-adrenergic signaling in, etiology and progression of, apoptosis in, gene therapy in. See Gene therapy, in heart failure. genetic models of, markers of, 232 myofilament and cytoskeletal disruptions in, 220 pathogenesis of, phospholamban in, progression to, targeting genes and cells in, transcription factors and, 225 transgenic models of, molecular models of heart disease and, tropomodulin overexpression in, 220 Heart field, secondary, in development of myocardium, Heart therapy, differences between á-blockers in, Heart tube, formation of, Heat shock protein 70, and heat shock protein 90, chaperone machinery of, Heat shock protein chaperones, small, 240 Hyperphosphorylation, in failing heart, 176 Hypertrophy, cardiac. See Cardiac hypertrophy. I I Ca, effects of membrane voltage and rate of depolaization on, 195, 196 Insulin-like growth factor-1, overexpression of, 228 Integrins, in cardiac response to mechanical stress, 264 Interstitial fibrosis, and cardiomyocyte hypertrophy, in mice, 187

5 INDEX 317 Intracellular signaling, in cardiac hypertrophy, Ion handling and protein transport, Ischemic injury, protein unfolding and aggregation in, 246 J Junction overexpression, K K + -channel overexpression, 224 Kinase signaling cascades, prosurvival, Kinases, and phosphatases, L L-type calcium channel overexpression, 225 Lectin (calreticulum-calnexin) complex, in chaperone machinery, Long QT syndrome, 174 acquired and genetic, reduced sodium currents during, 194, 195 arrhythmias in, 193 decreased sodium current during, 201 M Melusin, in cardiac response to mechanical stress, Membrane potential, and rate of depolarization, changes in, effects on calcium influx, Membrane voltage, and rate of depolarization, effects on I Ca, 195, 196 Metoprolol, 186 Mitochondria, in apoptosis, Mitochondrial chaperones, nomenclature of, 238 Mitochondrial outer membrane permeabilization, Mitochondrial proteins, folding of, 242 Mitochondrial respiration, cardiac function and, 278 Mitral valve disease, depressed contraction in, 172 Molecular chaperones, definition of, 237 properties of, 237 Molecular models of heart disease, transgenic models of heart failure and, Molecular targets, for intervention, in heart failure, 287 Molecular therapeutic approaches, in heart failure therapy, Muscle lim protein knockout, rescue of, by á-adrenergic receptor kinase-c-terminus expression, 231 by phospholamban knockout, 231 Myoblasts, skeletal, 304 in cell therapy, 308 Myocardial hypertrophy, as adaptive mechanism, 263 Myocardial infarction, acute, arrhythmias in, 193 decreased sodium current during, 201 cardiac remodeling after, NOS3 in, Myocardium, development of, endocardial-myocardial signaling in, 161 secondary heart field and, Myocyte, cardiac, calcium handling in, á-adrenoceptor control of, 172 Myocyte hypertrophy, cardiac, 276 MyoD, overexpression of, transformation of in-scar fibroblasts into contractile cells by, in cell therapy, N Na + -Ca 2+ exchanger overexpression, Nerve growth factor, overexpression of, 228 Neural crest cells, in outflow tract formation, 162 Neuregulin, ligand, role of, in trabeculation of ventricle, 160 Neurohumeral stimuli, cardiac hypertrophy and, Nitric acid, and cardiac remodeling, Nitric oxide, donor compounds, cardiac effects of, 278 effects on cardiac cells, 275 effects on cardiovasculature, 275 effects on myocardial systolic contractile function, 277 NOS3-derived, 279 in ventricular remodeling, 281

6 318 promotion of apoptosis by, 277 targeted to effector proteins, 278 Nitric oxide synthase 1, 279 Nitric oxide synthase 2, Nitric oxide synthase 3, Nitric oxide synthases, 276 calcium independent, effects on apoptosis, in heart failure, 277 modulation of hypertrophy by, 277 P Phosphoinositide 3-kinase signaling, Phospholamban, as therapeutic target, for heart failure, calcium cycling by, 210 effects of, PLN-heterozygous hearts studied for, studied in mouse models, 214 in cardiac function, in pathogenesis of heart failure, knockout, 222 mutations, nonphosphorylatable, overexpression of, 222 overexpression of, 222 phosphorylation of, 175, 176 protein, 268 levels of, gene therapy to reduce, 289 removal of, and cardiomyocyte, role in cardiac function, Phospholamban ablation, and sarcoplasmic reticulum-ca 2+ -ATPase overexpression, 231 Phospholamban knockout mice, crossbreeding of, with troponin I variants, 231 rescue of calsequestrin-overexpressing mice with, 230 rescue of muscle lim protein knockout by, 231 Phosphorylation, camp-dependent protein kinase and, 175, 176 of phosphalamban, 175, 176 of ryanodine receptor, in failing heart, 176 Polypeptides, newly synthesized, chaperone-assisted folding of, 237, 239 Protein(s), apoptosis, control of, 254 inhibitor of, 254 INDEX Ca 2+ handling, in failing myocardium, 173 chaperone, genetic mutations of, cystosolic, folding of, 237 degradation of, endoplasmic reticulum-associated, 243 in cytosol, 243 folding of, in mammalian heart, misfolded, in endoplasmic reticulum, misfolding, in human diseases, mitochondrial, folding of, 242 NCX, levels of, in failing myocardium, 173 unfolded, accumulation of, cellular responses to, destiny of, unfolding of, and aggregation of, in ischemic injury, 246 in cardiomyopathies, Protein-C mutation models, myosin-binding, of familial hypertrophic cardiomyopathy, Protein kinase B, cell survival and, Protein kinase-áii, constitutively active, 227 Protein kinase C, in cardiac hypertrophy, 267 Protein phospholamban, 268 R gp130 Receptor knockout, and constitutive gp130, Renin-angiotensin system, congestive heart failure and, 265 Retinoic acid receptor, overexpression of, 228 Ryanodine receptor, 173 phosphorylation of, in failing heart, 176 S Sarco(endo)plasmic reticulum chaperones, nomenclature of, 238 Sarcomere, constitution of, 264 Sarcoplasmic reticulum, cardiac junctional, in heart failure, in excitation-contraction coupling, 207, 208 in heart,

7 INDEX 319 Sarcoplasmic reticulum Ca 2+ -ATPase activity, gene therapy to restore, Sarcoplasmic reticulum Ca 2+ transport pump-1 and -2 overexpression, 223 Sarcoplasmic reticulum calcium load, decreases in sodium current and, Serum response factor, 160 overexpression of, 225 Sodium current(s), arrhythmic mechanism hypothesis, transient steady-state features of, factors affecting, reduced, and rate of depolarization and overshoot of cardiac action potential, 194, 195 and sarcoplasmic reticulum calcium load, during acquired and genetic long QT syndrome, during acute myocardial infarction, 201 during heart failure, 201 during long QT syndrome, 201 increased action potential duration due to, mechanisms of arrhythmias during, Stem cells, adult, 303, 304 in cell therapy, bone marrow-derived, , 307, 308 in cell therapy, cardiac, 306 embryonic, 303, 304 in cell therapy, 294 hematopoietic, 305 mesenchymal, multipotent, 304 plasticity of, 303 satellite, 304 Sympathetic nerve endings, noradrenaline from, stimulation of cardiomyocytes by, 183, 184 T TCP1 ring complex, in chaperone machinery, 240 Toxic aggregates, and amyloid, Transcription factors, heart failure and, 225 Transforming growth factor-á2 knockout, Transgenic models of heart failure, molecular models of heart disease and, Transthyretin cardiomyopathies, 246 Triadin 1 overexpression, 224 Tumor necrosis factor-à, overexpression of, 229 U Ubiquitin-proteasome system, 243, 248 Unfolding protein response, 237 V Valves, formation of, Vascular endothelial growth factor, Ventricles, development of, 160 Ventricular myocytes, I Na -induced arrhymogenic events in, Ventricular remodeling, 275 NOS3-derived nitric oxide in, 281 X Xamoterol, 186 Z Zebrafish, heart of, 273