Heart Failure Clin 1 (2005) 313 319 Index Note: Page numbers of article titles are in boldface type. A Action potential duration, increased, by decreases in sodium current, 201 202 Adenylyl cyclase, overexpression of, 230 Amyloid, toxic aggregates and, 246 247 Amyloidosis, 246 247 Amyloidotic cardiomyopathies, 247 Animal models, of heart failure, 219 220 Apoptosis, Bcl-2 family proteins in, 253 cardiac myocyte, 276 cardiomyocyte, in advanced heart failure, 256 cardiomyocyte resistance to, gene therapy to augment, 290 291 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, 256 257 in experimental models of heart failure, 257 in heart failure, 251 261 therapeutic implications of, 257 258 mechanisms of, 252 mitochondria in, 255 256 mitochondrial pathway of, 252 molecular regulation of, 252 256 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, 200 201 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, 193 205 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, 183 191 overexpression of, 229 230 pharmacogenomics of, 185 186 á-adrenergic signaling, dysregulation of, in heart failure, 184 185 gene therapy to manipulate, 289 á-adrenergic signaling system, in human heart, 183 184 á-adrenoceptor, in control of calcium handling in cardiac myocyte, 172 reduced responses of, in failing cardiomyocyte, 175 177 response in phenotype, of failing cardiomyocyte, 173 174 B á-blockers, differences between, in heart therapy, 186 187 Bcl-2 family proteins, end-stage cardiomyopathy of and, 254 in apoptosis, 253 proapoptotic, two groups of, 254 Bisoprolol, 186 1551-7136/05/$ see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/s1551-7136(05)00055-3 heartfailure.theclinics.com
314 INDEX Bone marrow-derived stem cells, 294 295, 304 306, 307, 308 Bucindolol, 186 C Ca 2+ homeostasis, endoplasmic reticulum chaperone function and, 242 Caenorhabditis elegans, 251 Calcineurin, 266 active, overexpression of, 225 226 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, 194 196 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, 209 212 Cardiac hypertrophy, cytokines in, 266 definition of, 263 growth factors in, 266 in mechanical overload, 264 265 intracellular signaling in, 266 268 mechanisms of, 263 273 neurohumeral stimuli and, 265 266 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, 273 274 Cardiac remodeling, after myocardial infarction, NOS3 in, 281 282 description of, 275 276 etiologies of, 276 fibrosis in, fibroblasts in, 277 278 nitric acid and, 275 286 NOS2 in, studies in mice, 280 NOS3 in, 282 studies in mice, 282 Cardiogenesis, and regulation of cardiac-specific gene expression, 272 284 Cardiomyocyte(s), apoptotic pathways in, 252 failing, 171 181 arrhythmias in, likelihood of, 174 characteristics of, 207 impaired relaxation in, diastolic dysfunction and, 173 174 reduced á-adrenoceptor responses of, in failing cardiomyocyte, 175 177 reduced contraction in, 171 173 role of á-adrenoceptor response in phenotype of, 177 removal of phospholamban and, 175 176 residual, reinduction to mitotic cycle, in cell therapy, 291 resistance to apoptosis, gene therapy to augment, 290 291 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, 221 222 sarcomere protein gene mutation models of, 221
INDEX 315 idiopathic dilated, 171 depressed contraction in, 172 protein unfolding in, 237 250 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, 291 295, 303 312 by injection of exgenous contractile cells into scar, 292 by naturally contractile cells, 292 294 by noncontracting cell transplantation, 292 by potentially contractile cells, 294 295 by reinduction of residual cardiomyocytes fo mitotic cycle, 291 by transformation of in-scar fibroblasts into contractile cells, 291 292 cell delivery in, survival/functional effect of, 296 297 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, 287 302 Chromatin, compaction and aggregation of, in apoptosis, 251 Conduction system, development of, 164 165 Congestive heart failure, renin-angiotensin system and, 265 Constitutive gp130, gp130 receptor knockout and, 228 229 Contractile cells, exogenous, injection into scar, in cell therapy, 292 natural, in cell therapy, 292 294 potential, in cell therapy, 294 295 Contraction, reduced, in failing cardiomyocyte, 173 174 Cyclosporine, 266 Cytokines, growth factors, and receptors, 227 230 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, 194 196 and membrane voltage, effects on I Ca, 195, 196 reduced sodium currents and, 194, 195 Diastolic dysfunction, impaired relaxation in failing cardiomyocyte and, 173 174 DiGeorge syndrome, 162 Diseases, human, misfolding proteins in, 245 248 Down syndrome, 163 Drosophila melanogaster, formation of heart of, 272 273 DSCR1 gene, 163 E Endoplasmic reticulum, misfolded proteins in, 247 248 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, 197 199 sarcoplasmic reticulum in, 207, 208
316 F Fabry s disease, 247 Fibroblasts, in-scar, transformation into contractile cells, in cell therapy, 291 292 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, 272 284 Gene therapy, in heart failure, 288 291 delivery systems for, 295 to augment cardiomyocyte resistance to apoptosis, 290 291 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, 288 289 transduction efficiency/functional effect of gene product in, 295 296 Genes, and cells, targeting of, in progression to heart failure, 287 302 Growth factors, cytokines, and receptors, 227 230 in cardiac hypertrophy, 266 Grp78/Grp94 complex, 241 242 Gsà, overexpression of, synergistic effects of, on familial hypertrophic cardiomyopathy, 232 H Heart, early morphogenesis of, 272 275 sarcoplasmic reticulum in, 207 209 Heart defects, congenital, incidence of, 272 Heart disease, molecular models of, transgenic models of heart failure and, 219 236 INDEX Heart failure, animal models of, 219 criteria for selection of, 219 220 reasons for, 219 apoptosis in, 251 261 arrhythmias in, 193 as complex syndrome, 268, 306 á-adrenergic receptors in, 183 191 cardiac troponin knockout in, 220 221 causes of, 171 cell therapy in, 291 295, 303 312 congestive, renin-angiotensin system and, 265 decreased sodium current during, 201 dysregulation of á-adrenergic signaling in, 184 185 etiology and progression of, apoptosis in, 256 257 gene therapy in. See Gene therapy, in heart failure. genetic models of, 220 222 markers of, 232 myofilament and cytoskeletal disruptions in, 220 pathogenesis of, phospholamban in, 207 218 progression to, targeting genes and cells in, 287 302 transcription factors and, 225 transgenic models of, molecular models of heart disease and, 219 236 tropomodulin overexpression in, 220 Heart field, secondary, in development of myocardium, 161 162 Heart therapy, differences between á-blockers in, 186 187 Heart tube, formation of, 159 160 Heat shock protein 70, and heat shock protein 90, chaperone machinery of, 237 240 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
INDEX 317 Intracellular signaling, in cardiac hypertrophy, 266 268 Ion handling and protein transport, 224 225 Ischemic injury, protein unfolding and aggregation in, 246 J Junction overexpression, 223 224 K K + -channel overexpression, 224 Kinase signaling cascades, prosurvival, 254 255 Kinases, and phosphatases, 225 227 L L-type calcium channel overexpression, 225 Lectin (calreticulum-calnexin) complex, in chaperone machinery, 240 241 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, 264 265 Membrane potential, and rate of depolarization, changes in, effects on calcium influx, 194 196 Membrane voltage, and rate of depolarization, effects on I Ca, 195, 196 Metoprolol, 186 Mitochondria, in apoptosis, 255 256 Mitochondrial chaperones, nomenclature of, 238 Mitochondrial outer membrane permeabilization, 255 256 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, 219 236 Molecular targets, for intervention, in heart failure, 287 Molecular therapeutic approaches, in heart failure therapy, 187 188 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, 281 282 Myocardium, development of, 160 161 endocardial-myocardial signaling in, 161 secondary heart field and, 161 162 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, 291 292 N Na + -Ca 2+ exchanger overexpression, 224 225 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, 265 266 Nitric acid, and cardiac remodeling, 275 286 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
318 promotion of apoptosis by, 277 targeted to effector proteins, 278 Nitric oxide synthase 1, 279 Nitric oxide synthase 2, 279 280 Nitric oxide synthase 3, 280 282 Nitric oxide synthases, 276 calcium independent, 276 277 effects on apoptosis, in heart failure, 277 modulation of hypertrophy by, 277 P Phosphoinositide 3-kinase signaling, 226 227 Phospholamban, as therapeutic target, for heart failure, 214 215 calcium cycling by, 210 effects of, PLN-heterozygous hearts studied for, 210 211 studied in mouse models, 214 in cardiac function, 209 212 in pathogenesis of heart failure, 207 218 knockout, 222 mutations, 213 214 nonphosphorylatable, overexpression of, 222 overexpression of, 222 phosphorylation of, 175, 176 protein, 268 levels of, gene therapy to reduce, 289 removal of, and cardiomyocyte, 175 176 role in cardiac function, 209 212 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, 245 246 cystosolic, folding of, 237 degradation of, endoplasmic reticulum-associated, 243 in cytosol, 243 folding of, in mammalian heart, 237 242 misfolded, in endoplasmic reticulum, 247 248 misfolding, in human diseases, 245 248 mitochondrial, folding of, 242 NCX, levels of, in failing myocardium, 173 unfolded, accumulation of, cellular responses to, 243 245 destiny of, 242 243 unfolding of, and aggregation of, in ischemic injury, 246 in cardiomyopathies, 237 250 Protein-C mutation models, myosin-binding, of familial hypertrophic cardiomyopathy, 221 222 Protein kinase B, cell survival and, 254 255 Protein kinase-áii, constitutively active, 227 Protein kinase C, in cardiac hypertrophy, 267 Protein phospholamban, 268 R gp130 Receptor knockout, and constitutive gp130, 228 229 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, 222 223 in excitation-contraction coupling, 207, 208 in heart, 207 209
INDEX 319 Sarcoplasmic reticulum Ca 2+ -ATPase activity, gene therapy to restore, 288 289 Sarcoplasmic reticulum Ca 2+ transport pump-1 and -2 overexpression, 223 Sarcoplasmic reticulum calcium load, decreases in sodium current and, 199 200 Serum response factor, 160 overexpression of, 225 Sodium current(s), arrhythmic mechanism hypothesis, transient steady-state features of, factors affecting, 202 203 reduced, and rate of depolarization and overshoot of cardiac action potential, 194, 195 and sarcoplasmic reticulum calcium load, 199 200 during acquired and genetic long QT syndrome, 193 194 during acute myocardial infarction, 201 during heart failure, 201 during long QT syndrome, 201 increased action potential duration due to, 201 202 mechanisms of arrhythmias during, 193 205 Stem cells, adult, 303, 304 in cell therapy, 294 295 bone marrow-derived, 304 306, 307, 308 in cell therapy, 294 295 cardiac, 306 embryonic, 303, 304 in cell therapy, 294 hematopoietic, 305 mesenchymal, 305 306 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, 246 247 Transcription factors, heart failure and, 225 Transforming growth factor-á2 knockout, 227 228 Transgenic models of heart failure, molecular models of heart disease and, 219 236 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, 162 163 Vascular endothelial growth factor, 162 163 Ventricles, development of, 160 Ventricular myocytes, I Na -induced arrhymogenic events in, 200 201 Ventricular remodeling, 275 NOS3-derived nitric oxide in, 281 X Xamoterol, 186 Z Zebrafish, heart of, 273