In contrast to hypertrophied skeletal muscle, chronically increased work eventually results in depressed contractility and relaxation of the hypertrophied heart. Compensated hypertrophy, which is characterized by abnormal chamber function but preserved muscle and myocyte function, evolves into a decompensated phase characterized by abnormal chamber, muscle, and myocyte function Fig. 5-1). Attempts to elucidate the underlying mechanisms for this transition have involved multidisciplinary studies of clinical end-stage heart failure, longitudinal studies in experimental animals, and characterization of cardiovascular function in genetically engineered mice, where attempts are made to mimic human disease Fig. 5-4) .M
Current information suggests that decompensated hypertrophy may result from a number of mechanisms that are both intrinsic and extrinsic to the cardiomyocyte. These include necrosis; apoptosis;85,86 altered growth secondary to altered signal transduction pathways; alterations in cardiomyocyte contractile, regulatory, calcium-cycling, and structural proteins; alterations in the extracellular matrix, and remodeling Fig. 5-4). Because of the complex combinatorial alterations that occur in human heart failure and conventional animal models of hypertrophy, studies in genetically engineered mice in which a protein of interest is either overexpressed or ablated using homologous recombination hold particular promise in determining the relative importance of various candidate genes. For example, mice bearing the mutation in the ft-MHC that occurs in familial cardiomyopathy have many features of the human disease.87 Overexpression of the a subunit of the G protein that couples to the ^-adrenergic receptor has produced dilated fibrotic hearts with altered cardiovascular function.88 Overexpression or ablation of genes involved in cardiomyocyte calcium-cycling proteins has been associated with altered heart function and abnormal calcium kinetics. It is of interest that, with few exceptions,89 the resultant cardiac phenotype has failed to reproduce completely human decompensated hypertrophy and failure. This observation further supports the multifactorial nature of the condition and the importance of genetic background on the phenotype observed after loss-of-function or gain-of-function genetic engineering.
A common prominent feature of many experimental and clinical studies of decompensated hypertrophy and failure is a derangement of cardiomyocyte calcium homeostasis (&»■□■ Fig. 5-3). Studies of human cardiomyocytes extracted from the hearts of patients with end-stage heart failure have revealed elevated diastolic calcium levels with either no change or a reduction in the amplitude of the calcium transient.90-93 Longitudinal studies of hypertrophy in experimental animals have revealed depression of steady-state mRNA levels94 and sarcoplasmic reticulum ATPase and phospholamban proteins in decompensated, but not compensated, pressure-overload hypertrophy.72 These changes were associated with distinctive contractile depression of isovolumically contracting heart function, increases in the EC50, and decreases in the Vmax for sarcoplasmic reticular membrane uptake of calcium. Transgenic overexpression of the sarcoplasmic reticulum ATPase inhibitor phospholamban depressed cardiomyocyte function and calcium kinetics, whereas targeted ablation of the phosphoprotein produced the opposite result. Whether altered levels of the calcium-cycling proteins occur by transcriptional, translational, or posttranslational levels is currently unknown. In addition to altered levels of the various calcium-cycling proteins in hypertrophy and heart failure, there is evidence that abnormal spatial organization of the /-channel and SR may be contributory. Specifically, increased distance between the /-channel and the ryanodine receptor may contribute to abnormal calcium cycling.95
In addition to altered calcium homeostasis, there is increasing evidence that abnormal signal transduction plays a critical role in the development of cardiac hypertrophy and failure. In vitro studies with neonatal myocytes have demonstrated that phenylephrine, endothelin, and angiotensin II cause cardiomyocyte hypertrophy. These vasoactive peptides have cognate receptors that signal via the d subunit of the Gq protein (see &H0; Fig. 5-2). Cardiac-specific overexpression of Gotq produced cardiac hypertrophy, apoptosis, and contractile depression in transgenic mice.96'97 By contrast, overexpression of a protein inhibitor of Gdq in a similar manner prevented cardiac hypertrophy due to pressure overload.98 Transgenic overexpression of receptors that couple through G0(q, such as Gtj and angiotensin II, produces a similar phenotype: cardiac-specific postnatal overexpression of the calcium-sensitive PKC isoform B produced cardiac hypertrophy and failure. Pretreatment of mice overexpressing PKC B with a highly specific inhibitor prevented or reversed this hypertrophy-heart failure phenotype.99 Part of the contractile depression observed with excess PKC B activity was due to phosphorylation of troponin I and resultant reduced myofilament calcium sensitivity.!00 Augmented PKC activity and elevated levels of the calcium-sensitive PKC d and f-' isoforms, but not Gotq, were found in human end-stage cardiomyopathic heart failure.101,102 It is also known that PKC may be stimulated by pathophysiologic levels of stretch!03 and ischemia-reperfusion and directly by oxidative stress.33 Taken together, these lines of evidence suggest that PKC mediated signal transduction plays a critical role in the development of cardiac hypertrophy and failure.i04
A variety of studies with end-stage human cardiomyopathic heart tissue, conventional animal models, and genetically engineered mice suggest that apoptosis may contribute to the heart failure phenotype.!05 The key issue that remains unclear is the quantitative importance of the phenomenon. This problem is further complicated by the fact that a number of signaling molecules (e.g., Gotq and TNF-Ot) produce both hypertrophy and apoptosis. By contrast, gpl30 heterodimerizes with LIF (leukemia inhibitory factor) receptor to permit binding of the interleukin-6 family of cytokines, such as cardiotrophin 1. Receptor binding stimulates the hypertrophic response while inhibiting apoptosis. Elimination of the gp130 by loss of function mutations of the gene results in mice that have structurally normal hearts. However, when a pressure overload is imposed, a rapidly progressive dilated cardiomyopathy ensues, which is associated with massive apoptosis.106 The application of molecular genetic and biological approaches to elucidate mechanisms responsible for myocardial hypertrophy, cardiac failure, arrhythmogenesis, and ischemic dysfunction will permit improved diagnostic and therapeutic approaches to congenital and acquired heart diseases.107
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