Inhibition of hypertrophy is a good therapeutic strategy in ventricular pressure overload

GG Schiattarella, JA Hill - Circulation, 2015 - Am Heart Assoc
Circulation, 2015Am Heart Assoc
1436 Circulation April 21, 2015 demand arising secondary to the loss of ventricular tissue. In
both cases, when the pressure overload state is persistent, the hypertrophic phenotype of
the myocardium inexorably progresses to a state of decompensation and clinical heart
failure. Mechanisms governing this transition from adaptive hypertrophy to maladaptive
failure remain poorly understood. Hypertrophic transformation of the cardiomyocyte involves
much more than simple cell growth. Rather, it entails a nearcomprehensive retooling of …
1436 Circulation April 21, 2015 demand arising secondary to the loss of ventricular tissue. In both cases, when the pressure overload state is persistent, the hypertrophic phenotype of the myocardium inexorably progresses to a state of decompensation and clinical heart failure. Mechanisms governing this transition from adaptive hypertrophy to maladaptive failure remain poorly understood. Hypertrophic transformation of the cardiomyocyte involves much more than simple cell growth. Rather, it entails a nearcomprehensive retooling of multiple aspects of cellular architecture and machinery. One element of this process is relative dedifferentiation of the cell and reactivation of numerous transcriptional, signaling, electrical, and metabolic events that characterized the cell during development. As part of this, a wide range of transcriptional and posttranslational events occur, including activation of a pattern of gene expression reminiscent of that observed during fetal development (fetal gene program). Indeed, the fetal gene program, which was extinguished shortly after birth, reignites rapidly in the setting of disease.
Based on the pattern of sarcomere reorganization, it is possible to distinguish 2 broad patterns of ventricular hypertrophy. 9 Pressure stress provokes concentric hypertrophy, which is characterized by recruitment of sarcomeres laid down in parallel; on the contrary, excess volume elicits eccentric hypertrophy in which cardiomyocytes respond with the addition of sarcomeres in series. 9 In both cases, increases in wall thickness occur.(Concentric hypertrophy is marked by increases in wall thickness with relatively little change in ventricular volume; eccentric hypertrophy is marked by increases in both wall thickness and ventricular cavity size.) According to the pioneering stress-adaptation hypothesis by Grossman et al, 10 these increases in wall thickness are an adaptive response; based on the law of laplace, ventricular wall stress is proportional to both ventricular pressure and cavity radius and inversely proportional to ventricular wall thickness. 11 Thus, increases in wall thickness tend to lessen wall stress and thereby diminish oxygen demand. Myocyte growth is dictated by a delicate balance between protein synthesis and protein degradation. In the setting of elevated afterload, protein synthesis predominates, culminating in hypertrophic growth. However, it is important to recognize that hypertrophic remodeling is not a simple process of the addition of new sarcomeres. Rather, this highly dynamic cellular response involves intricate coordination of de novo protein synthesis and organelle biogenesis, sarcomere remodeling, protein degradation, organelle breakdown, transcriptional reprogramming, and metabolic shifts. In many ways, the entire cellular architecture of the myocyte–frame, chassis, drive train, and engine–is retooled. In contrast to disease-related triggers, physiological stresses, such as endurance exercise and pregnancy, induce a hypertrophic response characterized by normal or enhanced contractile function coupled with normal architecture and organization of cardiac structure. 12 Beyond differences in growth triggers, biological phenotypes, and clinical outcomes, pathological
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