Inhibition of hypertrophy is a good therapeutic strategy in ventricular pressure overload.
Inhibition of hypertrophy is a good therapeutic strategy in ventricular pressure overload.
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DOI：
10.1161/circulationaha.115.013894
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发表时间：
2015-04-21
期刊：
影响因子：
37.8
通讯作者：
Hill JA
中科院分区：
文献类型：
--
作者：
Schiattarella GG;Hill JA
1436 Circulation， 2015年4月21日，因心室组织缺失引起的需求。在这两种情况下，当压力过载状态持续时，心肌的肥厚表型不可避免地进展到失代偿状态和临床心力衰竭。控制这种从适应性肥大到适应性不良的转变的机制仍然知之甚少。心肌细胞的肥厚转化涉及的不仅仅是简单的细胞生长。相反，它需要对细胞结构和机器的多个方面进行近乎全面的重组。这个过程的一个要素是细胞的相对去分化和许多转录、信号、电和代谢事件的重新激活，这些事件是细胞发育过程中的特征。作为这一过程的一部分，广泛的转录和翻译后事件发生，包括基因表达模式的激活，使人想起胎儿发育期间观察到的（胎儿基因程序）。事实上，出生后不久就熄灭的胎儿基因程序，在疾病的环境中迅速重新点燃。基于肌节重组的模式，可以区分两种广泛的心室肥厚。压力应力引起同心圆肥大，其特征是平行分布的肌节重新聚集；相反，过多的体积引起偏心肥大，心肌细胞以一系列肌节的增加作出反应。在这两种情况下，壁厚都会增加。（同心型肥厚表现为壁厚增加，心室容积变化相对较小；偏心型肥厚表现为壁厚和心室腔大小均增加。）根据Grossman等人开创性的应力适应假说，10壁厚的增加是一种适应性反应；根据拉普拉斯定律，心室壁应力与心室压力和腔半径成正比，与心室壁厚度成反比。因此，壁厚的增加往往会减轻壁应力，从而减少需氧量。肌细胞的生长是由蛋白质合成和蛋白质降解之间的微妙平衡决定的。在后负荷升高的情况下，蛋白质合成占主导地位，最终导致肥厚生长。然而，重要的是要认识到肥厚重塑并不是一个简单的增加新肌节的过程。相反，这种高度动态的细胞反应涉及蛋白质合成和细胞器生物发生、肌节重塑、蛋白质降解、细胞器分解、转录重编程和代谢转变的复杂协调。在许多方面，肌细胞的整个细胞结构——框架、底盘、传动系统和引擎——都被重新组装了。与疾病相关的触发因素相反，生理应激，如耐力运动和妊娠，可诱导以正常或增强的收缩功能以及正常的心脏结构和组织为特征的肥厚反应。除了生长诱因、生物表型和临床结果的差异之外，还有病理差异
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