Katz A M
Department of Medicine, University of Connecticut, Farmington.
Cardiology. 1990;77(5):346-56. doi: 10.1159/000174624.
The evolution of our understanding of the pathogenesis and therapy of heart failure can be described in terms of three paradigms that have also proven useful in describing the development of knowledge of cardiovascular regulation and the actions of angiotensin II. Organ physiology, the first paradigm, viewed the variable performance of the heart in terms of length-dependent changes in myocardial contractile function (Starling's Law), and angiotensin II as a pressor factor that elevated blood pressure. This paradigm focused treatment of heart failure on the major circulatory abnormalities: salt and water retention and vasoconstriction. According to the second paradigm, cell biochemistry, regulation of cardiac performance reflected altered calcium fluxes and changing myocardial contractility, and the clinical effects of angiotensin II as arising from altered calcium fluxes involved in the control of smooth muscle tension. Following this second paradigm, treatment of heart failure focused on powerful inotropic agents designed to increase myocardial contractility. The third paradigm, gene expression (molecular biology) describes what is probably the most primitive, and almost certainly the most complex of these regulatory mechanisms. Altered gene expression explains long-term regulation of cardiac performance in terms of adaptive changes in the architecture and composition of the heart, and key effects of angiotensin II as arising from increased protein synthesis and promotion of cell growth. In the case of heart failure, this third paradigm may explain the accelerated deterioration of the hypertrophied, failing heart as being due to altered myocardial cell growth composition. While the useful life of the normal human heart appears to be at least 80-90 years, overload-induced hypertrophy may reduce the heart's life span to about 5 years. This unwelcome consequence of myocardial hypertrophy may arise from the expression of fetal isoforms of key muscle proteins, a hypothesis that is supported by evidence that deterioration of the failing heart can be alleviated by the converting enzyme inhibitors which have important effects to inhibit cellular growth.
我们对心力衰竭发病机制及治疗方法的理解演变可以用三种范式来描述，这三种范式在描述心血管调节知识的发展以及血管紧张素II的作用方面也被证明是有用的。第一种范式是器官生理学，它从心肌收缩功能的长度依赖性变化（斯塔林定律）的角度看待心脏的不同表现，并将血管紧张素II视为一种升高血压的升压因子。这种范式将心力衰竭的治疗重点放在主要的循环异常上：盐和水潴留以及血管收缩。根据第二种范式，细胞生物化学，心脏功能的调节反映了钙通量的改变和心肌收缩力的变化，而血管紧张素II的临床作用源于参与控制平滑肌张力的钙通量改变。遵循这第二种范式，心力衰竭的治疗重点是旨在增加心肌收缩力的强效强心剂。第三种范式，基因表达（分子生物学）描述了可能是这些调节机制中最原始、几乎肯定也是最复杂的机制。基因表达改变从心脏结构和组成的适应性变化方面解释了心脏功能的长期调节，以及血管紧张素II的关键作用源于蛋白质合成增加和细胞生长促进。就心力衰竭而言，这第三种范式可能解释了肥厚性衰竭心脏加速恶化的原因是心肌细胞生长组成的改变。虽然正常人类心脏的使用寿命似乎至少为80 - 90岁，但超负荷诱导的肥大可能会将心脏的寿命缩短至约5年。心肌肥大这种不受欢迎的后果可能源于关键肌肉蛋白胎儿异构体的表达，这一假设得到了以下证据的支持：转换酶抑制剂可以缓解衰竭心脏的恶化，而转换酶抑制剂对抑制细胞生长有重要作用。
