Is heart failure an abnormality of myocardial cell growth?
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.
Katz
A M
AM
Department of Medicine, University of Connecticut, Farmington.
D002311:Cardiomyopathy, Dilated / Q000503:physiopathology / Q000628:therapy; D015870:Gene Expression; D006333:Heart Failure / Q000503:physiopathology* / Q000628:therapy; D006801:Humans; D009200:Myocardial Contraction; D009206:Myocardium / Q000473:pathology*