The long term objective of this application is to identify the pathophysiologic mechanisms implicated in myocyte cell death and reactive cellular growth processes which underlie the evolution of the cardiomyopathic heart of ischemic origin. Our principal working hypothesis is that sudden reductions in coronary artery luminal diameter impair ventricular function, resulting in diastolic Laplace overload, mechanical myocyte cell death and mural cell slippage, which are the major determinants of acute chamber dilation and thinning of the wall with ischemia. On the other hand, chronic ventricular remodeling is postulated to be dependent upon changes in number and size of myocytes which dictate the progression of the disease towards congestive heart failure. This anatomical-functional condition is brought about through abnormal increases in pressure and volume loads on the myocardium which are not normalized by compensatory growth mechanisms of the myocyte compartment of the tissue. The combination of these events is expected to lead to a reduction in ventricular mass-to-chamber volume ration and severe depression in cardiac pump performance which characterize decompensated eccentric ventricular hypertrophy. On this basis, the hypothesis is advanced that long-term ventricular dilation is the product of increases in myocyte length, without a proportionate expansion in myocyte diameter, and the in series addition of newly formed muscle cells by myocyte mitotic division. Therefore, it becomes relevant to determine whether differences in the nature and magnitude of the loading state on myocytes selectively activate specific surface receptors which may be coupled with increases in cell length, cell diameter and cell number. It is proposed that activation of surface alpha-adrenergic receptors mediates the lengthening of myocytes, whereas surface angiotensin II receptors are involved in the lateral expansion of these cells. Moreover, the expression and activation of the myocyte IGF, autocrine system is believed to be associated with induction of late growth related genes, DNA synthesis, nuclear mitotic division and myocyte proliferation. In conclusion, the recognition of the molecular control mechanisms of myocyte cellular hypertrophy and hyperplasia and their temporal sequence may provide new strategies to interrupt or direct these adaptive growth responses which condition the final dimensions of the heart. The benefits of such an approach may be seen in the possibility of modulating myocyte growth and consequently ventricular dilation, which ultimately determines end-stage cardiac failure.
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