The objective of this proposal is to demonstrate that postinfarction cardiomyopathy is dependent upon the changes in size, shape, and number of the surviving myocytes, whereas the alterations in the infarcted myocardium play a minimal role in the long-term evolution of ventricular remodeling and chamber dilation. work during this funding period has documented that the cellular events which characterize the reactive hypertrophy of the spared myocardium, acutely and at the completion of healing, fail to normalize ventricular pump function, leading to a persistent elevation in diastolic wall stress. This mechanical stimulus is postulated by be responsible for continuous myocyte lengthening and the in series addition of newly formed cells through the mechanism of myocyte cellular hyperplasia. Extreme degrees of ventricular dilation may be generated by these cellular growth processes and intractable ventricular dysfunction and failure may supervene. Such an unfavorable outcome lies in the inability of myocytes to increase in diameter and/or be added in parallel within the wall to expand mural thickness and counteract the elevation in diastolic wall stress dictated by the larger cavitary volume. In a similar fashion, hypertensive hypertrophy, with its attendant changes in myocyte diameter and cross section area, may have exhausted one of the most important compensatory reactions of myocytes, which would tend to attenuate the consequences of ventricular dilation after infarction. Thus, the detrimental impact of hypertension induced concentric hypertrophy, prior to coronary artery occlusion, may reflect this phenomenon. Therefore, the recognition of control mechanisms implicated in the transmission of mechanical signals to myocytes and the initiation of the molecular events leading to increases in myocyte diameter, myocyte length and myocyte number may have important clinical implications in the prevention and treatment of the cardiomyopathy generated by myocardial infarction alone or in combination with hypertension. Accordingly, the hypotheses have been made that activation of alpha1b adrenergic receptors and AII receptors, and transmission of signals by these receptors induce myocyte hypertrophy and selectively mediate the increases in myocyte cell length and diameter, respectively. On the other hand, cellular hyperplasia is believed to be triggered by the expression of growth factor receptors on myocytes. In summary, myocyte hypertrophy and hyperplasia are assumed to both contribute to accommodate the sudden increase in work load associated with myocardial infarction. When the acute phase has subsided, myocyte hypertrophy, characterized by lengthening of the cells, becomes the predominant factor responsible for ventricular dilation. However, long- term restructuring of the ventricle after infarction may occur exclusively by the addition in a series of newly formed myocytes which may lead to extreme degrees of ventricular dilation. Hypertension may accelerate this sequence of events worsening the myocardial response to infarction.
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