The goal of this project is to determine the sequence of morphologic and ultrastructural changes occurring in the myocardium and blood vessels of hearts subjected to chronic work overload which results in cardiac hypertrophy. These observations will be made during the development of hypertrophy and during regression of hypertrophy; i.e., after removal of the chronic work overload. By correlating these structural changes with regional myocardial function as determined by sonomicrometry in the different stages of hypertrophy, we will define the factors that characterize early irreversibility of cardiac hypertrophy. The interaction of the type of workload inducing hypertrophy and coronary perfusion pressure will be examined to see what changes occur in these different settings. Morphometric analysis of blood vessels will be conducted at the capillary and arteriolar levels. Changes at the capillary level might increase diffusion distance and affect oxygen transport to the myocardial cell while changes at the arteriolar level may alter myocardial blood flow distribution. Specifically, we will: A) Study different models of hypertrophy including pressure overload hypertrophy with normal or elevated coronary perfusion pressure, volume overload hypertrophy and hypertrophy induced by renal hypertension or exercise or thyroxine administration; B) Quantitate ultrastructural changes in myocardial cells of these different models. These changes will be studied during the development of hypertrophy and after the removal of the overload; i.e., during regression; C) Quantitate changes of cell size, capillary density and arteriolar dimensions in these different models during the development of hypertrophy and during regression; D) Determine regional myocardial function to correlate with morphologic changes of the collagen stress resistant network in the different stages of hypertrophy and during regression. These observations will provide a better understanding of the interaction of factors inducing an irreversible state of hypertrophy or leading to limited or complete reversal when chronic work overload is removed.
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