The long-term objective of this application is to obtain a quantitative description of the extent of myocardial damage induced by chronic coronary artery stenosis in the rat heart. Observations have shown that this disease model produces myocardial lesions of replacement and interstitial fibrosis similar to those found in humans with ischemic coronary artery disease (CAD). The morphometric estimation of these morphological changes combined with measurements of the physiological properties of the heart should contribute to a better understanding of the structural and functional phenomena that characterize CAD. Experiments will be performed with normal rats in order to establish whether: (a) chronic reductions in caliber of the left coronary artery lead to reductions in coronary blood flow (CBF) commensurate to the degree of stenosis and the severity of myocardial injury; and (b) impairment of ventricular function occurs as a result of an imbalance between myocardial damage and the regenerative capacity of the viable mycardium. Since hypertension and hypertrophy represent major risk factors of CAD, coronary constrictions will be made in rats with spontaneous hypertension (SHR) and two-kidney one-clip renal hypertension (RH). The hypotheses to be tested are: (a) that coronary artery stenosis in these animal models will lead to myocardial injury, and alterations of CBF and cardiac function more severe than those in normotensive rats; and (b) that the magnitude of damage will be greater in RH rats than in SHR rats. Normotensive and hypertensive rats will be subjected to coronary artery narrowing with expected reductions in luminal diameter of approximately 30%, 50% and 80%, and the animals will be sacrificed at one and three months after the operation. Morphometric measurements will be made of the degree of coronary narrowing; the percent loss of myocyte nuclei, the extent of fibrosis, the magnitude of myocyte hypertrophy, and the volume, surface area, and length of capillaries. These quantitative parameters will be examined in relation to the functional properties of the ventricle and the alterations in CBF.
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