The overall objective of this proposal is to test the hypothesis that scar anisotropy is a desired structural feature that contributes importantly to the normal function of adjacent myocardium. The applicant will examine for the roles that mechanical stretch, preexisting extracellular matrix and the upregulation of Transforming Growth Factor-b1 (TGF-b1) play in defining the anisotropic structure of the myocardial scar. Initial studies are designed to define the normal spatial gradient of finite deformation in myocardium adjacent to the healing scar in a pig model of myocardial infarction. To directly test the hypothesis that the unique structure of the scar influences function in adjacent myocardium the applicant proposes to modify scar structure by manipulating local levels of TGF-b1 during healing. Additional studies to be performed in the pig model of infarction and in vitro in cultured cardiac fibroblasts will test for the roles that mechanical deformations, preexisting matrix and TGF-b1 have on defining scar structure and function. Clinically, it is known that the timely reperfusion of acutely ischemic myocardium can reduce infarct size and preserve left ventricular function. This approach has become the treatment of choice within hours of coronary occlusion. There is evidence that strength and collagen content of reperfused scars differs from that of permanently occluded myocardium. However, beyond these observations little is known about scar structure and function of bordering myocardium in the setting of coronary occlusion and reperfusion. Thus, as a third aim of the proposal the applicant will examine in infarcted-reperfused pig myocardium the structural features and mechanical properties of scar tissue as well as function in bordering myocardium.
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