Effect of Mitral Regurgitation on Ischemic LV Remodeling

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DESCRIPTION (provided by applicant): Myocardial remodeling after myocardial infarction (MI) leads, through a cascade of cellular, humoral and hemodynamic events, to progressive enlargement and failure of the left ventricle (LV), with poorer prognosis. Adverse prognosis post-MI is also associated with mitral regurgitation (MR), a frequent complication which itself could potentially lead to LV dilatation and failure, in turn increasing MR in a vicious cycle that could be interrupted by treating the MR, for example, by early valve repair. It is therefore important to determine whether remodeling and regurgitation influence one another. This proposal will test the hypothesis that MRtype volume overload augments remodeling post-MI, and the corollary that repairing MR limits or reverses remodeling. Remodeling will be assessed as LV dilatation and dysfunction, and associated cellular and molecular changes, including altered cell shape and contractility, increased apoptosis, changes in hypertrophic signaling pathways, and altered extracellular matrix support. Three-dimensional echocardiography is well-suited for quantifying and comparing global and segmental LV remodeling over time as the LV deforms. Testing the combined anatomic and molecular hypothesis relating MR-type volume overload and post-MI remodeling requires varying MR independent of MI. Because they tend to occur together in inferior MI, a model of anterior MI will be used, with MR-type volume overload created by a left ventricular-to-atrial shunt, a published approach. Echocardiographic measures of remodeling will be compared over time between animals with and without MR post-MI (open shunt vs sham), and correlated with cellular and molecular markers of myocardial failure and remodeling, neurohumoral activation, and apoptosis. The LV-LA shunt will be closed to simulate mitral valve repair and test whether this reverses or limits both the remodeling and associated molecular changes compared with persistent shunt patency. Remodeling will also be compared in hearts with and without genetic overexpression of molecules affecting the key elements of cell contractility, cell survival, and extracellular matrix remodeling, with the hypothesis that favorably modifying any one of these interacting targets will diminish both LV dilatation and dysfunction. These studies have implications for potential therapeutic strategies and for guiding decision-making regarding mitral valve repair in patients with myocardial infarction.