DESCRIPTION (Applicant?s Abstract) Immediate Goals: To examine the mechanism and therapy of ischemic mitral regurgitation (MR) with the goal of applying this information to clinical studies. Career Development Plan: To obtain experience and skills in experimental methodology and application to clinical studies. Research Project: Mitral valve function can be understood in terms of the force-balance concept in which tethering forces from the papillary muscles balance left ventricle closing forces. In ischemic MR, this force-balance may be altered in ways that impair the ability of the mitral leaflets to close effectively at the annular level. We plan a combined, parallel clinical and experimental approach to evaluate the mechanism, progression and therapy of ischemic MR, all relating to the central hypothesis that ischemic MR is caused by an abnormal relationship of the mitral valve to its supporting ventricular structures. These altered relationships involve both abnormal tethering forces due to displacement of the papillary muscles as well as reduced closing forces due to LV contractile dysfunction. Specific testable questions related to this hypothesis include: 1) the progression of mitral regurgitation in patients with acute myocardial infarction relates to abnormalities in the mitral valve-ventricular relationship; 2) These mechanisms also cause persistent MR despite coronary revascularization surgery, thereby impairing exercise capacity and raising pulmonary pressures; 3) both externally applied devices and afterload reduction provide effective means of reducing ischemic mitral regurgitation by normalizing these relationships between the valve and the ventricle. The aims of the mentored award will be met by allowing the PI to translate her experimental expertise to direct clinical studies of progression and functional outcome of ischemic MR, and to make the transition from mechanism to therapy in models reflecting the clinical situation, with the ultimate goal of patient applications.