An integrated mechanism that explains mitral valve function based on the three-dimensional geometry of the leaflet attachments has been useful in understanding systolic anterior motion of the mitral valve. A conceptually related problem is the mechanism of ischemic mitral regurgitation (MR), a common complication of coronary artery disease that conveys adverse prognosis. Its mechanism and therapy remain controversial. This proposal aims to address the hypothesis that the mechanism of ischemic mitral regurgitation can be understood in terms of an altered force balance on the mitral leaflets in systole: a combination of increased tethering forces, restraining the leaflets from closing, and resulting from an altered three-dimensional geometry of leaflet attachments, and decreased ventricular forces acting to close the mitral leaflets. This mechanism will be studied using two recently developed noninvasive physiologic tools in experimental and clinical settings: three-dimensional echocardiographic reconstruction, to provide repeated, detailed and complete assessment of the geometric changes capable of altering the force balance on the leaflets; and the Doppler flow convergence technique, which can describe variations in the MR orifice area within the cardiac cycle to provide mechanistic insight. Elucidating this mechanism can suggest practical clinical approaches for reducing mitral regurgitation at the time of surgical coronary revascularization. Preliminary studies have successfully applied these research techniques in acute and chronic animal models of global and segmental ischemia as well as in patients; they have also suggested that 3D echo findings can guide the development of interventions that restore a more favorable leaflet tethering configuration to reduce or eliminate MR. Specific and measurable factors that will be tested in subhypotheses include the effect on MR of altering the three-dimensional geometry of mitral leaflet attachments, decreasing left ventricular force, increasing mitral leaflet and chordal length, reducing mitral annular size by ring implantation (which may not improve or may even exacerbate the abnormal tethering geometry), and reducing ventricular size through left ventricular remodeling surgery or angiotensin converting enzyme inhibition. These factors will be addressed in a series of in vivo models of ischemic MR that reflect the heterogeneity of wall motion abnormalities in patients with ischemic heart disease, and dissect out the rule of the different factors in a controlled manner to study the detailed force balance on the mitral leaflets.
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