ISCHEMIC MITRAL REGURGITATION: FROM MECHANISM TO THERAPY

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DESCRIPTION (provided by applicant): Project Summary. The candidate is a cardiologist who studies physiologic hypotheses regarding valvular heart disease using advanced noninvasive imaging techniques in an environment that fosters strong interactions between clinical and basic scientists. His immediate goal is to develop more effective therapies for ischemic mitral regurgitation (MR). The initial K24 Award has enabled extensive progress toward the following goals: 1) developing novel therapies for ischemic MR that address its fundamental mechanism; 2) expanding the scope of the scientific endeavor through new directions and collaborations: and 3) expanding opportunities for training and mentoring through these new research directions and co-mentorships. New directions include understanding the impact of ischemic MR on LV remodeling and the reversibility of such remodeling at a cellular and molecular level (with Dr. Roger Hajjar); applying cell and polymer approaches to ventricular restoration for reversing ischemic MR (with Prof. Philippe Menasche); determining the genetic basis of mitral valve prolapse (MVP), another cause of MR, and applying knowledge from bench to bedside to identify early, potentially treatable forms (with Dr. Susan Slaugenhaupt); and extending concepts from mitral to tricuspid regurgitation (with Dr. Carlos Duran). The candidate has a strong record of mentoring that supports transition to independent careers, as recognized by the Richard Popp Excellence in Teaching Award. Renewed K24 support is critical to build upon and fund interdisciplinary programs in cardiac imaging, LV remodeling and molecular genetics. The research program tests the central hypothesis that ischemic MR can be treated by realigning the leaflets with their ventricular attachments. The K24 renewal will support a new clinical direction, in collaboration with leaders in exercise physiology, to test the hypothesis that ischemic MR, fully appreciated with exercise, strongly predicts functional limitation, LV remodeling, and adverse prognosis following coronary interventions. Relevance: Ischemic MR is a common complication of coronary disease, doubling late mortality. Existing repairs are disappointing; new therapies that target fundamental changes in the LV are needed to reduce the associated remodeling and heart failure. MR in MVP can also cause lasting LV impairment, and discovering its responsible genetic defects has therapeutic promise. Both areas provide growing opportunities to mentor the next generation of successful investigators.