Sunday, May 11, 2025
5/11/2025
Mechanisms of Left Ventricular Fibrosis in Mitral Valve Prolapse - Abstract One in 40 Americans are estimated to have mitral valve prolapse (MVP). This disease is characterized by enlargement and mechanical incompetence of the mitral valve, eventually leading to billowing of the leaflets into the left atrium during systole and failure to properly coapt. It is a major contributor to morbidity and mortality, causing an estimated 35,000 deaths per year as well as 90,000 major surgeries in the United States. Currently, the only treatment for MVP is surgical correction. Despite adherence to current guidelines, one in five patients will develop new onset left ventricular dysfunction postoperatively, and this is associated with a decrease in long- term survival. A possible cause of postoperative LV dysfunction is myocardial fibrosis (MF), which has been described cross-sectionally in both autopsy studies of patients with MVP, as well as in MRI-based imaging studies. However, no studies exist that have mechanistically demonstrated how MVP, myocardial fibrosis, and LV dysfunction are linked. We have recently demonstrated that myocardial fibrosis is present with a regionalized distribution in patients who underwent surgical repair for severe MVP. Fibrosis is localized to the inferobasal myocardium and papillary muscles and is undetectable from apical and septal biopsies taken from the same patients. This regionalized pattern of fibrosis was validated in genetic mouse models of human MVP. The distribution of fibrosis within the myocardium supports our overarching hypothesis that regionalized myocardial fibrosis is a reactive process to increased mechanical tension in the setting of MVP. In this fellowship application, we aim to study the cellular and molecular mechanisms that translate pathogenic mechanical forces into myocardial fibrogenesis in MVP. In Aim 1, we will test the hypothesis that mitral valve prolapse can cause regionalized left ventricular fibrosis. In Aim 2, we will test the hypothesis that mechanical stress activates fibrogenesis through a mechanosensitive-ATP-Purinergic signaling mechanism. In Aim 3, we will test the hypothesis that integration of genomic and transcriptomic data can identify transcriptional regulators that initiate and sustain fibrosis programs. We will take advantage of available human samples, mouse models, and bioreactors developed by our group to define a mechano-molecular landscape underlying LV dysfunction in MVP. Through completion of these three aims, we will identify new cellular pathways involved in mechanically- induced fibrogenesis that could be manipulated in order to prevent or reverse myocardial fibrosis. Finally, a better understanding of how myocardial fibrosis occurs in MVP will be clinically informative and may encourage revision of current surgical guidelines in order to intervene earlier and decrease postoperative LV dysfunction. Collectively, the scientific approaches and experiences outlined in this fellowship will bring me to the cutting edge of cardiovascular research, significantly enhancing my clinical and research training, and serve as a springboard for success as I work towards achieving my goal of becoming an independent physician-scientist.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).