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.