sFlt and Metabolic Mechanisms of Peripartium Cardiomyopathy

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 DESCRIPTION (provided by applicant): Peripartum cardiomyopathy (PPCM) is marked by loss of cardiac contractile function in women late in pregnancy or soon after delivery. PPCM affects approximately 1:1000 births worldwide, and frequently leads to chronic heart failure, need for cardiac transplant, or death. The disease can thus be devastating to otherwise healthy young women and their new families. Little is known of the mechanisms underlying PPCM. We have recently proposed the novel notion that PPCM is a vascular disease, triggered by the secretion of potent anti- vascular factors from the placenta late during gestation. Most notable among these factors is sFlt1, a soluble decoy receptor and VEGF inhibitor. We propose here to formally test this hypothesis by inhibiting sFlt1 secretion during pregnancy in a murine model of PPCM. We also propose to delve into the mechanisms by which sFlt1 causes cardiomyopathy. We hypothesize that sFlt1 neutralizes VEGF signaling via both VEGFR2 and VEGFR1, thereby adversely affecting cardiac vascular density and nutrient flux, respectively. The hypothesis will be tested with genetically modified mouse models, cell culture experiments, and state-of- the-art assays and imaging modalities of cardiac metabolism. Finally, our recent human genetic data indicate that many women with PPCM bear mutations in titin, a large sarcomeric protein. We hypothesize that these mutations predispose to vascular/metabolic collapse during pregnancy and exposure to excess sFlt1, and will test this notion with genetically modified mice and viral delivery of sFlt1. Success in these studies will provide mechanistic insight into PPCM, a poorly understood disease, and would open novel therapeutic approaches for a disease that currently has no specific treatment.