Abstract 9400: Mitral Valve Prolapse Induces Regionalized Left Ventricular Fibrosis

Abstract

Introduction: Imaging studies patients with mitral valve prolapse (MVP) have previously shown cross sectional evidence of left ventricular (LV) fibrosis as well as increased risk for sudden cardiac death. This, along with evidence for post-repair ventricular dysfunction in Mitral valve surgery patients support a link between fibrosis and MVP. The development of fibrosis as a result of MVP, however, remains poorly understood. Hypothesis: Regionalized LV Fibrosis in MVP patients is driven by increased mechanical tension through the chordae tendineae by billowing leaflets. Methods: We performed histopathologic analysis on cardiac biopsies of 6 patients who underwent surgical repair for MV prolapse. We additionally performed longitudinal histopathologic analysis on hearts harvested from a mouse modal of human non-syndromic MVP (Dzip1 S14R/+). To assess the cellular response to increased mechanical tension, pathological stretch assays on human cardiac fibroblasts were performed in tandem with RNA seq, as well ATP luminescence assays to assess ATP release from stretched cells. Results: Biopsies from peripapillary regions, inferobasal wall, LV septum, and LV apex demonstrated regionalized myocardial fibrosis that correlated with increased macrophages and myofibroblasts. Our mouse model demonstrated similar regionalized deposition of collagen that increased over time, as well as an increase in macrophages and myofibroblasts. Stretching of human cardiac fibroblasts caused significant changes in 232 transcripts (Bonferroni corrected P value <1.72*10-6), and pushed fibroblasts into a pro-fibrotic state, upregulating alpha-Smooth Muscle actin, Collagen, PLOD1, and decreasing MMP1. Additionally, pathologic stretch of fibroblasts increased secretion of ATP, a known chemoattractant for innate inflammatory cells. Conclusions: A mouse model of human MVP phenocopied regionalized myocardial fibrosis seen in humans and will provide a useful tool to investigate mechanisms of myocardial fibrosis in MVP patients. Stretch initiates changes in pro-fibrotic gene transcription, and causes ATP release from human cardiac fibroblasts.