Abstract 12406: Mitral Valve Prolapse: Immune Response as a New Player

Abstract

Introduction: Mitral Valve Prolapse (MVP) is observed in 3% of the population. The pathophysiological mechanisms leading to MVP remain elusive and the only therapeutic option is to perform valve surgery. We previously identified FLNA as the first gene causing MVP and generated a unique knock-in (KI) rat model for the FLNA-P637Q mutation. Hypothesis: We assessed the hypothesis that MVP pathophysiology is multifactorial. Methods: 5 WT and 10 KI rats were morphologically, functionally and histologically evaluated at 3, 6 and 13 weeks based on 2D echocardiography, 3D micro computed tomography (μCT) and histology. Mitral valve (MV) RNA-sequencing was performed and metaclusters (MC) have been identified. Immunofluorescence and cytometry experiments on MV were used. Results: Echocardiographic and μCT imaging confirmed the presence of MV prolapse, elongated anterior leaflet (+12 to +14% for all time points p<0.01) and increased MV volume (+20 to +58% for all time points p<0.05) in KI rats vs WT. Histological analyses revealed a myxomatous remodelling in KI MV. 6 MC were identified by RNA-seq: chemotaxis, epithelial and immune cell migration, extracellular matrix, stress molecular pathways, endothelial to mesenchymal transition and oxidative stress (all GO-terms p<1x10-5). A higher proportion of CD45 + leukocytes (20% vs 14%, p=0.002), as well as a trend for CD206 + “resident macrophages” (28% vs 16%, p=0.09), and CD34 + stem cell progenitors (8% vs 15%, p=0.10) were observed in KI compared to WT rats. CD45 + and CD206 + cells were located in the medial third and atrial border of the MV leaflet in WT rats, and more diffusely observed in KI. Conclusions: Our results establish the KI FLNA-P637Q rat as a model of myxomatous MVP, a complex and multifactorial disease. Among others, we have characterized an increase of distinct immune cells in MVP. The course of cell recruitment, the cell-specific activity, and causality with the other MC need to be further studied.