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Immune Response As A New Player In Mitral Valve Prolapse
constance delwarde1, Pascal Aumond1, Claire Toquet2, amir h kayvanjoo3, Elvira Mass3, benjamin lauzier1, severine remy4, Ignacio Anegon4, Jean-Jacques Schott1, Thierry Le Tourneau2, jean Mérot1, romain capoulade1.
1Nantes Univ, CNRS, INSERM, thorax institute, Nantes, France, 2Nantes Univ, CHU Nantes, CNRS, INSERM, thorax institute, Nantes, France, 3Life and Medical Sciences Institute, Bonn, Bonn, Germany, 4Transgenic Rats Immunophenomic, Nantes, France.

OBJECTIVE: 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. The aim was to identify the signaling pathways involved in the development of MVP.
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%; p<0.01) and increased MV volume (+20 to +58%; p<0.05) in KI rats vs WT. Histological analyses revealed a myxomatous remodelling in KI MV. 5 MC were identified by RNA-seq: chemotaxis and immune cell migration, extracellular matrix, epithelial cell migration, endothelial to mesenchymal transition and molecular stress pathways (all GO-terms p<1x10-5). A higher proportion of CD45+ leukocytes (20% vs14%, 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.


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