Functional, structural and molecular characterization of a new mitral valve prolapse animal model: The FLNA-P637Q KI rat

Abstract

Mitral Valve Prolapse (MVP) affects 3% of the population and is characterized by a heterogeneous mitral leaflet remodeling. The pathophysiological mechanisms involved in MVP development are not fully understood, the only therapeutic option remains the surgical valve replacement. The first mutation causing MVP has been recently identified on the FLNA gene. The generation of a unique knock-in (KI) rat model for the FLNA-P637Q mutation paves the road to study the molecular mechanisms involved in MVP development. The aim of our study was to characterize the functional, morphological and molecular expression of the valvular disease in our unique KI rat model. 5 wild-type (WT) and 10 KI rats were evaluated at 3, 6 and 26 weeks. Comprehensive 2D echocardiography was performed to determine valve function and morphology. 3D quantitative analysis of the mitral valve (MV) remodelling was done using micro-tomodensitometry (microCT). MV tissue composition was analysed based on histological and immunohistochemistry. Based on the qualitative echocardiographic assessment of the valve, a high genotype-phenotype concordance was observed (100%, 93% and 100% for each time points). The anterior leaflet was longer in KI comparatively to WT rats (+ 12 to + 14% increase at all time points P < 0.01). Using microCT analysis, we confirmed the larger 3D MV volume in KI compared to WT (+ 20 to + 58%; all time points P < 0.05). Histological and immunohistological analyses pointed out towards a myxomatous valve disease (leaflet's thickening, hypercellularity, proteoglycans accumulation without calcification). Our results attest for the presence of a myxomatous MV dystrophy in the KI rat model comparable to the one described in MVP patients. These findings confirm this unique model is pertinent for the study of pathophysiological molecular mechanisms associated with MVP development and offers a new opportunity to identify potential therapeutic targets.