Abstract 17016: Mitral Valve Prolapse Induces Localized Left Ventricular Fibrosis in a Novel Large Animal Model

Abstract

Background: Mitral valve prolapse (MVP) has recently been associated with localized left ventricular (LV) fibrosis linked to malignant arrhythmia and sudden cardiac death. However, fibrosis mechanisms remain unknown, with no large animal model to distinguish mechanical and genetic influences. Goals: We tested the hypothesis that surgically induced MVP leads to localized myocardial fibrosis in LV regions mechanically linked to the mitral valve, aiming to establish a reproducible large animal model of MVP as a platform for mechanistic studies. Methods: In 6 adolescent sheep, MVP was created surgically by replacing primary chordae tendineae to P2 with longer artificial chords. Intraoperative echocardiography and LV pressure-volume loops were obtained. After 7 months recovery, cardiac MRI with gadolinium and T1-mapping were done before end-of-study surgery with repeat echo and pressure-volume loops. Three sham surgery sheep were similarly studied. Myocardial samples from valve-linked papillary muscle and inferobasal LV and control septal regions were analyzed by histology. Bulk RNA was sequenced on samples from 3 MVP and 3 sham sheep. Results: All 6 MVP sheep showed pronounced localized LV fibrosis in valve-linked regions but not control regions on MRI, with replacement fibrosis by Masson’s trichrome stain. Sham sheep had no fibrosis, with similar LV function and contractility at end-of-study. RNA sequencing revealed gene expression differences between the two LV regions in MVP sheep and the valve-linked regions of MVP vs sham sheep. Conclusions: In a novel surgically created large animal model of MVP, localized fibrosis is induced in formerly healthy LV myocardium. This suggests a mechanical mechanism is sufficient to create the localized LV fibrosis associated with arrhythmia in MVP patients. This model provides a platform to study fibrosis mechanisms and investigate therapeutic approaches to avoid catastrophic events in MVP patients.