Minimally Invasive, Echocardiography‐Guided Mouse Model of Degenerative Mitral Regurgitation Recapitulates Cardiac Remodeling and Arrhythmogenesis

BACKGROUND: Degenerative mitral regurgitation (MR) is a progressive valvular disorder that causes atrial enlargement, cardiac remodeling, heart failure, and arrhythmias. Current rodent models are limited by thoracotomy or intubation, which increase procedural risk and reduce reproducibility. METHODS AND RESULTS: We established a minimally invasive, transthoracic echocardiography-guided mouse model of MR by puncturing the anterior mitral leaflet with a 27G needle introduced through the left ventricular apex. Ten-week-old C57BL/6J mice underwent baseline imaging before MR induction, and sham controls received apical puncture without leaflet disruption. Color Doppler confirmed regurgitant jets and increased vena contracta width, with procedural survival exceeding 90%. At 2 weeks, MR mice exhibited significant left heart enlargement, reduced fractional shortening, and myocardial fibrosis compared with sham. Pressure-volume loop analysis demonstrated increased end-diastolic volume and reduced compliance. RNA sequencing of left atrial tissues revealed enrichment of calcium signaling, apoptosis, and shear stress pathways. Histology confirmed increased cardiomyocyte apoptosis, accompanied by Connexin-43 downregulation and elevated ryanodine receptor 2 phosphorylation. Programmed atrial pacing induced atrial fibrillation in MR mice, consistent with enhanced arrhythmogenicity and calcium-handling abnormalities. CONCLUSIONS: This closed-chest, echo-guided murine model reliably induces MR, avoids thoracotomy, and recapitulates key features of human disease, including chamber dilation, fibrosis, and arrhythmia susceptibility. It provides a scalable platform for mechanistic studies, genetic interventions, and drug testing in valvular heart disease.