Project Summary Our goal is to elucidate the mechanisms by which mitral regurgitation (MR) creates substrates for arrhythmias, both atrial and ventricular, and to identify targeted interventions. Valvular heart disease is the most common etiology of chronic atrial fibrillation (AF). Prospective, randomized trials have shown that surgical ablation is highly effective in restoring normal sinus rhythm in patients with mitral valve disease and there is clear evidence that it provides a survival benefit. Newer studies have shown that ventricular remodeling and arrhythmias following MR increase the risk of sudden cardiac death, especially in young women. In the previous cycle of the grant, we refined a canine open chest model of MR via chordae avulsion previously developed in our laboratory into a minimally invasive model that better mirrors the clinical picture. In our clinical practice, we treat MR patient with and without AF, and are able to characterize their cardiac anatomy and electrophysiology with delayed-enhancement MRI (DE-MRI) and electrocardiographic imaging (ECGI), respectively We propose to characterize the remodeling of the atria and ventricles following MR in our canine chordae avulsion model and in patients. As our preliminary data suggest an inflammatory-mediated mechanism, we will identify patterns of immune cell infiltration that correspond to anatomical and electrophysiological changes to facilitate the development of novel therapeutic strategies. We propose the following specific aims: Specific Aim 1. Define the anatomical and electrical substrates for AF and ventricular arrhythmias in a chronic canine model of MR. The anatomical substrate will be characterized using echocardiography and DE-MRI, the electrical substrate using in-vivo plaque mapping, optical mapping, and ECGI. We will obtain activation maps of the heart, including the most arrhythmogenic parts of the atria (the LAPW) and the ventricles (periannular region and papillary muscles) and correlate them with fibrosis as defined by DE-MRI. Specific Aim 2. In our canine MR model, we will determine if inflammatory leukocyte infiltration precedes remodeling following MR induction and whether its presence corresponds to changes in electrophysiology. We will perform single nuclear RNA (snRNA) analysis of the LAPW and correlate it with LAPW electrophysiology characterized in thin slices at baseline, 4 weeks, and 6 months after MR induction. In the ventricle, snRNA analysis of the mitral periannular region and papillary muscles at the same time points will be correlated with local electrophysiology. Specific Aim 3. Define the atrial and ventricular electrophysiological remodeling in MR patients with and without AF referred for surgery. ECGI will be used to detect changes in the atrial and ventricular activation sequences and to detect premature ventricular contractions. Electrical remodeling will be correlated with fibrosis and fiber orientation as well as atrial and ventricu...