PROJECT SUMMARY Degenerative mitral regurgitation (DMR) impacts approximately 3% of the general population and 10% of adults older than 75 years. Its treatment has significantly evolved with commercial availability of transcatheter edge-to- edge repair (TEER) in 2013, a percutaneous alternative to surgical repair. More than a decade later, differences in clinical effectiveness and patient-centered outcomes between transcatheter and surgical treatment of severe DMR are unclear, and critical, as TEER technology is increasingly applied broadly in younger patients. There are several gaps in knowledge in this regard that our study proposes to address. First, given that this field is in its relative infancy, and there are no head-to-head randomized clinical trials of TEER vs surgery in DMR, long- term comparative clinical outcomes between available treatment strategies are unknown. Our study will leverage the existing institutional infrastructure of our high-volume mitral valve disease referral center for longitudinal follow up of approximately 1800 patients (900 TEER and 900 surgical repair) with multimodality imaging to compare long-term clinical effectiveness, safety and durability outcomes upto 10 years. Second, postoperative left ventricular dysfunction occurs in 10-20% of patient who receive surgical repair, and is associated with worse outcomes, but its incidence after TEER is not known, and mechanistic insights are sparse. We hypothesize that left ventricular dysfunction occurs less frequently after TEER as it is performed without circulatory arrest, and that presence, severity and distribution of myocardial fibrosis may predict its occurrence after TEER or surgery. We will utilize advanced cardiac magnetic resonance (CMR) imaging techniques in a prospectively enrolled cohort of 300 patients (150 TEER and 150 surgical repair) to examine this relationship that will facilitate identification of targets of pharmacotherapy and timing of mitral valve intervention in DMR. Third, comparison of patient-reported outcome measures that characterize their postoperative recovery after TEER versus surgical treatment of DMR are imperative for guiding informed consent and shared decision-making in this aging population for whom quality of life may be as important as risk of complications or mortality. Our proposed study will have broad impact as we will provide timely long-term clinical effectiveness, safety and patient-reported outcomes data comparing TEER with surgery for DMR that will inform better patient selection, procedural techniques, and intensity of follow-up. We will also elucidate potential pathobiological impact of left ventricular fibrosis and other imaging biomarkers on postoperative left ventricular dysfunction, a marker of worse clinical prognosis, that will identify potential treatment targets against fibrosis to reduce rates of LV dysfunction and improve outcomes.