ABSTRACT/PROJECT SUMMARY Ischemic mitral regurgitation (IMR) is reflux of blood through the mitral valve, developing in patients surviving a myocardial infarction or chronic ischemic heart disease. 2.7 million Americans suffer from this condition and progressively develop congestive heart failure. Their hospitalization rates are higher and they present with significant risk of sudden death. Timely correction of IMR can halt adverse ventricular remodeling, but current techniques to repair IMR require open-heart surgery, a risky procedure in these patients. Several transcatheter strategies are in development, but all of them have demonstrated poor outcomes with significant remnant regurgitation or repair failure due to procedural complexity. We hypothesized that the most effective and durable technique to correct IMR is by extending the native leaflet lengths at the site of the regurgitation, restoring systolic leaflet edge parallelization, so that coaptation is restored and regurgitation is effectively eliminated. We developed a novel, flexible;; nitinol implant covered with expanded polytetrafluoroethylene, which when deployed on the anterior or posterior mitral valve leaflet extends the leaflet shelf and restores leaflet coaptation. The device integrates into the native leaflet with tissue encapsulation over 4-6 weeks, and the endothelialized tissue permanently adds to the native leaflet length for IMR correction. Strong preliminary data supporting the feasibility and safety of this concept have been generated in ex vivo and swine models. In this R01 application, we propose to advance this concept further, with a focus on optimizing the device design to best restore valve function and preserve valve mechanics. Three aims are proposed - (Aim 1) Optimize the device features to achieve best IMR reduction and highest leaflet coaptation, while preserving the native valve mechanics and fluid dynamics;; (Aim 2) investigate the durability of the device in correcting IMR in a progressively remodeling LV, investigate chronic device healing and tissue remodeling, and measure the thrombotic potential of the device in swine;; and (Aim 3) develop a trans-septal delivery catheter for image guided deployment of the device on the mitral valve, and assess the safety and efficacy of this procedure in swine. We have assembled a collaborative, multidisciplinary team with experience in biomedical device design & engineering, computational tissue and fluid mechanics, animal models and imaging, and clinical experience in transcatheter valve therapies, in an environment with a history of innovative cardiac research. There is high potential for clinical translation of this technology, and the proposed work will optimize the technology and mi...