Heart failure (HF), a leading cause of mortality in patients with myocardial infarction (MI), is especially progressive in the 20-25% of post-MI patients with ischemic mitral regurgitation (IMR). IMR drives a vicious cycle of left ventricular (LV) dilatation and MR caused by leaflet tethering to the LV walls. Ongoing remodeling drive leads to frequent failure of standard annuloplasty ring therapy, indicating the need to treat the ventricle as well as the valve. Our prior work has shown that post-MI LV remodeling is exacerbated by the added MR-induced volume overload, with downregulation of SERCA2a, a key calcium cycling pump, and increased fibrosis. Upregulating SERCA2a with intracoronary adeno associated virus (AAV) reduces remodeling when given early and also with late MR repair. Fibrosis can be reduced by AAV.CCN5, which reverses functional deterioration in HF induced by pressure overload. This proposal considers two clinical scenarios: acute MI, with potential to limit early remodeling as stimulus for progressive remodeling and IMR; and later remodeling, to improve long- term results from surgical repair of IMR by addressing myocardial remodeling as well. The central hypothesis is that LV remodeling in an IMI-induced model of progressive heart failure with IMR can be reduced at both early and late stages through a synergistic approach improving both myocardial and interstitial components of heart failure. We will test the following hypotheses: 1) Early administration of SERCA2a, CCN5 or both at the time of ischemia-reperfusion injury can prevent the remodeling that occurs despite revascularization. This is supported by recent evidence for transgene uptake in this context, and by our preliminary evidence that early preventive therapy with the combined vectors safely reduces both local infarct deformation and the ensuing cycle of MR and global remodeling. This aim simulates the scenario of patients with acute MI undergoing primary percutaneous intervention (PCI). 2) Upregulating SERCA2a, CCN5 or both can prevent or reverse remodeling in an established inferior MI model that produces important MR, simulating the clinical situation of treatment after remodeling has occurred, either early or late relative to compensatory pathway activation or exhaustion. 3) SERCA2a, CCN5 or both can prevent ongoing remodeling leading to recurrent MR when given during annuloplasty repair in an inferior MI model. LV remodeling and MR will be compared for ring alone, myocardial therapy alone (Aim 2), and the combination. In these aims we will address mechanistic hypotheses regarding CCN5 inhibition of fibrosis by decreasing post-MI endothelial-to-mesenchymal cell transformation and pro- fibrotic myofibroblast formation; SERCA2a reduction of remodeling by increasing contractility and decreasing apoptosis; and reduction of localized infarct deformation by early therapy in addition to reduced progression of global remodeling. The collaborative team combines strengths in surgical physiologic modeling, imaging and pathology of fibrosis, and myocardial biology with gene therapy. Results can support clinical studies of these strategies in patients undergoing mitral valve repair for ischemic MR and primary PCI for acute MI.