Project Summary More than 750,000 Americans will suffer a myocardial infarction (MI) each year. MI is the most common cause for heart failure (HF) worldwide which is attributed to 1 in 9 deaths globally. With the average age of the world’s population increasing, the number of patients living with heart failure is expected to increase dramatically. After an acute inflammatory response post-MI, the left ventricle (LV) wall will begin a cascade of events that initially aim to compensate for lost cardiac muscle but eventually result in deleterious effects on cardiac function and promote progression through the worsening stages of HF. Negative LV remodeling consists mostly of infarct expansion, wall thinning, cardiomyocyte hypertrophy, and fibrosis. Currently, early stage HF patients are given medications that aim to treat the symptoms while late stage patients must resort to more invasive surgical procedures such as LV assist device implantation, or whole heart transplantation. There are no FDA-approved therapeutics available for patients living with HF that aims to promote repair or regeneration within the infarct to halt or even reverse the progression of HF. Our lab has previously developed a tissue-specific injectable hydrogel derived from decellularized extracellular matrices of porcine LV myocardium, called myocardial matrix (MM) hydrogel, capable of mitigating negative LV remodeling in a sub-acute model of MI. This hydrogel retains the nanostructure of, and proteins and glycosaminoglycans (sGAG’s) found in native myocardium. We hypothesize that the MM hydrogel will be able to preserve LV function in a small animal rat model of chronic MI by promoting healthy cardiac metabolism, neovascularization while preventing fibrosis and hypertrophy. We propose investigating this hypothesis through the following three specific aims: · Aim 1: To demonstrate efficacy of the decellularized myocardial ECM in vivo for mitigating negative LV remodeling in a rat model of chronic myocardial infarction. · Aim 2: To determine the mechanism of action of the decellularized myocardial ECM in specific cell populations in a rat model of chronic myocardial infarction using single cell RNA sequencing. Showing efficacy of the MM hydrogel in a chronic model of MI would justify the continued study of the material in a large portion of the patient population. Understanding the mechanism of action of the material on specific cell populations in a chronic environment would expand the knowledge of the field and allow us to determine better treatment targets for these patients in the future.