Mitochondrial therapy in conjunction with guideline directed medical therapy in cardiomyopathy

PROJECT SUMMARY Heart failure (HF) is the leading diagnosis of hospital admission in the US. Despite significant advances in medical therapies during the last three decades, HF remains one of the leading causes of mortality and morbidity worldwide. Cardiac tissue from patients with cardiomyopathy exhibits mitochondrial structural abnormalities. Current guideline-directed medical therapy (GDMT) in HF, including beta-blockers and renin– angiotensin-aldosterone (RAS) antagonism, reduces cardiac workload and helps in cardiac remodeling, but their impact on the mitochondria is not known. New therapies are needed. Stem cell-derived mitochondria- based technologies offer a novel approach to myocardial protection and repair, and their potential interaction with current gold-standard therapy also needs to be studied for successful translation. This proposal presents a study using both GDMT and mitochondria-rich extracellular vesicles (M-EVs) to transfer their mitochondria into injured cardiomyocytes and myocardium to improve viability and function in HF. In my first aim, I will determine the mechanism of the protective effects of M-EVs in combination with GDMT by adapting an innovative induced cardiomyocyte (iCM) model of hypoxic injury. To test this, iCMs will be treated with combinations of beta blockers, RAS antagonists, M-EVs, and combinations of GDMT and M-EVs. iCM function and viability will then be rigorously assessed. In the second aim, the functional benefits of the M-EVs and GDMT will be studied in a mouse model. I will study the effects of combined therapy on mitochondrial augmentation and biogenesis by looking at proteomic and metabolomic profiles of the injured myocardium in relation to a key regulator, PGC-1α. This proposed study will improve our understanding of the interaction of mitochondria-based therapies with existing heart failure therapies and give critical insight into the future development of much-needed novel therapies.