Abstract 4373610: Effect of combined guideline-directed medical therapy and mitochondria-rich extracellular vesicles in a mouse infarct model

Introduction: Beta blockers, renin-angiotensin-aldosterone antagonists, and mineralocorticoid antagonists are mainstays of current guideline-directed medical therapy (GDMT) in heart failure with reduced left ventricular ejection fraction (LVEF). GDMT has been hypothesized to interact and have protective effects in bioenergetics in cardiac injury by reducing cardiac workload and energy demand. We have previously demonstrated in a human-induced pluripotent stem cell-derived cardiomyocytes (iCMs) hypoxia model that treatment with GDMT plus mitochondrial-rich extracellular vesicles (M-EVs) improves cell viability. Here, we demonstrate the effect of GDMT and M-EV treatment in an established mouse LAD-infarct model. Methods: A total of 16 CD1 mice (50% female and male) underwent left anterior descending artery (LAD) injury, divided into 4 groups plus control (3-4 mice/group after accounting for mortality): PBS sham, metoprolol at 30mg/kg/day, empagliflozin at 10mg/kg/day, M-EVs+ metoprolol, and M-EVs + empagliflozin. 1.0x10 9 M-EVs were directly injected into the peri-infarct region via thoracotomy approach shortly after LAD ligation in the applicable groups. Metoprolol and empagliflozin were administered via daily oral gavage. LV function was assessed by cardiac MRI at week 4 after LAD infarct. M-EVs were collected using differential ultracentrifugation of iCM-conditioned medium. Quality and concentrations are determined via nanoparticle analyzer. Results: The average LV ejection fraction of the normal saline sham group was 29.1%; metoprolol only group 32.2%; empagliflozin only group 32.7%; metoprolol + M-EV group 35.5%; empagliflozin + MEV group 37.2%. There was an 18% overall mortality rate after LAD ligation, all within the first 72 hours after surgery. There was a trend toward significance in the combination medications + M-EV groups. The MRI data is currently being processed for LV viability and scar area. Conclusion: In this initial small sample study of combination therapy of M-EV plus 2 GDMT, there was a trend toward significance in the improvement of mice LVEF after 4 weeks of treatment after LAD ligation. We hypothesize that the results may be from M-EV therapy in conjunction with GDMT, potentially conferring therapeutic benefit by an additive effect of mitochondrial augmentation and a decrease in energy consumption. These results will set up further studies of the additive effect and mechanisms of GDMT and M-EV therapy via multi-omics approaches.