Abstract 17400: Effects of Concurrent Extracellular Vesicle and Metformin Therapy in Porcine Model of Chronic Myocardial Ischemia and Metabolic Syndrome

Abstract

Introduction: We previously demonstrated using a swine model of chronic myocardial ischemia (CMI) that extracellular vesicle (EV) therapy improves cardiac function, perfusion, and angiogenic signaling, but these benefits were blunted in the setting of metabolic syndrome (MS). Hypothesis: We hypothesized that concurrent treatment with metformin may augment the cardiac effects of EV therapy in a swine model of CMI and MS. Methods: Twenty-nine Yorkshire swine were fed a high fat diet for four weeks to induce MS, then underwent placement of an ameroid constrictor to the left circumflex artery to induce CMI. Two weeks later, pigs receiving either oral placebo or 500mg metformin (MET) BID underwent intramyocardial injection of either vehicle or mesenchymal stem cell-derived EVs. This resulted in four groups: placebo+vehicle (CON, n=6), placebo+EV (EV, n=8), MET+vehicle (MET, n=7), and MET+EV (METEV, n=8). Five weeks after injection, pigs underwent functional measurements and harvest of ischemic myocardium. Perfusion, capillary density, and protein expression were measured by microspheres, immunofluorescence, and immunoblotting respectively. Results: Cardiac function was improved in EV compared to CON (SV p=0.02, SW p=0.01, CO p=0.03), and in MET compared to CON (SV p=0.03, SW p=0.09, CO p=0.2), though there were no differences between MET and METEV groups (p>0.5 for all). Contractility as measured by slope of PRSW relationship was improved with METEV compared to CON (p=0.04), with a trend towards improvement in MET compared to CON (p=0.21), but not with EV alone. During pacing, there was increased perfusion in MET (p=0.04) and METEV (p=0.04) groups compared to CON. At rest, there was increased perfusion in MET (p=0.05) group, with a trend towards increased perfusion in METEV group (p=0.29) compared to CON, without differences between MET and METEV (p>0.5). Capillary density was unchanged in METEV compared to CON (p>0.5). The MET and METEV groups had decreased expression of p-Akt (p=0.01, p=0.06) and p-ERK (p=0.09, p=0.03) compared to CON, without changes in p-eNOS (p>0.5), and all without differences between MET and METEV (p>0.5). Conclusions: In the setting of CMI and MS, the blunted effects of EVs are not augmented by concurrent metformin therapy.