This new RO1 proposal explores novel mechanisms of cardioprotection involving veno-arterial membrane oxygenation (VA-ECMO) as a platform to reduce myocardial damage after acute myocardial infarction (AMI). Use of VA-ECMO has grown exponentially in AMI over the past decade, however the impact of VA-ECMO on myocardial injury has not been rigorously studied. New mechanistic insight into the effect of VA-ECMO on reperfusion injury is needed. We recently reported the critical observation that VA-ECMO increases infarct size in swine models of AMI and in new data have now identified a novel paradigm whereby VA-ECMO depletes critical regulators of mitochondrial function and worsens heart damage in AMI. By employing highly translational large animal models and clinically relevant interventional approaches, we will now explore new mechanisms involving VA-ECMO and myocardial reperfusion injury, provide penetrating insight into cardioprotection, and generate proof of concept data for the development of new therapeutic approaches to limit left ventricular (LV) injury in AMI. The PI is an interventional cardiologist and advanced heart failure specialist who studies molecular mechanisms of cardiac remodeling, reperfusion injury, and the hemodynamic effects of circulatory support pumps. The current proposal integrates expertise in coronary and ventricular physiology, mechanical circulatory support, molecular biology, and interventional cardiology to the field of myocardial reperfusion injury, for which no specific therapy currently exists. We will test the novel hypothesis that VA-ECMO promotes myocardial damage by worsening myocardial oxygen supply-demand mismatch through increased LV wall stress and hyperoxemia-mediated injury resulting in loss of mitochondrial integrity and further that targeting these mechanisms will reduce infarct size in AMI. Exciting new preliminary data show that LV decompression or targeting normal arterial oxygen tension during VA-ECMO support can mitigate LV injury by reducing myocardial oxygen demand and increasing coronary blood flow. We observed for the first time that VA-ECMO decreases levels of tafazzin, a key enzyme controlling maturation of cardiolipin (CL), a master regulator of mitochondrial integrity. In exciting new findings, treatment with elamipretide, a CL-stabilizing compound, before initiation of VA- ECMO significantly reduced infarct size compared to reperfusion alone. These pioneering approaches address major knowledge gaps by studying the effect of VA-ECMO on ventricular load, coronary blood flow and overcome critical barriers associated with cardioprotection in AMI. To test our hypothesis we will employ translational studies in swine models to determine the impact of VA-ECMO on myocardial blood flow (SA1), mitochondrial integrity (SA2), and to test the therapeutic utility of a combined drug-device approach (SA3) to limit adverse cardiac remodeling after AMI. This proposal has tremendous potential to impact our unde...