ABSTRACT ST segment myocardial infarction (STEMI) is a serious acute coronary condition that affects 500,000 Americans each year and results in significant U.S. healthcare costs ($31B/year for acute MI treatment). STEMI mortality directly relates to the extent of the total myocardial injury and even with the gold standard of reperfusion, up to 50% of the total myocardial injury can be related to reperfusion injury (RI) that occurs directly following the restoration of blood flow to the ischemic myocardium. Mild hypothermia (MH - temperature ~ 34C) provides cardioprotection and may greatly diminish RI by reducing myocardial metabolic demand, free radical creation, platelet aggregation, and total infarct size. However, MH and all other current therapy options (pharmacologics, etc.) have been largely unsuccessful in the treatment of RI. This is due to the fact that the arterial obstruction does not allow for therapy delivery to the region of interest until PCI is completed, which would be too late to prevent RI. Thus, an innovative, percutaneous approach is needed for MH delivery prior to PCI. Selective auto-retroperfusion (SARP) is a novel and effective percutaneous approach for MH therapy delivery prior to PCI that does not require the opening of the arterial obstruction. MH-SARP supplies retrograde perfusion of cooled arterial blood through selected portions of the coronary venous system to the infarct region of interest, thus providing treatment to the infarct region prior to PCI to limit RI. Retroperfusion without MH has been significantly studied, but largely unadopted because complicated equipment is required to regulate the arterial perfusion pressure to avoid vascular and myocardial injury. We have previously shown that selective cannulation of portions of the coronary venous system (i.e., SARP) can avoid this possible damage and provide safe and effective therapy during a total arterial occlusion using auto-perfusion (patient's own arterial pressure as the driving force) through a quick connection to an arterial source regulated by a simple valve (no need for complicated equipment). However, we have not combined and validated SARP with MH to reduce RI. Thus, the purpose of this Phase I proposal is the validation of a MH-SARP catheter to deliver selective MH treatment and reduce RI and infarct size in swine with myocardial infarction. Based on our excellent preliminary in vivo results with SARP alone and our bench testing results demonstrating the flow and heat exchange capabilities of our catheter, the proposed system may provide a clinically relevant tool for the reduction of RI and infarct size in STEMI patients. This project has the ability to impact patients with multiple comorbidities and reach across various NIH Institutes and Centers including the NIDDK and NHLBI.