Background-Ischemia/reperfusion injury worsens infarct size, a major determinant of morbidity and mortality after acute myocardial infarction (MI). We tested the hypothesis that reducing left ventricular wall stress with a percutaneous left atrial-to-femoral artery centrifugal bypass system while delaying coronary reperfusion limits myocardial injury in a model of acute MI. Methods and Results-MI was induced by balloon occlusion of the left anterior descending artery in adult male swine. In the MI group (n=4), 120 minutes of left anterior descending artery occlusion was followed by 120 minutes of reperfusion without mechanical support. In the mechanically supported group (MI+unload; n=4), percutaneous left atrial-to-femoral artery bypass was initiated after 120 minutes of ischemia, and left anterior descending artery occlusion was prolonged for an additional 30 minutes, followed by 120 minutes of reperfusion with device support. All animals were euthanized after reperfusion, and infarct size was quantified by triphenyltetrazolium chloride staining. Compared with baseline, mean left ventricular wall stress and stroke work were not changed at any point in the MI group but were decreased after reperfusion in the MI+unload group (mean left ventricular wall stress, 44 658 versus 22 963 dynes/cm 2 ; stroke work, 2823 versus 655 mm Hg·mL, MI versus MI+unload). Phosphorylation of reperfusion injury salvage kinase pathway proteins from noninfarcted left ventricular tissue was unchanged in the MI group but was increased in the MI+unload group. Compared with the MI group, total infarct size was reduced in the MI+unload group (49% versus 28%, MI versus MI+unload). Conclusions-These Kapur et al Reducing Wall Stress in AMI 329regulated kinase (ERK) and the serine/threonine kinase Akt. [8][9][10][11][12] Other approaches to limit ischemia/reperfusion injury include systemic hypothermia, which has also shown promise as a method to reduce total body metabolic demand 13 ; however, this approach does not specifically target myocardial injury in AMI. Alternatively, the generation of repeated periods of myocardial ischemia and reperfusion with balloon angioplasty, known as ischemic conditioning, has also been shown to promote activity of the RISK pathway. [14][15][16] Although promising, critical barriers to these cardioprotective strategies include the multifactorial nature of reperfusion injury, thereby limiting the impact of a single-target pharmacological strategy; the potential for coronary vascular injury (dissection or perforation) with ischemic conditioning; and the mandate for rapid coronary reperfusion and thus insufficient time for a drug to penetrate into myocardial injury zones. A need exists for improved cardioprotective strategies that broadly affect the multiple levels of reperfusion injury without causing further myocardial damage. In this study, we explore the central hypothesis that initially reducing left ventricular (LV) wall stress by mechanically reducing LV preload while delaying coronary reperfusion activat...