This new RO1 proposal explores novel mechanisms of cardioprotection involving micro-axial flow pumps (TV- Pumps) as a platform to reduce myocardial damage and heart failure (HF) after an acute myocardial infarction (AMI). Prior attempts to limit reperfusion injury have failed in part due to the mandate for rapid coronary reperfusion, thereby limiting time for any beneficial impact of a therapeutic agent. We recently reported that mechanically unloading the left ventricle (LV) and delaying reperfusion (Primary Unloading) reduces infarct size and increases expression of the cardioprotective cytokine stromal derived factor 1 alpha (SDF1a). We will now explore new mechanisms regulating the cardioprotective effect of Primary Unloading and further test the durable impact of acutely reducing infarct size using this approach. The PI is an interventional cardiologist and advanced heart failure specialist who studies molecular mechanisms of cardiac remodeling 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 activating a TV-Pump and delaying coronary reperfusion (Primary Unloading) limits myocardial damage through a two-component mechanism involving: 1) reduced LV wall stress, myocardial oxygen demand, and increased collateral blood flow thereby reducing ischemic injury prior to reperfusion and 2) activation of a cardioprotective signaling program that requires intact SDF1a activity and further that these beneficial mechanisms will improve long term outcomes. Exciting new preliminary data shows that Primary Unloading for 30 minutes reduces infarct size by 50% and promotes a graded increase in collateral blood flow that reduces ischemic injury before reperfusion through the infarct related artery. Using intracoronary delivery of pharmacologic inhibitors and recombinant peptides during LV unloading, we further identified that Primary Unloading limits SDF1a degradation and sequestration, thereby promoting SDF1a activity. These pioneering approaches address major knowledge gaps by studying the effect of Primary Unloading on coronary blood flow and wave energetics and further overcome critical barriers associated with cardioprotection in AMI. To test our central hypothesis we will employ highly translational studies in large animal models to determine the physiologic (SA1) and molecular signaling (SA2) mechanisms underlying the cardioprotective effect of Primary Unloading and (SA3) to test the therapeutic utility of Primary Unloading to reduce late-term cardiac remodeling after AMI. This proposal has tremendous potential to impact our understanding of coronary and ventricular physiology, acute mechanical circulatory support, cardioprotection, and cardiac remodeling with important implications for AMI patients at risk of ischemic HF.

Public Health Relevance

Ischemic heart failure (HF) after an acute myocardial infarction (AMI) is a major cause of death for millions of individuals worldwide. Current therapy for AMI focuses on rapidly restoring blood flow through an occluded coronary artery. However, reperfusion itself can cause myocardial damage, known as ischemia-reperfusion injury. At present, no therapies to limit reperfusion injury exist due in part to the mandate for rapid coronary reperfusion. Based on extensive new data, this project explores a new paradigm whereby first unloading the left ventricle using a percutaneously delivered micro-axial flow pump and temporarily delaying reperfusion limits acute myocardial damage, improves survival, and promotes myocardial recovery. This highly translational project holds great promise for the development of new approaches to limit the onset of ischemic HF after AMI.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
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Schwartz, Lisa
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Tufts University
United States
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Esposito, Michele L; Zhang, Yali; Qiao, Xiaoying et al. (2018) Left Ventricular Unloading Before Reperfusion Promotes Functional Recovery After Acute Myocardial Infarction. J Am Coll Cardiol 72:501-514
Annamalai, Shiva K; Esposito, Michele L; Reyelt, Lara A et al. (2018) Abdominal Positioning of the Next-Generation Intra-Aortic Fluid Entrainment Pump (Aortix) Improves Cardiac Output in a Swine Model of Heart Failure. Circ Heart Fail 11:e005115
Kapur, Navin K; Jumean, Marwan F (2013) Defining the role for percutaneous mechanical circulatory support devices for medically refractory heart failure. Curr Heart Fail Rep 10:177-84