Increasing Ischemic Myocardial Tissue Perfusion by Mechanical LV Support

PROJECT ABSTRACT/SUMMARY Emerging evidence suggests a possible limitation of myocardial infarction (MI) size by acute mechanical left ventricular (LV) support. A phase II clinical trial of mechanical LV unloading for acute MI has begun enrolling after the recent completion of the Door-to-Unloading (DTU) STEMI Trial, which demonstrated both safety and feasibility of this approach. This is an exciting area of medicine, where no new therapy has become clinically routine for salvaging ischemic myocardium in MI after establishing coronary reperfusion. Despite the strong enthusiasm and repeatedly shown efficacy in animal experiments, limited knowledge exists on how it limits infarct size. This proposal focuses on understanding the physiological effects of mechanical LV support in acute MI and its mechanisms of infarct size reduction. Our preliminary data suggests that mechanical LV support increases ischemic myocardial tissue flow and perfusion by lowering LV diastolic wall stress. Based on our data, we expect that “reduced diastolic wall stress” and “improved tissue perfusion” play the key roles in infarct size reduction during mechanical LV support, rather than generally accepted mechanism that “reduced cardiac work” limits infarct size. To examine our hypothesis, we will use large animal models of myocardial ischemia/reperfusion and study the impact of acute LV support on coronary flow. In Aim 1, we will study the relationship between diastolic LV wall stress and ischemic tissue perfusion under different LV loading conditions. Comprehensive assessment of LV pressure/volume, coronary flow, and myocardial tissue perfusion during different LV loading conditions will offer improved mechanistic understanding. In Aim 2, we will determine the factors that regulate ischemic tissue perfusion during LV support. This Aim will define patient characteristics that benefit most from mechanical LV support in acute MI. In Aim 3, molecular mechanisms of coronary flow regulation is examined by focusing on microRNA-146. We expect that decreased diastolic LV wall stress increases exosomal microRNA-146 secretion from the heart, which inhibits coronary vascular oxidative stress and improves tissue perfusion. Understanding the mechanisms of infarct size reduction is essential to improve patient selection for this novel and promising, but invasive therapy for acute MI. Results of proposed studies will help define optimal support settings, establish effective clinical protocols, and identify appropriate patient population.