Increasing Ischemic Myocardial Tissue Perfusion by Mechanical LV Support

项目摘要/摘要 新的证据表明急性机械性心肌梗死(MI)的大小可能受到限制 左心室(LV)支持。机械左心室卸载治疗急性心肌梗死的II期临床试验已开始招募 在最近完成门到卸货(DTU)STEMI试验后，该试验证明了安全和 这一方法的可行性。这是一个令人兴奋的医学领域，没有新的治疗方法在临床上应用。 冠脉再通建立后抢救心肌缺血的常规方法。尽管强者 热情和在动物实验中反复显示的有效性，关于它如何限制脑梗塞的知识有限 尺码。 这项建议侧重于了解急性心肌梗死患者机械左心室支持的生理效应。 及其缩小心肌梗死面积的机制。我们的初步数据显示，机械LV支持 通过降低左心室舒张期壁应力，增加缺血心肌组织流量和灌注量。根据我们的数据， 我们认为“舒张期壁应力的减少”和“组织灌注量的改善”在脑梗塞范围中起着关键作用。 在机械左心室支持期间减少，而不是普遍接受的“减少心脏做功”的机制 限制梗塞范围。 为了验证我们的假设，我们将使用心肌缺血/再灌注的大型动物模型和 研究急性左心支持对冠脉血流的影响。在目标1中，我们将研究舒张期与 不同负荷条件下的室壁应力和缺血组织灌注量。综合评价 在不同的LV负荷条件下的LV压力/容量、冠脉流量和心肌组织灌注量 提供更好的机械性理解。在目标2中，我们将确定调节缺血组织的因素 左心室支持期间的灌流。这一目标将定义从机械LV中获益最多的患者特征 对急性心肌梗塞的支持。在目标3中，通过重点研究冠脉血流调节的分子机制 MicroRNA-146。我们预计舒张期左室壁应力降低会增加外体microRNA-146的分泌。 来自心脏，可抑制冠状动脉血管氧化应激，改善组织灌注量。 了解梗塞面积缩小的机制对于改善患者的选择至关重要。 新的和有希望的，但侵入性治疗急性心肌梗死。建议的研究结果将有助于确定最优 支持环境，建立有效的临床方案，并确定适当的患者群体。

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.