New Approaches to Mitigate Left Ventricular Injury with VA-ECMO in Acute Myocardial Infarction

这项新的RO 1提案探索了涉及静脉-动脉膜的心脏保护新机制 氧合（VA-ECMO）作为减少急性心肌梗死（AMI）后心肌损伤的平台。 在过去的十年中，VA-ECMO在AMI中的使用呈指数增长，但是VA-ECMO对AMI的影响 心肌损伤尚未得到严格的研究。VA-ECMO对肺功能影响的新机制 需要再灌注损伤。我们最近报道了VA-ECMO增加梗死面积的重要观察结果 在猪AMI模型和新的数据中，现在已经确定了一种新的范例， 线粒体功能的关键调节因子和AMI中心肌损伤的相关性。通过使用高度翻译的 大型动物模型和临床相关的干预方法，我们现在将探索新的机制 涉及VA-ECMO和心肌再灌注损伤，为心脏保护提供了深入的见解， 生成概念验证数据，用于开发限制左心室（LV）的新治疗方法 急性心肌梗死的损伤。PI是一名介入心脏病专家和高级心力衰竭专家，研究分子 心脏重塑、再灌注损伤和循环支持的血流动力学效应的机制 泵.目前的建议整合了冠状动脉和心室生理学，机械循环， 支持，分子生物学和介入心脏病学领域的心肌再灌注损伤， 目前还没有具体的治疗方法。我们将检验VA-ECMO促进心肌细胞增殖的新假设， 左心室壁应力增加导致心肌氧供需不匹配恶化， 导致线粒体完整性丧失的高氧血症介导的损伤， 机制将减少AMI中的梗死面积。令人兴奋的新的初步数据显示，左心室减压或 在VA-ECMO支持期间，靶向正常动脉氧分压可以通过减少心肌损伤来减轻LV损伤。 氧气需求和增加冠状动脉血流量。我们首次观察到VA-ECMO降低 tafazzin水平，一种控制心磷脂（CL）成熟的关键酶， 完整在令人兴奋的新发现中，在开始VA治疗前使用依拉普利肽（一种CL稳定化合物）治疗， 与单独再灌注相比，ECMO显著减少了梗死面积。这些开创性的方法解决了 通过研究VA-ECMO对心室负荷、冠状动脉血流量的影响， 与AMI中心脏保护相关的关键屏障。为了验证我们的假设，我们将使用翻译 在猪模型中进行的研究，以确定VA-ECMO对心肌血流量（SA 1）、线粒体 完整性（SA 2），并测试联合药物-器械方法（SA 3）的治疗效用，以限制不良反应 AMI后心脏重构这一提议有巨大的潜力影响我们对冠状动脉疾病的理解。 心室生理学、循环支持和心脏保护对AMI患者具有重要意义 以及用于心脏或呼吸衰竭的ECMO。

This new RO1 proposal explores novel mechanisms of cardioprotection involving veno-arterial membrane oxygenation (VA-ECMO) as a platform to reduce myocardial damage after acute myocardial infarction (AMI). Use of VA-ECMO has grown exponentially in AMI over the past decade, however the impact of VA-ECMO on myocardial injury has not been rigorously studied. New mechanistic insight into the effect of VA-ECMO on reperfusion injury is needed. We recently reported the critical observation that VA-ECMO increases infarct size in swine models of AMI and in new data have now identified a novel paradigm whereby VA-ECMO depletes critical regulators of mitochondrial function and worsens heart damage in AMI. By employing highly translational large animal models and clinically relevant interventional approaches, we will now explore new mechanisms involving VA-ECMO and myocardial reperfusion injury, provide penetrating insight into cardioprotection, and generate proof of concept data for the development of new therapeutic approaches to limit left ventricular (LV) injury in AMI. The PI is an interventional cardiologist and advanced heart failure specialist who studies molecular mechanisms of cardiac remodeling, reperfusion injury, 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 VA-ECMO promotes myocardial damage by worsening myocardial oxygen supply-demand mismatch through increased LV wall stress and hyperoxemia-mediated injury resulting in loss of mitochondrial integrity and further that targeting these mechanisms will reduce infarct size in AMI. Exciting new preliminary data show that LV decompression or targeting normal arterial oxygen tension during VA-ECMO support can mitigate LV injury by reducing myocardial oxygen demand and increasing coronary blood flow. We observed for the first time that VA-ECMO decreases levels of tafazzin, a key enzyme controlling maturation of cardiolipin (CL), a master regulator of mitochondrial integrity. In exciting new findings, treatment with elamipretide, a CL-stabilizing compound, before initiation of VA- ECMO significantly reduced infarct size compared to reperfusion alone. These pioneering approaches address major knowledge gaps by studying the effect of VA-ECMO on ventricular load, coronary blood flow and overcome critical barriers associated with cardioprotection in AMI. To test our hypothesis we will employ translational studies in swine models to determine the impact of VA-ECMO on myocardial blood flow (SA1), mitochondrial integrity (SA2), and to test the therapeutic utility of a combined drug-device approach (SA3) to limit adverse cardiac remodeling after AMI. This proposal has tremendous potential to impact our understanding of coronary and ventricular physiology, circulatory support, and cardioprotection with important implications for AMI patients and for ECMO use in cardiac or respiratory failure.