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

这一新的RO1方案探索了涉及静脉-动脉膜的心脏保护的新机制 氧合(VA-ECMO)作为减少急性心肌梗死(AMI)后心肌损害的平台。 在过去的十年中，VA-ECMO在急性心肌梗死中的应用呈指数级增长，然而VA-ECMO对急性心肌梗死的影响 心肌损伤还没有得到严格的研究。VA-ECMO作用机制的新见解 再灌注损伤是必要的。我们最近报道了VA-ECMO增加梗塞面积的关键观察结果 在急性心肌梗死的猪模型和新的数据中，现在已经确定了一种新的范式，即VA-ECMO耗尽 线粒体功能的关键调节器和加重急性心肌梗死的心脏损害。通过采用高度翻译的 大动物模型和临床相关的介入方法，我们现在将探索新的机制 涉及VA-ECMO和心肌再灌注损伤，提供了对心脏保护的透彻洞察力，以及 为开发限制左心室(LV)的新治疗方法生成概念验证数据 急性心肌梗死的损伤。PI是一名介入性心脏病专家和高级心力衰竭专家，研究分子 心脏重构、再灌注损伤的机制及循环支持对血流动力学的影响 打气筒。目前的方案综合了冠状动脉和心脏生理学、机械循环 支持、分子生物学和介入心脏病学对心肌再灌注损伤领域的支持 目前还没有特效的治疗方法。我们将检验VA-ECMO促进心肌梗死的新假说 通过增加室壁应力和心肌氧供需不匹配加重损伤 高氧血症介导的损伤导致线粒体完整性丧失，并进一步靶向这些 其机制将缩小急性心肌梗死的梗塞面积。令人振奋的新初步数据显示，LV减压或 VA-ECMO支持期间靶向正常动脉氧分压可通过减少心肌损伤来减轻左室损伤 氧气需求和增加冠脉血流量。我们首次观察到VA-ECMO减少 控制线粒体主要调节剂心磷脂(CL)成熟的关键酶他法津的水平 正直。在令人兴奋的新发现中，在VA开始之前，使用拉米普肽，一种稳定CL的化合物，治疗- 与单纯再灌流相比，ECMO显著缩小了梗塞面积。这些开创性的方法解决了 VA-ECMO对心脏负荷、冠脉血流量影响研究的主要知识空白及克服 与急性心肌梗死心脏保护相关的关键障碍。为了检验我们的假设，我们将使用翻译 用猪模型研究VA-ECMO对心肌血流量(SA1)、线粒体的影响 完整性(SA2)，并测试药物-装置联合方法(SA3)的治疗效用，以限制不良反应 急性心肌梗死后心脏重塑。这一提议具有巨大的潜力，将影响我们对冠心病的理解 和心脏生理学、循环支持和心脏保护对急性心肌梗死患者具有重要意义 并用于ECMO治疗心力衰竭或呼吸衰竭。

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.