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

VA-ECMO 减轻急性心肌梗死左心室损伤的新方法

• 批准号: 10454891
• 负责人: Navin Kumar Kapur
• 金额: $ 84.51万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10454891
• 关键词: Acute; Acute myocardial infarction; Address; Animal Model; Blood; Blood flow; Cardiac; Cardiac Myocytes; Cardiolipins; Cardiology; Cardiovascular system; Cicatrix; Clinical Trials; Coronary; Coronary artery; Data; Development; Devices; Drug Delivery Systems; Enzymes; Extracorporeal Membrane Oxygenation; Heart Arrest; Heart Transplantation; Heart failure; Hospital Mortality; Hospitalization; Impairment; Infarction; Injury; Intervention; Knowledge; Left; Left Ventricular Function; Left ventricular structure; Mechanics; Mediating; Medicine; Membrane; Metabolism; Mitochondria; Modeling; Molecular; Molecular Biology; Morbidity - disease rate; Myocardial; Myocardial Reperfusion; Myocardial Reperfusion Injury; Outcome; Oxidative Stress; Oxygen; Patients; Pharmaceutical Preparations; Physiology; Pump; Recovery; Reperfusion Injury; Reperfusion Therapy; Reporting; Respiratory Failure; Risk; Role; Self-Help Devices; Specialist; Stress; System; Systemic blood pressure; Testing; Time; Treatment Efficacy; United States; Venous; Ventricular; base; cardiac magnetic resonance imaging; cardioprotection; clinically relevant; heart damage; heart dimension/size; hemodynamics; implantation; improved; improved outcome; insight; mechanical circulatory support; mortality; myocardial damage; myocardial infarct sizing; myocardial injury; new therapeutic target; novel; novel strategies; novel therapeutic intervention; porcine model; preservation; prevent; therapeutic evaluation; translational model; translational study; ventricular assist device

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.

这个新的RO1提案探讨了涉及静脉膜的心脏保护的新型机制 氧合（VA-ECMO）是减少急性心肌梗塞（AMI）后心肌损伤的平台。 在过去的十年中，VA-ECMO的使用在AMI中成倍增长，但是VA-ECMO对 心肌损伤尚未受到严格的研究。对VA-ECMO对影响的新机械洞察力 需要再灌注损伤。我们最近报道了VA-ECMO增加梗塞大小的关键观察结果 在AMI和新数据中的猪模型中，VA-ECMO耗尽了一种新型范式 线粒体功能的关键调节剂，并使AMI心脏损伤恶化。通过采用高度翻译 大型动物模型和临床相关的介入方法，我们现在将探索新机制 涉及VA-ECMO和心肌再灌注损伤，提供对心脏保护的深入了解，并 生成概念数据，以开发新的治疗方法以限制左心室（LV） AMI受伤。 PI是研究分子的介入心脏病专家和晚期心力衰竭专家 心脏重塑，再灌注损伤的机制和循环支持的血液动力学作用 泵。当前的建议将冠状动脉和心室生理学，机械循环系统的专业知识整合在一起 对心肌再灌注损伤领域的支持，分子生物学和介入心脏病学 目前尚无特定疗法。我们将测试VA-ECMO促进心肌的新颖假设 通过增加LV壁应力和 高氧血症介导的损伤导致线粒体完整性丧失，进一步针对这些损伤 机制将减少AMI中的梗塞大小。令人兴奋的新初步数据表明LV减压或 在VA-ECMO支持期间靶向正常的动脉氧张力可以通过减少心肌来减轻LV损伤 氧气需求和冠状动脉血流增加。我们首次观察到VA-ECMO减少 Tafazzin的水平，Tafazzin是一种控制心磷脂成熟（CL）的关键酶，线粒体的主要调节剂 正直。在令人兴奋的新发现中，在开始VA-之前，用Elamipretide（一种Cl稳定化合物）处理 与仅再灌注相比，ECMO显着降低了梗塞大小。这些开创性方法解决 通过研究VA-ECMO对心室负荷，冠状动脉血流和克服的影响，主要知识差距 与AMI心脏保护相关的关键障碍。为了检验我们的假设，我们将采用翻译 猪模型的研究以确定VA-ECMO对心肌流动（SA1），线粒体的影响 完整性（SA2），并测试合并​​药物磁盘方法（SA3）的治疗效用以限制不良 AMI后心脏重塑。该提议具有影响我们对冠状动脉的理解的巨大潜力 以及心室生理，循环支持和心脏保护作用，对AMI患者有重要影响 以及用于心脏或呼吸衰竭的ECMO。