BACKGROUND:Cardiolipin is a mitochondrial-specific phospholipid that maintains integrity of the electron transport chain (ETC) and plays a central role in myocardial ischemia/reperfusion injury. Tafazzin is an enzyme that is required for cardiolipin maturation. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) use to provide hemodynamic support for acute myocardial infarction has grown exponentially, is associated with poor outcomes, and is under active clinical investigation, yet the mechanistic effect of VA-ECMO on myocardial damage in acute myocardial infarction remains poorly understood. We hypothesized that VA-ECMO acutely depletes myocardial cardiolipin and exacerbates myocardial injury in acute myocardial infarction.METHODS:We examined cardiolipin and tafazzin levels in human subjects with heart failure and healthy swine exposed to VA-ECMO and used a swine model of closed-chest myocardial ischemia/reperfusion injury to evaluate the effect of VA-ECMO on cardiolipin expression, myocardial injury, and mitochondrial function.RESULTS:Cardiolipin and tafazzin levels are significantly reduced in the left ventricles of individuals requiring VA-ECMO compared with individuals without VA-ECMO before heart transplantation. Six hours of exposure to VA-ECMO also decreased left ventricular levels of cardiolipin and tafazzin in healthy swine compared with sham controls. To explore whether cardiolipin depletion by VA-ECMO increases infarct size, we performed left anterior descending artery occlusion for a total of 120 minutes followed by 180 minutes of reperfusion in adult swine in the presence and absence of MTP-131, an amphipathic molecule that interacts with cardiolipin to stabilize the inner mitochondrial membrane. Compared with reperfusion alone, VA-ECMO activation beginning after 90 minutes of left anterior descending artery occlusion increased infarct size (36±8% versus 48±7%; P<0.001). VA-ECMO also decreased cardiolipin and tafazzin levels, disrupted mitochondrial integrity, reduced electron transport chain function, and promoted oxidative stress. Compared with reperfusion alone or VA-ECMO before reperfusion, delivery of MTP-131 before VA-ECMO activation reduced infarct size (22±8%; P=0.03 versus reperfusion alone and P<0.001 versus VA-ECMO alone). MTP-131 restored cardiolipin and tafazzin levels, stabilized mitochondrial function, and reduced oxidative stress in the left ventricle.CONCLUSIONS:We identified a novel mechanism by which VA-ECMO promotes myocardial injury and further identify cardiolipin as an important target of therapy to reduce infarct size and to preserve mitochondrial function in the setting of VA-ECMO for acute myocardial infarction.

中文翻译：

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心磷脂作为减轻静脉动脉体外膜氧合引起的心肌损伤的治疗靶点的新作用

背景：心磷脂是一种线粒体特异性磷脂，可维持电子传递链（ETC）的完整性，在心肌缺血/再灌注损伤中发挥核心作用。 Tafazzin 是心磷脂成熟所需的一种酶。静脉动脉体外膜肺氧合（VA-ECMO）为急性心肌梗死提供血流动力学支持的应用呈指数增长，与不良预后相关，并且正在积极进行临床研究，但 VA-ECMO 对急性心肌梗死心肌损伤的机制作用仍然知之甚少。我们假设 VA-ECMO 会急剧消耗心肌心磷脂并加剧急性心肌梗死时的心肌损伤。 方法：我们检测了患有心力衰竭的人类受试者和暴露于 VA-ECMO 的健康猪的心磷脂和他法嗪水平，并使用了闭胸猪模型心肌缺血/再灌注损伤，以评估 VA-ECMO 对心磷脂表达、心肌损伤和线粒体功能的影响。 结果：与未使用 VA-ECMO 的个体相比，需要 VA-ECMO 的个体左心室中心磷脂和他法嗪水平显着降低心脏移植前。与假对照组相比，暴露于 VA-ECMO 六小时也降低了健康猪左心室心磷脂和他法嗪的水平。为了探讨 VA-ECMO 导致的心磷脂消耗是否会增加梗塞面积，我们对成年猪进行了 120 分钟的左前降支闭塞，然后在存在和不存在 MTP-131（一种相互作用的两亲性分子）的情况下进行了 180 分钟的再灌注。与心磷脂一起稳定线粒体内膜。与单独再灌注相比，左前降支闭塞 90 分钟后开始的 VA-ECMO 激活增加了梗塞面积（36±8% 对比 48±7%；P <0.001）。 VA-ECMO还降低心磷脂和tafazzin水平，破坏线粒体完整性，降低电子传递链功能，并促进氧化应激。与单独再灌注或再灌注前VA-ECMO相比，VA-ECMO激活前递送MTP-131减少了梗塞面积（22±8%；与单独再灌注相比， P =0.03；与单独VA-ECMO相比， P <0.001）。 MTP-131恢复心磷脂和tafazzin水平，稳定线粒体功能，减少左心室氧化应激。结论：我们确定了VA-ECMO促进心肌损伤的新机制，并进一步确定心磷脂作为减少梗塞的重要治疗靶点大小并在 VA-ECMO 治疗急性心肌梗死的情况下保持线粒体功能。