Mechanistic Insights to A Translatable Therapy for Acute Reperfused Hemorrhagic Myocardial Infarctions

项目摘要 以主要心血管不良事件（MACE）为高潮的慢性心力衰竭在美国已成为流行病， 既往心肌梗死（MI）患者。根据疾病控制中心的数据， 在美国，每年有100万人死于慢性心力衰竭。慢性心力衰竭的长期预测因素 是梗死面积。然而，晚期微血管阻塞，即MI中微血管血流 尽管心外膜冠状动脉再灌注，但领土丢失，已成为另一个独立的 慢性心力衰竭的预测因子值得注意的是，晚期微血管阻塞通常与 心肌内出血和出血性MI（hMI）最易发生MACE。因此，委员会认为， hMI患者的治疗干预将大大抑制MACE：确定原因、机制 hMI与MACE风险相关的事件发生时间是关键。与hMI相关的几个重要观察结果 已经报道了MI的急性和慢性阶段，但是出血如何驱动MI的总体机制是， 整个梗死后时期的不良结果尚不清楚。关键研究表明，在再灌注 急性心肌梗塞（a）大的心肌梗塞通常有出血;（B）再灌注本身可引起心肌内明显的氧化应激， MI区;和（c）铁是促进驱动心肌细胞氧化应激的关键催化剂 死亡然而，尚不清楚富含铁的出血是否会加剧再灌注损伤， 导致梗死面积扩大在MI的慢性期，研究表明，及时解决 促炎细胞因子是至关重要的，否则它会损害瘢痕形成并加速不良反应。 重塑但是，为什么一些MI具有长期的促炎性负担并继续进行不利的重塑， 不知道。重要的是，目前的疗法对hMI患者和先前研究的疗法没有益处。 没有针对铁出血。我们假设，出血的演变变化， 梗死区沉淀（a）急性心肌梗死中存活心肌细胞的血红素铁介导的死亡（铁凋亡） MI阶段;（B）巨噬细胞内三价铁晶体的形成，试图将其去除，从而发生极化 在MI的慢性阶段，将它们转变为促炎状态;以及（c）考虑暂时性炎症的治疗。 出血的变化可以挽救心脏免于梗塞扩大和快速不利的LV重构。到 通过研究这些假说，目标1将建立出血促进 MI后心脏的时间依赖性损伤;目标2将确定时间依赖性变化 改变出血中铁的特征，以调整治疗策略的发展; 将确定最佳的铁螯合策略，以减少以下出血的不良影响： 再灌注为了实现这些目标，本提案汇集了一个跨学科团队， 出血如何促进不良结局的总体框架，然后用于测试治疗 针对hMI。因此，该提案是遏制美国慢性心力衰竭流行病的重要一步。

PROJECT SUMMARY Chronic heart failure culminating in major adverse cardiovascular events (MACE) has become epidemic in patients with prior myocardial infarction (MI). According to the Centers for Disease Control, >300,000 deaths per year are attributable to chronic heart failure in the US. A long-established predictor of chronic heart failure is infarct size. However, late microvascular obstruction, a condition where microvascular blood flow in the MI territory is lost despite reperfusion of the epicardial coronary artery, has emerged as another independent predictor of chronic heart failure. Notably, late microvascular obstruction is often associated with intramyocardial hemorrhage and that hemorrhagic MIs (hMI) are the most prone to MACE. Accordingly, therapeutic intervention for hMI patients will substantially curb MACE: establishing the causes, mechanisms and timing of events linking hMI to MACE risk is key. Several important observations relevant to hMIs in the acute and chronic phases of MI have been reported, but an overarching mechanism of how hemorrhage drives adverse outcomes throughout post-infarction period is not known. Key studies have shown that in reperfused acute MIs (a) large MIs often have hemorrhage; (b) reperfusion itself can cause marked oxidative stress within the MI zone; and (c) that iron is a critical catalyst contributing to the oxidative stress that drives cardiomyocyte death. However, it is not known whether hemorrhage, which is rich in iron, exacerbates reperfusion injury and causes infarct expansion. In the chronic phase of MI, studies have shown that timely resolution of proinflammatory cytokines is critical, which can otherwise impair scar formation and accelerate adverse remodeling. But why some MIs have prolonged proinflammatory burden and continue to adversely remodel is not known. Importantly, current therapies are not beneficial for hMI patients and previously studied therapies have not targeted iron from hemorrhage. We hypothesize that the evolving changes of hemorrhage within the infarct zone precipitates (a) a heme-iron mediated death (ferroptosis) of surviving cardiomyocytes in the acute phase of MI; (b) the formation of ferric-iron crystals within macrophages that attempt to remove them polarize them to a proinflammatory state in chronic phase of MI; and (c) a therapy that accounts for the temporal changes in hemorrhage can rescue the hearts from infarct expansion and rapid adverse LV remodeling. To investigate these hypotheses, Aim 1 will establish the mechanistic framework by which hemorrhage promotes time-dependent damage to the heart in the post MI period; Aim 2 will determine the time-dependent changes that alter the features of iron within hemorrhage to tune the development of therapeutic strategies; and Aim 3 will determine optimal iron chelation strategies to reduce the adverse effects of hemorrhage following reperfusion. To address these Aims, this proposal brings together an interdisciplinary team to derive an overarching framework of how hemorrhage promotes adverse outcomes, which is then used to test therapies against hMI. Hence, this proposal is a major step toward curbing the chronic heart failure epidemic in the US.