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

项目概要 最终导致主要不良心血管事件（MACE）的慢性心力衰竭已成为流行病 既往患有心肌梗塞 (MI) 的患者。据疾病控制中心称，超过 30 万人死亡 在美国，每年有 1 起因慢性心力衰竭所致。长期确定的慢性心力衰竭预测因子 是梗塞面积。然而，晚期微血管阻塞，即心肌梗塞中微血管血流的一种情况 尽管心外膜冠状动脉再灌注，但其领土仍丢失，已成为另一种独立的冠状动脉 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心肌梗死 (hMI) 最容易发生 MACE。据此， hMI 患者的治疗干预将大大遏制 MACE：确定原因、机制 将 hMI 与 MACE 风险联系起来的事件发生的时间是关键。与 hMI 相关的几个重要观察结果 心肌梗死的急性期和慢性期已有报道，但出血驱动的总体机制 整个梗塞后期间的不良后果尚不清楚。重要研究表明，在再灌注 急性心梗 (a) 较大的心梗常有出血； (b) 再灌注本身可引起体内明显的氧化应激 MI 区； (c) 铁是促进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和 导致梗塞扩大。研究表明，在 MI 慢性期，及时解决 促炎细胞因子至关重要，否则会损害疤痕形成并加速不良反应 重塑。但为什么一些心肌梗塞具有长期的促炎负担并继续进行不利的重塑是 不知道。重要的是，当前的疗法对 hMI 患者和之前研究的疗法均无益 没有针对出血中的铁。我们假设出血的演变变化 梗死区在急性心肌梗塞中会导致血红素铁介导的存活心肌细胞死亡（铁死亡） 心肌梗死阶段； (b) 巨噬细胞内形成三价铁晶体，试图将其去除极化 在 MI 慢性期，它们会进入促炎状态； (c) 一种考虑到时间的疗法 出血的变化可以挽救心脏免受梗塞扩张和快速不利的左心室重塑。至 研究这些假设，目标 1 将建立出血促进的机制框架 心肌梗死后时期对心脏的时间依赖性损害；目标 2 将确定随时间变化的变化 改变出血中铁的特征以调整治疗策略的制定；和目标 3 将确定最佳的铁螯合策略，以减少术后出血的不利影响 再灌注。为了实现这些目标，该提案汇集了一个跨学科团队，以得出 出血如何促进不良后果的总体框架，然后用于测试疗法 反对 hMI。因此，该提案是遏制美国慢性心力衰竭流行的重要一步。

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.