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

项目总结 慢性心力衰竭最终导致主要不良心血管事件(MACE)已在#年流行 既往有心肌梗死(MI)患者。根据疾病控制中心的数据，死亡人数为30万人 在美国，每年可归因于慢性心力衰竭。慢性心力衰竭的长期预测指标 就是脑梗塞的面积。然而，晚期微血管阻塞，一种微血管血流在MI中流动的情况 尽管心外膜冠状动脉再通，但领土丢失，已成为另一个独立的 慢性心力衰竭的预测指标。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。因此， 对HMI患者的治疗干预将大大遏制MACE：建立原因、机制 而将HMI与Mace风险联系起来的事件的时机是关键。与HMI相关的几个重要观察结果 已有急性期和慢性期心肌梗塞的报道，但出血驱动的主要机制 整个梗死期的不良后果尚不得而知。关键研究表明，在再灌流中 急性心肌梗死(A)大面积心肌梗死常有出血；(B)再灌注本身可引起明显的氧化应激反应。 以及(C)铁是促进氧化应激的关键催化剂，从而驱动心肌细胞 死亡。然而，目前尚不清楚富含铁的出血是否会加剧再灌注损伤和 会导致梗塞扩大。在心肌梗塞的慢性期，研究表明，及时解决 致炎细胞因子至关重要，否则会损害疤痕的形成并加速不良反应。 改建。但为什么一些误诊患者有长期的促炎负担，并继续进行不利的重塑？ 不知道。重要的是，目前的治疗方法对HMI患者和以前研究的治疗方法都没有好处。 没有针对失血的铁元素。我们假设脑部出血的演变变化 梗死区导致(A)血红素-铁介导的存活心肌细胞死亡(铁下垂)。 心肌梗死时相；(B)巨噬细胞内铁-铁晶体的形成，试图将其极化。 在心肌梗塞慢性期的促炎状态；以及(C)对暂时性心梗的治疗。 出血的改变可以使心脏免于梗塞扩大和快速不良的左室重构。至 研究这些假设，目标1将建立出血促进的机制框架 心肌梗死后对心脏的时间依赖性损害；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；以及目标3 将确定最佳的铁络合策略，以减少以下出血的不良影响 再灌流。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，然后用来测试治疗方法 针对人机界面。因此，这项建议是朝着遏制美国慢性心力衰竭流行迈出的重要一步。

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.