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

急性再灌注出血性心肌梗塞可转化疗法的机制见解

• 批准号: 9887771
• 负责人: Rohan Dharmakumar
• 金额: $ 84.24万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-05 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9887771
• 关键词: Acute; Acute myocardial infarction; Address; Adverse effects; Animal Model; Autophagocytosis; Biological; Blood flow; Cardiac; Cardiac Myocytes; Cardiovascular system; Caring; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chelation Therapy; Chronic; Chronic Phase; Cicatrix; Clinical; Communities; Congestive Heart Failure; Coronary artery; Crystallization; Data; Deposition; Epidemic; Event; Extravasation; FDA approved; Foundations; Health Care Costs; Heart; Heart Diseases; Heme; Heme Iron; Hemorrhage; Image; Impairment; Infarction; Inflammasome; Iron; Iron Chelating Agents; Iron Chelation; Left Ventricular Remodeling; Link; Location; Mediating; Mitochondria; Muscle Cells; Myocardial; Myocardial Infarction; Obstruction; Organ; Oxidative Stress; Pathway interactions; Patients; Pharmacologic Substance; Phase; Phenotype; Reperfusion Injury; Reperfusion Therapy; Reporting; Research; Resolution; Risk; Savings; Site; Testing; Therapeutic Intervention; Time; Tissues; Translations; adverse outcome; base; catalyst; clinically relevant; crystallinity; cytokine; extracellular; fluoroform; heart damage; heme a; improved; insight; iron chelation therapy; macrophage; myocardial infarct sizing; optimal treatments; oxidation; recruit; targeted treatment; therapeutic development

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.

项目摘要 重大不良心血管事件（MACE）的慢性心力衰竭已在流行病中流行 先前心肌梗塞（MI）的患者。根据疾病控制中心，> 300,000人死亡 每年归因于美国的慢性心力衰竭。慢性心力衰竭的长期预测指标 是梗塞的大小。然而，晚期微血管阻塞，在MI中微血管血流的情况 尽管心外膜冠状动脉再灌注，但领土仍然丧失，但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，晚期的微血管阻塞通常与 心肌内出血和出血性MIS（HMI）是最容易容易出现的狼牙棒。因此， HMI患者的治疗干预措施将基本遏制MACE：建立原因，机制 将HMI与MACE风险联系起来的事件的时机是关键。与HMI有关的几个重要观察 已经报道了MI的急性和慢性阶段，但出血驱动的总体机制 整个进攻后期的不良结果尚不清楚。重要的研究表明，在重复中 急性mis（a）大MIS经常出血； （b）再灌注本身会在内部引起明显的氧化应激 MI区； （c）铁是促进心肌细胞的氧化应激的关键催化剂 死亡。但是，尚不知道有富铁，加剧再灌注损伤和 导致梗塞扩张。在MI的慢性阶段，研究表明，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 重塑。但是，为什么有些MIS长时间促炎性负担并继续进行不利的重塑是 不知道。重要的是，目前的疗法对HMI患者无益，并且先前研究了疗法 没有从出血中靶向铁。我们假设在 梗塞区沉淀（a）急性中幸存的心肌细胞的血红素铁介导的死亡（铁肉芽） Mi阶段； （b）巨噬细胞中试图去除它们极化的巨噬细胞中铁晶体的形成 他们在MI的慢性阶段处于促炎状态； （c）一种临时的疗法 出血的变化可以使心脏从梗塞扩张和快速不良LV重塑中挽救。到 研究这些假设，AIM 1将建立出血促进的机械框架 在MI后时期，时间依赖于心脏的损害； AIM 2将确定时间相关的变化 这会改变出血中铁的特征，以调整治疗策略的发展；和目标3 将确定最佳铁螯合策略，以减少出血的不良影响 再灌注。为了解决这些目标，该提案汇集了一个跨学科团队，以得出 出血如何促进不良结果的总体框架，然后用于测试疗法 反对HMI。因此，这一提议是遏制美国慢性心力衰竭流行的主要步骤。