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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

基本信息

批准号：
10630055
负责人：
Rohan Dharmakumar
金额：
$ 74.99万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-05 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10630055
关键词：
Acceleration Acute Acute myocardial infarction Address Adverse effects Animal Model Autophagocytosis Biological Blood Vessels 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 Data Deposition Epidemic Event Extravasation FDA approved Foundations Health Care Costs Heart Heart Diseases Heme Heme Iron Hemorrhage Image Impairment Infarction Inflammasome Inflammatory Injury Iron Iron Chelating Agents Iron Chelation Left Ventricular Remodeling Link Location Macrophage Mediating Mitochondria Muscle Cells Myocardial Infarction Myocardial Reperfusion Obstruction Organ Oxidative Stress Pathway interactions Patients Persons Pharmacologic Substance Phase Phenotype Reperfusion Injury Reperfusion Therapy Reporting Research Resolution Risk Site Testing Therapeutic Intervention Time Tissues Translations adverse outcome catalyst clinically relevant cytokine extracellular fluoroform heart damage heme a improved insight iron chelation therapy myocardial infarct sizing myocardial injury optimal treatments oxidation recruit targeted treatment therapeutic development

项目摘要

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.

项目总结