Developing a MRI-guided Disease-Modifying Therapy for Post Infarction Chronic Heart Failure

开发 MRI 引导的梗死后慢性心力衰竭疾病缓解疗法

• 批准号: 9756228
• 负责人: Rohan Dharmakumar
• 金额: $ 86.72万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9756228
• 关键词: Acute; Acute myocardial infarction; Address; Animal Model; Animals; Arteries; Attenuated; Automobile Driving; Biology; Blood; Blood flow; Cardiac; Cardiovascular system; Caring; Cell Culture Techniques; Cellular biology; Cessation of life; Chelating Agents; Chemicals; Chemistry; Chronic; Chronic Phase; Clinical; Congestive Heart Failure; Coronary artery; Crystallization; Data; Deposition; Disease; Epidemic; Event; Extravasation; Fatty acid glycerol esters; Functional disorder; Gout; Heart; Hemorrhage; Hospitalization; Infarction; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1 beta; International; Iron; Iron Chelating Agents; Iron Chelation; Iron Metabolism Disorders; Lead; Magnetic Resonance Imaging; Mediating; Methods; Microcirculatory Bed; Monitor; Myocardial Infarction; Myocardial Ischemia; Obstruction; Patients; Pharmaceutical Preparations; Phenotype; Play; Positron-Emission Tomography; Production; Reperfusion Therapy; Reporting; Risk; Role; Safety; Survival Rate; Testing; Thinness; Time; Toxic effect; Translating; Treatment Efficacy; Urate; clinical care; clinically relevant; cytokine; heart imaging; improved; insight; iron chelation therapy; macrophage; myocardial infarct sizing; nanocrystal; prevent; therapeutic target

PROJECT SUMMARY Re-establishment of blood flow (reperfusion) through coronary arteries has reduced immediate death from acute myocardial infarctions (MI). However, the long-term complications in the chronic phase of MI, particularly chronic heart failure (CHF) culminating in major adverse cardiovascular events (MACE: hospitalization or death), have become epidemic. Currently, ~2 million MI patients in the US are living with CHF and their 5-year survival rate is < 50%. An important and long-established predictor of chronic heart failure is the acute MI size; but reducing acute MI size is limited by time to reperfusion. Over the past two decades, advances in cardiac MRI (CMR) have established that persistent microvascular obstruction (PMO) is another independent predictor of CHF. PMO is an acute feature of MI where microvascular blood flow to the MI territory is lost despite reperfusion. PMOs are estimated to be present in >60% of all acute MIs. Notably, results from an international consortium recently reported that the presence of PMO carries a 4-fold greater risk for MACE than acute MI size in the chronic period. Accordingly, therapeutic targeting of PMOs holds great promise for patients otherwise at risk of developing CHF. Yet, currently available post MI medications are not specific to patients with PMO; and they have not shown any incremental benefit to the patients with PMO over other MI types. Furthermore, although a significant effort has been spent on preventing PMO from occurring, it has not yet been possible to consistently achieve this. These observations have led to recent emphatic calls for improved understandings of how PMOs drive adverse remodeling in the chronic phase of MI so that effective therapeutics may be developed. Using animal models of chronic MI, in this proposal we aim to demonstrate that (a) PMOs resolve into iron crystals, which play a central role in driving the adverse remodeling; and (b) chelation of iron from the heart with deferiprone can significantly reduce adverse remodeling. Aim 1 will develop a CMR approach for accurate quantification of iron within MI zones; Aim 2 will demonstrate the mechanism driving the adverse remodeling; and Aim 3 will show that reducing iron within MI reduces adverse remodeling. To address these Aims, this proposal brings together a group of experts in cardiac imaging (MRI and PET), macrophage biology, post infarction remodeling, iron-chelation therapy and chemistry. Successful completion of this proposal will significantly impact clinical care of MI patients as the proposed iron chelation therapy will be rapidly translatable owing to its established clinical profile for safety and efficacy in treating other cardiac iron disorders.

项目概要 通过冠状动脉的血流重建（再灌注）已减少了即时 死于急性心肌梗塞（MI）。然而，慢性病的长期并发症 MI 阶段，特别是慢性心力衰竭 (CHF)，最终导致严重的心血管不良 事件（MACE：住院或死亡）已成为流行病。目前，约有 200 万 MI 患者 在美国，CHF 患者的 5 年生存率 < 50%。 慢性心力衰竭的一个重要且长期确定的预测因素是急性心肌梗死的大小。但 减少急性心肌梗死的大小受到再灌注时间的限制。过去二十年，技术进步 心脏 MRI (CMR) 已确定持续性微血管阻塞 (PMO) 是另一个原因 CHF 的独立预测因子。 PMO 是 MI 的一个急性特征，其中微血管血液流向 尽管再灌注，心肌梗死区域仍会丢失。据估计，超过 60% 的急性 MI 中都存在 PMO。 值得注意的是，一个国际财团最近报告的结果表明，PMO 的存在 慢性期发生 MACE 的风险是急性 MI 大小的 4 倍。因此， PMO 的治疗靶向为那些面临发展风险的患者带来了巨大的希望 瑞士法郎。然而，目前可用的 MI 后药物并非专门针对 PMO 患者。而他们 与其他 MI 类型相比，尚未显示出 PMO 患者有任何增量益处。此外， 尽管为防止 PMO 的发生付出了巨大的努力，但尚未得到有效解决。 能够持续实现这一目标。这些观察结果导致最近强烈呼吁 更好地了解 PMO 如何在 MI 慢性期推动不良重塑，以便 可能会开发出有效的治疗方法。 使用慢性 MI 动物模型，在本提案中，我们旨在证明 (a) PMO 分解成铁晶体，铁晶体在驱动不良重塑中发挥核心作用； (b) 用去铁酮螯合心脏中的铁可以显着减少不良重塑。目标1 将开发一种 CMR 方法，用于准确定量 MI 区内的铁；目标2将 展示逆向重塑的驱动机制；目标 3 将表明还原铁 MI 内减少不良重塑。为了实现这些目标，该提案汇集了 心脏成像（MRI 和 PET）、巨噬细胞生物学、梗死后专家组 重塑、铁螯合疗法和化学。本提案的顺利完成将 显着影响 MI 患者的临床护理，因为拟议的铁螯合疗法将迅速 由于其在治疗其他心脏病方面的安全性和有效性已建立的临床特征，因此可转化 铁失调。