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: 9981537
• 负责人: Rohan Dharmakumar
• 金额: $ 86.74万
• 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 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981537
• 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.

项目总结 冠状动脉血流(再灌流)的重建减少了即刻 死于急性心肌梗死(MI)。然而，慢性肝炎的长期并发症 心肌梗塞阶段，特别是慢性心力衰竭(CHF)，最终导致主要不良心血管事件 事件(重大事件：住院或死亡)，已成为流行病。目前，约有200万心肌梗死患者 在美国，他们患有CHF，他们的5年存活率为50%。 慢性心力衰竭的一个重要和长期确立的预测指标是急性心肌梗死的大小； 急性心肌梗死的缩小受再灌注时间的限制。在过去的二十年里，在 心脏磁共振(CMR)已证实持续性微血管阻塞(PMO)是另一种 CHF的独立预测因子。PMO是心肌梗死的一个急性特征，微血管血流到 尽管再灌流，心肌梗死的范围还是消失了。据估计，在所有急性心肌梗死患者中，有60%存在PMOS。 值得注意的是，一个国际财团最近的结果报告称，PMO的存在 在慢性期，发生MACE的风险是急性心肌梗塞的4倍。因此， PMOs的靶向治疗为其他有发展风险的患者带来了巨大的希望 瑞士法郎。然而，目前可用的心肌梗塞后药物并不是针对PMO患者的；而且他们 与其他类型的心肌梗死相比，PMO患者并未显示出任何递增的益处。此外， 尽管已经花费了大量的努力来防止PMO的发生，但它还没有 有可能始终如一地实现这一目标。这些观察结果导致了最近强烈的呼吁 提高了对PMO如何在MI慢性期推动不利重构的理解，从而 可能会开发出有效的治疗方法。 使用慢性心肌梗死的动物模型，在这项建议中，我们的目的是证明(A)PMO 分解成铁晶体，它在驱动不利的重塑中发挥核心作用；和(B) 用去铁酮螯合心脏中的铁可以显著减少不良的重塑。目标1 将开发一种CMR方法，用于准确量化MI区内的铁；目标2将 演示驱动不利重塑的机制；目标3将显示还原铁 心肌梗死内减少不良重塑。为了实现这些目标，这项提议汇集了一个 心脏成像(核磁共振和正电子发射计算机断层扫描)、巨噬细胞生物学、梗塞后专家组 重塑、铁络合疗法和化学。成功完成这项提案将 对心肌梗塞患者的临床护理产生重大影响，因为拟议的铁络合疗法将迅速 由于其在治疗其他心脏疾病方面的安全性和有效性而建立的临床简档可翻译 铁代谢紊乱。