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.

项目摘要 通过冠状动脉重新建立血液（再灌注）已立即减少 急性心肌梗死（MI）死亡。但是，慢性的长期并发症 MI阶段，尤其是慢性心力衰竭（CHF）最终导致主要不良心血管 事件（狼牙棒：住院或死亡）已成为流行病。目前，约200万MI患者 在美国，有瑞士法郎居住，其5年生存率<50％。 慢性心力衰竭的一个重要且悠久的预测指标是急性MI大小。但 减少急性MI大小受到再灌注的时间受到限制。在过去的二十年中，进步 心脏MRI（CMR）已经确定持续的微血管阻塞（PMO）是另一个 CHF的独立预测指标。 PMO是MI的急性特征，其中微血管血液流向 尽管再灌注，MI领土还是丢失了。 PMO估计存在于所有急性错误的60％中。 值得注意的是，来自国际财团的结果最近报道了PMO的存在 在慢性时期，比急性MI大小的MACE风险大4倍。因此， PMO的治疗靶向对患者有着巨大的希望 瑞士法郎。但是，目前可用的MI药物并非针对PMO患者。和他们 与其他MI类型相比，PMO患者没有显示出任何增量益处。此外， 尽管已经为防止PMO发生而花费了巨大的努力，但尚未 可以始终如一地实现这一目标。这些观察结果导致了最近的强调呼吁 对PMO在MI的慢性阶段中如何驱动不良重塑的理解得到了提高的理解 可以开发有效的治疗剂。 使用慢性MI的动物模型，在此提案中，我们旨在证明（a）PMOS 解决铁晶体，在驱动不良重塑中起着核心作用。 （b） 用脱佛酮从心脏中螯合铁可以显着减少不良重塑。目标1 将开发一种CMR方法，以准确量化MI区域内的铁； AIM 2意志 演示驱动不良重塑的机制； AIM 3将表明减少铁 在MI中减少不良重塑。为了解决这些目标，该提议汇集了 心脏成像专家（MRI和PET），巨噬细胞生物学，梗塞后 重塑，铁授予疗法和化学。该提案的成功完成将 由于提出的铁螯合治疗将迅速影响MI患者的临床护理 由于其既定的临床特征，可在治疗其他心脏方面的安全性和功效 铁疾病。