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

项目摘要 通过冠状动脉的血流重建（再灌注）减少了直接的 急性心肌梗死（MI）死亡。然而，在慢性并发症的长期 MI阶段，特别是慢性心力衰竭（CHF），最终导致严重不良心血管事件 不良事件（MACE：住院或死亡）已成为流行病。目前，约200万MI患者 在美国，患有CHF并且他们的5年存活率<50%。 慢性心力衰竭的一个重要且长期确立的预测因素是急性心肌梗死的大小;但 减少急性MI大小受到再灌注时间的限制。在过去的二十年里， 心脏MRI（CMR）已经确定，持续性微血管阻塞（PMO）是另一种 CHF的独立预测因子。PMO是MI的急性特征，其中微血管血液流向 尽管再灌注，MI区域仍丢失。估计PMO存在于>60%的急性MI中。 值得注意的是，最近一个国际财团的结果报告说， 发生MACE的风险是慢性期急性心肌梗死的4倍。因此，委员会认为， PMO的治疗靶向为患者带来了很大的希望，否则就有可能发生 瑞士法郎。然而，目前可用的MI后药物并不专用于PMO患者; 未显示PMO患者相对于其他MI类型的任何增量获益。此外，委员会认为， 尽管在防止PMO发生方面已经投入了大量的努力，但尚未 能够始终如一地做到这一点。这些观察结果导致了最近的反倾销呼吁， 提高了对PMO如何在MI慢性期驱动不良重塑的理解， 可以开发有效的治疗剂。 使用慢性MI的动物模型，在本提案中，我们旨在证明（a）PMO 分解成铁晶体，其在驱动不利重塑中起核心作用;和（B） 来自心脏的铁与去铁酮的螯合作用可显著降低不利的重构。要求1 将开发CMR方法，以准确量化MI区域内的铁;目标2将 证明了驱动不良重塑的机制;目标3将表明， 减少了不良重塑。为了实现这些目标，本建议汇集了一个 心脏成像（MRI和PET）、巨噬细胞生物学、梗死后 重塑铁螯合疗法和化学疗法成功完成此提案将 显著影响MI患者的临床护理，因为所提出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的临床特征， 铁紊乱

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.