Myocardial Steatosis in Women with Coronary Microvascular Dysfunction: Defining the Pathway to Heart Failure with Preserved Ejection Fraction (HFpEF)

项目摘要 射血分数正常的心力衰竭（HFpEF）继续对医疗保健系统造成重大负担， 女性发生HFpEF的可能性是男性的两倍，并且不存在针对HFpEF的靶向治疗。冠状 微血管功能障碍（CMD），定义为心脏内小微血管功能受损，是一种 广泛流行但知之甚少的疾病，也主要影响妇女。HFpEF是最 经常经历的病态结果的妇女与CMD，谁往往是年轻的比那些与其他 HFpEF表型。虽然我们和其他人已经表明HFpEF存在于多达三分之一的CMD女性中， CMD相关HFpEF的病理生物学仍不清楚。CMD导致慢性心肌缺血， 导致心肌细胞内代谢向葡萄糖利用增加、游离脂肪酸减少 氧化和甘油三酯（TG）在心肌中积累-导致心肌脂肪变性，我们 与舒张功能障碍有关，这是HFpEF前的特征。因为患有CMD的女性比男性更有可能 我们的中心假设是，CMD相关的慢性缺血 以及随后的心肌脂肪变性是CMD女性患者发生HFpEF的关键因素。 我们小组的新数据强调了慢性炎症（即类花生酸）途径的重要性 在控制对缺血、心肌细胞内代谢变化和心脏机械应激的反应中， 与CMD和HFpEF病理生理学有关。因此，这个早期阶段的目标 研究者R 01的应用是：（1）确定慢性缺血与心肌梗死之间的关系。 脂肪变性和心肌脂肪变性介导缺血和临床前 CMD中的HFpEF;和（2）鉴定作为CMD相关心肌梗死风险基础的特定类花生酸分子 脂肪变性、临床前HFpEF特征和临床HFpEF。在一个前瞻性队列的220名CMD妇女接受 综合心脏磁共振（CMR）成像和光谱学，我们将确定临床HFpEF 状态和定量：（i）心肌TG含量和脂肪变性;（ii）慢性缺血负荷，和（iii）临床前 CMR HFpEF特征与慢性缺血和心肌脂肪变性相关。来自队列的血浆生物样本将 进行高通量分析以鉴定与心肌脂肪变性相关的不同类二十烷酸谱。 18F-FDG PET的探索性分析将类花生酸谱与心肌特异性炎症联系起来。 还将在一个大型社区队列中测试类花生酸谱的事件HFpEF，该队列具有超过十年的 HFpEF结局。了解心脏脂肪变性在CMD相关缺血中的作用， 炎症和HFpEF特征有望揭示预防和治疗HFpEF的新靶点，特别是 在女人身上。

PROJECT SUMMARY Heart failure with preserved ejection fraction (HFpEF) continues to pose a major burden to the healthcare system, women are twice as likely as men to develop HFpEF, and no targeted therapies for HFpEF exist. Coronary microvascular dysfunction (CMD), defined as impaired function of the small microvessels within the heart, is a widely prevalent yet poorly understood condition that also predominantly affects women. HFpEF is the most frequently experienced morbid outcome in women with CMD, who are often younger than those with other HFpEF phenotypes. While we and others have shown that HFpEF is present in up to a third of women with CMD, the pathobiology of CMD-related HFpEF remains unclear. CMD leads to chronic myocardial ischemia, which results in an intra-cardiomyocyte metabolic shift towards increased glucose utilization, reduced free fatty acid oxidation, and triglyceride (TG) accumulation in the myocardium – leading to myocardial steatosis, which we have associated with diastolic dysfunction, a pre-HFpEF trait. Because women with CMD are more likely than men to suffer chronic ischemia for longer durations, our central hypothesis is that CMD-related chronic ischemia and subsequent myocardial steatosis are key contributors to the development of HFpEF in women with CMD. Emerging data from our group underscores the importance of chronic inflammatory (i.e. eicosanoid) pathways in governing responses to the ischemic, intra-cardiomyocyte metabolic shifts, and cardiac mechanical stressors that have been implicated in CMD and HFpEF pathophysiology. Therefore, the aims of this Early Stage Investigator R01 application are to: (1) determine the relationship between chronic ischemia and myocardial steatosis and the extent to which myocardial steatosis mediates associations between ischemia and pre-clinical HFpEF in CMD; and, (2) identify specific eicosanoid molecules that underlie risk for CMD-related myocardial steatosis, pre-clinical HFpEF traits, and clinical HFpEF. In a prospective cohort of 220 CMD women undergoing comprehensive cardiac magnetic resonance (CMR) imaging and spectroscopy, we will determine clinical HFpEF status and quantify: (i) myocardial TG content and steatosis; (ii) chronic ischemia burden, and (iii) pre-clinical CMR HFpEF traits to relate chronic ischemia with myocardial steatosis. Plasma biosamples from the cohort will undergo high-throughput analyses to identify distinct eicosanoid profiles associated with myocardial steatosis. An exploratory analysis with 18F-FDG PET will relate the eicosanoid profiles to myocardial-specific inflammation. The eicosanoid profiles will also be tested for incident HFpEF in a large community cohort with over a decade of HFpEF outcomes. Understanding the role of cardiac steatosis with respect to CMD-related ischemia, inflammation, and HFpEF traits promises to reveal novel targets for preventing and treating HFpEF, especially in women.