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

患有冠状动脉微血管功能障碍的女性的心肌脂肪变性：通过保留射血分数（HFpEF）定义心力衰竭的途径

• 批准号: 10665607
• 负责人: Janet Wei
• 金额: $ 63.72万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665607
• 关键词: Affect; Animal Model; Aorta; Automobile Driving; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiovascular system; Caring; Chronic; Clinical; Clinical Trials; Communities; Coronary; Coronary Arteriosclerosis; Data; Development; Diagnosis; Diffuse; Disease Progression; EFRAC; Eicosanoids; Electrocardiogram; Family; Fibrosis; Functional disorder; Glucose; Healthcare Systems; Heart; Heart Atrium; Heart failure; Human; Impairment; Inflammation; Inflammatory; Ischemia; Left; Left Ventricular Remodeling; Lipids; Magnetic Resonance; Magnetic Resonance Spectroscopy; Mass Spectrum Analysis; Measures; Mechanics; Mediating; Mediator; Metabolic; Methods; Microvascular Dysfunction; Monitor; Myocardial; Myocardial Ischemia; Myocardium; Nonesterified Fatty Acids; Outcome; Pathway interactions; Perfusion; Phenotype; Plasma; Prevalence; Process; Prospective cohort; Research Personnel; Risk; Role; Specificity; Spectrum Analysis; Testing; Tissues; Triglycerides; Ventricular; Woman; adjudication; cardiac magnetic resonance imaging; clinical phenotype; cohort; experience; fatty acid oxidation; fluorodeoxyglucose; fluorodeoxyglucose positron emission tomography; high throughput analysis; indexing; men; novel; novel therapeutics; offspring; phenotypic data; pre-clinical; preservation; prevent; response; stressor; systemic inflammatory response; targeted treatment; trait

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.

项目总结 射血分数保留的心力衰竭(HFpEF)继续给医疗保健系统带来主要负担， 女性发生HFpEF的可能性是男性的两倍，而且目前还没有针对HFpEF的靶向治疗方法。冠状动脉 微血管功能障碍(CMD)，定义为心脏内小血管功能受损，是一种 广泛流行但知之甚少的疾病，也主要影响女性。HFpEF是世界上最 患有CMD的妇女经常经历病态结局，她们通常比患有其他疾病的妇女年轻 HFpEF表型。虽然我们和其他人已经表明，高达三分之一的CMD女性存在HFpEF， CMD相关HFpEF的病理生物学机制尚不清楚。慢性心肌病会导致慢性心肌缺血， 结果心肌细胞内代谢转变为增加葡萄糖利用率，减少游离脂肪酸 氧化和甘油三酯(TG)在心肌中堆积-导致心肌脂肪变性，我们 都与舒张期功能障碍有关，这是HFpEF前的一个特征。因为患有CMD的女性更有可能比 男性遭受慢性缺血的时间更长，我们的中心假设是与CMD相关的慢性缺血 随后的心肌脂肪变性是女性CMD患者发生HFpEF的关键因素。 来自我们小组的新数据强调了慢性炎症(即二十烷类)途径的重要性 在调控对缺血、心肌细胞内代谢变化和心脏机械应激源的反应中 与CMD和HFpEF病理生理学有关。因此，这个早期阶段的目标是 研究人员R01的应用是：(1)确定慢性缺血与心肌梗死的关系 脂肪变性和心肌脂肪变性在多大程度上调节缺血和临床前的联系 CMD中的HFpEF；以及，(2)识别导致CMD相关心肌风险的特定二十烷类分子 脂肪变性、临床前HFpEF特征和临床HFpEF。在220名接受CMD治疗的女性的前瞻性队列中 综合心脏磁共振(CMR)成像和波谱，我们将确定临床HFpEF 状态和量化：(I)心肌甘油三酯含量和脂肪变性；(Ii)慢性缺血负荷；(Iii)临床前 慢性心肌缺血与心肌脂肪变性相关的CMR HFpEF特征。队列中的血浆生物样本将 进行高通量分析，以确定与心肌脂肪变性相关的不同的二十烷类化合物特征。 18F-FDGPET的探索性分析将把二十烷类物质的分布与心肌特异性炎症联系起来。 二十烷类药物的特征也将在一个大型社区队列中进行HFpEF事件的测试，该队列具有超过十年的 HFpEF结果。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。