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.

项目摘要 保留的射血分数（HFPEF）的心力衰竭继续对医疗系统造成重大燃烧， 妇女发展HFPEF的可能性是男性的两倍，并且没有针对HFPEF的有针对性疗法。冠状动脉 微血管功能障碍（CMD）被定义为心脏内部小丝的功能受损，是一个 广泛流行但知之甚少的状况，这也主要影响女性。 HFPEF是最大的 CMD女性经常经历的病态结果，她们通常比其他人年轻 HFPEF表型。虽然我们和其他人表明，HFPEF在CMD的三分之一的女性中存在，但 CMD相关HFPEF的病理生物学尚不清楚。 CMD导致慢性心肌缺血，这是 导致降低葡萄糖利用率增加，自由脂肪酸降低的端肌细胞代谢转移 氧化和甘油三酸酯（TG）在心肌中积累 - 导致心肌脂肪变性，我们 与舒张功能障碍（一种前HFPEF特征）相关。因为CMD的女性比 男性会持续更长的慢性缺血，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CMD女性HFPEF发展的关键因素。 来自我们小组的新兴数据强调了慢性炎症（即类固醇）途径的重要性 在管理对缺血性，内形成型代谢转移和心脏机械应激源的反应时 在CMD和HFPEF病理生理学中隐含的。因此，这个早期阶段的目的 研究者R01的应用是：（1）确定慢性缺血与心肌之间的关系 脂肪变性以及心肌脂肪变性介导缺血与临床前之间的关联的程度 CMD中的HFPEF; （2）确定具有CMD相关的心肌风险的特定eicosanaid分子 脂肪变性，临床前HFPEF特征和临床HFPEF。在预期的220 CMD妇女中 综合心脏磁共振（CMR）成像和光谱法，我们将确定临床HFPEF 状态和量化：（i）心肌TG含量和脂肪变性； （ii）慢性缺血负担和（iii）临床前 CMR HFPEF特征将慢性缺血与心肌脂肪变性相关联。队列中的血浆生物样本将 进行高通量分析，以识别与心肌脂肪变性相关的不同类素素谱。 用18F-FDG PET进行的探索性分析将将类花生酸的特征与心肌特异性炎症联系起来。 eicosanoid概况还将在一个大型社区队列中测试HFPEF的事件，十多年 HFPEF结果。了解心脏脂肪变性在与CMD相关的缺血方面的作用， 炎症和HFPEF特征有望揭示预防和治疗HFPEF的新颖目标，尤其是 在女性中。