Eicosanoid Profiles as Determinants of HFpEF

类二十烷酸分布作为 HFpEF 的决定因素

• 批准号: 9427278
• 负责人: Jennifer E Ho
• 金额: $ 82.87万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-15 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9427278
• 关键词: Affect; Analytical Chemistry; Anti-inflammatory; Arachidonic Acids; Bioinformatics; Biological Assay; Biological Process; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiopulmonary; Cardiovascular system; Clinical; Communities; Comorbidity; Complement; Complex; Development; Disease; EFRAC; Eicosanoids; Eicosapentaenoic Acid; Evaluation; Event; Exercise; Exercise Physiology; Foundations; Functional disorder; Future; Genetic Markers; Heart; Heart failure; Hospitals; Human; Hypertension; Image; Inflammation; Inflammation Mediators; Inflammatory; Investigation; Knowledge; Left Ventricular Hypertrophy; Leukotrienes; Light; Lipids; Lipoxins; Lung; Magnetic Resonance Imaging; Mass Spectrum Analysis; Mediator of activation protein; Metabolism; Methods; Modification; Molecular; Morbidity - disease rate; Myocardial Infarction; Obesity; Omega-3 Fatty Acids; Outcome; Participant; Pathogenesis; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Phenotype; Physiological; Plasma; Play; Polyunsaturated Fatty Acids; Prevention approach; Prevention therapy; Prostaglandins; Proxy; Public Health; Research; Research Personnel; Risk Factors; Role; Signal Transduction; Testing; Therapeutic; Thromboxanes; Tissues; Treatment Efficacy; Vascular Diseases; base; body system; circulating biomarkers; clinical epidemiology; clinical heterogeneity; clinical risk; cohort; disorder prevention; effective therapy; hemodynamics; improved; individualized medicine; inflammatory marker; insight; mortality; multidisciplinary; novel; optimal treatments; prospective; public health relevance; secondary analysis; small molecule; therapeutic target; trait

Project Summary/Abstract Heart failure (HF) is a major public health problem worldwide, and half of patients presenting with HF have preserved (HFpEF), rather than reduced ejection fraction. However, HFpEF remains a therapeutic challenge, given current limited understanding of causal and contributing factors, and clinical heterogeneity within HFpEF subphenotypes. Comorbidities such as obesity and hypertension are thought to induce a systemic pro- inflammatory state that, in turn, drives cardiovascular dysfunction and remodeling leading to HFpEF. Indeed, downstream markers of inflammation have been observed in HFpEF. However, accumulating evidence suggests that upstream mediators of inflammation are more likely to play a causal role in disease pathogenesis and, in turn, serve as effective therapeutic targets. Upstream initiation of inflammation in humans is governed primarily by small molecule effectors of arachidonic acid metabolism, termed eicosanoids. These bioactive lipids include thromboxanes, prostaglandins, lipoxins, and leukotrienes, and harbor pro- and anti-inflammatory activity, vasoactivity, and direct modulation of cardiomyocyte signaling and contractile function. To date, the interaction between eicosanoid pathways and development of HFpEF remain poorly understood, thus limiting our ability to harness their therapeutic potential. Advanced methods using mass spectrometry now allow for the rapid and accurate quantification of >150 upstream eicosanoid mediators representing multiple enzymatic origins. To provide a more detailed understanding of how upstream eicosanoid pathways may underlie the progression from risk factors to HFpEF, and shed light onto HFpEF subphenotypes, we will pursue two related lines of investigation: In Aim 1, we will investigate the association of circulating eicosanoids with clinical risk factors, subclinical cardiac remodeling, and incident HFpEF in the community. In Aim 2, we will examine the association of eicosanoid profiles with HFpEF subphenotypes, including distinct cardiac and extracardiac vascular dysfunction among clinical HFpEF patients. This proposal leverages a unique multidisciplinary team of collaborators with expertise in clinical epidemiology, advanced imaging, exercise physiology, bioinformatics, analytical chemistry, and lipidomics. Our systematic approach to comprehensively investigating the components of upstream inflammatory activity in two large, well-phenotyped community-based cohorts, complemented by a group of clinical HFpEF patients with comprehensive exercise hemodynamic evaluations and deep physiologic phenotyping to assess distinct aspects of cardiovascular dysfunction, promises to yield important insights into the molecular determinants of HFpEF. Importantly, these studies will lay the foundation for future investigations focused on disease prevention and optimal therapies tailored to HFpEF subphenotype.

项目总结/摘要 心力衰竭（HF）是世界范围内的主要公共卫生问题，并且呈现HF的患者中有一半患有心力衰竭。 保留（HFpEF），而不是减少射血分数。然而，HFpEF仍然是一个治疗挑战， 鉴于目前对HFpEF的因果和影响因素以及临床异质性的了解有限 亚表型肥胖和高血压等合并症被认为会诱导全身性促炎， 炎症状态，其反过来驱动心血管功能障碍和重塑，导致HFpEF。的确， 已经在HFpEF中观察到炎症的下游标志物。然而，积累证据 表明炎症上游介质更有可能在疾病发病机制中发挥因果作用 并反过来作为有效的治疗靶点。人类炎症的上游启动受 主要通过花生四烯酸代谢的小分子效应物，称为类花生酸。这些生物活性 脂质包括血栓素、脂氧素、白细胞三烯，并具有促炎和抗炎作用。 活性、血管活性和心肌细胞信号传导和收缩功能的直接调节。迄今为止 类花生酸途径和HFpEF发生之间相互作用仍然知之甚少，因此限制了 我们利用他们治疗潜力的能力使用质谱的先进方法现在允许 快速准确定量>150种上游类花生酸介质，代表多种酶促 起源.为了更详细地了解上游类二十烷酸途径是如何构成 从危险因素到HFpEF的进展，并阐明HFpEF的亚表型，我们将研究两个相关的 研究路线：在目标1中，我们将研究循环类二十烷酸与临床风险的相关性 因素、亚临床心脏重构和社区HFpEF事件。在目标2中，我们将检查 类花生酸谱与HFpEF亚表型的相关性，包括不同的心脏和心外 临床HFpEF患者的血管功能障碍。该提案利用了独特的多学科团队 在临床流行病学、先进成像、运动生理学、生物信息学、 分析化学和脂质组学。我们的系统方法，全面调查 在两个大型的、表型良好的基于社区的队列中， 辅以一组具有综合运动血流动力学评价的临床HFpEF患者 和深生理表型，以评估心血管功能障碍的不同方面，有望产生 对HFpEF的分子决定因素的重要见解。重要的是，这些研究将奠定基础 未来的研究重点是疾病预防和针对HFpEF亚表型的最佳治疗。