Eicosanoid Profiles as Determinants of HFpEF

类二十烷酸分布作为 HFpEF 的决定因素

• 批准号: 10063013
• 负责人: Jennifer E Ho
• 金额: $ 59.27万
• 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 2021-11-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063013
• 关键词: Affect; Analytical Chemistry; Anti-Inflammatory Agents; Arachidonic Acids; Bioinformatics; Biological Assay; Biological Process; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiopulmonary; Cardiovascular system; Clinical; Communities; 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; Vascular Diseases; base; body system; circulating biomarkers; clinical epidemiology; clinical heterogeneity; clinical risk; cohort; comorbidity; disorder prevention; effective therapy; hemodynamics; improved; individualized medicine; inflammatory marker; insight; lipidomics; mortality; multidisciplinary; novel; optimal treatments; preservation; prospective; public health relevance; secondary analysis; small molecule; systemic inflammatory response; therapeutic target; therapeutically effective; 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.

项目概要/摘要 心力衰竭（HF）是世界范围内的一个主要公共卫生问题，一半的心力衰竭患者患有心力衰竭（HF）。 保留（HFpEF），而不是降低射血分数。然而，HFpEF 仍然是一个治疗挑战， 鉴于目前对 HFpEF 的因果因素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发全身性促 炎症状态反过来会导致心血管功能障碍和重塑，从而导致 HFpEF。的确， 在 HFpEF 中观察到炎症下游标志物。然而，不断积累证据 表明炎症的上游介质更有可能在疾病发病机制中发挥因果作用 反过来，作为有效的治疗靶点。人类炎症的上游起始受到控制 主要是通过花生四烯酸代谢的小分子效应物（称为类二十烷酸）实现的。这些生物活性 脂质包括血栓素、前列腺素、脂氧素和白三烯，具有促炎和抗炎作用 活性、血管活性以及心肌细胞信号传导和收缩功能的直接调节。迄今为止， 类二十烷酸途径与 HFpEF 发展之间的相互作用仍知之甚少，因此限制了 我们有能力利用它们的治疗潜力。使用质谱的先进方法现在可以 快速准确地定量代表多种酶的 >150 个上游类二十烷酸介质 起源。为了更详细地了解上游类二十烷酸途径如何构成 为了从危险因素发展为 HFpEF，并阐明 HFpEF 亚表型，我们将追求两个相关的 研究方向：在目标 1 中，我们将研究循环类二十烷酸与临床风险的关联 因素、亚临床心脏重塑和社区中的 HFpEF 事件。在目标 2 中，我们将检查 类二十烷酸谱与 HFpEF 亚表型的关联，包括不同的心脏和心外亚型 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 具有临床流行病学、高级成像、运动生理学、生物信息学专业知识的合作者， 分析化学和脂质组学。我们采用系统方法全面调查 两个大型、表型良好的基于​​社区的队列中上游炎症活动的组成部分， 辅以一组临床 HFpEF 患者的综合运动血流动力学评估 和深度生理表型分析来评估心血管功能障碍的不同方面，有望产生 对 HFpEF 分子决定因素的重要见解。重要的是，这些研究将为 未来的研究重点是针对 HFpEF 亚表型的疾病预防和最佳治疗。