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.

项目摘要/摘要 心力衰竭（HF）是全球一个主要的公共卫生问题，有一半的HF患者有 保留（HFPEF），而不是减少射血分数。但是，HFPEF仍然是一个治疗挑战， 鉴于当前对HFPEF内因果关系和促成因素以及临床异质性的了解有限 亚表征。肥胖和高血压等合并症被认为会引起全身性研究 炎症状态表明，进而驱动心血管功能障碍并重塑导致HFPEF。的确， 在HFPEF中已经观察到了炎症的下游标记。但是，积累证据 表明炎症上游介体更有可能在疾病发病机理中发挥因果作用 反过来，作为有效的治疗靶标。人类炎症的上游开始 主要是由小蛛酸代谢的小分子效应子称为eicosanoids。这些生物活性 脂质包括血栓氨酰，前列腺素，lipoxin和白细胞，以及港口亲和抗炎 心肌信号传导和收缩功能的活性，血管活性和直接调节。迄今为止， 类花生酸途径与HFPEF的发展之间的相互作用仍然很少理解，因此限制了 我们利用其治疗潜力的能力。使用质谱法的高级方法现在允许 > 150个上游类固醇介体的快速准确定量代表多种酶促的介体 起源。为了提供对上游类eicosanoid途径的更详细的理解 从危险因素到HFPEF的发展，并将灯光放到HFPEF亚表格上，我们将追求两个相关的 调查线：在AIM 1中，我们将调查循环类花生酸与临床风险的关联 社区中的因素，亚临床心脏重塑和事件HFPEF。在AIM 2中，我们将检查 类eicosanoid剖面与HFPEF亚表料的关联，包括不同的心脏和外心形型 临床HFPEF患者的血管功能障碍。该建议利用独特的多学科团队 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的合作者 分析化学和脂肪组学。我们全面研究的系统方法 两个大型，良好的基于​​社区的同伙的上游炎症活动的组成部分， 一组具有全面运动血液动力学评估的临床HFPEF患者的补充 以及评估心血管功能障碍不同方面的深层生理表型，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 对于未来的研究，侧重于预防疾病和针对HFPEF亚型量身定制的最佳疗法。