Mediators of Systemic Inflammation and Heart Failure Risk in the Community

社区中全身炎症和心力衰竭风险的中介因素

• 批准号: 10443548
• 负责人: Susan Cheng
• 金额: $ 80.87万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10443548
• 关键词: Acids; Adverse event; Analytical Chemistry; Animal Model; Animals; Anti-Inflammatory Agents; Arachidonic Acids; Atherosclerosis Risk in Communities; Biological Assay; Biological Factors; Biological Markers; Biological Process; Cardiac; Cardiac Myocytes; Cardiovascular Physiology; Cessation of life; Chronic; Clinical; Cohort Studies; Communities; Complex; Conflict (Psychology); Development; Disease; EFRAC; Eicosanoids; Eicosapentaenoic Acid; Epidemiology; Equilibrium; Exhibits; Experimental Models; Exposure to; Family; Follow-Up Studies; Framingham Heart Study; Goals; Heart Diseases; Heart failure; Hospitalization; Human; Hypertension; Image; Incidence; Individual; Inflammation; Inflammation Mediators; Inflammatory; Injury; Leukotrienes; Linoleic Acids; Lipids; Lipoxins; Longitudinal Studies; Mass Spectrum Analysis; Measures; Mediating; Mediation; Mediator of activation protein; Methods; Morbidity - disease rate; Mus; Myocardial dysfunction; Natriuresis; Obesity; Outcome; Participant; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Physiological; Plasma; Play; Polyunsaturated Fatty Acids; Prognosis; Prostaglandins; Risk; Risk Factors; Role; Sample Size; Serum; Signal Transduction; Source; Stress; Symptoms; TNF gene; Time; Tissues; Variant; Woman; Work; adverse outcome; antagonist; base; cardiogenesis; clinical risk; cohort; constriction; experimental study; fatty acid metabolism; gamma-Linolenic Acid; hemodynamics; improved; inflammatory marker; insight; ischemic injury; lipid mediator; longitudinal animal study; men; mortality; mouse model; novel; preservation; pressure; prospective; stressor; systemic inflammatory response; therapeutic target; therapeutically effective; trait; ventricular hypertrophy

PROJECT SUMMARY/ABSTRACT Chronic inflammation, defined by a persistent elevation of local and systemic pro-inflammatory factors, has been implicated in the development and progression of heart failure in the community. Nonetheless, evidence in humans is scant and conflicting regarding the potential for specific inflammatory pathways to serve as key mechanistic drivers of disease and, in turn, as potentially high-yield therapeutic targets. This problem has arisen, in part, from a predominant prior focus on downstream rather than upstream mediators of inflammation. Accumulating evidence suggests that upstream mediators of inflammation are more likely to play a causal role in disease pathogenesis and, thus, serve as effective therapeutic targets. The upstream initiation of inflammation in humans is governed primarily by small lipid molecule effectors of polyunsaturated fatty acid metabolism, termed eicosanoids. These bioactive lipid species exhibit both pro- and anti-inflammatory activity and include prostaglandins, lipoxins, and leukotrienes. To date, the interactions between eicosanoid pathways and heart failure traits and outcomes remain poorly understood. Therefore, we proposed to provide a more detailed understanding of how upstream eicosanoid pathways can be variably active, imbalanced, and perturbed in relation to an individual’s propensity for developing heart failure. Advanced mass spectrometry methods now allow for the rapid and accurate quantification of up to hundreds of upstream eicosanoid mediators representing multiple enzymatic origins. We will use these methods to comprehensively assay distinct pro- and anti-inflammatory eicosanoids and examine their relation to heart failure risk factors and outcomes in a longitudinal study of men and women living in the community. In parallel, we will profile eicosanoids in a longitudinal study of an animal model of impending heart failure. Our specific aims are: (1) to assess whether circulating eicosanoid mediators of inflammation are associated with heart failure risk factors and incidence in the community; (2) to relate circulating eicosanoids with adverse outcomes in the setting of established heart failure; and, (3) to investigate the temporal and tissue-specific correlates of eicosanoid variation in an experimental model of heart failure. Our systematic approach to comprehensively investigating the components of upstream inflammatory activity in relation to heart failure outcomes across the spectrum of risk promises to yield important insights into the determinants of clinically important cardiac dysfunction. Given its focus on upstream inflammatory activity, this work will pave the way for follow-up studies investigating the efficacy of anti-inflammatory therapies (both existing and novel agents) for modulating variation in distinct eicosanoids as well as outcomes.

项目概要/摘要 慢性炎症是指局部和全身促炎因子持续升高， 尽管如此，有证据表明它与社区心力衰竭的发生和进展有关。 关于特定炎症途径作为关键的潜力，在人类中的研究很少且相互矛盾 疾病的机械驱动因素，进而作为潜在的高产治疗目标。 部分原因是先前主要关注炎症的下游介质而不是上游介质。 越来越多的证据表明炎症的上游介质更有可能发挥因果作用 疾病发病机制中，因此，作为有效的治疗靶点。 人类炎症主要由多不饱和脂肪酸的小脂质分子效应子控制 这些生物活性脂质具有促炎和抗炎活性。 包括前列腺素、脂氧素和白三烯迄今为止，类二十烷酸途径之间的相互作用。 心力衰竭的特征和结果仍然知之甚少，因此，我们建议提供更多信息。 详细了解上游类二十烷酸途径如何变化活跃、不平衡和 与个人发生心力衰竭的倾向相关的干扰。 现在的方法可以快速准确地定量多达数百种上游类二十烷酸 我们将使用这些方法来综合分析代表多种酶起源的介质。 不同的促炎和抗炎类二十烷酸，并检查它们与心力衰竭危险因素的关系， 同时，我们将对社区中的男性和女性进行纵向研究的结果。 我们的具体目标是：（1）在即将发生心力衰竭的动物模型中使用类二十烷酸。 评估循环类二十烷酸炎症介质是否与心力衰竭危险因素相关 和社区中的发病率；(2) 将循环类二十烷酸与不良后果联系起来 确定心力衰竭；(3) 研究类二十烷酸的时间和组织特异性相关性 我们全面研究心力衰竭实验模型的变异。 与心力衰竭结果相关的上游炎症活动的组成部分 风险有望对临床上重要的心脏功能障碍的决定因素产生重要的见解。 由于其重点关注上游炎症活动，这项工作将为调查后续研究铺平道路 抗炎疗法（现有的和新的药物）对于调节不同的变化的功效 类二十烷酸以及结果。