Mediators of Systemic Inflammation and Heart Failure Risk in the Community

项目总结/摘要 慢性炎症，定义为局部和全身促炎因子的持续升高， 与社区心力衰竭的发展和进展有关。尽管如此，证据 在人类中，关于特定炎症途径作为关键的潜在作用， 疾病的机械驱动因素，反过来，作为潜在的高产治疗靶点。这个问题 这部分是由于先前主要关注炎症的下游而不是上游介质。 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 在疾病发病机理中起作用，因此可作为有效的治疗靶点。上游启动 人类炎症主要由多不饱和脂肪酸的小脂质分子效应物控制 代谢，称为类二十烷酸。这些生物活性脂质物质表现出促炎和抗炎活性 包括洋地黄素、脂氧素和白三烯。迄今为止，类花生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，我们建议提供一个更 详细了解上游类二十烷酸途径如何可以是非活性的，不平衡的， 与个体发展心力衰竭的倾向有关的干扰。高级质谱法 现在的方法可以快速和准确地定量高达数百个上游类二十烷酸 代表多种酶源的介质。我们将用这些方法综合分析 不同的促炎和抗炎类花生酸，并检查它们与心力衰竭危险因素的关系， 对生活在社区中的男女进行的纵向研究的结果。与此同时，我们将侧写 类花生酸在即将发生心力衰竭的动物模型的纵向研究中的应用。我们的具体目标是：（1） 评估循环类花生酸炎症介质是否与心力衰竭危险因素相关 和社区发病率;（2）在以下情况下，将循环类花生酸与不良结局联系起来： 建立心力衰竭;（3）研究类花生酸的时间和组织特异性相关性 心力衰竭实验模型的变异。我们系统地全面调查 与心力衰竭结局相关的上游炎症活性组分， 风险承诺产生重要的见解临床上重要的心功能不全的决定因素。给定 其重点是上游炎症活动，这项工作将为后续研究铺平道路， 抗炎疗法（现有的和新的药剂）调节不同的炎症因子的变化的功效 类花生酸以及结果。

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.