Eicosanoid Profiles as Determinants of HFpEF

项目摘要/摘要 心力衰竭(HF)是世界范围内的一个主要公共健康问题，有一半的心衰患者患有 保存(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的病因和影响因素以及临床异质性的了解有限 亚型。肥胖症和高血压等并存疾病被认为会导致系统性的亲和性疾病。 炎症状态，进而导致心血管功能障碍和重塑，导致HFpEF。的确， 在HFpEF中观察到下游炎症标志物。然而，随着证据的积累 提示上游炎症介质更有可能在疾病发病机制中起因果作用。 反过来，它们又是有效的治疗靶点。人类炎症的上游始发受到控制 主要是通过花生四烯酸代谢的小分子效应物，称为二十烷类化合物。这些生物活性 脂类包括血栓烷、前列腺素、脂素和白三烯，并含有促炎和抗炎作用。 心肌细胞信号和收缩功能的活性、血管活性和直接调节。到目前为止， 二十烷类途径和HFpEF的发展之间的相互作用仍然知之甚少，因此限制了 我们利用它们治疗潜力的能力。使用质谱学的先进方法现在允许 代表多种酶的&gt；150上游二十烷基类介体的快速准确定量 起源。为了提供更详细的了解上游二十烷类通路如何可能成为 从危险因素到HFpEF的进展，并阐明HFpEF亚型，我们将追踪两个相关的 研究路线：在目标1中，我们将调查循环二十烷类化合物与临床风险的关系。 社区中的因素、亚临床心脏重构和HFpEF事件。在目标2中，我们将研究 二十烷类化合物与HFpEF亚型的相关性，包括不同的心脏和心外 临床HFpEF患者的血管功能障碍。这项提议利用了一个独特的多学科团队 具有临床流行病学、高级成像、运动生理学、生物信息学、 分析化学和脂类组学。我们以系统的方法全面调查 两个大型、表型良好的社区队列中上游炎症活动的成分， 辅以一组临床HFpEF患者进行全面的运动血流动力学评估 和深入的生理表型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，这些研究将奠定基础 未来的研究重点是针对HFpEF亚型的疾病预防和最佳治疗。

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.