Characterization of Molecular and Physiologic Signatures of Impaired Multi-Organ System Reserve Capacity During Exercise in Heart Failure with Preserved Ejection Fraction

项目摘要/摘要 射血分数保留的心力衰竭(HFpEF)占所有心衰的一半，发病率高， 流行率在不断增长。传统的HF疗法不能改善HFpEF的预后，可能是因为 对HFpEF本身的不同定义。HFpEF的社会和临床试验定义缺乏共识， 主要依靠以心脏为中心的静息措施(例如肥厚、舒张期充盈、充盈压力)和 利钠肽水平。此外，HFpEF的主要表现是劳累不耐受(伴有或 没有明显的充血)，其病因通常不能通过静止的特征来捕捉。我们的 集团使用综合心肺运动试验(CPET)作为全球 心衰患者的代谢能力(VO2峰值)和多器官储备指标。通过同步 有创血流动力学、血气、心功能、动脉压和气体交换的定量 常规定义为HFpEF的个体在运动中的模式，我们已经开始描绘 心、肺、血管和外周肌肉骨骼储备能力受损的贡献 在休息时并不明显。我们进一步假设，这些发现背后有明显的新陈代谢缺陷， 在人类和动物中鉴定与定义心力衰竭表型相关的选定循环代谢物 模特们。虽然这些初步研究表明，绘制运动期间的代谢反应图可能 解决HFpEF内的表型异质性，研究在具有以下特征的大种群中解决这种方法 在运动过程中缺乏具有良好特征的表型。在这里，我们通过以下特征来解决这一差距 通过测量交感神经系统、心脏、血管和肌肉骨骼来怀疑HFpEF 1312名受试者运动时代谢功能的CPET和代谢物分析。我们假设 运动将揭示代表独特的HFpEF的主要器官储备不足 “病理表型。”我们进一步假设，与这些病理表型相关的代谢模式将 在HFpEF进展的早期就被失调，识别HFpEF的中心靶向通路。在目标1中，我们 1312例疑似肾功能衰竭患者的主要器官特异性病理表型 本中心的前瞻性队列研究(MGH-EXS研究)。在目标2中，我们确定了HFpEF的代谢相关因素 在MGH-EXS中通过靶向代谢物分析的病理表型，并评估这些代谢物-病理表型 社区中的协会(弗雷明翰心脏研究[FHS]第三代)。在目标3中，我们测试关联性 代谢产物和CPET为基础的HFpEF病理表型在MGH-EXS和MGH-EXS中的长期HF 社区(健康ABC研究；FHS)。我们的团队在运动生理学、HF、 代谢物分析和生物信息学非常适合这一应用。成功完成后将增强 精确-HFpEF的定义，并将为科学研究提供独特的资源(CPET和代谢物数据) 社区。

Project Summary/Abstract Heart failure with preserved ejection fraction (HFpEF) comprises half of all HF, has high morbidity and is growing in prevalence. Traditional HF therapy does not improve outcomes in HFpEF, potentially owing to heterogeneous definitions of HFpEF itself. Societal and clinical trial definitions of HFpEF lack consensus, relying largely on resting cardio-centric measures (e.g., hypertrophy, diastolic filling, filling pressure) and natriuretic peptide levels. Furthermore, the cardinal manifestation of HFpEF is exertional intolerance (with or without overt congestion), the etiology of which is frequently not captured by resting characterization. Our group has used comprehensive cardiopulmonary exercise testing (CPET) as a quantitative probe of global metabolic capacity (peak VO2) alongside measures of multi-organ reserve in HF. Through simultaneous quantitation of invasive hemodynamics, blood gases, cardiac function, arterial tonometry and gas exchange patterns during exercise in individuals with conventionally defined HFpEF, we have started to delineate contributions of impaired cardiac, pulmonary, vascular, and peripheral musculoskeletal reserve capacity that are not evident at rest. We further hypothesized that distinct metabolic defects underlie these findings, identifying selected circulating metabolites associated with HF-defining phenotypes in humans and animal models. While these preliminary studies suggest that mapping metabolic responses during exercise may resolve phenotypic heterogeneity within HFpEF, studies addressing this approach in large populations with well-characterized phenotypes during exercise are lacking. Here, we address this gap by characterizing suspected HFpEF via measures of sympathetic nervous system, cardiac, vascular, and musculoskeletal metabolic function during exercise in 1312 individuals via CPET and metabolite profiling. We hypothesize that exercise will unmask predominant organ-specific reserve deficits representing distinct HFpEF “pathophenotypes.” We further hypothesize that metabolic patterns associated with these pathophenotypes will be dysregulated early in HFpEF progression, identifying targetable pathways central to HFpEF. In Aim 1, we identify predominant organ-specific pathophenotypes in 1312 individuals with suspected HFpEF in a prospective cohort study at our center (MGH-ExS study). In Aim 2, we identify metabolic correlates of HFpEF pathophenotypes via targeted metabolite profiling in MGH-ExS and evaluate these metabolite-pathophenotype associations in the community (Framingham Heart Study [FHS] 3rd Generation). In Aim 3, we test association of metabolite- and CPET-based HFpEF pathophenotypes with long-term HF in the MGH-ExS and in the community (Health ABC study; FHS). Our team has extensive experience in exercise physiology, HF, metabolite profiling, and bioinformatics uniquely suited to this application. Successful completion will enhance precision-definitions of HFpEF and will provide a unique resource (CPET and metabolite data) for the scientific community.