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

项目概要/摘要 射血分数正常的心力衰竭（HFpEF）占所有HF的一半，发病率高， 越来越流行传统HF治疗不能改善HFpEF的结局，可能是由于 HFpEF本身的异构定义。HFpEF的社会和临床试验定义缺乏共识， 主要依赖于静息心脏为中心的测量（例如，肥大、舒张期充盈、充盈压）和 利钠肽水平。此外，HFpEF的主要表现是劳力不耐受（伴有或 没有明显的充血），其病因常常不能通过静息表征来捕获。我们 一个研究小组使用全面的心肺运动试验（CPET）作为全球性的定量探针， 代谢能力（峰值VO2）以及HF中多器官储备的测量。通过同时 有创血流动力学、血气、心脏功能、动脉张力测定和气体交换的定量 在传统定义的HFpEF患者的运动模式中，我们已经开始描绘 心脏、肺、血管和外周肌肉骨骼储备能力受损， 在静止时并不明显。我们进一步假设，这些发现的基础是不同的代谢缺陷， 鉴定与人类和动物中HF定义表型相关的选定循环代谢物 模型虽然这些初步研究表明，在运动过程中绘制代谢反应， 解决HFpEF中的表型异质性，研究在具有以下特征的大群体中解决了这种方法： 缺乏在运动期间充分表征的表型。在这里，我们通过描述 通过交感神经系统、心脏、血管和肌肉骨骼测量疑似HFpEF 通过CPET和代谢物谱分析对1312名个体进行运动期间的代谢功能研究。我们假设 运动将揭示代表不同HFpEF的主要器官特异性储备缺陷 "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进展的早期失调，确定HFpEF的靶向通路。目标1： 在1312例疑似HFpEF患者中鉴定主要器官特异性病理表型， 我们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的代谢相关性， 通过MGH-ExS中的靶向代谢物谱分析确定病理表型，并评价这些代谢物-病理表型 心脏病研究（FHS）第三代。在目标3中，我们测试关联 在MGH-ExS和MH-ExS中，基于代谢物和CPET的HFpEF病理表型与长期HF 健康ABC研究（Health ABC Study）我们的团队在运动生理学，HF， 代谢物谱分析和生物信息学特别适用于该应用。成功完成将提高 HFpEF的精确定义，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.