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

射血分数保留的心力衰竭运动期间多器官系统储备能力受损的分子和生理特征的表征

• 批准号: 10402772
• 负责人: Gregory Dyer Lewis
• 金额: $ 67.03万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10402772
• 关键词: Address; Animal Model; Biochemical; Bioinformatics; Blood Vessels; Blood gas; Cardiac; Cardiopulmonary; Cardiovascular Physiology; Citric Acid Cycle; Clinical; Clinical Trials; Communities; Community Health; Conceptions; Congestive; Consensus; Coupling; Data; Defect; Disease; EFRAC; Etiology; Evaluation; Exercise; Exercise Physiology; Exercise Test; Exertion; Failure; Framingham Heart Study; Gases; Generations; Heart Rate; Heart failure; Heterogeneity; Hypertrophy; Impairment; Individual; Lung; Mass Spectrum Analysis; Measures; Metabolic; Metabolic Pathway; Mission; Molecular; Morbidity - disease rate; Musculoskeletal; National Heart, Lung, and Blood Institute; Natriuretic Peptides; Nitric Oxide Pathway; Obesity; Organ; Pathway interactions; Pattern; Peripheral; Phenotype; Physiological; Physiology; Plant Roots; Population; Populations at Risk; Prevalence; Prospective cohort study; Purines; Resolution; Resources; Rest; Risk; Risk Factors; Sympathetic Nervous System; System; Testing; Therapeutic Intervention; Translations; Ventricular; Ventricular Function; arterial tonometry; base; clinical risk; clinical translation; exercise intolerance; experience; functional disability; heart function; heart imaging; hemodynamics; human model; improved outcome; learning strategy; mortality; novel; population health; pre-clinical; preservation; pressure; prognostic; pulmonary function; response; statistical learning; success

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.

项目摘要/摘要 心力衰竭，保留的射血分数（HFPEF）包括所有HF的一半，具有高发病率，是 患病率增长。传统的HF疗法不能改善HFPEF的结果，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， 主要依赖于以心脏为中心的措施（例如肥大，舒张压，充满压力）和 纳特里尔乳辣椒水平。此外，HFPEF的基本表现是勤奋的intlerance（带有或 没有明显的拥塞），其病因通常不会被静止特征捕获。我们的 小组已使用全面的心肺运动测试（CPET）作为全球的定量探测 代谢能力（峰值VO2），以及HF中多器官储备的测量。通过同时 侵入性血液动力学，血液气体，心脏功能，动脉渗透和气体交换的定量 在具有常规定义的HFPEF的个体运动过程中，我们已经开始描述 心脏，肺，血管和周围肌肉骨骼储备能力受损的贡献 我们进一步假设，这些发现是这些发现的基础的不同代谢缺陷， 识别人类和动物中与HF定义表型相关的选定循环代谢产物 型号。尽管这些初步研究表明，在运动过程中绘制代谢反应可能 解决HFPEF内表型异质性 锻炼过程中缺乏良好的表征。在这里，我们通过表征来解决这一差距 可疑的HFPEF通过交感神经系统，心脏，血管和肌肉骨骼的测量 在1312个人中，通过CPET和代谢物分析在运动过程中的代谢功能。我们假设这一点 练习将揭露主要器官特异性储备定义代表独特的HFPEF “病理表现。”我们进一步假设与这些病理表单型相关的代谢模式将 在HFPEF进展中，在HFPEF进展中的早期失调，确定了HFPEF中心的可靶向途径。在AIM 1中，我们 在A中识别1312名可疑HFPEF的人中的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AIM 2中，我们确定了HFPEF的代谢相关性 通过MGH-EXS中有针对性的代谢物分析的病理表征，并评估这些代谢产物 - 病理表型 社区的协会（Framingham心脏研究[FHS]第三代）。在AIM 3中，我们测试协会 在MGH-EXS中，具有长期HF的代谢物和CPET的HFPEF病理表型 社区（健康ABC研究； FHS）。我们的团队在运动生理学方面拥有丰富的经验，HF， 代谢物分析和生物信息学独特地适合此应用。成功完成将增强 HFPEF的精确定义，并将为科学提供独特的资源（CPET和代谢数据） 社区。