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）是所有HF的一半，高病态的一半，是IS是IS是IS是IS IS IS IS IS IS IS IS IS IS IS IS IS IS IS IS IS。 患病率的增长。 HFPEF本身的异质定义和临床试验试验试验审判定义HFPEF缺乏共识 依靠更大的静止心脏中心措施（例如肥大，舒张压填充，充满压力）和 NATRIARITE肽水平。 没有公开的竞争），其病因是由我们的静止特征提出的 小组已使用补偿性心肺运动测试（CPET）作为全球的定量探测 代谢容量（峰值VO2）以及同时在HF中的多器官储备量 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 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，肺部，血管和周围肌肉核心骨骼固定的贡献。 在休息时并不明显。 确定与人类和动物中与HF定义表型相关的选定的循环代谢产物 模型。 解决HFPEF内表型异质性 在这里，我们缺乏锻炼过程中的表征。 可疑的HFPEF通过交感神经系统，心脏，血管和肌肉骨骼的措施 在1312个个体中，我们通过CPET和代谢物分析的代谢功能 锻炼将揭露主要器官特异性的储备缺陷，压抑不同的HFPEFF “病理型。”我们进一步假设与这些病理表单相关的代谢模式将 在HFPEF进程中遇到异常，以确定目标1 AIM 1的目标途径。 在1312名可疑HFPEF的人中识别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）。 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 社区中的协会（Framingham心脏研究[FHS]第三代）。 在MGH-EXS中具有长期HF的代谢物和基于CPET的HFPEF Pathenotypes 社区（健康ABC研究； FHS）。 代谢物分析和生物信息学独特地适合该应用程序。 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。