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.

项目总结/文摘