Metabolic Signatures of Impaired Cardiorespiratory Fitness: Correlates, Prognostic Significance and Modulation with Exercise Training

心肺健康受损的代谢特征：相关性、预后意义以及运动训练的调节

• 批准号: 10459683
• 负责人: Matthew G. Nayor
• 金额: $ 19.98万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459683
• 关键词: Accelerometer; Advisory Committees; Aerobic; Aerobic Exercise; Affect; Age; Award; Biological Markers; Biostatistical Methods; Blood; Blood Circulation; Body Composition; Cardiac Surgery procedures; Cardiac rehabilitation; Cardiometabolic Disease; Cardiopulmonary; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Clinical; Communities; Data; Development; Disease; Disease Outcome; Dual-Energy X-Ray Absorptiometry; Echocardiography; Employee; Enrollment; Epidemiologic Methods; Exercise; Exercise Physiology; Exercise Test; Foundations; Framingham Heart Study; Future; Gases; Goals; Hand Strength; Heart; Heart failure; Hospitalization; Hospitals; Human; Impairment; Incidence; Individual; Lung; Measures; Medicine; Mentors; Metabolic; Metabolic Pathway; Metabolic syndrome; Metabolism; Methods; Oxygen; Participant; Pathogenesis; Pathway interactions; Patients; Phenotype; Physical Exercise; Physical activity; Physicians; Physiological; Population; Prevention; Program Development; Research; Research Personnel; Resources; Rest; Risk; Risk Factors; Risk Marker; Sampling; Sampling Studies; Scientist; Standardization; Stress; Stroke; Supervision; Techniques; Testing; Time; Training; base; cardiometabolic risk; cardiometabolism; cardiorespiratory fitness; cardiovascular disorder risk; cardiovascular health; career; career development; clinical risk; clinically relevant; cohort; design; disease phenotype; exercise program; exercise training; fitness; heart disease risk; improved; insight; metabolic phenotype; mortality; novel; prognostic; prognostic significance; response; risk prediction; sedentary; sex; skills; small molecule; tonometry; trait; translational physician; translational scientist; uptake

Current methods to evaluate cardiovascular disease (CVD) risk are primarily based on assessments made in the resting state, but human circulation and metabolism evolved to respond to physiologic stress. The systemic response to exercise-induced perturbations may carry key prognostic information regarding cardiovascular health and reserve capacity. In particular, impaired cardiorespiratory fitness, representing low peak oxygen uptake, is a potent predictor of CVD outcomes across strata of risk. However, the extent to which impaired cardiorespiratory fitness reciprocally influences derangements in distinct metabolic pathways remains unclear. This application will combine two state-of-the-art techniques – advanced cardiopulmonary exercise testing (CPET) with comprehensive gas exchange measures and high-throughput profiling of ~290 circulating metabolites (measured at rest and peak exercise) – to deeply phenotype the metabolic responses to incremental exercise. We postulate that impaired cardiorespiratory fitness associates with discrete metabolite signatures, that these metabolite signatures relate to prevalent subclinical CVD traits and incident CVD outcomes, and that these signatures are modified by aerobic exercise training. In Aim 1, we will evaluate the metabolite signatures of impaired cardiorespiratory fitness in 3040 participants enrolled in the community- based Framingham Heart Study. We will also analyze the relations of these metabolite signatures to clinical risk factors, novel risk markers, subclinical disease measures, and exercise-related excursions in select pathway biomarkers. In Aim 2, we will examine the relations of these metabolite signatures to incident CVD and metabolic syndrome in the Framingham Heart Study, and to CVD hospitalization and death in 1040 patients in a hospital-based referral cohort. In Aim 3, we will investigate the effect of aerobic exercise training on longitudinal changes in metabolite signatures of impaired cardiorespiratory fitness and CPET gas exchange variables in three distinct and clinically relevant hospital-based samples (total N=60). The overarching goal of this proposal is to evaluate the premise that the metabolic responses to exercise provide incremental information regarding the transition from cardiometabolic risk factors to overt CVD. This research will be accomplished in the setting of a comprehensive career development program designed to provide Dr. Nayor, an early career investigator and cardiologist, with the skills needed to become an independent physician- scientist in cardiovascular medicine. His long-term career goal is to use in-depth characterization of physiologic exercise responses to identify early CVD phenotypes that will further our understanding of disease pathogenesis and enable discovery of novel targets for prevention. An outstanding mentoring team and an advisory committee of established scientists in the fields of exercise physiology, metabolite profiling, and advanced epidemiological and biostatistical methods will guide the candidate in his transition to scientific independence over the course of the award period.

评估心血管疾病（CVD）风险的当前方法主要基于评估 静止状态，但是人类的循环和新陈代谢进展为应对生理压力。系统性 对运动引起的扰动的反应可能会带有有关心血管的关键预后信息 健康和储备能力。特别是，心肺健康受损，代表低峰值氧气 吸收是在风险层面上的CVD结果的潜在预测指标。但是，损害的程度 心肺适应性在不同的代谢途径中相互影响的演变尚不清楚。 该应用程序将结合两种最先进的技术 - 高级心肺运动测试 （CPET）具有全面的气体交换措施和〜290的高通量分析 代谢物（在休息和峰值运动时测量） - 深层表型的代谢反应 增量运动。我们假设患有离散代谢物的心肺健康伴侣受损 签名，这些代谢物签名与普遍的亚临床CVD特征和事件CVD有关 结果，这些签名是通过有氧运动训练来修改的。在AIM 1中，我们将评估 3040名参与者的心脏呼吸健康适应性受损的代谢签名参加了社区 - 基于Framingham心脏研究。我们还将分析这些代谢物特征与临床的关系 危险因素，新型风险标志物，亚临床疾病措施以及与运动相关的游览 途径生物标志物。在AIM 2中，我们将研究这些代谢物签名与事件CVD的关系 弗雷明汉心脏研究中的代谢综合征，以及1040年的CVD住院和死亡 基于医院的转诊队列的患者。在AIM 3中，我们将研究有氧运动训练的效果 关于心肺健身和CPET气体交换的代谢物特征的纵向变化 三个不同和临床相关的基于医院的样本中的变量（总n = 60）。总体目标 该提议是评估前提的前提，即运动的代谢反应提供了增量 有关从心脏代谢风险因素过渡到明显CVD的信息。这项研究将是 在旨在为Nayor博士提供的全面职业发展计划的设置中完成 早期职业调查员和心脏病专家，需要成为独立医生的技能 - 心血管医学科学家。他的长期职业目标是使用生理学的深入特征 锻炼反应以识别早期的CVD表型，这将进一步了解我们对疾病的理解 发病机理并能够发现新的预防目标。一支杰出的心理团队和一个 运动生理学，代谢物分析和 高级流行病学和生物统计学方法将指导候选人过渡到科学 在整个奖项期间的独立性。

项目成果

Molecular Aspects of Lifestyle and Environmental Effects in Patients With Diabetes: JACC Focus Seminar.

糖尿病患者生活方式和环境影响的分子方面：JACC 焦点研讨会。

• DOI: 10.1016/j.jacc.2021.02.070
• 发表时间: 2021
• 期刊: Journal of the American College of Cardiology
• 影响因子: 24
• 作者: Nayor,Matthew;Shah,SvatiH;Murthy,Venkatesh;Shah,RaviV
• 通讯作者: Shah,RaviV

Feasibility, Methodology, and Interpretation of Broad-Scale Assessment of Cardiorespiratory Fitness in a Large Community-Based Sample.

• DOI: 10.1016/j.amjcard.2021.07.020
• 发表时间: 2021-10-15
• 期刊: AMERICAN JOURNAL OF CARDIOLOGY
• 影响因子: 2.8
• 作者: Nayor, Matthew;Shah, Ravi, V;Tanguay, Melissa;Blodgett, Jasmine B.;Chernofsky, Ariel;Miller, Patricia E.;Xanthakis, Vanessa;Malhotra, Rajeev;Houstis, Nicholas E.;Velagaleti, Raghava S.;Larson, Martin G.;Vasan, Ramachandran S.;Lewis, Gregory D.
• 通讯作者: Lewis, Gregory D.