Comprehensive Metabolic Profiling of Exercise to Predict Cardiometabolic Risk

 简介(申请人提供)：心血管疾病(CVD)是美国三分之一的死亡原因，预计2015年至2030年期间，心血管疾病的成本将从5000亿美元增加到1.2万亿美元。鉴于心血管疾病的社会负担，人们对心血管疾病的主要风险因素给予了相当大的关注。有必要承认、理解和广泛查明其他可提起诉讼的心血管疾病风险因素。人们越来越认识到，更大的运动能力(例如，心肺健康)可以减轻慢性病的负担，促进心血管健康，提高生活质量，并推迟心血管疾病和死亡率。尽管健康状况已被证明是未来心血管疾病和整体健康结果的最有力的预测因素之一，但它目前是目前仅有的没有在普通或专门临床中常规和定期评估的主要风险因素之一。 设置。除了可以量化健康状况外，短暂(~10分钟)的锻炼也可以揭示早期的心血管疾病。我们和其他人已经证明，在人群研究中，在锻炼期间简单地测量心率和血压，比在休息时测量同样的心率和血压具有更高的预后价值。最近的技术进步现在允许测量广泛的循环代谢物和气体交换模式，这些模式反映了对运动的复杂代谢反应。这一建议的中心假设是，通过运动期间的心肺运动试验(CPET)结合代谢物分析来精确测量运动的代谢反应，将与临床和遗传特征以及亚临床心血管疾病相关，并将比标准的心血管危险因素评估(静息状态)更具预测未来心血管疾病和心脏代谢性疾病的增量价值。目标1将全面确定标准风险因素、生活方式测量(包括基于精确加速度量学的体力活动测量)、遗传变异和家族特征如何与运动的代谢反应有关，这是通过对递增运动的气体交换变量和代谢物水平的变化来衡量的。目的2将确定以前确定的亚临床疾病指标(导管动脉僵硬、冠状动脉钙化、心肌肥厚)与运动代谢反应之间的关系。目标3将确定在弗雷明翰心脏研究和单独的转介队列中，容易获得的CPET气体交换变量和循环代谢物的变化是否将逐步预测未来的心脏代谢和心血管疾病结果。总体而言，我们的建议将有助于识别和描述社区运动期间代谢变化的频谱，并评估它们的横断面相关性和长期预后意义。我们希望找到一种微创的方法来测试心血管疾病和代谢储备能力，以识别和提炼可作为干预措施预防心血管疾病的目标的危险因素。

 DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is responsible for one third of all deaths in the United States, with the estimated costs anticipated to increase from $500 billion to $1,200 billion between 2015 and 2030. Given the societal burden of CVD, considerable attention has been directed at major risk factors for CVD. Recognition, understanding and widespread ascertainment of additional actionable CVD risk factors is necessary. Greater exercise capacity (e.g. cardiorespiratory fitness) is increasingly recognized to decrease the burden of chronic diseases, promote cardiovascular health, improve quality of life, and delay CVD and mortality. Although fitness has been shown to be among the most potent predictors of future CVD and overall health outcomes, it is currently one of the only major risk factors that is not routinely and regularly assessed in either general or specialized clinical settings. Beyond permitting quantification of fitness, brief (~10min) exposure to exercise can also unmask early forms of CVD. We and others have shown that simple measurements of heart rate and blood pressure during exercise in population studies are of incremental prognostic value over the same measurements made at rest. Recent technological advances now permit measurement of a broad array of circulating metabolites and gas exchange patterns that reflect the complex metabolic responses to exercise. The central hypothesis of this proposal is that precise measurements of metabolic responses to exercise through cardiopulmonary exercise testing (CPET) combined with metabolite profiling during exercise will relate to clinical and genetic traits as well as subclinical CVD, and will be of incremental value beyond standard CV risk factor assessment (in the resting state) for predicting future CVD and cardiometabolic disease. Aim 1 will comprehensively determine how standard risk factors, life-style measures (including precise accelerometry-based physical activity measures), genetic variation and familial traits relate to metabolic responses to exercise, as measured by changes in gas exchange variables and metabolite levels in response to incremental exercise. Aim 2 will determine how previously ascertained subclinical disease measures (conduit artery stiffness, coronary artery calcium, ventricular hypertrophy) relate to metabolic responses to exercise. Aim 3 will determine whether easily acquired CPET gas exchange variables and changes in circulating metabolites in response to exercise will incrementally predict future cardiometabolic and CVD outcomes in the Framingham Heart Study and in a separate referral cohort. Overall, our proposal will help identify and characterize the spectrum of metabolic changes during exercise in the community, and assess their cross-sectional correlates and long-term prognostic significance. We hope to identify a minimally invasive means to test CV and metabolic reserve capacity that will identify and refine risk factors that can be targeted for interventions to prevet CVD.