Sub-Clinical Vascular Dysfunction in American-Style Football Players: Temporal Trends, Mechanisms, and Effects on Ventriculo-Arterial Coupling

 描述(申请人提供)：尽管美式足球(ASF)仍然是美国年轻人中最受欢迎的团队运动，但研究表明，在大学ASF参与者中，高血压的患病率很高，并有亚临床动脉硬化的证据。引起公众健康关注的是最近的一项发现，与普通人群相比，退役职业ASF一线人员的心血管死亡率有所增加。对于超耐力运动员，最近的数据表明，长期和过度的耐力运动可能会导致运动性右室心肌病的发生。然而，对这些观察结果缺乏更明确的见解，包括详细说明ASF诱导的血管功能障碍的机制。这项研究将使用一系列全面的心脏成像、血管功能测试和高分辨率、液-质联用代谢组学，以充分表征ASF参与和耐力锻炼对一大批高中和大学ASF运动员心血管结构、功能和代谢的影响。这项研究的科学目标是：1)深入了解ASF诱导的血管功能障碍的机制和病理生理学；2)对运动专项运动训练方案中存在的代谢表型适应进行新的表征。该项目的工作假设是：1)ASF诱导的动脉僵硬开始于高中ASF参与者，并预测ASF参与者的左心室肥厚(LVH)增加和组织多普勒衍生的舒张期参数降低；2)ASF参与者和耐力运动员将表现出不同的代谢特征，这将与特定的临床特征和心血管表型模式相关；3)ASF导致血管功能障碍的机制是多因素的，包括氧化应激、未诊断和未治疗的阻塞性睡眠呼吸暂停，以及过度使用非类固醇抗炎药物。目标1将阐述与ASF参与相关的动脉僵硬指标的时间变化，以及季后赛ASF参与者血管功能变化与心脏结构和功能适应的关系。目的2研究ASF参与者和耐力运动员代谢特征的变化，以及这些运动员的代谢表型变化与心脏结构和功能、临床特征和血管功能变化的关系。目的3是一个探索性目标，将调查导致ASF诱发高血压和血管功能障碍的可能机制，包括体重增加、氧化应激、阻塞性睡眠呼吸暂停和过度使用非类固醇抗炎药物。为了获得K23导师职业发展奖，我将从一个多学科的专家导师团队(Arshed A.Quyyumi博士、Aaron L.Baggish博士、Dean P.Jones和Laurence S.Sperling博士)那里获得新的导师研究和培训。职业发展计划的主要目标是培养临床研究(理学硕士)、先进成像技术、血管功能测试和高分辨率代谢组学方面的专业知识，用于未来面向临床的运动心脏病学研究。这将补充我到目前为止的运动心脏病学训练，并区别于我未来的职业生涯。拟议的研究，与结构化的指导和培训计划相结合，将促进我的长期目标，即开发一个独立资助的临床和翻译运动心脏病学研究计划，与NHLBI的使命保持一致。

 DESCRIPTION (provided by applicant): Although American-style football (ASF) remains the most popular team sport among American youths, research has demonstrated a high prevalence of hypertension and evidence of sub-clinical arterial stiffening in collegiate ASF participants. Of concern to public health is the recent finding of increased cardiovascular mortality in retired professional ASF linemen compared to the general population. For ultra-endurance athletes, recent data suggest the possibility that long-term and excessive endurance exercise may lead to the development of an exercise-induced right ventricular cardiomyopathy. However, more definitive insights to these observations, including detailing the mechanisms underlying ASF-induced vascular dysfunction, are lacking. This research will use a comprehensive array of cardiac imaging, vascular function testing, and high- resolution, liquid chromatography-mass spectrometry metabolomics to fully characterize the impact of ASF participation versus endurance exercise on cardiovascular structure and function and metabolism in a large cohort of high school and collegiate ASF athletes. The scientific goals of this research are to: 1) provide insight into the mechanisms and pathophysiology of ASF-induced vascular dysfunction; and 2) generate novel characterization of metabolic phenotypic adaptations present in sport-specific athletic training regimens. The working hypotheses of this project are: 1) ASF-induced arterial stiffness begins during high school ASF participation and predicts increased left ventricular hypertrophy (LVH) and reduced tissue-Doppler derived diastolic parameters in ASF participants, 2) ASF participants and endurance athletes will demonstrate distinct metabolic profiles that will be associated with specific clinical characteristics and cardiovascular phenotypic patterns, and 3) mechanisms underlying ASF-induced vascular dysfunction are multi-factorial and include oxidative stress, undiagnosed and untreated obstructive sleep apnea, and over-used non-steroidal anti- inflammatory medications. Aim 1 will address the temporal change in metrics of arterial stiffness associated with ASF participation and the relationships of changes in vascular function with cardiac structural and functional adaptations in post-season ASF participants. Aim 2 will investigate changes in the metabolic profile of ASF participants and endurance athletes and the relationships of changes in the metabolic phenotype of these athletes with changes in cardiac structure and function, clinical characteristics, and vascular function. Aim 3 is an exploratory aim that will investigate possible mechanisms responsible for the development of ASF- induced hypertension and vascular dysfunction including weight gain, oxidative stress, obstructive sleep apnea, and overused non-steroidal anti-inflammatory medications. For this K23 Mentored Career Development Award, I will gain new mentored research and training from a multidisciplinary team of expert mentors (Drs. Arshed A. Quyyumi, Aaron L. Baggish, Dean P. Jones, and Laurence S. Sperling). The primary goal of the career development plan is to develop expertise in clinical research (Master of Science), advanced imaging techniques, vascular function testing, and high-resolution metabolomics for use in future clinically oriented sports cardiology research. This will complement my sports cardiology training to-date and distinguish my career moving forward. The proposed research, in combination with the structured mentoring and training plan will facilitate my long-term goal of developing an independently funded clinical and translational sports cardiology research program consistent with the mission of the NHLBI.