Aortic Dilatation in Endurance Athletes: A Physiologic and Mechanistic Study

项目概要/摘要 该候选人最近加入了马萨诸塞州总医院 (MGH) 心血管科的工作人员。 绩效计划 (CPP)，一个独特的团体，其目标包括开展顶级人类健康和 性能研究。 CPP 的核心使命是以耐力运动员为榜样，通过这种方式 研究运动对心血管系统的影响。本提案应用该框架来评估 详细介绍运动对主动脉的影响。 该提议源于双重观察：a) 心肌对运动训练的适应是一个 公认的过程，被认为是适应性的而不是病理性的，而主动脉的可塑性却没有 已被记录，并且b）患有主动脉扩大的耐力运动员在临床中很常见 练习。因此，候选人进行了一项初步研究，招募了约 450 名运动员并记录了 与既定的人群标准相比，该人群主动脉扩张的患病率较高。这个 研究提案旨在定义自然历史、基础生理学和潜在机制 耐力运动员主动脉扩张的这种表型，其总体目标是帮助确定是否 这可能代表了一种与运动相关的适应与一种新形式的过度使用病理学。 为了实现这些目标，申请人建议以他之前的工作为基础，利用大量的 他招募参加初始研究的运动员。将对运动员受试者进行纵向随访 使用超声心动图来反映指数评估。一个子集将进行详细的比较 通过心肺运动测试、先进的超声心动图技术进行生理表型分析 包括心内和主动脉血流模式、血管功能分析的无创评估，以及 通过计算机断层扫描进行详细的解剖成像。如果可能，测试将在休息时进行 对生理刺激的反应。将比较有和没有的运动员的表型特征 主动脉扩张和主动脉扩张对照受试者以评估生理差异和潜力 机制。分子评估将重点关注血浆 microRNA (miRNA)，这是一类具有良好特性的分子。 建立了运动反应性以及与主动脉疾病和循环的已知机制关联 将在运动前后评估这些组的 miRNA 谱。 候选人的职业发展计划包括运动生理学、心脏病学等方面的高级培训 成像和生理表型、转化科学和研究方法，全部在 独特的多学科团队的指导。拟议的科学科学将为未来奠定基础 研究评估该人群的临床结果并整合额外的运动转化研究 相关的主动脉疾病，这将构成候选人未来 R01 提案的基础。整个过程中 K23奖的候选人的目标是发展成为一名独立的临床和转化研究者。

PROJECT SUMMARY / ABSTRACT The candidate recently joined the staff at Massachusetts General Hospital (MGH) in the Cardiovascular Performance Program (CPP), a unique group whose goals include conducting top-caliber human health and performance research. A core mission of the CPP is to use endurance athletes as a model through which to study the impacts of exercise on the cardiovascular system. This proposal applies this framework to evaluate in detail on the impact of exercise on the aorta. This proposal emerged from the dual observations that a) myocardial adaptation to exercise training is a well-established process that is felt to be adaptive rather than pathologic, while plasticity of the aorta has not been documented, and b) endurance athletes with aortic enlargement are commonly encountered in clinical practice. The candidate accordingly performed an initial study enrolling ~450 athletes and documenting an elevated prevalence of aortic dilatation in this population as compared to established population norms. This research proposal aims to define natural history, underlying physiology, and potential mechanisms underlying this phenotype of aortic dilation in endurance athletes, with the overarching goal of helping to establish whether this may represent an exercise-associated adaptation vs a novel form of overuse pathology. To achieve these goals, the applicant proposes to build off his prior work, leveraging the large cohort of athletes whom he enrolled into the initial study. Longitudinal follow-up will be performed on athlete subjects using echocardiography to mirror the index assessment. A subset will undergo detailed comparative physiologic phenotyping with cardiopulmonary exercise testing, advanced echocardiographic techniques including non-invasive evaluation of intracardiac and aortic blood flow patterns, vascular function profiling, and detailed anatomic imaging with computed tomography. Where possible, testing will be performed at rest and in response to physiologic provocation. Phenotypic profiles will be compared across athletes with and without aortic dilatation and control subjects with aortic dilatation to assess physiologic differences and potential mechanisms. Molecular evaluation will focus on plasma microRNA (miRNA), a class of molecules with well- established exercise responsiveness and known mechanistic associations with aortic disease, and circulating miRNA profiles will be assessed across these groups before and after exercise. The candidate’s career development plan includes advanced training in exercise physiology, cardiac imaging and physiologic phenotyping, translational science, and research methodology, all under the mentorship of a unique multidisciplinary team. The proposed science science will set the stage for future studies to assess clinical outcomes in this population and integrate additional translational study of exercise- associated aortic disease, which will form the basis of the candidate’s future R01 proposals. Over the course of the K23 award, the candidate’s goal is to develop into an independent clinical and translational investigator.