Aortic Dilatation in Endurance Athletes: A Physiologic and Mechanistic Study

项目总结/摘要 这位候选人最近加入了马萨诸塞州总医院（MGH）的心血管科工作人员。 绩效计划（CPP），一个独特的小组，其目标包括进行一流的人类健康和 性能研究。CPP的核心使命是以耐力运动员为榜样， 研究运动对心血管系统的影响。本建议采用该框架来评估 运动对主动脉的影响 这一提议源于双重观察：a）心肌对运动训练的适应是一种 这是一个公认的过程，被认为是适应性的，而不是病理性的，而可塑性的主动脉还没有 B）耐力运动员主动脉扩张在临床上是常见的 实践因此，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 与已确定的人群标准相比，该人群中主动脉扩张的患病率升高。这 一项研究提案旨在定义自然历史，潜在的生理学和潜在的机制， 耐力运动员主动脉扩张的这种表型，其首要目标是帮助确定 这可能代表了一种与运动相关的适应，而不是一种新形式的过度使用病理学。 为了实现这些目标，申请人建议在其先前工作的基础上，利用 他招募的运动员参加了最初的研究。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 生理表型与心肺运动试验，先进的超声心动图技术 包括心内和主动脉血流模式的非侵入性评估、血管功能分析，以及 详细的解剖成像和计算机断层扫描。如有可能，将在静止和静止状态下进行测试。 对生理刺激的反应。表型特征将在运动员之间进行比较， 主动脉扩张和主动脉扩张的对照受试者，以评估生理差异和潜力 机制等分子评估将集中在血浆microRNA（miRNA），一类分子， 已确定的运动反应性和已知的与主动脉疾病的机械相关性，以及循环 将在运动前后对这些组的miRNA谱进行评估。 候选人的职业发展计划包括运动生理学，心脏， 成像和生理表型，转化科学和研究方法，所有这些都在 一个独特的多学科团队的指导。拟议中的科学将为未来的科学奠定基础。 评估该人群临床结局的研究，并整合额外的运动转化研究- 相关的主动脉疾病，这将成为候选人未来R 01提案的基础。过程中 在K23奖项中，候选人的目标是发展成为一名独立的临床和翻译研究者。

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.