Determinants and Prognostic Significance of Proximal Aortic Stiffness

描述（由申请人提供）：总体主动脉僵硬度（AoS）增加与显著的发病率和死亡率相关，并影响大量老龄化人群。AoS相关心血管疾病（CVD）的发病机制可能是由于近端主动脉、左心室（LV）和远端血管系统之间的相互作用产生的异常血流动力学所致，并由其增强。静息近端AoS和运动诱导的AoS增加都可能在LV重塑、收缩和舒张功能以及LV射血分数保留的心力衰竭（HFPEF）的演变中发挥重要作用，由于年龄相关的AoS增加更大，女性可能特别容易受到影响。近端主动脉的弹性成分反映了其独特性和顺应性，与远端主动脉不同。然而，由于传统成像技术的局限性，该区域尚未得到很好的评价。该应用将利用心血管磁共振（CMR）对近端主动脉和主动脉弓进行全面成像，以研究局部升主动脉和近端降主动脉以及局部主动脉弓的特性（统称为CMR AoS）。Dr. Tsao将研究CMR AoS与以下因素的关系：1）LV和中央主动脉血流动力学（在医院患者和社区居民个体中进行休息/运动），2）超声心动图LV收缩和舒张功能障碍以及颈动脉内膜中层厚度增加反映的亚临床CVD，以及3）不良临床CVD结局的预后，并与全球AoS的风险预测进行比较。她还将在CMR AoS与其感兴趣的表型的关系中按性别进行效应修饰分析。她的初步数据证明了使用CMR靶向主动脉的这一关键部分的可行性，并表明与年龄、女性性别、运动血压以及不良LV重塑和功能的测量相关。总之，来自这些研究的数据将提高科学界对AOS的病理生理关系的理解，并最终旨在确定预防和治疗的目标。 Connie Tsao博士是一位非侵入性心脏病专家，在CMR技术和心血管流行病学方面具有临床和研究经验，其目标是继续以患者为导向的流行病学研究，应用非侵入性成像技术在学术环境中研究血管疾病的病理生理学。目前的建议将扩大曹博士在血管生理学和成像研究方面的经验和培训，以及她将在未来扩展工作中采用的纵向流行病学方法。她的职业发展计划利用她的机构的资源，贝丝以色列女执事医疗中心/哈佛医学院和心脏病研究，提供继续学习的机会，并合成一个优秀的导师，顾问和合作研究者团队，在此应用的各个方面具有互补的专业知识。曹博士的导师和顾问都是地位稳固、资金充足的临床和翻译研究人员，他们将监督她的培训，并支持她向独立过渡。

DESCRIPTION (provided by applicant): Increased global aortic stiffness (AoS) is associated with significant morbidity and mortality and impacts the large aging population. The pathogenesis of AoS-related cardiovascular disease (CVD) may be due to and potentiated by abnormal hemodynamics created by the interactions between the proximal aorta, left ventricle (LV), and distal vasculature. Both resting proximal AoS and exercise-induced increases in AoS likely play fundamental roles in LV remodeling, systolic and diastolic function, and the evolution of heart failure with a preserved LV ejection fraction (HFPEF), to which women may be particularly susceptible due to greater age- associated increases in AoS. The uniqueness and compliance of proximal aorta are reflected in its elastic composition, distinct from that of the distal aorta. Yet, this region has not been well evaluated due to limitations of traditional imagin techniques. This application will utilize cardiovascular magnetic resonance (CMR), which fully images the proximal aorta and aortic arch, to study the properties of the local ascending and proximal descending aorta and regional aortic arch (collectively labeled CMR AoS). Dr. Tsao will investigate the relationships of CMR AoS with: 1) LV and central aortic hemodynamics (with rest/exercise in both hospital- based patients and community-dwelling individuals), 2) subclinical CVD reflected in echocardiographic LV systolic and diastolic dysfunction and increased carotid intima-medial thickness, and 3) prognosis of adverse clinical CVD outcomes, with comparison to risk prediction by global AoS. She will also conduct analyses of effect modification by gender in the relations of CMR AoS with her phenotypes of interest. Her preliminary data demonstrate the feasibility of using CMR to target this crucial segment of the aorta and suggest associations with age, female sex, exercise blood pressure, and measures of adverse LV remodeling and function. Together, data from these studies will enhance the scientific community's understanding of the pathophysiologic relationships of AoS, and ultimately aim to identify targets for prevention and therapy. Dr. Connie Tsao is a non-invasive cardiologist with clinical and research experience in CMR techniques and cardiovascular epidemiology, with a goal to continue patient-oriented and epidemiologic research applying non-invasive imaging to investigate vascular disease pathophysiology in an academic setting. The current proposal will expand Dr. Tsao's experience and training in the study of vascular physiology and imaging, as well as the longitudinal epidemiologic methods that she will employ in future expansion of her work. Her career development plan leverages the resources of her institutions, Beth Israel Deaconess Medical Center/ Harvard Medical School and the Framingham Heart Study, to provide opportunities for continued learning and to synthesize a superb team of mentors, advisors, and co-investigators with complementary expertise in all aspects of this application. Dr. Tsao's mentors and advisors are all well-established and well-funded clinical and translational researchers who will supervise her training and support her transition to independence.