Determinants and Prognostic Significance of Proximal Aortic Stiffness

描述(由申请人提供)：全球主动脉僵硬(AoS)增加与显著的发病率和死亡率相关，并影响大量老龄人口。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而造成的血流动力学异常并得到加强。静息近端AoS和运动诱导的AoS增加可能在LV重塑、收缩和舒张期功能以及保留LV射血分数(HFPEF)的心力衰竭的演变中发挥基础性作用，女性可能特别容易受到这种情况的影响，因为AoS的年龄相关性增加更大。近端主动脉的独特性和顺应性体现在其弹性成分上，有别于远端主动脉。然而，由于传统成像技术的局限性，该区域还没有得到很好的评估。这项应用将利用心血管磁共振(CMR)来研究局部升主动脉、近端降主动脉和局部主动脉弓(统称为CMR AoS)的特性。曹博士将研究CMR AoS与：1)LV和中心动脉血流动力学(医院患者和社区居民都有休息/运动)的关系；2)超声心动图LV收缩和舒张期功能障碍及颈动脉内膜-中层厚度增加所反映的亚临床CVD；3)不良临床CVD预后的预后，并与全球AoS风险预测进行比较。她还将对CMR AoS与她感兴趣的表型之间的关系中的性别效应修正进行分析。她的初步数据证明了使用CMR来靶向主动脉这一关键部分的可行性，并建议与年龄、女性、运动血压以及不良左室重构和功能的测量有关。总之，来自这些研究的数据将加强科学界对AoS的病理生理关系的了解，并最终旨在确定预防和治疗的目标。康妮·曹博士是一位在CMR技术和心血管流行病学方面拥有临床和研究经验的非侵入性心脏病专家，目标是继续进行以患者为导向的流行病学研究，应用非侵入性成像在学术环境中研究血管疾病的病理生理学。目前的提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，以及她在未来扩大工作时将采用的纵向流行病学方法。她的职业发展计划利用她所在机构的资源，贝丝以色列女执事医学中心/哈佛医学院和弗雷明翰心脏研究，为继续学习提供机会，并组建一支由导师、顾问和合作调查员组成的优秀团队，在这一应用程序的各个方面具有互补的专业知识。曹医生的导师和顾问都是久负盛名、资金雄厚的临床和翻译研究人员，他们将监督她的培训，并支持她向独立的过渡。

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.