Determinants and Prognostic Significance of Proximal Aortic Stiffness

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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.