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.

Public Health Relevance

Global stiffening of the aorta occurs with aging and is associated with cardiovascular risk factors and poor outcomes, including coronary heart disease and stroke. However, the proximal aorta, the direct segment which couples the left ventricle to the neurovasculature and distal aorta, is distinct in structure and function from the distal aorta and has not been well described. This project's investigations of the hemodynamic and clinical associations of proximal aortic stiffness will increase our understanding of the development and consequences of increased central arterial stiffness, a growing problem in our aging population and a precursor of strokes, heart attacks, and heart failure.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZHL1-CSR-X (O1))
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Scott, Jane
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Beth Israel Deaconess Medical Center
United States
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Seiler, Stephan; Fletcher, Evan; Hassan-Ali, Kinsy et al. (2018) Cerebral tract integrity relates to white matter hyperintensities, cortex volume, and cognition. Neurobiol Aging 72:14-22
Tsao, Connie W; Lyass, Asya; Enserro, Danielle et al. (2018) Temporal Trends in the Incidence of and Mortality Associated With Heart Failure With Preserved and Reduced Ejection Fraction. JACC Heart Fail 6:678-685
Vasan, Ramachandran S; Xanthakis, Vanessa; Lyass, Asya et al. (2018) Epidemiology of Left Ventricular Systolic Dysfunction and Heart Failure in the Framingham Study: An Echocardiographic Study Over 3 Decades. JACC Cardiovasc Imaging 11:1-11
Fahmy, Ahmed S; Neisius, Ulf; Tsao, Connie W et al. (2018) Gray blood late gadolinium enhancement cardiovascular magnetic resonance for improved detection of myocardial scar. J Cardiovasc Magn Reson 20:22
Ho, Jennifer E; McCabe, Elizabeth L; Wang, Thomas J et al. (2017) Cardiometabolic Traits and Systolic Mechanics in the Community. Circ Heart Fail 10:
Nayor, Matthew; Larson, Martin G; Wang, Na et al. (2017) The association of chronic kidney disease and microalbuminuria with heart failure with preserved vs. reduced ejection fraction. Eur J Heart Fail 19:615-623
Maillard, Pauline; Mitchell, Gary F; Himali, Jayandra J et al. (2017) Aortic Stiffness, Increased White Matter Free Water, and Altered Microstructural Integrity: A Continuum of Injury. Stroke 48:1567-1573
Tsao, Connie W; Lyass, Asya; Larson, Martin G et al. (2016) Prognosis of Adults With Borderline Left Ventricular Ejection Fraction. JACC Heart Fail 4:502-10
Maillard, Pauline; Mitchell, Gary F; Himali, Jayandra J et al. (2016) Effects of Arterial Stiffness on Brain Integrity in Young Adults From the Framingham Heart Study. Stroke 47:1030-6
Yeon, Susan B; Salton, Carol J; Gona, Philimon et al. (2015) Impact of age, sex, and indexation method on MR left ventricular reference values in the Framingham Heart Study offspring cohort. J Magn Reson Imaging 41:1038-45

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