This is the second resubmission of a CSR&D CDA-2 proposal to provide five years of research and salary support to Adam Gepner, MD. The CDA will prepare him to become an independent VA geriatric cardiovascular disease investigator with clinical research expertise in geriatric cardiology, exercise physiology, arterial pathophysiology. This application combines clearly defined training activities, continuous collaboration with a multidisciplinary mentorship committee, and a novel research plan. Dr. Gepner proposes to non-invasively measure acute changes in arterial stiffness parameters to identify older Veterans with greater ?arterial reserve? - the ability of the arteries to rapidly respond to changes in blood flow and pressure with stress and then rapidly return to baseline. The central hypothesis is that arterial reserve, determined by change in arterial stiffness measures following acute exercise or administration of sublingual nitroglycerin, will be greater in non- hypertensives and those with controlled blood pressure than in those with poorly controlled blood pressure. His proposal aligns with VA priorities because undertreatment of hypertension is well-recognized in the VA system. Dr. Gepner hopes to provide new tools to personalize hypertensive care by identifying individuals that can tolerate more aggressive blood pressure treatment goals thereby reducing adverse cardiovascular disease (CVD) events. Resting arterial stiffness predicts future CVD events, is tightly linked with blood pressure, and progresses most rapidly in older individuals with poorly controlled hypertension. Arterial stiffness is dynamic and responds acutely to both exercise and administration of antihypertensive medications. The arterial response to exercise and blood pressure medications is variable in older individuals, likely due to differences in arterial reserve. The primary scientific objective of this CDA is to investigate acute changes in arterial stiffness parameters with exercise and nitroglycerin administration in participants with varying degrees of blood pressure control and those without hypertension.
Three specific aims will be pursued in a prospective study of 180 ambulatory, community dwelling, Veterans ?60 years old who will be recruited from the Care Coordination Home Telehealth Network (CCHT) and Madison VA primary care clinics:
Aims 1 and 2 are to determine if changes in arterial stiffness parameters following 1) exercise and 2) acute blood pressure reduction with short-acting sublingual nitroglycerin are associated with differences in baseline blood pressure control in older hypertensive Veterans and compared to a non-hypertensive age- and sex-matched non-hypertensive control group.
Aim 3 is to determine associations between exercise capacity and changes arterial stiffness parameters among older hypertensive Veterans to ensure that the effects of lower blood pressure do not negatively impact functional capacity. Dr. Gepner will complete didactic training focusing on clinical trial design and conduct. He also will gain expertise in exercise physiology, fluid dynamics and the biomechanical properties arteries. He will participate in a structured curriculum to improve his skills as a geriatric cardiovascular specialist to improve care for older Veterans. Dr. Gepner?s primary mentor is Dr. Cindy Carlsson, a VA clinician-investigator with expertise in geriatrics and CVD biomarkers. Secondary mentors include Dr. Dane Cook, an exercise scientist and the Director of the Human Exercise Lab, which will allow for hands-on training in exercise physiology; Dr. Naomi Chesler, an expert in the mechanical aspects of arterial stiffness and Dr. Sanjay Asthana, the director of the Madison VA GRECC. Successful completion of the proposed research will provide a framework for understanding changes in arterial stiffness in older Veterans with hypertension and allow Dr. Gepner to build his own VA laboratory to study age-related vascular physiology. Unmasking how these changes impact antihypertensive goals and medication tolerability are imperative in older Veterans and will provide a platform for Dr. Gepner?s next career step, to apply for MERIT funding to test the effects of specific antihypertensive treatment intensities and to derive novel targets for antihypertensive treatment in Veterans with difficult to control blood pressure.

Public Health Relevance

Arterial stiffness is linked to hypertension, poor BP control, and cardiovascular disease (CVD) events. Many older Veterans have suboptimally controlled blood pressure, in part because of inconsistent guideline recommendations for BP treatment goals and fear of side-effects from pharmacotherapy. Exercise and administration of sublingual nitroglycerin acutely alter arterial stiffness. We hypothesize that arterial reserve, determined by change in arterial stiffness measures following acute exercise or administration of sublingual nitroglycerin, will be greater in those with controlled blood pressure than in those with poorly controlled blood pressure or those without high blood pressure. A non-invasive arterial stress test that evaluates dynamic arterial stiffness in older hypertensive Veterans could determine who will better tolerate more aggressive BP goals, minimizing CVD events with fewer adverse side-effects.

National Institute of Health (NIH)
Veterans Affairs (VA)
Veterans Administration (IK2)
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Special Emphasis Panel (ZRD1)
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Wm S. Middleton Memorial Veterans Hosp
United States
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