Cerebral Blood Flow Model for Normo/Hypertensive Elderly

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The purpose of this investigation is to determine mechanisms of cerebrovascular autoregulation during orthostatic stress and their alterations due to aging and hypertension using a mathematical model based on principles of fluid dynamics. The specific aim is to develop a lumped parameter model that can reproduce a dynamic changes of pulsatile blood flow velocity (BFV) and pressure (BP) in the middle cerebral artery (MCA) during posture change from sitting to standing, and use this model to unravel differences in regulatory mechanisms governing cerebral blood flow (CBF) in two groups of subjects: (i) normotensive elderly subjects and (ii) elderly subjects with untreated hypertension. Extensive data on pulsatile BFV in the MCA and BP have already been gathered in Dr. Lipsitz's laboratory. We will analyze these data using the mathematical model and extract parameters, such as systemic and peripheral cerebrovascular resistance and compliance. Once differences among the groups of normotensive and untreated hypertensive subjects and between males and females have been established, we will (in a full RO1 proposal) investigate side effects related to vasodilator treatment of hypertension and effects related to vasovagal syncope. This study builds upon previous modeling work by Drs. Olufsen, Nadim, and Lipsitz, showing a biphasic cerebrovascular response to acute posture change in healthy young subjects, characterized by initial (baroreflex-mediated) vasoconstriction (and increased pulsatility), followed by autoregulatory cerebral vasodilation that restores blood flow to normal. Based on these results and preliminary observations of MCA blood flow in hypertensive subjects lack initial increase in cerebral pulsatility during posture change due to impairments in initial (baroreflex-mediated) peripheral cerebral vasoconstriction and cardioacceleration, (ii) this defect is exaggerated in untreated hypertensive elders. This work represents a unique collaboration between a clinical investigator in cardiovascular aging, Dr. Lipsitz and mathematicians specialized in modeling circulatory dynamics in branched arterial systems, Drs. Olufsen and Nadim. The proposed study responds to the goal of the RFA and helps Dr. Olufsen continue to build a successful independent research career in the important areas of cardiovascular physiology and aging.