Cerebral Blood Flow Model for Normo/Hypertensive Elderly

本研究的目的是利用基于流体动力学原理的数学模型来确定立位应激期间脑血管自动调节的机制以及由于衰老和高血压而引起的脑血管自动调节的改变。具体目的是开发一个集总参数模型，该模型可以再现从坐到站的姿势变化期间大脑中动脉（MCA）中脉动血流速度（BFV）和压力（BP）的动态变化，并使用该模型来阐明两组受试者中控制脑血流（CBF）的调节机制的差异：（i）血压正常的老年受试者和（ii）患有未经治疗的高血压的老年受试者。Lipsitz博士的实验室已经收集了有关MCA和BP中搏动性BFV的大量数据。我们将使用数学模型分析这些数据并提取参数，例如全身和外周脑血管阻力和顺应性。一旦确定了血压正常和未经治疗的高血压受试者之间以及男性和女性之间的差异，我们将（在完整的RO 1提案中）研究与血管扩张剂治疗高血压相关的副作用和与血管迷走性晕厥相关的作用。这项研究建立在Olufsen，Nadim和Lipsitz博士先前的建模工作基础上，显示了健康年轻受试者对急性姿势变化的双相脑血管反应，其特征是初始（压力反射介导的）血管收缩（和脉动性增加），随后是自动调节脑血管舒张，使血流恢复正常。基于这些结果和高血压受试者的MCA血流的初步观察缺乏初始增加，在姿势改变过程中，由于在初始（压力反射介导的）外周脑血管收缩和心脏加速的损害，（ii）这种缺陷是夸大了未经治疗的高血压老年人的脑脉动。这项工作代表了心血管衰老临床研究者Lipsitz博士和专门研究分支动脉系统循环动力学建模的数学家Olufsen博士和Nadim博士之间的独特合作。这项拟议的研究响应了RFA的目标，并帮助Olufsen博士继续在心血管生理学和衰老的重要领域建立成功的独立研究生涯。

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.