Coronary Blood Flow: Integrated Theory and Experiments

冠状动脉血流：理论与实验相结合

• 批准号: 8731967
• 负责人: DANIEL A BEARD
• 金额: $ 66.42万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-10 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8731967
• 关键词: Accounting; Acting Out; Acute; Adrenergic Agents; Adrenergic Receptor; Affect; Animal Model; Anterior; Anterior Descending Coronary Artery; Arteries; Behavior; Biochemical; Blood; Blood Vessels; Blood flow; Calcium; Caliber; Cardiac; Cell membrane; Cells; Chemicals; Computer Simulation; Computers; Contracts; Coronary; Coronary Arteriosclerosis; Coronary Circulation; Coronary Vessels; Coronary artery; Coronary sinus structure; Coupling; Data; Disease; Electrophysiology (science); Endothelial Cells; Erythrocytes; Exercise; Family suidae; Feedback; Generations; Goals; Grant; Healthcare; Heart; Homeostasis; Individual; Intervention; Left; Link; Measurement; Mechanics; Mediating; Membrane Potentials; Metabolic; Metabolism; Modeling; Muscle function; Myocardial; Myocardium; Nutrient; Organ; Oxygen; Oxygen Consumption; Pathway interactions; Peroxides; Physiological; Physiological Processes; Process; Property; Protocols documentation; Pulsatile Flow; Pump; Regulation; Resistance; Rest; Series; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Stenosis; Stimulus; System; Testing; Tissues; Vasodilation; Venous; Ventricular; Work; adrenergic; awake; base; design; electric impedance; in vivo; metabolic rate; models and simulation; multi-scale modeling; pressure; receptor; research study; response; simulation; theories

DESCRIPTION (provided by applicant): Blood flow and rate of oxygen consumption are closely matched in vivo under normal conditions. Coronary flow is regulated through the combined action of metabolic, adrenergic, and mechanical (myogenic and shear) mechanisms. Since vascular mechanical processes are linked to the mechanics of cardiac contraction, understanding flow regulation requires a model that accounts for mechanics from the microvessel to the whole-organ level. Accordingly, the overall objective of this grant is to develop a validated multi-scale model of coronary autoregulation that accounts for the various major determinants of coronary flow regulation. To accomplish this goal, we set the following three Specific Aims: Aim 1: To construct a multi-scale mechanistic model of coronary flow regulation integrating cell-level models of endothelial and smooth-muscle function, single-vessel mechanics of coronary resistance arteries, autonomic function, network-level myocardium- coronary vessel interaction and conducted metabolic response; Aim 2: To validate the ability of the model of Aim 1 to predict physiological dynamics observed in the awake exercising pig; and Aim 3: To use the models from Aim 1, refined by data from Aim 2 to understand the multiscale effects of stenosis on pulsatile flow in coronary arteries. We will test the hypothesis that the multiple parallel control mechanisms fail when coronary arteries become stenotic because they act out of sync and interfere. The model predictions will be compared to data from three complimentary protocols: (1) dynamic measurements of flow, pressure, and diameter in coronary arteries ranging from 50 mm to the large epicardial vessels; (2) steady-state measurements of venous (coronary sinus) pO2 versus left-ventricular oxygen consumption in different exercise states; and (3) measurement of the dynamic reactive hyperemic response flow following acute transient occlusion of the left anterior descending coronary artery. Protocols will be conducted with and without specific pharmacological interventions to inhibit receptors and channels represented in the cell-level models. The validated model will be used to investigate critical questions, including: What is the principle mechanism coupling coronary blood flow to metabolism in vivo? How is high resting oxygen extraction functionally linked to the ability of the system to effectively respond to increased demand in exercise?

描述（由申请人提供）：在正常条件下，血流量和耗氧率在体内密切匹配。冠状动脉血流通过代谢、肾上腺素能和机械（肌源性和剪切）机制的联合作用来调节。由于血管机械过程与心脏收缩的力学有关，因此理解流量调节需要一个模型，该模型可以解释从微血管到整个器官水平的力学。因此，这项资助的总体目标是开发一个经验证的冠状动脉自动调节的多尺度模型，该模型解释了冠状动脉流量调节的各种主要决定因素。为了实现这一目标，我们设定了以下三个具体目标：目标1：构建冠状动脉血流调节的多尺度机制模型，该模型整合了内皮和平滑肌功能的细胞水平模型、冠状动脉阻力动脉的单血管力学、自主神经功能、网络水平心肌-冠状动脉血管相互作用和传导代谢反应;目标2：验证目标1模型预测清醒运动猪中观察到的生理动力学的能力;目标3：使用目标1的模型，通过目标2的数据进行细化，以了解狭窄对冠状动脉脉动流的多尺度影响。我们将检验这样的假设：当冠状动脉狭窄时，多个平行控制机制失效，因为它们的行为不同步并相互干扰。模型预测将与来自三个补充协议的数据进行比较：（1）从50 mm到大心外膜血管的冠状动脉中的流量、压力和直径的动态测量;（2）静脉血管的稳态测量。不同运动状态下冠状窦pO 2与左心室耗氧量的关系;（3）左冠状动脉前降支急性短暂闭塞后动态反应性充血反应血流的测量。协议 将在有或没有特定药理学干预的情况下进行，以抑制细胞水平模型中代表的受体和通道。经验证的模型将用于研究关键问题，包括：什么是耦合冠状动脉血流代谢在体内的原则机制？高静息氧提取与系统有效响应运动需求增加的能力在功能上有何联系？