Coronary Blood Flow: Integrated Theory and Experiments

描述（由申请人提供）：正常情况下，血流量和耗氧量在体内密切匹配。冠状动脉血流是通过代谢、肾上腺素能和机械（肌生成和剪切）机制的共同作用来调节的。由于血管力学过程与心脏收缩力学有关，因此理解血流调节需要一个从微血管到整个器官水平的力学模型。因此，这项资助的总体目标是开发一个有效的冠状动脉自动调节的多尺度模型，该模型可以解释冠状动脉血流调节的各种主要决定因素。为实现这一目标，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，包括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-冠状血管相互作用和传导代谢反应；目的2：验证目的1模型预测清醒运动猪生理动力学的能力；和Aim 3：使用Aim 1的模型，并通过Aim 2的数据进行改进，以了解狭窄对冠状动脉搏动血流的多尺度影响。当冠状动脉变得狭窄时，我们将测试多个平行控制机制失效的假设，因为它们的行为不同步和干扰。模型预测将与三个互补方案的数据进行比较：(1)冠状动脉流量、压力和直径的动态测量，范围从50mm到大的心外膜血管；(2)不同运动状态下静脉（冠状窦）pO2与左心室耗氧量的稳态测量；(3)急性一过性冠状动脉左前降支闭塞后动态反应性充血反应血流的测定。协议

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?