Coronary Blood Flow: Integrated Theory and Experiments

描述(申请人提供)：在正常情况下，体内的血流量和耗氧率非常匹配。冠状动脉血流是通过代谢、肾上腺素能和机械(肌源性和剪切性)机制的共同作用来调节的。由于血管机械过程与心脏收缩的机制有关，理解血流调节需要一个模型来解释从微血管到整个器官水平的机制。因此，这笔赠款的总体目标是开发一个经过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血流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：构建一个多尺度的冠状动脉血流调节机制模型，该模型集成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模型、自主神经功能、网络水平的心肌-冠状动脉相互作用和传导代谢反应；目标2：验证目标1的模型预测清醒运动猪观察到的生理动力学的能力；以及目标3：使用目标1的模型，并通过目标2的数据改进，以了解狭窄对冠状动脉搏动性血流的多尺度影响。我们将测试这一假设，即当冠状动脉狭窄时，多个并行控制机制失败，因为它们的行为不同步和干扰。模型预测将与来自三个补充方案的数据进行比较：(1)动态测量冠状动脉的流量、压力和直径，范围从50 mm到心外膜大血管；(2)稳态测量不同运动状态下静脉(冠状静脉窦)PO2与左心室耗氧量的关系；以及(3)测量急性一过性冠状动脉前降支闭塞后的动态反应性充血反应流量。协议 将在有和没有特定药物干预的情况下进行，以抑制细胞水平模型中所代表的受体和通道。经过验证的模型将用于研究关键问题，包括：体内冠脉血流与新陈代谢的主要机制是什么？高位静息吸氧功能如何与系统对运动中增加的需求做出有效反应的能力有关？

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?