Coronary Blood Flow: Integrated Theory and Experiments

冠状动脉血流：理论与实验相结合

基本信息

批准号：
9457478
负责人：
DANIEL A BEARD
金额：
$ 65.05万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
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/9457478
关键词：
Acute Adrenergic Agents Adrenergic Receptor Affect Animal Model Anterior Anterior Descending Coronary Artery Arteries Behavior Biochemical Blood Blood Vessels Blood flow Calcium Caliber Cardiac Cells Chemicals Computer Simulation 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 Mathematics Measurement Mechanics Mediating Membrane Potentials Metabolic Metabolism Modeling Muscle function Myocardial Myocardium Names Nutrient Organ Oxygen Oxygen Consumption Pathway interactions Peroxides Pharmacology 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 Vascular Smooth Muscle Vasodilation Venous Ventricular Weight Work awake base coronary vasculature design electric impedance experimental study in vivo metabolic rate models and simulation multi-scale modeling predictive modeling pressure receptor response simulation theories

项目摘要

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（申请人提供）：正常条件下，体内血流量和耗氧率密切匹配。冠状动脉血流通过代谢、肾上腺素能和机械（肌源性和剪切）机制的联合作用进行调节。由于血管机械过程与心脏收缩的力学相关，因此了解血流调节需要一个能够解释从微血管到整个器官水平的力学的模型。因此，这笔拨款的总体目标是开发一种经过验证的冠状动脉自动调节多尺度模型，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，整合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；目标 2：验证目标 1 的模型预测在清醒运动的猪中观察到的生理动态的能力；目标 3：使用目标 1 的模型并根据目标 2 的数据进行细化，以了解狭窄对冠状动脉脉动血流的多尺度影响。我们将检验这样一个假设：当冠状动脉变得狭窄时，多个并行控制机制会失败，因为它们的行为不同步并产生干扰。该模型预测将与来自三个补充协议的数据进行比较：（1）动态测量冠状动脉的流量、压力和直径，范围从 50 毫米到大型心外膜血管； (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)测量左冠状动脉前降支急性短暂闭塞后的动态反应性充血反应血流。协议将在有或没有特定药理干预的情况下进行，以抑制细胞水平模型中代表的受体和通道。经过验证的模型将用于研究关键问题，包括：冠状动脉血流与体内代谢耦合的原理机制是什么？高静息摄氧量与系统有效应对运动中增加的需求的能力有何功能联系？