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?

Public Health Relevance

The coronary circulation provides oxygen and nutrients to the heart to match demand. The objective of this proposal is to provide a validated mathematical integration of the various mechanisms that contribute to the supply-demand matching and to understand why such matching fails in case of coronary artery disease which is a major healthcare problem.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL118738-06
Application #
9457478
Study Section
Special Emphasis Panel (ZEB1)
Program Officer
Luo, James
Project Start
2013-09-10
Project End
2019-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Physiology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Huo, Yunlong; Kassab, Ghassan S (2018) Coronary Blood Flow Is Increased in RV Hypertrophy, but the Shape of Normalized Waves Is Preserved Throughout the Arterial Tree. Front Physiol 9:675
Huo, Yunlong; Chen, Huan; Kassab, Ghassan S (2018) Acute Tachycardia Increases Aortic Distensibility, but Reduces Total Arterial Compliance Up to a Moderate Heart Rate. Front Physiol 9:1634
Namani, Ravi; Kassab, Ghassan S; Lanir, Yoram (2018) Integrative model of coronary flow in anatomically based vasculature under myogenic, shear, and metabolic regulation. J Gen Physiol 150:145-168
Kiel, Alexander M; Goodwill, Adam G; Noblet, Jillian N et al. (2017) Regulation of myocardial oxygen delivery in response to graded reductions in hematocrit: role of K+ channels. Basic Res Cardiol 112:65
Goodwill, Adam G; Dick, Gregory M; Kiel, Alexander M et al. (2017) Regulation of Coronary Blood Flow. Compr Physiol 7:321-382
Dick, Gregory M; Tune, Johnathan D (2017) Dynamic Regulation of the Subunit Composition of BK Channels in Smooth Muscle. Circ Res 121:594-595
Zhang, Yanhang; Barocas, Victor H; Berceli, Scott A et al. (2016) Multi-scale Modeling of the Cardiovascular System: Disease Development, Progression, and Clinical Intervention. Ann Biomed Eng 44:2642-60
Pradhan, Ranjan K; Feigl, Eric O; Gorman, Mark W et al. (2016) Open-loop (feed-forward) and feedback control of coronary blood flow during exercise, cardiac pacing, and pressure changes. Am J Physiol Heart Circ Physiol 310:H1683-94
Goodwill, Adam G; Fu, Lijuan; Noblet, Jillian N et al. (2016) KV7 channels contribute to paracrine, but not metabolic or ischemic, regulation of coronary vascular reactivity in swine. Am J Physiol Heart Circ Physiol 310:H693-704
Goodwill, Adam G; Noblet, Jillian N; Sassoon, Daniel et al. (2016) Critical contribution of KV1 channels to the regulation of coronary blood flow. Basic Res Cardiol 111:56

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