Multiscale model of the physiological control of myocardial perfusion to delineate putative metabolic feedback mechanisms

Abstract

Coronary blood flow is tightly regulated to ensure that myocardial oxygen delivery meets local metabolic demand via the concurrent action of myogenic, neural, and metabolic mechanisms. While several competing hypotheses exist, the specific nature of the local metabolic mechanism(s) remains poorly defined. To gain insights into the viability of putative metabolic feedback mechanisms and into the coordinated action of parallel regulatory mechanisms, we applied a multi-scale modeling framework to analyze experimental data on coronary pressure, flow, and myocardial oxygen delivery in the porcine heart in vivo. The modeling framework integrates a previously established lumped-parameter model of myocardial perfusion used to account for transmural hemodynamic variations and a simple vessel mechanics model used to simulate the vascular tone in each of three myocardial layers. Vascular tone in the resistance vessel mechanics model is governed by input stimuli from the myogenic, metabolic, and autonomic control mechanisms. Seven competing formulations of the metabolic feedback mechanism are implemented in the modeling framework, and associated model simulations are compared to experimental data on coronary pressures and flows under a range of experimental conditions designed to interrogate the governing control mechanisms. Analysis identifies a maximally likely metabolic mechanism among the seven tested models, in which production of a metabolic signaling factor is proportional to MVO2 and delivery proportional to flow. Finally, the identified model is validated based on comparisons of simulations to data on the myocardial perfusion response to conscious exercise that were not used for model identification.