Overview of mathematical modeling of myocardial blood flow regulation.

The oxygen consumption by the heart and its extraction from the coronary arterial blood are the highest among all organs. Any increase in oxygen demand due to a change in heart metabolic activity requires an increase in coronary blood flow. This functional requirement of adjustment of coronary blood flow is mediated by coronary flow regulation to meet the oxygen demand without any discomfort, even under strenuous exercise conditions. The goal of this article is to provide an overview of the theoretical and computational models of coronary flow regulation and to reveal insights into the functioning of a complex physiological system that affects the perfusion requirements of the myocardium. Models for three major control mechanisms of myogenic, flow, and metabolic control are presented. These explain how the flow regulation mechanisms operating over multiple spatial scales from the precapillaries to the large coronary arteries yield the myocardial perfusion characteristics of flow reserve, autoregulation, flow dispersion, and self-similarity. The review not only introduces concepts of coronary blood flow regulation but also presents state-of-the-art advances and their potential to impact the assessment of coronary microvascular dysfunction (CMD), cardiac-coronary coupling in metabolic diseases, and therapies for angina and heart failure. Experimentalists and modelers not trained in these models will have exposure through this review such that the nonintuitive and highly nonlinear behavior of coronary physiology can be understood from a different perspective. This survey highlights knowledge gaps, key challenges, future research directions, and novel paradigms in the modeling of coronary flow regulation.