A microstructurally motivated framework to study autoregulation in the coronary circulation.

Coronary autoregulation maintains relatively constant myocardial blood flow over a wide range of perfusion pressures through myogenic, shear-dependent and metabolic control mechanisms. Understanding this phenomenon is challenging due to the coupled nature of these mechanisms and their heterogeneous effects throughout the coronary tree. In this study, we developed a framework to study coronary autoregulation based on constrained mixture theory. The framework simulates autoregulation at three myocardial depths (subepicardium, midwall and subendocardium), calibrated using extensive literature data. Coronary trees at each myocardial depth are constructed via a homeostatic optimization approach to determine morphological and haemodynamic characteristics. Each vessel is endowed with passive and active mechanical properties, governed by a microstructurally motivated wall model. Autoregulatory stimuli from myogenic, metabolic and shear-dependent mechanisms modulate vascular smooth muscle tone, enabling the framework to reproduce autoregulatory responses, experimentally measured transmural flow ratios and vessel diameter changes with variations in perfusion pressure. The framework also incorporates phasic dynamics by extending Womersley's theory to account for time-varying intramyocardial pressures, successfully capturing key features of coronary flow waveforms. Sensitivity analysis highlights metabolic mechanisms as primary contributors to autoregulatory function, with the myogenic response playing an important role and shear-dependent control having minimal contribution. Additionally, the framework demonstrates how changes in vessel microstructure (e.g. collagen stiffening or impaired smooth muscle contractility) affect autoregulatory capacity, providing mechanistic insight into pathophysiological states. This microstructurally motivated framework offers a novel approach for hypothesis testing in coronary autoregulation while providing a unified platform for describing processes spanning short-term tone regulation and long-term vascular remodelling. KEY POINTS: Coronary autoregulation is defined as the capability of the coronary circulation to maintain the blood supply to the heart over a range of perfusion pressures. This phenomenon is facilitated through intrinsic mechanisms that control the vascular resistance by regulating the function of smooth muscle cells. This paper presents a microstructurally motivated coronary autoregulation framework that uses a non-linear continuum mechanics approach to account for the morphometry and vessel wall composition in three coronary trees in the subepicardial, midwall and subendocardial layers of the myocardium. The model is calibrated against diverse experimental data from the literature and is used to study heterogeneous autoregulatory response in the coronary trees. This model drastically differs from previous models and is suited to the study of long-term pathophysiological growth and remodelling phenomena in coronary vessels.