Disentangling the Mechanisms of Coronary Blood Flow Regulation through Multi-scale Modeling

Disentangling the Mechanisms of Coronary Blood Flow Regulation through Multi-scale Modeling The coronary circulation is regulated by numerous mechanisms that precisely modulate myocardial perfusion to ensure that myocardial oxygen delivery (supply) is adequate to meet the metabolic requirements for ATP production (demand). This balance between coronary blood flow and myocardial oxygen consumption (MVO2) is preserved over a variety of patho-physiologic perturbations, including critical reductions in perfusion pressure which occur distal to sites of atherosclerotic stenosis. The innate ability of the coronary circulation to maintain blood flow constant as driving pressures are reduced to values as low as 40-60 mmHg is an essential phenomenon that mitigates hypoperfusion, cardiac dysfunction, and overt ischemic injury. Despite the crucial nature of this intrinsic response, understanding the mechanisms responsible for coronary pressure-flow autoregulation remains one of the most fundamental questions in the coronary field today. The most prominent theories to explain coronary autoregulatory behavior are the local metabolic and myogenic hypotheses. However, given that these pathways share common end-effector pathways and microvascular responses, differ transmurally across layers of the myocardium, and are influenced by structural and contractile properties of the myocardium, our knowledge remains rather phenomenological. The primary goal of this proposal is to address this deficit through computational and experimental studies to build, test, and refine competing hypotheses for the metabolic mechanism in the context of a multi-scale model of coronary flow regulation. Our approach builds on our recent efforts with constrained mixture theory models and in vivo assessment of coronary pressure at zero-flow (Pzf), an index of underlying myogenic tone. Applying this experimental and modeling framework to test and refine hypotheses regarding pathologically over-active myogenic response in coronary microvascular dysfunction associated with obesity will provide further insight into short- vs. long-term impact of microvascular adaptions in health and disease.