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

冠状动脉血流调节机制的多尺度模型研究 冠状动脉循环是由许多机制，精确地调节心肌灌注 确保心肌氧输送（供应）足以满足ATP的代谢需求 需求（demand）。冠状动脉血流量和心肌耗氧量（MVO 2）之间的平衡 在各种病理生理扰动下，包括灌注严重减少， 动脉粥样硬化狭窄部位远端的压力。冠状动脉循环的固有能力， 当驱动压力降低到低至40-60 mmHg时保持血流恒定是必要的 这是一种缓解灌注不足、心功能障碍和明显缺血性损伤的现象。尽管至关重要的 这种内在反应的性质，了解负责冠状动脉压力-流量的机制 自动调节仍然是当今冠状动脉领域中最基本的问题之一。 解释冠状动脉自身调节行为的最突出的理论是局部代谢和肌源性 假设然而，考虑到这些途径共享共同的末端效应途径和微血管， 反应，不同的跨层心肌，并受到结构和收缩的影响， 心肌的性质，我们的知识仍然是现象学的。这个的主要目标 一项建议是通过计算和实验研究来解决这一缺陷，以建立，测试和完善 冠状动脉血流多尺度模型背景下代谢机制的竞争性假设 调控我们的方法建立在我们最近的努力与约束混合物理论模型和体内 评估零流量时的冠状动脉压力（Pzf），这是潜在肌源性张力的指标。应用该 实验和建模框架，以测试和完善关于病理性过度活跃的假设 与肥胖相关的冠状动脉微血管功能障碍的肌源性反应将提供进一步的认识 微血管适应对健康和疾病的短期和长期影响。

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.