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

多尺度建模解开冠脉血流调节机制的研究 冠脉循环受到许多机制的调节，这些机制可以精确地调节心肌灌注。 确保心肌供氧(供)充足以满足ATP代谢需求 生产(需求)。冠脉血流量和心肌耗氧量(MVO2)之间的这种平衡 在各种病理生理紊乱中保存下来，包括严重的血流灌注减少 发生在动脉粥样硬化性狭窄部位远端的压力。冠脉循环的先天能力 当驾驶压力降低到40-60毫米汞柱时，保持血流恒定是必不可少的 减轻低灌注率、心功能障碍和明显的缺血性损伤的现象。尽管关键的是 这一内在反应的性质，了解冠状动脉压力-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，鉴于这些通路共享共同的末端效应器通路和微血管 不同心肌层的反应是不同的，受结构和收缩的影响。 关于心肌的特性，我们的知识仍然是现象学的。这样做的主要目标是 建议是通过计算和实验研究来解决这一缺陷，以构建、测试和改进 冠脉血流多尺度模型中代谢机制的相互竞争假说 监管。我们的方法建立在我们最近用受限混合理论模型和活体模型所做的努力之上 评估冠状动脉零流量时的压力(Pzf)，这是一种潜在的肌源性张力指数。应用这一点 用于测试和完善有关病理性过度活动的假说的实验和建模框架 肥胖相关冠脉微血管功能障碍的肌源性反应将提供进一步的洞察力 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.