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

通过多尺度建模阐明冠状动脉血流调节机制

• 批准号: 10592338
• 负责人: DANIEL A BEARD
• 金额: $ 65.47万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592338
• 关键词: Accounting; Address; Adrenergic Agents; Affect; Anatomy; Anesthesia procedures; Animal Experiments; Automobile Driving; Behavior; Blood Vessels; Blood capillaries; Blood flow; Cardiac Output; Cardiovascular system; Catecholamines; Cells; Compensation; Conscious; Coronary; Coronary Circulation; Coupling; Data Analyses; Disease; Distal; Electrophysiology (science); Endothelium; Equilibrium; Family suidae; Feedback; Goals; Health; Heart; Histologic; Homeostasis; Hypoxemia; Impairment; Infusion procedures; Ischemia; Knowledge; Lesion; Measurement; Measures; Mechanics; Mediating; Mediator; Membrane; Metabolic; Metabolic Control; Metabolic Pathway; Microvascular Dysfunction; Modeling; Morbidity - disease rate; Myocardial; Myocardial dysfunction; Myocardial perfusion; Myocardium; Nature; Obesity; Oxygen; Oxygen Consumption; Pathologic; Pathway interactions; Perfusion; Peripheral Resistance; Physiological; Potassium Channel; Production; Property; Regulation; Resistance; Signal Pathway; Signal Transduction; Site; Smooth Muscle; Smooth Muscle Myocytes; Stenosis; Structural Models; System; Testing; Vascular Smooth Muscle; Vasodilation; Vasodilator Agents; Venous; Ventricular; Work; antagonist; arteriole; computer studies; computerized tools; coronary perfusion; coronary vasculature; electrical property; experimental study; hypoperfusion; improved; in vivo; indexing; insight; instrument; ischemic injury; mechanical properties; models and simulation; mortality; multi-scale modeling; neural; novel; patch clamp; phenome; phenomenological models; physiologic model; porcine model; preservation; pressure; receptor; response; simulation; theories

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.

通过多尺度建模来解开冠状动脉流动调节的机制 冠状动脉循环受许多机制的调节，这些机制精确调节心肌灌注 确保心肌氧（供应）足以满足ATP的代谢要求 生产（需求）。冠状动脉血流与心肌氧的消耗之间的平衡（MVO2） 保留在多种病态生理学扰动中，包括灌注的临界减少 距离动脉粥样硬化狭窄部位远端发生的压力。冠状动脉循环的先天能力 保持血流恒定，因为驾驶压力降低到低至40-60 mmHg是必不可少的 减轻灌注不足，心脏功能障碍和明显缺血性损伤的现象。尽管至关重要 这种内在响应的性质，了解负责冠状动脉压力的机制 自动调节仍然是当今冠状动脉领域中最根本的问题之一。 解释冠状动脉自动调节行为的最突出的理论是局部代谢和肌原性 假设。但是，鉴于这些途径共享常见的最终效应途径和微血管 反应在心肌的层间经传播，并受结构和收缩的影响 心肌的特性，我们的知识仍然相当现象。这个主要目标 建议是通过计算和实验研究来解决这一赤字，以建立，测试和完善 在多尺度模型的冠状动脉流程中，代谢机制的竞争假设 规定。我们的方法是基于我们最近通过有限的混合理论模型和体内的努力来建立的 评估零流量（PZF）的冠状动脉压力，这是基础肌吻合的指数。应用此 实验和建模框架，以测试和完善有关病理过度活跃的假设 与肥胖相关的冠状动脉微血管功能障碍中的肌源性反应将提供进一步的见解 短期与微血管适应对健康和疾病的长期影响。