Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
J Physiol. 2022 Apr;600(8):1913-1932. doi: 10.1113/JP282237. Epub 2022 Mar 6.
Coronary blood flow is tightly regulated to ensure that myocardial oxygen delivery meets local metabolic demand via the concurrent action of myogenic, neural and metabolic mechanisms. Although several competing hypotheses exist, the specific nature of the local metabolic mechanism(s) remains poorly defined. To gain insights into the viability of putative metabolic feedback mechanisms and into the co-ordinated action of parallel regulatory mechanisms, we applied a multiscale modelling framework to analyse experimental data on coronary pressure, flow and myocardial oxygen delivery in the porcine heart in vivo. The modelling framework integrates a previously established lumped-parameter model of myocardial perfusion used to account for transmural haemodynamic variations and a simple vessel mechanics model used to simulate the vascular tone in each of three myocardial layers. Vascular tone in the resistance vessel mechanics model is governed by input stimuli from the myogenic, metabolic and autonomic control mechanisms. Seven competing formulations of the metabolic feedback mechanism are implemented in the modelling framework, and associated model simulations are compared with experimental data on coronary pressures and flows under a range of experimental conditions designed to interrogate the governing control mechanisms. Analysis identifies a maximally probable metabolic mechanism among the seven tested models, in which production of a metabolic signalling factor is proportional to myocardial oxygen consumption and delivery is proportional to flow. Finally, the identified model is validated based on comparisons of simulations with data on the myocardial perfusion response to conscious exercise that were not used for model identification. KEY POINTS: Although several competing hypotheses exist, we lack knowledge of specific nature of the metabolic mechanism(s) governing regional myocardial perfusion. Moreover, we lack an understanding of how parallel myogenic, adrenergic/autonomic and metabolic mechanisms work together to regulatory oxygen delivery in the beating heart. We have developed a multiscale modelling framework to test competing hypotheses against experimental data on coronary pressure, flow and myocardial oxygen delivery in the porcine heart in vivo. The analysis identifies a maximally probable metabolic mechanism among seven tested models, in which the production of a metabolic signalling factor is proportional to myocardial oxygen consumption and delivery is proportional to flow.
冠状动脉血流受到严格调节，以确保通过肌源性、神经和代谢机制的协同作用，使心肌氧输送满足局部代谢需求。尽管存在几种相互竞争的假说，但局部代谢机制的具体性质仍未得到很好的定义。为了深入了解潜在代谢反馈机制的可行性以及并行调节机制的协同作用，我们应用多尺度建模框架分析了活体猪心冠状动脉压力、流量和心肌氧输送的实验数据。该建模框架集成了先前建立的心肌灌注集总参数模型，用于解释跨壁血流动力学变化，以及一个简单的血管力学模型，用于模拟三个心肌层中的血管张力。阻力血管力学模型中的血管张力由肌源性、代谢和自主控制机制的输入刺激控制。在建模框架中实现了七种代谢反馈机制的竞争公式，并且与在一系列旨在研究控制机制的实验条件下获得的冠状动脉压力和流量的实验数据相关联的模型模拟进行了比较。分析在七种测试模型中确定了一个最可能的代谢机制，其中代谢信号因子的产生与心肌耗氧量成正比，输送与流量成正比。最后，根据与未用于模型识别的清醒运动引起的心肌灌注反应数据的模拟比较，对所识别的模型进行了验证。要点：尽管存在几种相互竞争的假说，但我们缺乏调节局部心肌灌注的代谢机制的具体性质的知识。此外，我们还缺乏了解平行的肌源性、肾上腺素能/自主和代谢机制如何协同工作，以调节心跳中的氧输送。我们已经开发了一种多尺度建模框架，以根据活体猪心冠状动脉压力、流量和心肌氧输送的实验数据对竞争假说进行测试。分析在七种测试模型中确定了一个最可能的代谢机制，其中代谢信号因子的产生与心肌耗氧量成正比，输送与流量成正比。
