Kursanov Alexander, Balakina-Vikulova Nathalie A, Solovyova Olga, Panfilov Alexander, Katsnelson Leonid B
Institute of Immunology and Physiology of the Ural Branch of the Russian Academy of Sciences, Ekaterinburg, Russia.
Laboratory of Mathematical Modeling in Physiology and Medicine Based on Supercomputers, Ural Federal University, Ekaterinburg, Russia.
Front Physiol. 2023 Mar 10;14:1123609. doi: 10.3389/fphys.2023.1123609. eCollection 2023.
Although fibroblasts are about 5-10 times smaller than cardiomyocytes, their number in the ventricle is about twice that of cardiomyocytes. The high density of fibroblasts in myocardial tissue leads to a noticeable effect of their electromechanical interaction with cardiomyocytes on the electrical and mechanical functions of the latter. Our work focuses on the analysis of the mechanisms of spontaneous electrical and mechanical activity of the fibroblast-coupled cardiomyocyte during its calcium overload, which occurs in a variety of pathologies, including acute ischemia. For this study, we developed a mathematical model of the electromechanical interaction between cardiomyocyte and fibroblasts and used it to simulate the impact of overloading cardiomyocytes. In contrast to modeling only the electrical interaction between cardiomyocyte and fibroblasts, the following new features emerge in simulations with the model that accounts for both electrical and mechanical coupling and mechano-electrical feedback loops in the interacting cells. First, the activity of mechanosensitive ion channels in the coupled fibroblasts depolarizes their resting potential. Second, this additional depolarization increases the resting potential of the coupled myocyte, thus augmenting its susceptibility to triggered activity. The triggered activity associated with the cardiomyocyte calcium overload manifests itself in the model either as early afterdepolarizations or as extrasystoles, i.e., extra action potentials and extra contractions. Analysis of the model simulations showed that mechanics contribute significantly to the proarrhythmic effects in the cardiomyocyte overloaded with calcium and coupled with fibroblasts, and that mechano-electrical feedback loops in both the cardiomyocyte and fibroblasts play a key role in this phenomenon.
尽管成纤维细胞比心肌细胞小5 - 10倍，但它们在心室中的数量约为心肌细胞的两倍。心肌组织中成纤维细胞的高密度导致它们与心肌细胞的机电相互作用对后者的电和机械功能产生显著影响。我们的工作重点是分析在包括急性缺血在内的各种病理情况下发生钙超载时，成纤维细胞耦合心肌细胞的自发电活动和机械活动的机制。在本研究中，我们建立了心肌细胞与成纤维细胞之间机电相互作用的数学模型，并使用它来模拟心肌细胞超载的影响。与仅模拟心肌细胞与成纤维细胞之间的电相互作用的模型相比，考虑了相互作用细胞中的电和机械耦合以及机械电反馈回路的模型模拟中出现了以下新特征。首先，耦合成纤维细胞中机械敏感离子通道的活动使其静息电位去极化。其次，这种额外的去极化增加了耦合心肌细胞的静息电位，从而增强了其对触发活动的易感性。与心肌细胞钙超载相关的触发活动在模型中表现为早期后去极化或早搏，即额外的动作电位和额外的收缩。对模型模拟的分析表明，力学在钙超载且与成纤维细胞耦合的心肌细胞的促心律失常作用中起重要作用，并且心肌细胞和成纤维细胞中的机械电反馈回路在这一现象中起关键作用。
