Khokhlova Anastasia, Konovalov Pavel, Iribe Gentaro, Solovyova Olga, Katsnelson Leonid
Institute of Immunology and Physiology, Russian Academy of Sciences, Yekaterinburg, Russia.
Institute of Natural Sciences and Mathematics, Ural Federal University, Yekaterinburg, Russia.
Front Physiol. 2020 Mar 17;11:171. doi: 10.3389/fphys.2020.00171. eCollection 2020.
Transmural differences in ventricular myocardium are maintained by electromechanical coupling and mechano-calcium/mechano-electric feedback. In the present study, we experimentally investigated the influence of preload on the force characteristics of subendocardial (Endo) and subepicardial (Epi) single ventricular cardiomyocytes stretched by up to 20% from slack sarcomere length (SL) and analyzed the results with the help of mathematical modeling. Mathematical models of Endo and Epi cells, which accounted for regional heterogeneity in ionic currents, Ca handling, and myofilament contractile mechanisms, showed that a greater slope of the active tension-length relationship observed experimentally in Endo cardiomyocytes could be explained by greater length-dependent Ca activation in Endo cells compared with Epi ones. The models also predicted that greater length dependence of Ca activation in Endo cells compared to Epi ones underlies, via mechano-calcium-electric feedback, the reduction in the transmural gradient in action potential duration (APD) at a higher preload. However, the models were unable to reproduce the experimental data on a decrease of the transmural gradient in the time to peak contraction between Endo and Epi cells at longer end-diastolic SL. We hypothesize that preload-dependent changes in viscosity should be involved alongside the Frank-Starling effects to regulate the transmural gradient in length-dependent changes in the time course of contraction of Endo and Epi cardiomyocytes. Our experimental data and their analysis based on mathematical modeling give reason to believe that mechano-calcium-electric feedback plays a critical role in the modulation of electrophysiological and contractile properties of myocytes across the ventricular wall.
心室心肌的跨壁差异通过机电耦合和机械钙/机械电反馈得以维持。在本研究中，我们通过实验研究了前负荷对从松弛肌节长度（SL）拉伸高达20%的心内膜下（Endo）和心外膜下（Epi）单个心室心肌细胞力特性的影响，并借助数学建模对结果进行了分析。Endo和Epi细胞的数学模型考虑了离子电流、钙处理和肌丝收缩机制中的区域异质性，结果表明，与Epi心肌细胞相比，Endo心肌细胞实验中观察到的主动张力-长度关系斜率更大，这可以通过Endo细胞中更强的长度依赖性钙激活来解释。这些模型还预测，与Epi细胞相比，Endo细胞中更强的钙激活长度依赖性，通过机械钙电反馈，是导致更高前负荷下心室壁动作电位时程（APD）跨壁梯度降低的原因。然而，这些模型无法再现舒张末期SL较长时Endo和Epi细胞之间收缩峰值时间跨壁梯度降低的实验数据。我们假设，除了Frank-Starling效应外，还应涉及前负荷依赖性的粘度变化，以调节Endo和Epi心肌细胞收缩时程中长度依赖性变化的跨壁梯度。我们的实验数据及其基于数学建模的分析有理由相信，机械钙电反馈在调节心室壁心肌细胞的电生理和收缩特性中起着关键作用。
