Dynamical mechanisms of pacemaker generation in cardiac myocytes: a comprehensive study based on bifurcation theory with application to biological pacemaker engineering

本研究旨在阐明心肌细胞产生起搏点的动力学机制，以及从心室肌细胞中构建生物起搏细胞的最佳方法。我们制定了一个人心室肌细胞模型，它可以重现异常自律性，以及适用于分叉分析，并开发了系统的计算机程序，用于分析该模型和窦房结（SA）节点模型的参数依赖的分叉结构。通过对这些模型的分叉分析，我们研究了1）长QT综合征心室肌细胞早期后除极（埃兹的动力学机制，2）内向整流钾电流（I_<K1>）下调的人心室肌细胞起搏产生的机制，3）起搏电流对心室起搏产生和调制的影响，（4）窦房结起搏机制的区域差异。结果如下：1）慢激活T细胞， 关于我们 慢激活延迟整流钾电流（I_2<Ks>）是长QT综合征（LQT2和3）2相埃兹的基础，可被视为短暂的极限环，可被加速I_2激活显著抑制<Ks>。2）抑制I_2<K1>是从人心室肌细胞产生生物起搏细胞的必要条件，表达超极化激活的阳离子电流（Ih）可使其更易发生。3）表达持续性内向电流（Ist）最显著地改善了心室起搏器对非起搏器细胞的电紧张负荷的结构稳定性，而Ih没有。4）外周SA结细胞比中央SA结细胞对超极化负荷更鲁棒。钠通道电流（INa）是维持心脏起搏和驱动所必需的细胞结构稳定性的重要因素，这一发现为心脏自律性的调控和具有强大起搏和驱动功能的生物起搏系统的工程化提供了理论基础。少

The aim of this study was to elucidate the dynamical mechanisms of pacemaker generation in cardiac myocytes, and the optimal method for engineering of biological pacemaker cells from ventricular myocytes. We formulated a human ventricular myocyte model, which can reproduce abnormal automaticity as well as suitable for bifurcation analyses, and developed the system of computer programs for analyzing parameter-dependent bifurcation structures of this model and sinoatrial (SA) node models. By bifurcation analyses of these models, we investigated 1) dynamical mechanisms of early afterdepolarizations (EADs) to emerge in ventricular myocytes of the long QT syndrome, 2) mechanisms of pacemaker generation in the inward-rectifier K^+ current (I_<K1>)-downregulated human ventricular myocyte, 3) effects of pacemaker currents on creation and modulation of ventricular pacemaker, and 4) regional difference in SA node pacemaker mechanisms. The results are summarized as follows.1) Slow activation of t … More he slowly-activating delayed-rectifier K^+ current (I_<Ks>) underlies the development of phase 2 EADs in long QT syndromes (LQT2 and 3), which can be regarded as transient limit cycles and were dramatically suppressed by accelerating I_<Ks> activation.2) Inhibition of I_<K1> was a requisite for the creation of biological pacemaker cells from human ventricular myocytes, which was facilitated by expressing the hyperpolarization-activated cation current (Ih).3) Expression of the sustained inward current (Ist) most dramatically improved the structural stability of the ventricular pacemaker to electrotonic loads of non-pacemaker cells, whereas that of Ih did not.4) The peripheral SA node cell is more robust to hyperpolarizing loads than the central SA node cell. The sodium channel current (INa) contributes to the relatively high structural stability of the peripheral cell, indispensable for robust pacemaking and driving of the pacemaker system.These findings would provide a theoretical background for regulation of cardiac automaticity and engineering of biological pacemaker systems with robust pacemaking and driving. Less