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

本研究的目的是阐明心脏起搏器在心肌细胞中产生的动力学机制，以及从心室肌细胞中工程化生物起搏器细胞的最佳方法。我们建立了一个人心室肌细胞模型，该模型可以再现异常自律性，并适合于分岔分析，并开发了计算机程序系统，用于分析该模型和窦房结模型的参数相关分岔结构。通过对这些模型的分岔分析，我们研究了1)长QT综合征心室肌细胞早期后去极化（EADs）出现的动力学机制，2)向内整流K^+电流（I_<K1>）下调的人心室肌细胞中起搏器产生的机制，3)起搏器电流对心室起搏器产生和调节的影响，以及4)窦房结起搏器机制的区域差异。结果总结如下：缓慢激活的延迟整流K^+电流（I_<Ks>）是长QT综合征（LQT2和3）2期EADs发展的基础，可视为瞬态极限环，并通过加速I_<Ks>激活而得到显著抑制。2)抑制I_<K1>是人心室肌细胞产生生物起搏器细胞的必要条件，这是通过表达超极化激活的阳离子电流（Ih）促进的。3)持续向内电流（Ist）的表达最显著地提高了心室起搏器对非起搏器细胞电紧张负荷的结构稳定性，而Ih的表达则没有。4)与中央窦房结细胞相比，周围窦房结细胞对超极化负载的耐受性更强。钠通道电流（INa）有助于外周细胞相对较高的结构稳定性，对于心脏起搏器系统的稳健起搏和驱动是必不可少的。这些发现将为心脏自动性的调节和具有强大起搏和驱动的生物起搏器系统的工程提供理论背景。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