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肌细胞产生起搏器的动力学机制，以及从心室肌细胞工程生物起搏器细胞的最佳方法。我们建立了一个既能复制异常自律性又能进行分叉分析的人心室肌细胞模型，并开发了用于分析该模型和窦房结模型参数相关分叉结构的计算机程序系统。通过对这些模型的分叉分析，我们研究了1)长QT综合征患者心室肌细胞出现早期后除极(EAD)的动力学机制，2)内向整流钾电流(I&lt；K1&gt；)下调的人心室肌细胞产生起搏器的机制，3)起搏器电流对起搏器产生和调制的影响，以及4)SA结起搏机制的区域差异。结果如下：1)t-…激活缓慢在长QT综合征(LQT_2和LQT_3)中，更多的缓慢激活延迟整流钾电流(I_lt；Ks&gt；)是第二相EADS发展的基础，可被视为暂时性极限环，并被加速激活显著抑制。2)抑制I_&lt；K1&gt；3)持续内向电流(Ist)的表达最显著地提高了起搏器对非起搏细胞电渗性负荷的结构稳定性，而Ih的表达不能显著提高起搏器的结构稳定性。4)外周SA结细胞比中央SA结细胞对超极化负荷的耐受性更强。钠离子通道电流(INA)是维持起搏系统稳定的外周细胞结构的重要因素，这些发现为心脏自律性的调控和强健起搏和驱动生物起搏器系统的工程设计提供了理论基础。较少

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