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

点击翻译按钮获取中文摘要

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