Li Jin, Maguy Ange, Duverger James Elber, Vigneault Patrick, Comtois Philippe, Shi Yanfen, Tardif Jean-Claude, Thomas Dierk, Nattel Stanley
Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montréal, Québec, Canada; Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montréal, Québec, Canada.
Heart Rhythm. 2014 Nov;11(11):2092-100. doi: 10.1016/j.hrthm.2014.07.040. Epub 2014 Jul 31.
Autoantibodies directed against various cardiac receptors have been implicated in cardiomyopathy and heart rhythm disturbances. In a previous study among patients with dilated cardiomyopathy, autoantibodies targeting the cardiac voltage-gated KCNQ1 K(+) channel were associated with shortened corrected QT intervals (QTc). However, the electrophysiologic actions of KCNQ1 autoimmunity have not been assessed experimentally in a direct fashion.
The purpose of this study was to investigate the cardiac electrophysiologic effects of KCNQ1 autoantibody production induced by vaccination in a rabbit model.
Rabbits were immunized with KCNQ1 channel peptide. ECG recordings were obtained during a 1-month follow-up period. Rabbits then underwent in vivo electrophysiologic study, after which cardiomyocytes were isolated for analysis of slow delayed rectifier current (IKs) and action potential properties via patch-clamp.
KCNQ1-immunized rabbits exhibited shortening of QTc compared to sham-immunized controls. Reduced ventricular effective refractory periods and increased susceptibility to ventricular tachyarrhythmia induction were noted in KCNQ1-immunized rabbits upon programmed ventricular stimulation. Action potential durations were shortened in cardiomyocytes isolated from KCNQ1-immunized rabbits compared to the sham group. IKs step and tail current densities were enhanced after KCNQ1 immunization. Functional and structural changes of the heart were not observed. The potential therapeutic significance of KCNQ1 immunization was then explored in a dofetilide-induced long QT rabbit model. KCNQ1 immunization prevented dofetilide-induced QTc prolongation and attenuated long QT-related arrhythmias.
Induction of KCNQ1 autoimmunity accelerates cardiac repolarization and increases susceptibility to ventricular tachyarrhythmia induction through IKs enhancement. On the other hand, vaccination against KCNQ1 ameliorates drug-induced QTc prolongation and might be useful therapeutically to enhance repolarization reserve in long QT syndrome.
针对各种心脏受体的自身抗体与心肌病和心律紊乱有关。在先前一项针对扩张型心肌病患者的研究中，靶向心脏电压门控KCNQ1钾通道的自身抗体与校正QT间期（QTc）缩短有关。然而，KCNQ1自身免疫的电生理作用尚未通过直接方式进行实验评估。
本研究旨在探讨在兔模型中接种疫苗诱导产生KCNQ1自身抗体对心脏电生理的影响。
用KCNQ1通道肽免疫兔子。在1个月的随访期内进行心电图记录。然后对兔子进行体内电生理研究，之后分离心肌细胞，通过膜片钳分析慢延迟整流电流（IKs）和动作电位特性。
与假免疫对照组相比，KCNQ1免疫的兔子QTc缩短。在程序性心室刺激时，KCNQ1免疫的兔子心室有效不应期缩短，对室性快速心律失常诱导的易感性增加。与假手术组相比，从KCNQ1免疫的兔子分离的心肌细胞动作电位时程缩短。KCNQ1免疫后IKs阶跃电流和尾电流密度增强。未观察到心脏的功能和结构变化。然后在多非利特诱导的长QT兔模型中探讨KCNQ1免疫的潜在治疗意义。KCNQ1免疫可预防多非利特诱导的QTc延长，并减轻长QT相关心律失常。
诱导KCNQ1自身免疫可通过增强IKs加速心脏复极，并增加对室性快速心律失常诱导的易感性。另一方面，针对KCNQ1的疫苗接种可改善药物诱导的QTc延长，可能在治疗上有助于增强长QT综合征的复极储备。
