title: Induced KCNQ1 autoimmunity accelerates cardiac repolarization in rabbits: potential significance in arrhythmogenesis and antiarrhythmic therapy.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  The purpose of this study was to investigate the cardiac electrophysiologic effects of KCNQ1 autoantibody production induced by vaccination in a rabbit model.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montréal, Québec, Canada; Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montréal, Québec, Canada.
authors.forename: Ange
authors.initials: A
authors.lastname: Maguy
authors.affiliation: Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montréal, Québec, Canada; Institute of Biomedical Engineering and Department of Physiology, University of Montreal; Montreal, Quebec, Canada.
authors.forename: James Elber
authors.initials: JE
authors.lastname: Duverger
authors.affiliation: Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montréal, Québec, Canada.
authors.forename: Patrick
authors.initials: P
authors.lastname: Vigneault
authors.affiliation: Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montréal, Québec, Canada; Institute of Biomedical Engineering and Department of Physiology, University of Montreal; Montreal, Quebec, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Comtois
authors.affiliation: Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montréal, Québec, Canada.
authors.forename: Yanfen
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montréal, Québec, Canada.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Tardif
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Dierk
authors.initials: D
authors.lastname: Thomas
authors.affiliation: Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montréal, Québec, Canada. Electronic address: stanley.nattel@icm-mhi.org.
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D004195:Disease Models, Animal; D004452:Echocardiography; D004562:Electrocardiography; D051657:KCNQ1 Potassium Channel / Q000276:immunology*; D008133:Long QT Syndrome / Q000276:immunology* / Q000503:physiopathology*; D008297:Male; D032383:Myocytes, Cardiac / Q000276:immunology*; D018408:Patch-Clamp Techniques; D011817:Rabbits; D017180:Tachycardia, Ventricular / Q000276:immunology* / Q000503:physiopathology
chemical_list: D001323:Autoantibodies; D051657:KCNQ1 Potassium Channel
keywords: Autoimmunity; KCNQ1; Long QT syndrome; QT; Vaccination; Ventricular tachyarrhythmia