title: Ventricular repolarization time, location of pacing stimulus and current pulse amplitude conspire to determine arrhythmogenicity in mice.
abstract: In this study, we investigate the impact of altered action potential durations (APD) on ventricular repolarization time and proarrhythmia in mice with and without genetic deletion of the K+-channel-interacting protein 2 (KChIP2-/-and WT respectively). Moreover, we examine the interrelationship between the dispersion of repolarization time and current pulse amplitude in provoking ventricular arrhythmia.
  
  
  
  Intracardiac pacing in anesthetized mice determined refractory periods and proarrhythmia susceptibility. Regional activation time (AT), APD and repolarization time (=AT + APD) were measured in isolated hearts using floating microelectrodes.
  
  
  
  Proarrhythmia in WT and KChIP2-/-was not sensitive to changes in refractory periods. Action potentials were longer in KChIP2-/-hearts compared to WT hearts. Isolated WT hearts had large apico-basal dispersion of repolarization time, whereas hearts from KChIP2-/-mice had large left-to-right ventricular dispersion of repolarization time. Pacing from the right ventricle in KChIP2-/-mice in vivo revealed significant lower current pulse amplitudes needed to induce arrhythmias in these mice.
  
  
  
  Large heterogeneity of repolarization time is proarrhythmic when pacing is delivered from the location of earlier repolarization time. Ventricular repolarization time, location of the pacing stimulus and the amplitude of the stimulating current pulse are critical parameters underlying arrhythmia vulnerability.
authors.affiliation: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: T
authors.initials: T
authors.lastname: Speerschneider
authors.affiliation: Department of Veterinary Clinical and Animal Science, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: S
authors.initials: S
authors.lastname: Grubb
authors.affiliation: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: S P
authors.initials: SP
authors.lastname: Olesen
authors.affiliation: Department of Veterinary Clinical and Animal Science, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: K
authors.initials: K
authors.lastname: Calloe
authors.affiliation: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: M B
authors.initials: MB
authors.lastname: Thomsen
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D004594:Electrophysiology; D006352:Heart Ventricles / Q000503:physiopathology*; D051605:Kv Channel-Interacting Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: C496755:Kcnip2 protein, mouse; D051605:Kv Channel-Interacting Proteins
keywords: KChIP2; dispersion of action potential duration; fibrillation threshold; floating microelectrode technique; proarrhythmia mechanisms