title: Arrhythmogenic left atrial cellular electrophysiology in a murine genetic long QT syndrome model.
abstract: OBJECTIVE
  Increasing evidence indicates that congenital long QT syndromes (LQTSs) promote atrial fibrillation. The atrial action potential (AP) has a short plateau, and whether LQTS atrial cardiomyocytes generate triggered activity via early afterdepolarizations (EADs) is unclear. Atrial cellular arrhythmia mechanisms have not been defined in congenital LQTS. Therefore, we studied atrial cardiomyocyte electrophysiology in mice with an LQTS3 SCN5A inactivation-impairing mutation (ΔKPQ heterozygotes).
  
  
  RESULTS
  Peak and late Na(+) current (I(NaP) and I(NaL)) were measured with whole-cell patch clamp in left atrial (LA) cardiomyocytes. APs were recorded in multicellular LA preparations with floating microelectrodes. I(NaL) was increased by 110% in LA cardiomyocytes of ΔKPQ mice, whereas I(NaP) was unchanged. AP duration (APD) was prolonged over all frequencies in ΔKPQ mice, but particularly at lower frequencies [e.g. APD(90) at 0.5 Hz: 197 ± 8 ms vs. wild-type (WT) 82 ± 2 ms, P< 0.001]. EADs occurred at 0.5 Hz in 10/18 ΔKPQ (56%) vs. 1/10 WT (10%) atria (P< 0.05). EADs immediately preceded premature APs in other LA regions, suggesting triggered activity. Ranolazine preferentially inhibited I(NaL) (50% inhibitory concentration: 12.5 vs. 151.8 µM for I(NaP)) in ΔKPQ myocytes. At 10 µM, ranolazine shortened APD (e.g. APD(90) at 0.5 Hz to 122 ± 4 ms, P= 0.01) without changing APD in WT and suppressed EAD occurrence and triggered activity (from 10/18 to 1/9 preparations, 11%, P< 0.05).
  
  
  CONCLUSIONS
  This study implicates increased I(NaL) in excessive atrial APD prolongation and arrhythmic EAD occurrence in a congenital LQTS3 mouse model. Our observations provide the first direct demonstration of atrial EADs and triggered activity in a genetically defined animal model of human LQTS and have potential clinically-relevant mechanistic and therapeutic implications.
authors.affiliation: Department of Medicine, Montreal Heart Institute Research Centre and Université de Montréal, 5000 Belanger Street East, Montreal, QC, Canada H1T 1C8.
authors.forename: Marc D
authors.initials: MD
authors.lastname: Lemoine
authors.forename: James Elber
authors.initials: JE
authors.lastname: Duverger
authors.forename: Patrice
authors.initials: P
authors.lastname: Naud
authors.forename: Denis
authors.initials: D
authors.lastname: Chartier
authors.forename: Xiao Yan
authors.initials: XY
authors.lastname: Qi
authors.forename: Philippe
authors.initials: P
authors.lastname: Comtois
authors.forename: Larissa
authors.initials: L
authors.lastname: Fabritz
authors.forename: Paulus
authors.initials: P
authors.lastname: Kirchhof
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
mesh_terms: D000083:Acetanilides / Q000494:pharmacology; D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology*; D004195:Disease Models, Animal; D006325:Heart Atria / Q000503:physiopathology*; D008133:Long QT Syndrome / Q000503:physiopathology*; D008297:Male; D051379:Mice; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010879:Piperazines / Q000494:pharmacology; D000069458:Ranolazine; D015222:Sodium Channels / Q000235:genetics / Q000502:physiology
chemical_list: D000083:Acetanilides; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010879:Piperazines; C568320:SCN5A protein, human; C568321:Scn5a protein, mouse; D015222:Sodium Channels; D000069458:Ranolazine