title: Knock-in gain-of-function sodium channel mutation prolongs atrial action potentials and alters atrial vulnerability.
abstract: BACKGROUND
  Patients with long QT syndrome (LQTS) are at increased risk not only for ventricular arrhythmias but also for atrial pathology including atrial fibrillation (AF). Some patients with "lone" AF carry Na(+)-channel mutations.
  
  
  OBJECTIVE
  The purpose of this study was to determine the mechanisms underlying atrial pathology in LQTS.
  
  
  METHODS
  In mice with a heterozygous knock-in long QT syndrome type 3 (LQT3) mutant of the cardiac Na(+) channel (ΔKPQ-SCN5A) and wild-type (WT) littermates, atrial size, function, and electrophysiologic parameters were measured in intact Langendorff-perfused hearts, and histologic analysis was performed.
  
  
  RESULTS
  Atrial action potential duration, effective refractory period, cycle length, and PQ interval were prolonged in ΔKPQ-SCN5A hearts (all P < .05). Flecainide (1 μM) reversed atrial action potential duration prolongation and induced postrepolarization refractoriness (P < .05). Arrhythmias were infrequent during regular rapid atrial rate in both WT and ΔKPQ-SCN5A but were inducible in 15 (38%) of 40 ΔKPQ-SCN5A and 8 (29%) of 28 WT mice upon extrastimulation. Pacing protocols generating rapid alterations in rate provoked atrial extrasystoles and arrhythmias in 6 (66%) of 9 ΔKPQ-SCN5A but in 0 (0%) of 6 WT mice (P < .05). Atrial diameter was increased by nearly 10% in ΔKPQ-SCN5A mice > 5 months old without increase in fibrotic tissue.
  
  
  CONCLUSIONS
  Murine hearts bearing an LQT3 mutation show abnormalities in atrial electrophysiology and subtle changes in atrial dimension, including an atrial arrhythmogenic phenotype on provocation. These results support clinical data suggesting that LQTS mutations can cause atrial pathology and arrhythmogenesis and indicate that murine sodium channel LQTS models may be useful for exploring underlying mechanisms.
authors: Department of Cardiology and Angiology, University Hospital Münster, Münster, Germany.
authors: Andreas
authors: A
authors: Blana
authors: Sven
authors: S
authors: Kaese
authors: Lisa
authors: L
authors: Fortmüller
authors: Sandra
authors: S
authors: Laakmann
authors: Dierk
authors: D
authors: Damke
authors: Kelly
authors: K
authors: van Bragt
authors: Jens
authors: J
authors: Eckstein
authors: Ilaria
authors: I
authors: Piccini
authors: Uwe
authors: U
authors: Kirchhefer
authors: Stanley
authors: S
authors: Nattel
authors: Günter
authors: G
authors: Breithardt
authors: Peter
authors: P
authors: Carmeliet
authors: Edward
authors: E
authors: Carmeliet
authors: Ulrich
authors: U
authors: Schotten
authors: Sander
authors: S
authors: Verheule
authors: Paulus
authors: P
authors: Kirchhof
authors: Larissa
authors: L
authors: Fabritz
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001281:Atrial Fibrillation / Q000235:genetics / Q000503:physiopathology; D015150:Echocardiography, Doppler; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D005355:Fibrosis; D005424:Flecainide / Q000494:pharmacology; D055879:Gene Knock-In Techniques; D006325:Heart Atria / Q000473:pathology / Q000503:physiopathology*; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000235:genetics*; D008133:Long QT Syndrome / Q000235:genetics* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D020127:Recovery of Function / Q000235:genetics; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D000889:Anti-Arrhythmia Agents; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568321:Scn5a protein, mouse; D015222:Sodium Channels; D005424:Flecainide