Knock-in gain-of-function sodium channel mutation prolongs atrial action potentials and alters atrial vulnerability.
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.
Blana
Andreas
A
Department of Cardiology and Angiology, University Hospital Münster, Münster, Germany.
Kaese
Sven
S
Fortmüller
Lisa
L
Laakmann
Sandra
S
Damke
Dierk
D
van Bragt
Kelly
K
Eckstein
Jens
J
Piccini
Ilaria
I
Kirchhefer
Uwe
U
Nattel
Stanley
S
Breithardt
Günter
G
Carmeliet
Peter
P
Carmeliet
Edward
E
Schotten
Ulrich
U
Verheule
Sander
S
Kirchhof
Paulus
P
Fabritz
Larissa
L
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*
D000889:Anti-Arrhythmia Agents; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568321:Scn5a protein, mouse; D015222:Sodium Channels; D005424:Flecainide