Knock-in gain-of-function sodium channel mutation prolongs atrial action potentials and alters atrial vulnerability.

Blana A, Kaese S, Fortmüller L, Laakmann S, Damke D, van Bragt K, Eckstein J, Piccini I, Kirchhefer U, Nattel S, Breithardt G, Carmeliet P, Carmeliet E, Schotten U, Verheule S, Kirchhof P, Fabritz L

Abstract

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.The purpose of this study was to determine the mechanisms underlying atrial pathology in LQTS.In mice with a heterozygous knock-in long QT syndrome type 3 (LQT3) mutant of the cardiac Na(+) channel (?KPQ-SCN5A) and wild-type (WT) littermates, atrial size, function, and electrophysiologic parameters were measured in intact Langendorff-perfused hearts, and histologic analysis was performed.Atrial action potential duration, effective refractory period, cycle length, and PQ interval were prolonged in ?KPQ-SCN5A hearts (all P < .05). Flecainide (1 ?M) reversed atrial action potential duration prolongation and induced postrepolarization refractoriness (P < .05). Arrhythmias were infrequent during regular rapid atrial rate in both WT and ?KPQ-SCN5A but were inducible in 15 (38%) of 40 ?KPQ-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 ?KPQ-SCN5A but in 0 (0%) of 6 WT mice (P < .05). Atrial diameter was increased by nearly 10% in ?KPQ-SCN5A mice > 5 months old without increase in fibrotic tissue.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.