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Lemoine, Marc D; Duverger, James Elber; Naud, Patrice; Chartier, Denis; Qi, Xiao Yan; Comtois, Philippe; Fabritz, Larissa; Kirchhof, Paulus; Nattel, Stanley
Cardiovascular research, 10/2011, Volume: 92, Issue: 1Journal Article
Aims 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). Methods and 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. APD90 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. APD90 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). Conclusion 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.
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