Arrhythmogenic left atrial cellular electrophysiology in a murine genetic long QT syndrome model

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 (Delta KPQ 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 Delta KPQ mice, whereas I-NaP was unchanged. AP duration (APD) was prolonged over all frequencies in Delta KPQ 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 Delta KPQ (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 mu M for I-NaP) in Delta KPQ myocytes. At 10 mu M, 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). 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.