EDITORIAL COMMENTARY SCN5A mutations in atrial fibrillation Ahmad S. Amin, MD,* Zahurul A. Bhuiyan, MD, PhD † From the *Department of Experimental Cardiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, and † Laboratoire de Génétique Moléculaire, Service de Génétique Médicale, CHUV, Lausanne, Switzerland. Atrial fibrillation, characterized by rapid and irregular atrial firing, is the most prevalent clinically relevant arrhyth- mia. It is a major cause of morbidity and mortality because it increases the risk for stroke and heart failure and compels the use of drugs that not only affect atrial electrophysiology but also exert proarrhythmic effects on ventricular electrical activity. 1–3 Atrial fibrillation also can occur in individuals with no risk factors (“lone atrial fibrillation”). Mutations in genes encoding cardiac sodium or potassium channels re- cently have been linked to lone atrial fibrillation. 4 Virtually all mutations in genes encoding cardiac potassium channels increase the outward potassium currents and thereby pro- mote atrial fibrillation by shortening the effective refractory period (ERP) and facilitating the maintenance of reentrant circuits. In contrast, mutations in SCN5A, the gene encoding the pore-forming ion-conducting -subunit of the cardiac sodium channel Na v 1.5, may promote atrial fibrillation by different mechanisms. The cardiac sodium channel conducts the inward sodium current I Na , which is responsible for depolarization of atrial and ventricular myocytes and thereby cardiac excitability and electrical conduction velocity. Normally, Na + channels close (“inactivate”) rapidly after depolarization and there- fore conduct no current during the subsequent repolariza- tion. Both loss-of-function and gain-of-function mutations in SCN5A are linked to lone atrial fibrillation. 5–7 Loss-of- function mutations are suggested to increase risk of atrial fibrillation by decreasing I Na and thereby slowing intraatrial conduction. 5 This is supported by the high prevalence of atrial fibrillation, accompanied by prolonged intraatrial con- duction times, in Brugada syndrome, a disease also linked to loss-of-function mutations in SCN5A. 8 In contrast, little is known about the mechanism by which SCN5A gain-of- function mutations cause atrial fibrillation. 6,7 Traditionally, SCN5A gain-of-function mutations are associated with con- genital long QT syndrome type 3 (LQT3), a disease char- acterized by QT-interval prolongation, torsades de pointes (TdP) ventricular tachycardia, and ventricular fibrillation, leading to syncope and sudden death. 4 LQT3 patients are also at increased risk for atrial fibrillation. 9,10 Gain-of-func- tion mutations are speculated to promote atrial fibrillation by increasing I Na , and thereby atrial excitability, through two different mechanisms: (1) by delaying repolarization, thereby triggering early afterdepolarizations (EADs) through reactivation of L-type Ca 2+ channels; or (2) by enhancing Na + entry into atrial myocytes between two subsequent action potentials, leading to delayed afterdepo- larizations. 6,7 In this issue of Heart Rhythm, Blana et al 11 describe the effects of a classic LQT3-linked mutation (deletion of amino acids 1505–1507 [KPQ] of Na v 1.5; KPQ mutation) on atrial electrophysiology and structure of Langendorff- perfused hearts from mice heterozygous for a knock-in of the KPQ mutation. 11 This mutation has been previously found to delay cardiac repolarization by disrupting Na + channel inactivation and thereby enabling persistent Na + entry (persistent I Na ) during repolarization. 12 Lower spon- taneous firing rates, prolonged action potential duration (APD), and increased ERP were found in the atria of KPQ-SCN5A mice compared to wild-type mice. More- over, increasing the cycle length induced further atrial APD prolongation in KPQ-SCN5A mice but not in wild-type mice. These findings are in agreement with QT shortening at faster heart rates in patients with the KPQ mutation 13 and with rate-dependent reduction of persistent I Na through KPQ-SCN5A channels at faster stimulation rates in vitro. 14 Taken together, these data suggest that the KPQ mutation affects atrial and ventricular electrophysiology in a similar manner. Of note, Blana et al found no differences in intraatrial conduction velocities between wild-type and KPQ-SCN5A mice. Increased ERP in combination with unchanged conduction is not expected to promote reentry and atrial fibrillation risk. Indeed, without extrastimulation, atrial tachyarrhythmias were infrequently observed in both mouse genotypes. However, rapid alterations in atrial rate, as achieved by repetitive high-rate burst pacing with inter- mittent pauses, provoked EADs and atrial tachyarrhythmias in KPQ-SCN5A mice. EADs initiating atrial tachyarrhyth- mias occurred particularly after the transition from rapid pacing to spontaneous rhythm when the cycle length and Address reprint requests and correspondence: Dr. Zahurul A. Bhuiyan, Laboratoire de Génétique Moléculaire, Service de Génétique Médicale, CHUV, Falaises 1, CH 1011 Lausanne, Switzerland. E-mail address: Z.A.Bhuiyan@chuv.ch. 1547-5271/$ -see front matter © 2010 Heart Rhythm Society. All rights reserved. doi:10.1016/j.hrthm.2010.09.012