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Int J Cardiol. 2018 Sep 1;266:128-132. doi: 10.1016/j.ijcard.2017.09.010. Epub 2018 Apr 30.

SCN5A mutation type and topology are associated with the risk of ventricular arrhythmia by sodium channel blockers.

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Heart Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address:
Heart Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Department of Cardiology, Clínic Thorax Institute, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain.
Cardiovascular Genetics Center, Department of Medicine, Montreal Heart Institute and Université de Montréal, Canada.
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Heart Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia.



Ventricular fibrillation in patients with Brugada syndrome (BrS) is often initiated by premature ventricular contractions (PVCs). Presence of SCN5A mutation increases the risk of PVCs upon exposure to sodium channel blockers (SCB) in patients with baseline type-1 ECG. In patients without baseline type-1 ECG, however, the effect of SCN5A mutation on the risk of SCB-induced arrhythmia is unknown. We aimed to establish whether presence/absence, type, and topology of SCN5A mutation correlates with PVC occurrence during ajmaline infusion.


We investigated 416 patients without baseline type-1 ECG who underwent ajmaline testing and SCN5A mutation analysis. A SCN5A mutation was identified in 88 patients (S+). Ajmaline-induced PVCs occurred more often in patients with non-missense mutations (Snon-missense) or missense mutations in transmembrane or pore regions of SCN5A-encoded channel protein (Smissense-TP) than patients with missense mutations in intra-/extracellular channel regions (Smissense-IE) and patients without SCN5A mutation (S-) (29%, 24%, 9%, and 3%, respectively; P<0.001). The proportion of patients with ajmaline-induced BrS was similar in different mutation groups but lower in S- (71% Snon-missense, 63% Smissense-TP, 70% Smissense-IE, and 34% S-; P<0.001). Logistic regression indicated Snon-missense and Smissense-TP as predictors of ajmaline-induced PVCs.


SCN5A mutation is associated with an increased risk of drug-induced ventricular arrhythmia in patients without baseline type-1 ECG. In particular, Snon-missense and Smissense-TP are at high risk.


Ajmaline; Arrhythmia; Brugada syndrome; Mutation; PVC; SCN5A

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