Ventricular conduction is a marker for arrhythmic risk in SCN5A-E1784K overlap sodium channel disease

EP Europace Journal

11 May 2026

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Abstract

AbstractAims

SCN5A-E1784K (c.5350G>A) is the most common variant associated with the long QT (LQTS) and Brugada syndromes (BrS). It can manifest variably as LQTS, BrS, and/or conduction disorders. This presents a challenge for risk stratification. We aimed to describe clinical and ECG characteristics and identify risk markers that associate with arrhythmic events.

Methods and results

We undertook a retrospective observational multicentre study of a large cohort of 231 subjects with SCN5A-E1784K from Europe, USA, and Japan. Comprehensive demographic and clinical data, including initial presentation ECG and follow-up, were collected. ‘Lethal events’ were defined as sudden death, non-fatal cardiac arrest, and documented sustained VT or VF. ‘Cardiac events’ were defined as arrhythmic syncope plus any lethal events. Clinical characteristics and ECG parameters corrected for age were investigated for association with lethal and/or cardiac events. Fourteen (6%) subjects experienced a lethal event and 45 (19%) a cardiac event. PR interval and QRS duration were associated with lethal and cardiac events. In multivariable models, both PR interval and QRS duration were associated with lethal events, but only QRS duration was associated with cardiac events. Only age-corrected QRS (rQRS) was associated with lethal and cardiac event-free survival from birth after correction for multiple testing.

Conclusion

Ventricular myocardial conduction appears likely to play a role in the risk of arrhythmic events in patients with SCN5A-E1784K. This provides an important opportunity for the personalization of management and has the potential to guide preventative therapies.