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

Abstract Background and Aims SCN5A-E1784K (c.5350G&amp;gt;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 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. Results 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 personalisation of management and has the potential to guide preventative therapies.

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Publication Details

Journal
EP Europace
Published
2026-05-09
DOI
https://doi.org/10.1093/europace/euag113
Primary Topic
Cardiac electrophysiology and arrhythmias
Type
article
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article

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

Yanushi D. Wijeyeratne, Martijn Bos, Julien Barc, Martin Borggrefe et al.
EP Europace
Cardiac electrophysiology and arrhythmias
article

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

Yanushi D. Wijeyeratne, Martijn Bos, Julien Barc, Martin Borggrefe, Jean‐Jacques Schott, Pascal McKeown, Richard Redon, I Denjoy, Joseph Galvin, JEAN BAPTISTE GOURRAUD, Stephen P Page, David J. Tester, Michael John Ackerman, Hariharan Raju, Matteo Pedrazzini, Federica Dagradi, Kazuhiro Takahashi, A.J.L. Muir, Edward Petzer, Chiara Alberio, Seiko Ohno, Wataru Shimizu, Taisuke Ishikawa, Carla Haglund-Turnquist, Martina Muggenthaler, Vincent Probst, Minoru Horie, Michael Papadakis, Peter J Schwartz, Sanjay Sharma, Michael W T Tanck, Naomasa Makita, Takeshi Aiba, Christian Veltmann, Elijah R Behr, Lia Crotti, Dan M Roden
article en

Abstract

Abstract Background and Aims SCN5A-E1784K (c.5350G&amp;gt;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 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. Results 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 personalisation of management and has the potential to guide preventative therapies.

EP Europace
Queen's University Belfast (GB), Heart Rhythm Society (US), Belfast Health and Social Care Trust (GB), Centre National de la Recherche Scientifique (FR), Inserm (FR), Shiga University of Medical Science (JP), University of Bremen (DE), Vanderbilt University (US), Université Paris Cité (FR), Heidelberg University (DE), Leeds Teaching Hospitals NHS Trust (GB), Royal Devon & Exeter NHS Foundation Trust (GB), St George’s University Hospitals NHS Foundation Trust (GB), Mater Misericordiae University Hospital (IE), Assistance Publique – Hôpitaux de Paris (FR), National Cerebral and Cardiovascular Center (JP), Dartford And Gravesham NHS Trust (GB), Keiyukai Sapporo Hospital (JP), IRCCS Istituto Auxologico Italiano (IT), Institut du Thorax (FR), Hôpital Bichat-Claude-Bernard (FR), Public Health Service of Amsterdam (NL), Aizawa Hospital (JP), University Medical Centre Mannheim (DE), Toujinkai Hospital (JP), University of Milano-Bicocca (IT), Nippon Medical School (JP), University of Amsterdam (NL), Nantes Université (FR), Macquarie University (AU)
Good health and well-being
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Cardiac electrophysiology and arrhythmias
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