Long-term prognosis of patients with an SCN5A loss-of-function variant and progressive cardiac conduction disorder or Brugada syndrome

Fenna Tuijnenburg; Virginnio M Proost; Aurélie Thollet; Julien Barc; Alexander J A Groffen; Christiaan C Veerman; Saskia N van der Crabben; Vincent R van der Pas; Florence Kyndt; Sean J Jurgens; Michael W T Tanck; Pieter G Postema; J Peter van Tintelen; Connie R Bezzina; Vincent Probst; Arthur A M Wilde; Jean-Baptiste Gourraud; Ahmad S Amin

doi:10.1016/j.hrthm.2024.10.057

Long-term prognosis of patients with an SCN5A loss-of-function variant and progressive cardiac conduction disorder or Brugada syndrome

Heart Rhythm. 2024 Nov 2:S1547-5271(24)03518-5. doi: 10.1016/j.hrthm.2024.10.057. Online ahead of print.

Authors

Fenna Tuijnenburg¹, Virginnio M Proost², Aurélie Thollet³, Julien Barc³, Alexander J A Groffen⁴, Christiaan C Veerman², Saskia N van der Crabben⁴, Vincent R van der Pas⁵, Florence Kyndt³, Sean J Jurgens¹, Michael W T Tanck⁶, Pieter G Postema⁷, J Peter van Tintelen⁸, Connie R Bezzina⁹, Vincent Probst³, Arthur A M Wilde⁷, Jean-Baptiste Gourraud³, Ahmad S Amin¹⁰

Affiliations

¹ Department of Experimental Cardiology, Heart Center, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.
² Department of Clinical Cardiology, Heart Center, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.
³ Nantes Université, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, Nantes, France; European Reference Network for rare, low prevalence, and complex diseases of the heart (ERN GUARD-Heart), Amsterdam, The Netherlands.
⁴ European Reference Network for rare, low prevalence, and complex diseases of the heart (ERN GUARD-Heart), Amsterdam, The Netherlands; Department of Human Genetics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.
⁵ European Reference Network for rare, low prevalence, and complex diseases of the heart (ERN GUARD-Heart), Amsterdam, The Netherlands; Department of Cardiology, Medical Spectrum Twente, Enschede, The Netherlands.
⁶ Department of Epidemiology and Data Science, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.
⁷ Department of Clinical Cardiology, Heart Center, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands; European Reference Network for rare, low prevalence, and complex diseases of the heart (ERN GUARD-Heart), Amsterdam, The Netherlands.
⁸ European Reference Network for rare, low prevalence, and complex diseases of the heart (ERN GUARD-Heart), Amsterdam, The Netherlands; Department of Genetics, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands.
⁹ Department of Experimental Cardiology, Heart Center, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands; European Reference Network for rare, low prevalence, and complex diseases of the heart (ERN GUARD-Heart), Amsterdam, The Netherlands.
¹⁰ Department of Clinical Cardiology, Heart Center, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands; European Reference Network for rare, low prevalence, and complex diseases of the heart (ERN GUARD-Heart), Amsterdam, The Netherlands. Electronic address: a.s.amin@amsterdamumc.nl.

PMID: 39491571
DOI: 10.1016/j.hrthm.2024.10.057

Abstract

Background: The long-term prognosis of patients with a loss-of-function variant in the cardiac sodium channel gene SCN5A is unknown.

Objective: This study aimed to evaluate the long-term arrhythmic risk in patients with an SCN5A loss-of-function variant to identify predictors of arrhythmic events.

Methods: Probands and family members with (likely) pathogenic SCN5A loss-of-function variants were retrospectively included. Clinical and electrocardiographic data at baseline and last follow-up were collected. Patients with a history of cardiac arrest, sustained ventricular tachycardia, symptomatic or documented atrial tachy- or bradyarrhythmia, or arrhythmogenic syncope were categorized as symptomatic. Arrhythmic events at follow-up were defined as sudden death, aborted cardiac arrest, documented ventricular fibrillation, and/or sustained ventricular tachycardia.

Results: We included 615 patients (349 men, 242 probands, 157 with a spontaneous type 1 Brugada electrocardiogram, and 111 symptomatic at baseline). During a median follow-up of 9.5 (Q1,Q3 5.0-14.3) years, arrhythmic events occurred in 41 patients (6.7%), equating an overall event rate of 0.7%/y: 2.0%/y in symptomatic and 0.3%/y in asymptomatic patients. In the overall study population, symptoms at baseline, male sex, and QRS prolongation were identified as independent predictors of arrhythmic events. In asymptomatic patients, male sex and QRS prolongation were also identified as predictors. Asymptomatic women with QRS interval < 100 ms did not experience arrhythmic events at follow-up.

Conclusion: Key predictors of arrhythmic risk in patients with an SCN5A loss-of-function variant, regardless of a Brugada syndrome diagnosis, are symptoms at baseline, male sex, and prolonged QRS interval. Our findings may enable more tailored management strategies in patients with an SCN5A loss-of-function variant based on their individual risk profiles.

Keywords: Arrhythmic events; Brugada syndrome; Loss-of-function; Na(v)1.5; Prognosis; SCN5A.