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

Abstract

The long-term prognosis of patients with a loss-of-function variant in the cardiac sodium channel gene SCN5A is unknown. 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. Probands and family members with (likely-)pathogenic SCN5A loss-of-function variants were retrospectively included. Clinical and ECG 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. We included 615 patients (349 males, 242 probands, 157 spontaneous type-1 Brugada-ECG and 111 symptomatic at baseline). During 9.5 (5.0-14.3) years follow-up, arrhythmic events occurred in 41 patients (6.7%), equating an overall event rate of 0.7%/year; 2.0%/year in symptomatic and 0.3%/year 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, also male sex and QRS prolongation were identified as predictors. Asymptomatic women with QRS <100ms did not experience arrhythmic events at follow-up. 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. Our findings may enable more tailored management strategies in patients with an SCN5A loss-of-function variant based on their individual risk profiles.