Nonmodifiable Risk Factors Predict Outcomes in Brugada Syndrome.

Background: Risk stratification in Brugada syndrome (BrS) is based on the occurrence of dynamic factors, such as unexplained syncope and documentation of spontaneous type 1 pattern. At odds with other channelopathies, the role of nonmodifiable risk factors such as sex or genetics remains uncertain.

Objectives: This study aims to identify nonmodifiable risk factors for the occurrence of life-threatening arrhythmic events (LAEs) and define their clinical utility.

Methods: Clinical and genetic data from consecutive, unrelated Italian patients with Brugada syndrome screened on the sodium voltage-gated channel alpha subunit 5 (SCN5A) gene and 3 pivotal single-nucleotide variations (formerly single-nucleotide polymorphisms) associated with BrS (rs11708996, rs10428132, and rs9388451) were analyzed using multivariable Cox proportional hazards model.

Results: In 2,182 unrelated patients with BrS (81% males; median age at diagnosis: 41.6 years [Q1-Q3: 33.4-50.3 years]), male sex (HR: 3.6; 95% CI: 1.9-6.9; P = 0.0001), missense SCN5A mutations in BrS-enriched domains (HR: 2.3; 95% CI: 1.2-4.3; P = 0.008), nonmissense SCN5A mutations (HR: 3.2; 95% CI: 1.8-5.7; P < 0.001), and polygenic risk score for BrS (HR: 1.3; 95% CI: 1.0-1.6; P = 0.041) were all independently associated with a significantly higher risk of a first LAE since birth. Based on these results, we derived the nonmodifiable risk of each patient with BrS, and the division of nonmodifiable risk into tertiles identified 3 distinct risk profiles. In an analysis at follow-up, nonmodifiable risk was independently associated with LAE at follow-up (HR: 1.8; 95% CI: 1.1-2.7; P = 0.014), alongside classical predictors including: history of LAE before diagnosis (HR: 13.8; 95% CI: 8.1-23.7; P < 0.0001), history of unexplained syncope before diagnosis (HR: 4.1; 95% CI: 2.4-6.8; P < 0.0001), and spontaneous type 1 pattern at diagnosis (HR: 2.1; 95% CI: 1.2-3.8; P = 0.010). The model was internally validated, and we derived the equation permitting to calculate the granular 5-year risk of experiencing an LAE at follow-up for each patient with BrS, which may be used to facilitate clinical decision-making.

Conclusions: Our data show that male sex, type of SCN5A mutation, and polygenic risk score for BrS define the nonmodifiable risk of each patient with BrS. Nonmodifiable risk is independently associated with LAE, regardless of symptoms or pattern type.