Safety profile of ajmaline testing in Brugada syndrome: influence of SCNA5 mutations

Background Sodium channel blocker (SCB) testing is a key diagnostic tool for Brugada syndrome (BrS), but it carries a non-negligible risk of complications. Whether genetic background, particularly SCN5A mutation status, influences the risk profile has not been systematically assessed in large series. Methods We retrospectively analyzed consecutive patients who underwent an ajmaline or flecainide challenge at our centers between 1994 and 2025. Clinical data, ECG parameters, genetic results, and complications during testing were systematically collected. Logistic regression was used to identify predictors of complications, with a particular focus on SCN5A mutation status. Results A total of 3192 patients were included, of whom 409 (13%) carried a pathogenic or likely pathogenic SCN5A variant, 90 (3%) had a variant of uncertain significance, and 2693 (84%) were non-carriers. Sustained ventricular tachycardia (SVT) was rare (0.47% overall) but markedly more frequent in the mutated group (3.5%) compared to almost no cases in other groups. Ventricular fibrillation (VF) occurred in four patients (0.12% overall): two in the mutated group (0.49%) and two in the VUS group (2.3%), with no cases in the non-mutated group. In univariate analysis, younger age, SCN5A mutation, prolonged baseline PR and QRS intervals, and a positive[JBG1] test response were significantly associated with complications. In multivariate analysis, only SCN5A mutation status (OR 30.5 [5.81–564], p=0.001), longer PR interval (OR 1.02 [1.01–1.03], p=0.003), and prolonged QRS duration (OR 1.04 [1.01–1.07], p=0.006) remained independent predictors. Importantly, SCN5A carriers had a markedly higher risk of ventricular fibrillation compared with non-carriers. Conclusion Our data corroborate and refine existing evidence: SCN5A mutation carriers are at increased risk of a positive drug test, conduction slowing, and arrhythmic complications. In contrast, non-mutation carriers have an extremely low risk of complication during the test.