LAUSR

Abstract Background The ajmaline challenge is a key diagnostic tool for unmasking Brugada syndrome (BrS) in patients with suspected arrhythmogenic substrates. The relationship between genotype and phenotypical penetrance is not completely understood. Objective To investigate the correlation between carriers of a pathogenic loss of function SCN5A variant and the response to the ajmaline challenge. Methods All ambulatory ajmaline provocation tests performed between 2012 and 2021 in a tertiary care hospital were included in a retrospective registry. Only patients who had a full-disclosure electrocardiogram (ECG) available were included in the analysis. Tests were performed under continuous 12-lead ECG monitoring with leads V4-6 in a high right precordial position at the 3rd intercostal space. Ajmaline was administered by bolus injection of 10mg every 2 minutes with the maximum dose not exceeding 1mg/kg. All genetic tests performed within this cohort were extracted to correlate genetic findings with ajmaline test outcomes and ECG parameters. Only variants in SCN5A were included in this analysis as this is the only established Brugada syndrome gene according to ClinGen. Variants were scored per the ACMG criteria. In addition to patient characteristics and the indications for ajmaline testing, baseline and post-peak dose ECG parameters were extracted. Results A total of 654 patients (mean age 40.0±15.5 years; 38.2% female) where analyzed, of which 279 (42.7%) had genetic analysis available. Patients were categorized into 4 groups according to their SCN5A status and the result of their ajmaline challenge (table 1). 178 (63.8%) patients had a negative ajmaline test and did not carry a pathogenic SCN5A variant, while 46 (16.5%) had a positive drug test but had no genetic substrate. Of the 202 patients with a negative ajmaline test, 24 (11.9%) carried a likely or pathogenic (class 4 or 5) SCN5A variant. Of the 55 SCN5A positive patients, only 31 (56.4%) had a positive ajmaline test, indicating that penetrance of the Brugada syndrome phenotype is rather low in SCN5A positive patients in this cohort. No adverse events occurred during the ajmaline infusion. Patients with a class 4 or 5 mutation had a significantly longer PR interval and QRS width at baseline (154.4 ± 23.8ms vs 181.6 ± 25.2ms; p<0.001 and 93.9 ± 11.6ms vs 105.0 ± 14.6; p<0.001). Conclusion Our findings show a substantial discordance between pathogenic SCN5A carriers and penetrance of the Brugada syndrome phenotype after ajmaline challenge. This further demotes the value of the ajmaline challenge in carriers of a pathogenic SCN5A variant.Table 1