Genetic variants associated with ventricular arrhythmias during ajmaline test in Brugada syndrome

Abstract Background Ventricular arrhythmias (VA) occur in approximately 2-18% of patients with Brugada syndrome (BrS) undergoing sodium channel blockers (SCBs) testing. While these arrhythmias have been linked to the SCN5A gene, the impact of specific gene variants and their long-term clinical outcomes remain poorly understood. Purpose The aim of this study is to assess genotype-phenotype correlation between specific SCN5A gene variants and ajmaline induced VA during SCBs testing. Methods All consecutive patients with BrS were prospectively enrolled. Inclusion criteria were: (1) BrS diagnosis; (2) Genetic analysis for SCN5A; and (3) Recent re-classification of gene variants following current ACMG guidelines. Ajmaline testing (AJT) was performed with a standard protocol of 1 mg/kg over 5 minutes. Patients with a spontaneous type I ECG were excluded. AJT-induced VA was defined as ventricular fibrillation (VF) or sustained ventricular tachycardia (VT). The primary endpoint was VA occurrence at follow-up. Results A total of 462 patients were included (mean age at diagnosis 39.3 ± 16.7 years, 52.3% males), with 16 patients (3.4%) experiencing AJM-induced VA and 446 patients (96.5%) without AJM-induced VA. One external DC shock was required to terminate the arrhythmia in all patients with AJM-induced VA, except in 2 patients requiring three shocks and multiple shocks, respectively. The latter patient eventually underwent a veno-arterial extracorporeal membrane oxygenator placement to restore sinus rhythm. An ICD was implanted in all patients with VA during AJM. Patients experiencing AJM-induced VA were younger [27.4 years vs. 39.4 years, p=0.03], had a higher incidence of SCD in the family [7 patients (43.8%) vs. 60 patients (13.5%), p=0.004], personal history of aborted SCD [5 patients (31.2%) vs 14 patients (3.1%), p<0.001], longer PQ interval [192.0 ms vs 162.2 ms, p<0.001], longer QRS interval [110.0 ms vs 98.8 ms, p=0.016]. Patients with AJM-induced VA more frequently had a pathogenic/likely pathogenic (P/LP) variant in SCN5A compared to the rest of the cohort [8 patients (50.0%) vs 74 patients (16.6%), p=0.003], Figure 1. A total of 4 different P/LP SCN5A variants were identified in AJM-induced VA patients, all in the pore region. Three patients had the c.2632C>T variant and were all members of the same family. Another three patients had the c.4719C>T variant; two patients were related (mother and daughter), and one was unrelated (patient with refractory VF and ECMO placement). Each of the other two patients was a carrier of one of the remaining variants. At a median follow-up of 109.2 months, AJM-induced VA patients experienced more VA compared with the remaining cohort [8 patients (50.0%) vs. 30 patients (6.7%), p<0.001]. Conclusions In conclusion, AJM-induced VA in BrS can be associated with specific SCN5A gene variants and is associated with a higher long-term arrhythmic risk. AJM might be avoided in patients with high-risk variants.Figure 1