Impact of sodium channel dysfunction on arrhythmogenesis in brugada syndrome

(Background) Patients with Brugada syndrome (BS) have sodium channel (Na-Ch) SCN5A mutations (20%) as well as calcium channel (Ca-Ch) mutations (8%) that reduce the inward current and affect the action potential (AP). We investigated the affects of Na-Ch dysfunction on arrhythmogenesis in patients with BS and in experimental models of BS to understand the mechanisms of arrhythmogenesis and the origins of the ECG characteristics of BS. (Methods) Clinical study: we evaluated 80 BS patients [22 with prior ventricular fibrillation (VF) and implantation of a cardioverter defibrillator], and compared ECG parameters and recurrent VF episodes between the patients with and without SCN5A mutation. Experimental study: We created 2 experimental models of BS in 18 canine right ventricular preparations: 1) Na-Ch dysfunction model (Na-model) by using pilsicainide and pinacidil (n=11); and 2) Ca-Ch dysfunction model (Ca-model) by using verapamil (n=7). We then optically mapped multisite APs on the transmural surface of these tissue models, and analyzed the mechanisms of arrhythmogenesis and origins of characteristic BS ECGs. (Results) Clinical Study: Patients with the SCN5A mutation had longer PQ interval (202 ± 31 ms) than patients without the mutation (182 ± 31 ms, p<0.05), but no differences in ST elevation. Patients with mutation experienced earlier recurrence of VF (2.0 ± 0.9 months) than patients without mutation (12.7 ± 19 months, p<0.05). Experimental study: Transmural activation time (endocardial stimulation to epicardial breakthrough) took longer in the Na-model than in the Ca-model (50 ± 11, vs. 34 ± 10 ms, p<0.01). The Na-model also had prominent epicardial AP heterogeneity, which promoted frequent ventricular arrhythmias (VA) via phase 2 reentry (incidence of VAs: Na-model 50% vs. Ca-model 0%, p<0.01). (Conclusion) Conduction disturbances and AP heterogeneity (especially in the epicardium of the right ventricle) were the underlying causes of frequent VAs and ECG characteristics in Brugada syndrome with Na-Ch dysfunction.