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We explored the hypothesis that increased cholinergic tone exerts its proarrhythmic effects in Brugada syndrome (BrS) through increasing dispersion of transmural repolarization in patients with spontaneous and drug-induced BrS.BrS and supraventricular tachycardia patients were studied after deploying an Ensite Array in the right ventricular outflow tract and a Cardima catheter in the great cardiac vein to record endo and epicardial signals, respectively. S1-S2 restitution curves from the right ventricular apex were conducted at baseline and after edrophonium challenge to promote increased cholinergic tone. The local unipolar electrograms were then analyzed to study transmural conduction and repolarization dynamics.The study included 8 BrS patients (5 men:3 women; mean age, 56 years) and 8 controls patients with supraventricular tachycardia (5 men:3 women; mean age, 48 years). Electrophysiological studies in controls demonstrated shorter endocardial than epicardial right ventricular activation times (mean difference: 26 ms; P<0.001). In contrast, patients with BrS showed longer endocardial than epicardial activation time (mean difference: −15 ms; P=0.001). BrS hearts, compared with controls, showed significantly larger transmural gradients in their activation recovery intervals (mean intervals, 20.5 versus 3.5 ms; P<0.01), with longer endocardial than epicardial activation recovery intervals. Edrophonium challenge increased such gradients in both controls (to a mean of 16 ms [P<0.001]) and BrS (to 29.7 ms; P<0.001). However, these were attributable to epicardial and endocardial activation recovery interval prolongations in control and BrS hearts, respectively. Dynamic changes in repolarization gradients were also observed across the BrS right ventricular wall in BrS.Differential contributions of conduction and repolarization were identified in BrS which critically modulated transmural dispersion of repolarization with significant cholinergic effects only identified in the patients with BrS. This has important implications for explaining the proarrhythmic effects of increased vagal tone in BrS, as well as evaluating autonomic modulation and epicardial ablation as therapeutic strategies.