Backgrounds: Brugada syndrome (BrS) is an inherited and rare cardiac arrhythmogenic disease associated with an increased risk of ventricular fibrillation (VF) and sudden cardiac death (SCD). Inflammation can cause malignant ventricular arrhythmias. However, few studies explored the roles inflammation in BrS and its underlying mechanisms.

Objectives: The aim of study is to investigate whether inflammation can exacerbate the phenotypic changes of BrS and which mechanism underlies the effects inflammation on BrS.

Methods: Human induced stem cell derived cardiomyocytes (hiPSC-CMs) generated from two healthy donors (D1 and D2) and one BrS-patient with SCN5A-polymorphism (c.3148G>A) and an isogenic control hiPS cell line were used. Lipopolysaccharide (LPS, 2 ng/ml for 6 h) was applied to simulate inflammation in hiPSC-CMs. Patch-clamp measurements were carried out to measure changes in the action potentials (APs), sodium channel currents and gating kinetics.

Results: The Nav1.5 expression, peak sodium channel currents (I_Na) and maximal depolarization velocity (V_max) of APs in cardiomyocytes from the BrS-patient were reduced compared to that in wild-type and isogenic control cells. LPS treatment exacerbated the phenotypic changes of BrS (reduction of SCN5A protein level and peak I_Na) and further increased levels of autophagy in hiPSC-CMs from the BrS-patient. Inhibition of autophagy before LPS treatment increased the expression of Nav1.5, peak sodium currents and V_max of APs in BrS-hiPSC-CMs. LPS treatment also exacerbated the reduction of phosphorylation levels of PI3K/Akt/mTOR signaling pathway in BrS cell line. IGF-1 treatment, an inhibitory of autophagy, reduced autophagy levels and increased the expression of Nav1.5, peak sodium currents and V_max of APs in BrS-hiPSC-CMs in presence of LPS.

Conclusions: LPS could exacerbate the phenotypic changes of BrS by further activating autophagy via inhibiting PI3K/Akt/mTOR signaling pathway; inflammation may play an important role in the pathogenesis of BrS-patients.