Background:

 It is known that not only genetic mutations but also some environmental factors contribute to the pathogenesis of Brugada syndrome (BrS). Fever is a well-known trigger for arrhythmias in BrS-patients. Given that fever is usually an inflammatory response, we designed the study to investigate possible contributions of inflammation to arrhythmogenesis of BrS.

Methods: Human-induced stem cell-derived cardiomyocytes (hiPSC-CMs) from three healthy donors and a BrS-patient with a SCN5A mutation (c.3148G>A/p. Ala1050Thr) were treated with lipopolysaccharide (LPS, 2mg/ml for 24h) to establish a cellular model of inflammation response. Patch-clamp was used to assess the cellular electrophysiological changes.   

Results: After treatment of LPS, the peak sodium current (INa) density decreased significantly in BrS-hiPSC-CMs but not in healthy donor-hiPSC-CMs.  The voltage-dependent activation curves were not changed. However, the voltage-dependent inactivation curves were shifted to more negative potentials and the recovery from the inactivation was decelerated. Action potentials (AP) were also recorded, Vmax of AP reduced after treatment of LPS in the BrS cells, consistent with the reduction of peak INa. Strikingly, the LPS effects on INa could be prevented by N-acetyl-L-cysteine (NAC, 1 mM for 24 h), a ROS (reactive oxygen species) blocker, and mimicked by hydrogen peroxide (H2O2, 200 uM for 90 min). LPS enhanced ROS production, suggesting the involvement of ROS-signaling in the LPS-effects on INa. Moreover, a PKC blocker (chelerythrine) could inhibit ROS the effect on INa.