Background: Fever and inflammation can exacerbate the phenotype of Brugada syndrome (BrS) . However, experimental studies exploring the  underlying mechanisms of fever or inflammation  are still insufficient. NLRP3 (NOD- , LRR- and pyrin domain-containing protein 3) inflammasome is activated in infections .  This study aimed to study possible roles of NLRP3  inflammasome in effects of inflammation on the phenotype of BrS  .  

Method:  The human induced pluripotent stem cell (hiPSC) lines generated from fibroblasts of a BrS patient harboring a mutation (c.3148G>A, p.Ala1050Thr)) in SCN5A, and a healthy donor and a site-corrected (using CRISPR/ CAS9) cell line were used for differentiation of cardiomyocytes cells (hiPSC-CMs). qPCR analysis was performed to measure the mRNA level of PKC subtype (P KC α , PKC β , and PKC ε ) after treatment with LPS or LPS plus  MCC950, an NLRP3 inflammasome inhibitor. Calcium transient analysis assessed arrhythmic events in BrS-hiPSC-CMs and healthy or isogenic control.  Sodium channel currents (INa) were measured by patch clamp. 

Result: LPS reduced peak INa and increased the number of cells showing arrhythmic events in BrS-hiPSC-CMs but not in healthy donor-hiPSC-CM s , implying that LPS can exacerbate BrS phenotype. LPS increased the expression level of PKC subtypes including PKC- a , PKC- b  and PKC- e  in healthy - donor-hiPSC-CMs and isogenic cells but reduced their expression in BrS-hiPSC-CMs, suggesting involvement of protein kinase C (PKC ) in LPS effects. Strikingly, the LPS effects on PKC level could be inhibited by the NLRP3 inflammasome inhibitor  ( MCC950 ).In addition, the arrhythmia-enhancing effect of LPS was inhibited by MCC950, too. 

Conclusion:  The NLRP3 inflammasome may contribute to arrhythmogenesis relating to inflammation in BrS patient s  by reducing  PKC α , PKC β , and PKC ε . The NLRP3 inflammasome may  be a potential therapeutic target for BrS.