Background Fever may enhance the Brugada syndrome (BrS) phenotype in some but not all patients. However, the underlying mechanism in human cardiomyocytes has not yet been clarified.
Methods Human induced pluripotent stem cell (hiPSC) lines generated from fibroblasts of three BrS patients harboring variants in SCN10A (abbreviated as BrS1) and CACNB2 (abbreviated as BrS2), SCN5A (abbreviated as BrS3) and one healthy donor (abbreviated as WT) and a site-corrected (using CRISPR/Cas9) hiPSC line of each BrS patient (abbreviated as isogenic1, isogenic2 and isogenic3) were used for differentiation into cardiomyocytes (hiPSC-CMs). Western blot, patch clamp and calcium transient analyses were carried out.
Results All 3 BrS cell lines showed a significantly reduced peak sodium current (INa) compared with isogenic or WT cells at baseline. Hyperthermia challenge (40⁰C) significantly decreased INa and enhanced arrhythmogeneity in BrS1 and BrS3 but not in BrS2 cells. Hyperthermia reduced significantly the Vmax and slightly reduced APA at 1-3 Hz BrS1 cells. However, high temperature showed no significant effect on Vmax or APA of BrS2 cells. Moreover, high temperature also decreased the Vmax of AP in BrS3 cell line. Hyperthermia showed stronger effect on Vmax in BrS3 than BrS1 and on effect on INa, AP in WT or isogenic control cells. The hyperthermia effects involved PKA reduction.
Conclusions Hyperthermia exacerbated the BrS phenotype in hiPSC-CMs carrying SCN10A and SCN5A variants, but not CACNB2 variant. Hyperthermia effects on BrS phenotype may be genotype-dependent.
