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Background <p>Fever or inflammation state 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.</p> Methods <p>Human induced pluripotent stem cell (hiPSC) lines generated from fibroblasts of three BrS patients harboring variants in <i>SCN10A</i> (abbreviated as BrS1) and <i>CACNB2</i> (abbreviated as BrS2), <i>SCN5A</i> (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.</p> Results <p>All 3 BrS cell lines showed a significantly reduced peak sodium current (I<sub>Na</sub>) compared with isogenic or WT cells at baseline. Hyperthermia challenge (40&#xa0;°C) significantly decreased I<sub>Na</sub> and enhanced arrhythmogeneity in BrS1 and BrS3 but not in BrS2 cells. The hyperthermia effects involved PKA reduction. The lipopolysaccharide (LPS) challenge exacerbated the phenotype in electrophysiological characteristics in all 3 BrS cell lines. ROS-Blocker abolished the LPS effects in all BrS hiPSC-CMs, while an interleukin-6 receptor blocker abolished the proarrhythmic effect of LPS in BrS1 and BrS3 hiPSC-CMs but not in hiPSC-CMs of BrS2.</p> Conclusions <p>Hyperthermia exacerbated the BrS phenotype in hiPSC-CMs carrying SCN10A and SCN5A variants, whereas LPS aggravated the phenotype in all three BrS variants through distinct mechanisms; Hyperthermia and LPS effects on BrS phenotype may be genotype-dependent.</p> Graphical abstract <p></p>

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Phenotypes in Brugada syndrome with different genotypes triggered by fever or inflammation using gene-edited iPSCs

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月1日

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  • Yingrui Li,
  • Lena Rose,
  • Timo Prädel,
  • Mandy Kleinsorge,
  • Xuehui Fan,
  • Zenghui Meng,
  • Chen Yan,
  • Rui Liu,
  • Xinhao Lei,
  • Binyi Zhao,
  • Guoqiang Yang,
  • Zhenxing Liao,
  • Hendrik Dinkel,
  • Alexandra Viktoria Busley,
  • Rujia Zhong,
  • Feng Zhang,
  • Qiang Xu,
  • Lasse Maywald,
  • Assem Aweimer,
  • Mengying Huang,
  • Alexander Moscu-Gregor,
  • Nazha Hamdani,
  • Luca Schneider,
  • Yeweynwuha Zemedi,
  • Saltanat Zhazykbayeva,
  • Alyssa Hohn,
  • Zhen Yang,
  • Lin Qiao,
  • Andreas Mügge,
  • Lukas Cyganek,
  • Xiaobo Zhou,
  • Ibrahim Akin,
  • Ibrahim El-Battrawy

摘要

Background

Fever or inflammation state 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 (40 °C) significantly decreased INa and enhanced arrhythmogeneity in BrS1 and BrS3 but not in BrS2 cells. The hyperthermia effects involved PKA reduction. The lipopolysaccharide (LPS) challenge exacerbated the phenotype in electrophysiological characteristics in all 3 BrS cell lines. ROS-Blocker abolished the LPS effects in all BrS hiPSC-CMs, while an interleukin-6 receptor blocker abolished the proarrhythmic effect of LPS in BrS1 and BrS3 hiPSC-CMs but not in hiPSC-CMs of BrS2.

Conclusions

Hyperthermia exacerbated the BrS phenotype in hiPSC-CMs carrying SCN10A and SCN5A variants, whereas LPS aggravated the phenotype in all three BrS variants through distinct mechanisms; Hyperthermia and LPS effects on BrS phenotype may be genotype-dependent.

Graphical abstract