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

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

Journal: Stem cell research & therapy 2025;16(1):670

PMID: 41327470

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Abstract

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 (I_Na) compared with isogenic or WT cells at baseline. Hyperthermia challenge (40 °C) significantly decreased I_Na 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.

Address: First Department of Medicine, Faculty of Medicine Mannheim, University Medical Centre Mannheim (UMM), Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.; Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.; DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim, 68167, Mannheim, Germany.; First Department of Medicine, Faculty of Medicine Mannheim, University Medical Centre Mannheim (UMM), Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.; DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim, 68167, Mannheim, Germany.; Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, 37075, Göttingen, Germany.; DZHK (German Center for Cardiovascular Research), Partner Site Göttingen, 37075, Göttingen, Germany.; First Department of Medicine, Faculty of Medicine Mannheim, University Medical Centre Mannheim (UMM), Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.; Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, Sichuan, China.; DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim, 68167, Mannheim, Germany.; First Department of Medicine, Faculty of Medicine Mannheim, University Medical Centre Mannheim (UMM), Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.; First Department of Medicine, Faculty of Medicine Mannheim, University Medical Centre Mannheim (UMM), Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.; Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, Sichuan, China.; Department of Cardiology and Angiology, Bergmannsheil University Hospitals, Ruhr University of Bochum, 44789, Bochum, Germany.; Center for Human Genetics and Laboratory Medicine, Martinsried, Germany.; Department of Cellular and Translational Physiology, Institute of Physiology, Ruhr University, Bochum, Germany.; Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University, Bochum, Germany.; First Department of Medicine, Faculty of Medicine Mannheim, University Medical Centre Mannheim (UMM), Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany. [email protected].; Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, Sichuan, China. [email protected].; DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim, 68167, Mannheim, Germany. [email protected].; Department of Cardiology and Angiology, Bergmannsheil University Hospitals, Ruhr University of Bochum, 44789, Bochum, Germany.; Department of Cellular and Translational Physiology, Institute of Physiology, Ruhr University, Bochum, Germany.; Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University, Bochum, Germany.

DOI: 10.1186/s13287-025-04793-6

MeSH Terms: Humans, Brugada Syndrome, Induced Pluripotent Stem Cells, Inflammation, Phenotype, Myocytes, Cardiac, Fever, NAV1.5 Voltage-Gated Sodium Channel, Genotype, Gene Editing, NAV1.8 Voltage-Gated Sodium Channel, Cell Differentiation, Lipopolysaccharides, Cell Line, Male