Clinical characteristics and electrophysiologic properties of SCN5A variants in fever-induced Brugada syndrome

作者：Ganxiao Chen, Héctor Barajas-Martínez, Giuseppe Ciconte, Cheng‐I Wu, Michelle M. Monasky, Hao Xia, Bian Li, John A. Capra, Kai Guo, Zhonghe Zhang, Xiu Chen, Bo Yang, Hong Jiang, Gary Tse, Chloe Miu Mak, Yoshiyasu Aizawa, Michael H. Gollob, Charles Antzelevitch, Arthur A.M. Wilde, Carlo Pappone, Dan Hu · 发表于：EBioMedicine · 年份：2022 · DOI：10.1016/j.ebiom.2022.104388 · 被引用次数：12 · 研究领域：Cardiac electrophysiology and arrhythmias、Ion channel regulation and function、Cardiac Arrhythmias and Treatments

BACKGROUND: Brugada syndrome (BrS) is a severe inherited arrhythmia syndrome that can be unmasked by fever. METHODS: A multicentre clinical analysis was performed in 261 patients diagnosed with fever-induced BrS, including 198 (75.9%) and 27 (10.3%) patients who received next-generation genetic sequencing and epicardial arrhythmogenic substrate (AS) mapping, respectively. FINDINGS: In fever-induced BrS patients, pathogenic or likely pathogenic (P/LP) SCN5A variant carriers developed fever-induced BrS at a younger age, and more often in females and those of Caucasian descent. They exhibited significant electrophysical abnormalities, including a larger epicardial AS area, and more prolonged abnormal epicardial electrograms. During a median follow-up of 50.5 months (quartiles 32.5-81.5 months) after the diagnosis, major cardiac events (MCE) occurred in 27 (14.4%) patients. Patients with P/LP SCN5A variants had a higher ratio of MCE compared with the rest. Additionally, history of syncope, QRS duration, and Tpe interval could also predict an increased risk for future MCE according to univariate analysis. Multivariate analysis indicated that only P/LP SCN5A variants were independent significant predictors of MCE. Computational structural modelling showed that most variants are destabilizing, suggesting that Nav1.5 structure destabilization caused by SCN5A missense variants may contribute to fever-induced BrS. INTERPRETATION: In our cohort, P/LP SCN5A variant carriers with fever-in...