TY - JOUR
T1 - Clinical characteristics and electrophysiologic properties of SCN5A variants in fever-induced Brugada syndrome
AU - Chen, Gan Xiao
AU - Barajas-Martínez, Hector
AU - Ciconte, Giuseppe
AU - Wu, Cheng I.
AU - Monasky, Michelle M.
AU - Xia, Hao
AU - Li, Bian
AU - Capra, John A.
AU - Guo, Kai
AU - Zhang, Zhong He
AU - Chen, Xiu
AU - Yang, Bo
AU - Jiang, Hong
AU - Tse, Gary
AU - Mak, Chloe Miu
AU - Aizawa, Yoshiyasu
AU - Gollob, Michael H.
AU - Antzelevitch, Charles
AU - Wilde, Arthur A.M.
AU - Pappone, Carlo
AU - Hu, Dan
N1 - Funding Information: The authors are grateful to Bo Cheng from Renmin Hospital of Wuhan University, China for technical assistance. The current work was supported by the National Natural Science Foundation Project of China (Nos. 82270332 & 81670304 ), The Fundamental Research Funds for the Central Universities of China - Independent Research Project of Wuhan University (No. 2042022kf1217 ) from China; the National Institutes of Health of USA [ NIH R56 (HL47678) , NIH R01 (HL138103) , and NIH R01 (HL152201) ], the W. W. Smith Charitable Trust and the Wistar and Martha Morris Fund , Sharpe-Strumia Research Foundation , the American Heart Association Postdoctoral Fellowship ( 20POST35220002 ) from United States; the Netherlands CardioVascular Research Initiative : the Dutch Heart Foundation , Dutch Federation of University Medical Centers , the Netherlands Organisation for Health Research and Development , and the Royal Netherlands Academy of Sciences (PREDICT2) from the Netherlands. Publisher Copyright: © 2022 The Authors
PY - 2023/1
Y1 - 2023/1
N2 - 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-induced BrS are more prevalent among patients of Caucasian descent, females, and younger patients. These patients exhibit aggressive electrophysiological abnormalities and worse outcome, which warrants closer monitoring and more urgent management of fever. Funding: None.
AB - 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-induced BrS are more prevalent among patients of Caucasian descent, females, and younger patients. These patients exhibit aggressive electrophysiological abnormalities and worse outcome, which warrants closer monitoring and more urgent management of fever. Funding: None.
KW - Brugada syndrome
KW - Fever
KW - Genetics
KW - Sudden cardiac death
KW - Ventricular arrhythmias
UR - http://www.scopus.com/inward/record.url?scp=85143733865&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.ebiom.2022.104388
DO - https://doi.org/10.1016/j.ebiom.2022.104388
M3 - Article
C2 - 36516610
SN - 2352-3964
VL - 87
JO - eBioMedicine
JF - eBioMedicine
M1 - 104388
ER -