Distinct Features of Probands With Early Repolarization and Brugada Syndromes Carrying SCN5A Pathogenic Variants.
Distinct Features of Probands With Early Repolarization and Brugada Syndromes Carrying SCN5A Pathogenic Variants.
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早期复极先证者和携带SCN5A致病变异的Brugada综合征的显著特征。
DOI：
10.1016/j.jacc.2021.08.024
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发表时间：
2021-10-19
影响因子：
24
通讯作者：
Hu, Dan
中科院分区：
文献类型：
--
作者：
Zhang, Zhong-He;Barajas-Martinez, Hector;Xia, Hao;Li, Bian;Capra, John A.;Clatot, Jerome;Chen, Gan-Xiao;Chen, Xiu;Yang, Bo;Jiang, Hong;Tse, Gary;Aizawa, Yoshiyasu;Gollob, Michael H.;Scheinman, Melvin;Antzelevitch, Charles;Hu, Dan
Two major forms of inherited J wave syndrome (JWS) are recognized: early repolarization syndrome (ERS) and Brugada syndrome (BrS). We sought to assess the distinct features between ERS and BrS patients carrying pathogenic variants in SCN5A. Clinical evaluation and next-generation sequencing were performed in 262 BrS and 104 ERS probands. Nav1.5 and Kv4.3 channels were studied using patch-clamp techniques. A computational model was employed to investigate the protein structure. The SCN5A+ yield in ERS was significantly lower than in BrS (9.62% vs. 22.90%, p=0.004). Patients diagnosed with ERS displayed shorter QRS and QTc than BrS patients. More than 2 pathogenic SCN5A variants were found in five probands. These patients displayed longer PR intervals, QRS duration and experienced more major arrhythmia events (MAE) compared to those carrying only a single pathogenic variant. SCN5A-L1412F, detected in a fever-induced ERS patient, led to total loss-of-function, destabilized the Nav1.5 structure, and showed a dominant-negative effect, which was accentuated during a febrile state. ERS-related SCN5A-G452C did not alter INa when SCN5A was expressed alone, but reduced peak INa by 44.52% and increased Ito by 106.81% when co-expressed with KCND3. Our findings point to SCN5A as a major susceptibility gene in ERS as it is in BrS.whereas the lower SCN5A+ ratio in ERS indicates the difference in underlying electrophysiology. We also identify the first case of fever-induced ERS, demonstrate a critical role of Ito in JWS and a higher risk for MAE in JWS probands carrying multiple pathogenic variants in SCN5A. We compared clinical and electrophysiologic characteristics of 104 ERS and 262 BrS probands carrying pathogenic variants in SCN5A. Ten new variants were uncovered in ERS and two in BrS. The yield of SCN5A variants in ERS is significantly lower than in BrS. ERS patients displayed shorter QRS and QTc. Five probands with multiple SCN5A pathogenic variants displayed longer PR interval, QRS duration, and experienced more major arrhythmia events. Our findings point to SCN5A+ as a major susceptibility gene in ERS as in BrS, identify the first fever-induced ERS case, and demonstrate a critical role for Ito in JWS.
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影响因子：
5.5
作者：
Burashnikov, Elena;Pfeiffer, Ryan;Barajas-Martinez, Hector;Delpon, Eva;Hu, Dan;Desai, Mayurika;Borggrefe, Martin;Haeissaguerre, Michel;Kanter, Ronald;Pollevick, Guido D.;Guerchicoff, Alejandra;Laino, Ruben;Marieb, Mark;Nademanee, Koonlawee;Nam, Gi-Byoung;Robles, Roberto;Schimpf, Rainer;Stapleton, Dwight D.;Viskin, Sami;Winters, Stephen;Wolpert, Christian;Zimmern, Samuel;Veltmann, Christian;Antzelevitch, Charles
通讯作者：
Antzelevitch, Charles
影响因子：
20.1
作者：
Bezzina, Connie R.;Lahrouchi, Najim;Priori, Silvia G.
通讯作者：
Priori, Silvia G.
影响因子：
5.5
作者：
Hu, Dan;Viskin, Sami;Antzelevitch, Chares
通讯作者：
Antzelevitch, Chares
利多卡因诱导的布鲁格达综合征表型与心脏钠通道的新型双突变有关。
影响因子：
20.1
作者：
Barajas-Martinez, Hector M.;Hu, Dan;Cordeiro, Jonathan M.;Wu, Yuesheng;Kovacs, Richard J.;Meltser, Henry;Kui, Hong;Elena, Burashnikov;Brugada, Ramon;Antzelevitch, Charles;Dumaine, Robert
通讯作者：
Dumaine, Robert
影响因子：
10.8
作者：
Keller, DI;Rougier, JS;Abriel, H
通讯作者：
Abriel, H