Department of Cardiology and Cardiovascular Research Institute, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China.
Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, USA; Lankenau Heart Institute, Wynnewood, Pennsylvania, USA; Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
J Am Coll Cardiol. 2021 Oct 19;78(16):1603-1617. doi: 10.1016/j.jacc.2021.08.024.
Two major forms of inherited J-wave syndrome (JWS) are recognized: early repolarization syndrome (ERS) and Brugada syndrome (BrS).
This study sought to assess the distinct features between patients with ERS and BrS carrying pathogenic variants in SCN5A.
Clinical evaluation and next-generation sequencing were performed in 262 probands with BrS and 104 with ERS. Nav1.5 and Kv4.3 channels were studied with the use of patch-clamp techniques. A computational model was used 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 patients with BrS. More than 2 pathogenic SCN5A variants were found in 5 probands. These patients displayed longer PR intervals and QRS duration and experienced more major arrhythmia events (MAE) compared with 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 the inward sodium current (INa) when SCN5A was expressed alone, but when coexpressed with KCND3 it reduced peak INa by 44.52% and increased the transient outward potassium current (Ito) by 106.81%.
These findings point to SCN5A as a major susceptibility gene in ERS as much as it is in BrS, whereas the lower SCN5A+ ratio in ERS indicates the difference in underlying electrophysiology. These findings also identify the first case of fever-induced ERS and demonstrate a critical role of Ito in JWS and a higher risk for MAE in JWS probands carrying multiple pathogenic variants in SCN5A.
两种主要形式的遗传性 J 波综合征（JWS）已被识别：早期复极综合征（ERS）和 Brugada 综合征（BrS）。
本研究旨在评估携带 SCN5A 致病性变异的 ERS 和 BrS 患者的特征。
对 262 例 BrS 和 104 例 ERS 先证者进行临床评估和下一代测序。使用膜片钳技术研究 Nav1.5 和 Kv4.3 通道。使用计算模型研究蛋白质结构。
ERS 中的 SCN5A+阳性率明显低于 BrS（9.62% vs 22.90%；P=0.004）。诊断为 ERS 的患者的 QRS 和 QTc 较 BrS 患者短。5 例先证者发现超过 2 种致病性 SCN5A 变异。与携带单一致病性变异的患者相比，这些患者的 PR 间期和 QRS 持续时间更长，且经历更多的主要心律失常事件（MAE）。在发热诱发的 ERS 患者中检测到的 SCN5A-L1412F 导致完全失活，使 Nav1.5 结构不稳定，并表现出显性负效应，在发热状态下更为明显。单独表达 SCN5A 时，ERS 相关的 SCN5A-G452C 不会改变内向钠电流（INa），但与 KCND3 共表达时，它会使峰值 INa 减少 44.52%，并使瞬时外向钾电流（Ito）增加 106.81%。
这些发现表明 SCN5A 是 ERS 与 BrS 一样的主要易感基因，而 ERS 中的 SCN5A+比例较低表明其潜在电生理学的差异。这些发现还确定了首例发热诱发的 ERS，并证明 Ito 在 JWS 中的关键作用，以及在携带 SCN5A 多个致病性变异的 JWS 先证者中 MAE 的风险更高。
