目的:患有Brugada综合征(BrS)的患者易患危及生命的心律失常。由于难以捉摸的心电图(ECG)特征通常需要非常规的ECG导联放置和药物挑战来检测,因此诊断是具有挑战性的。尽管NaV1.5钠通道功能障碍是BrS公认的病理生理机制,只有25%的患者有可检测的SCN5A变异体.鉴于自身免疫在心脏离子通道功能中的新兴作用,本研究探讨了抗NaV1.5自身抗体在BrS患者中的存在和潜在影响.
方法:使用表达重组NaV1.5蛋白的工程化HEK293A细胞,来自50例BrS患者和50例对照的血浆通过蛋白质印迹筛选抗NaV1.5自身抗体,具有免疫沉淀和免疫荧光证实的特异性。在细胞模型中并通过在野生型小鼠中注射血浆来评估这些自身抗体对钠电流密度的影响及其病理生理学作用。
结果:在90%的BrS患者中检测到抗NaV1.5自身抗体,与6%的对照组,曲线下的诊断面积为.92,特异性为94%,敏感性为90%。这些发现在不同的患者人口统计学上是一致的,并且与SCN5A突变状态无关。电生理学研究表明,钠电流密度显着降低。值得注意的是,注射BrS血浆的小鼠显示Brugada样心电图异常,支持这些自身抗体的致病作用。
结论:该研究表明,大多数BrS患者中存在抗NaV1.5自身抗体,表明该综合征的免疫致病成分超出了遗传易感性。这些自身抗体,可以作为额外的诊断标记,也促使重新考虑BrS的潜在机制,它们在野生型小鼠中诱导该综合征的ECG特征中的作用证明了这一点。这些发现鼓励了更全面的诊断方法,并指出了治疗研究的新途径。
OBJECTIVE: Patients suffering from Brugada syndrome (BrS) are predisposed to life-threatening cardiac arrhythmias. Diagnosis is challenging due to the elusive electrocardiographic (ECG) signature that often requires unconventional ECG lead placement and drug challenges to be detected. Although
NaV1.5 sodium channel dysfunction is a recognized pathophysiological mechanism in BrS, only 25% of patients have detectable SCN5A variants. Given the emerging role of autoimmunity in cardiac ion channel function, this study explores the presence and potential impact of anti-NaV1.5 autoantibodies in BrS patients.
METHODS: Using engineered HEK293A cells expressing recombinant
NaV1.5 protein, plasma from 50 BrS patients and 50 controls was screened for anti-
NaV1.5 autoantibodies via western blot, with specificity confirmed by immunoprecipitation and immunofluorescence. The impact of these autoantibodies on sodium current density and their pathophysiological effects were assessed in cellular models and through plasma injection in wild-type mice.
RESULTS: Anti-
NaV1.5 autoantibodies were detected in 90% of BrS patients vs. 6% of controls, yielding a diagnostic area under the curve of .92, with 94% specificity and 90% sensitivity. These findings were consistent across varying patient demographics and independent of SCN5A mutation status. Electrophysiological studies demonstrated a significant reduction specifically in sodium current density. Notably, mice injected with BrS plasma showed Brugada-like ECG abnormalities, supporting the pathogenic role of these autoantibodies.
CONCLUSIONS: The study demonstrates the presence of anti-
NaV1.5 autoantibodies in the majority of BrS patients, suggesting an immunopathogenic component of the syndrome beyond genetic predispositions. These autoantibodies, which could serve as additional diagnostic markers, also prompt reconsideration of the underlying mechanisms of BrS, as evidenced by their role in inducing the ECG signature of the syndrome in wild-type mice. These findings encourage a more comprehensive diagnostic approach and point to new avenues for therapeutic research.