转移性乳腺癌中 NaV 自身抗体的心脏交叉反应性:心脏性猝死的可能诱因

Carlo Pappone, Adriana Tarantino, Dario Melgari, Marco Piccoli, Giuseppe Ciconte, Anthony Frosio, Emanuele Micaglio, Serena Calamaio, Chiara Vantellino, Federica Cirillo, Pasquale Creo, Valerio Castoldi, Rachele Prevostini, Alessandro De Toma, Antonio Boccellino, Gabriele Negro, Luigi Giannelli, Zarko Calovic, Letizia Leocani, Vincenzo Santinelli, Domenico De Toma, Ilaria Rivolta, Luigi Anastasia
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摘要

背景和目的转移性乳腺癌患者发生心脏性猝死(SCD)的风险增加,而心脏毒性治疗无法完全解释这一现象。最近的证据显示,针对 Brugada 综合征(BrS)患者心脏 NaV1.5 钠通道的自身抗体可引发心律失常并增加 SCD 风险。同样,在转移性乳腺癌患者中也发现了针对新生儿 NaV1.5 同工型的自身抗体。鉴于这些 NaV1.5 同工型之间的高度同源性,我们研究了这些自身抗体是否会与心脏同工型发生交叉反应,从而可能导致这一人群中的 SCD。方法使用表达 NaV1.5 蛋白的 HEK293A 细胞对 20 名转移性乳腺癌患者的血浆进行抗 NaV1.5 自身抗体分析,然后进行 Western 印迹。在细胞模型和野生型小鼠中评估了这些自身抗体对钠电流密度的影响,并在输注血浆后进行了心电图监测。结果15份来自转移性乳腺癌患者的血浆样本检测出抗NaV1.5自身抗体阳性,显著降低了体外钠电流密度。注射了这些血浆样本的小鼠出现了严重的心律失常和类似布鲁格达综合征的心电图模式。与此相反,不含自身抗体或去除了 IgG 的血浆样本没有显示出这种效应,这突出了 IgG 在钠电流降低中的作用,并证实了自身抗体的致病性。结论这项研究表明,转移性乳腺癌患者体内的抗 NaV1.5 自身抗体可与心脏 NaV1.5 同工酶发生交叉反应,从而可能导致致命性心律失常。这些发现凸显了这一人群 SCD 高发的新机制,并建议应谨慎使用钠阻滞剂疗法,以避免加剧这一风险。目前迫切需要可靠的诊断测试和靶向疗法来降低受影响患者的 SCD 风险。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Cardiac Cross-Reactivity of NaV Autoantibodies in Metastatic Breast Cancer: A Possible Trigger for Sudden Cardiac Death
Background and Aims Patients with metastatic breast cancer have an increased risk of sudden cardiac death (SCD) that cannot be fully explained by cardiotoxic treatments. Recent evidence shows that autoantibodies targeting the cardiac NaV1.5 sodium channel in Brugada syndrome (BrS) can trigger arrhythmias and elevate SCD risk. Similarly, autoantibodies against the neonatal NaV1.5 isoform have been found in metastatic breast cancer patients. Given the high homology between these NaV1.5 isoforms, we investigated whether these autoantibodies cross-react with the cardiac isoform, potentially contributing to SCD in this population. Methods Plasma from twenty metastatic breast cancer patients was analyzed for anti-NaV1.5 autoantibodies using HEK293A cells expressing the NaV1.5 protein, followed by Western blotting. The effects of these autoantibodies on sodium current density were assessed in cellular models and wild-type mice, with electrocardiographic monitoring after plasma infusion. Results Fifteen plasma samples from metastatic breast cancer patients tested positive for anti-NaV1.5 autoantibodies, significantly reducing sodium current density in vitro. Mice injected with these plasma samples developed severe arrhythmias and a Brugada syndrome-like ECG pattern. In contrast, plasma samples either without the autoantibodies or with IgG depletion showed no such effects, underscoring the role of IgG in sodium current reduction and confirming the pathogenicity of the autoantibodies. Conclusions This study demonstrates that anti-NaV1.5 autoantibodies in metastatic breast cancer patients can cross-react with the cardiac NaV1.5 isoform, potentially leading to fatal arrhythmias. These findings highlight a novel mechanism for the high SCD rate in this population and suggest that therapies involving sodium blockers should be used with caution to avoid exacerbating this risk. Reliable diagnostic tests and targeted therapies are urgently needed to mitigate SCD risk in affected patients.
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