Abstract Fri046: NaV1.5 Autoantibodies as a Common Autoimmune Driver of Sudden Cardiac Death

Sudden cardiac death (SCD) frequently occurs in patients without structural heart disease or known genetic predispositions. While inherited channelopathies have historically been implicated, growing evidence points to autoimmunity as a central contributor. We recently demonstrated that autoantibodies targeting the cardiac NaV1.5 sodium channel are pathogenic in Brugada syndrome (BrS). Separately, several metastatic cancers are known to overexpress the immunogenic neonatal NaV1.5 isoform, potentially triggering an autoimmune response. This raises the possibility of a unifying autoimmune mechanism linking disparate diseases to increased arrhythmic risk. To investigate this hypothesis, plasma from patients with BrS, different metastatic cancers, and healthy controls was screened for NaV1.5 autoantibodies using Western blotting and immunofluorescence on HEK293A cells expressing NaV1.5. Electrophysiological studies assessed sodium current density reductions. Wild-type mice injected with patient plasma were monitored for arrhythmias via ECG. IgG depletion experiments were performed to confirm antibody specificity. NaV1.5 autoantibodies were detected in the majority of BrS and metastatic cancer patients. These autoantibodies significantly reduced sodium current density in vitro. In mice, injection of autoantibody-positive plasma induced arrhythmias and Brugada-like ECG abnormalities, effects that were abolished after IgG depletion. The overexpression of the neonatal NaV1.5 isoform in cancer likely initiates the autoimmune response, which cross-reacts with cardiac NaV1.5 channels, compromising electrophysiological stability. Our findings establish NaV1.5 autoantibodies as a shared autoimmune mechanism contributing to SCD across distinct diseases. These results broaden the concept of autoimmune channelopathies, highlighting the need for diagnostic and therapeutic strategies targeting NaV1.5 autoantibodies to prevent arrhythmic events in susceptible populations.