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.