Basic Cardiovascular Sciences 2025  /  Poster Session and Reception 3  /  NaV1.5 Autoantibodies as a Common Autoimmune Driver of Sudden Cardiac Death
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American Heart Association

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Final ID: Fri046

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

Abstract Body: 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.
  • Anastasia, Luigi  ( Vita-Salute San Raffaele University , MIlan , Italy )
  • Tarantino, Adriana  ( IRCCS Policlinico San Donato , San Donato Milanese , Italy )
  • Melgari, Dario  ( IRCCS Policlinico San Donato , San Donato Milanese , Italy )
  • Piccoli, Marco  ( IRCCS Policlinico San Donato , San Donato Milanese , Italy )
  • Ciconte, Giuseppe  ( IRCCS Policlinico San Donato , San Donato Milanese , Italy )
  • Frosio, Anthony  ( IRCCS Policlinico San Donato , San Donato Milanese , Italy )
  • Giavaldi, Aurora  ( IRCCS Policlinico San Donato , San Donato Milanese , Italy )
  • Micaglio, Emanuele  ( IRCCS Policlinico San Donato , San Donato Milanese , Italy )
  • Calamaio, Serena  ( IRCCS Policlinico San Donato , San Donato Milanese , Italy )
  • Cirillo, Federica  ( IRCCS Policlinico San Donato , San Donato Milanese , Italy )
  • Creo, Pasquale  ( IRCCS Policlinico San Donato , San Donato Milanese , Italy )
  • Castoldi, Valerio  ( Vita-Salute San Raffaele University , MIlan , Italy )
  • Prevostini, Rachele  ( IRCCS Policlinico San Donato , San Donato Milanese , Italy )
  • De Toma, Alessandro  ( ASST Santi Paolo & Carlo , Milan , Italy )
  • Boccellino, Antonio  ( IRCCS Policlinico San Donato , San Donato Milanese , Italy )
  • Negro, Gabriele  ( IRCCS Policlinico San Donato , San Donato Milanese , Italy )
  • Giannelli, Luigi  ( IRCCS Policlinico San Donato , San Donato Milanese , Italy )
  • Calovic, Zarko  ( IRCCS Policlinico San Donato , San Donato Milanese , Italy )
  • Leocani, Letizia  ( Vita-Salute San Raffaele University , MIlan , Italy )
  • De Toma, Domenico  ( Policlinico di Monza , Monza , Italy )
  • Rivolta, Ilaria  ( University of Milano-Bicocca , Monza , Italy )
  • Pappone, Carlo  ( IRCCS Policlinico San Donato , San Donato Milanese , Italy )
    • Author Disclosures:
    Luigi Anastasia: DO NOT have relevant financial relationships | Federica Cirillo: DO NOT have relevant financial relationships | Pasquale Creo: No Answer | Valerio Castoldi: No Answer | Rachele Prevostini: No Answer | Alessandro De Toma: No Answer | Antonio Boccellino: DO NOT have relevant financial relationships | Gabriele Negro: No Answer | Luigi Giannelli: No Answer | Zarko Calovic: No Answer | Letizia Leocani: No Answer | Adriana Tarantino: DO NOT have relevant financial relationships | Domenico De Toma: No Answer | Ilaria Rivolta: No Answer | Carlo Pappone: No Answer | Dario Melgari: No Answer | Marco Piccoli: DO NOT have relevant financial relationships | Giuseppe Ciconte: No Answer | Anthony Frosio: No Answer | Aurora Giavaldi: No Answer | Emanuele Micaglio: No Answer | Serena Calamaio: No Answer
Meeting Info:

Basic Cardiovascular Sciences 2025

2025

Baltimore, Maryland

Session Info:

Poster Session and Reception 3

Friday, 07/25/2025 , 04:30PM - 07:00PM

Poster Session and Reception

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