Autoimmune Atrial Fibrillation.

Area of Science:

• Cardiology
• Immunology
• Electrophysiology

Background:

• Atrial fibrillation (AF) is the most common cardiac arrhythmia, with idiopathic AF occurring in ~3% of individuals.
• Emerging research suggests a role for autoantibodies in cardiac arrhythmias.
• This study investigates autoantibodies targeting cardiac ion channels as a cause of unexplained AF.

Purpose of the Study:

• To explore the potential role of autoantibodies against cardiac ion channels in unexplained atrial fibrillation.
• To identify specific autoantibodies associated with AF and elucidate their functional impact.

Main Methods:

• Peptide microarray screening of patient samples to detect autoantibodies.
• Comparison of patients with unexplained AF (n=51) against age- and sex-matched controls (n=37).
• In vitro (patch clamp on cardiomyocytes) and in vivo (mouse immunization model) functional validation of identified autoantibodies.

Main Results:

• A common autoantibody response against K_ir3.4 protein was identified in patients with AF, even preceding clinical diagnosis.
• Anti-K_ir3.4 IgG from AF patients shortened atrial action potentials and enhanced the I_KACh current in human cardiomyocytes.
• K_ir3.4 autoimmunity in mice reduced atrial effective refractory period and increased AF susceptibility by 2.8-fold.

Conclusions:

• This study presents the first evidence of an autoimmune pathogenesis for AF mediated by K_ir3.4 autoantibodies.
• Autoimmune targeting of K_ir3.4 represents a novel mechanism underlying unexplained atrial fibrillation.
• Findings open new avenues for understanding and potentially treating AF.