Whereas autoantibodies against ion channels have been linked to ventricular arrhythmias, research on autoimmune atrial fibrillation (AF) has focused mostly on G-protein-coupled receptors (including M2-muscarinic acetylcholine and β1-adrenergic receptors). However, Maguy et al. have now identified autoantibodies against Kir3.4 (a subunit of the acetylcholine-gated inwardly rectifying potassium channel KACh) in the blood of people with AF. Indeed, purified autoantibodies against Kir3.4 reduced action potential duration and increased the acetylcholine-activated inwardly rectifying potassium current (IKACh) in human induced pluripotent-stem-cell-derived atrial cardiomyocytes (hiPSC-aCMCs). Furthermore, the arrhythmogenic properties of these autoantibodies were confirmed in an experimental mouse model of Kir3.4 autoimmunity.
Using a peptide microarray displaying the cardiac ion channel repertoire, the researchers wanted first to establish the autoantibody profile of patients with AF. In a small human cohort, IgG autoantibodies were detected in samples from all groups: 37 patients with preexisting and unexplained AF, 37 age-matched and sex-matched healthy people (controls), and 14 people who developed AF during the mean 52 months of follow-up (pre-AF). However, one single antibody, which targeted the Kir3.4 protein (Kir3.4 autoantibody), was exclusive to people with AF (16.2%) or pre-AF (35.7%). Electrophysiology (patch-clamp) studies showed reduced atrial refractoriness in hiPSC-aCMCs treated with Kir3.4 IgG antibody purified from blood samples of patients with AF. Of note, Kir3.4 autoantibodies increased the IKACh current in hiPSC-aCMCs in the absence of muscarinic cholinergic stimulation, which suggests that they affect the constitutively active component of the IKACh current. In in vivo intracardiac electrophysiological experiments, Kir3.4-immunized mice (that is, mice producing Kir3.4 antibodies) had a significantly shorter atrial effective refractory period than that of sham-immunized mice. Furthermore, fast-pacing protocols induced AF in 8 of 10 Kir3.4-immunized mice (compared with 4 of 14 control seronegative mice), which indicates that Kir3.4 antibodies confer a 2.8 relative risk of increased susceptibility to AF in mice.
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