Autoimmune Atrial Fibrillation.

Abstract

Atrial fibrillation (AF) is by far the most common cardiac arrhythmia. In about 3% of individuals, AF develops as a primary disorder without any identifiable trigger (idiopathic or historically termed lone AF). In line with the emerging field of autoantibody-related cardiac arrhythmias, the objective of this study was to explore whether autoantibodies targeting cardiac ion channels can underlie unexplained AF. Peptide microarray was used to screen patient samples for autoantibodies. We compared patients with unexplained AF (n=37 pre-existent AF; n=14 incident AF on follow-up) to age- and sex-matched controls (n=37). Electrophysiological properties of the identified autoantibody were then tested in vitro with the patch clamp technique and in vivo with an experimental mouse model of immunization. A common autoantibody response against K_ir3.4 protein was detected in patients with AF and even before the development of clinically apparent AF. K_ir3.4 protein forms a heterotetramer that underlies the cardiac acetylcholine-activated inwardly rectifying K⁺ current, <i>I</i>_KACh. Functional studies on human induced pluripotent stem cell-derived atrial cardiomyocytes showed that anti-K_ir3.4 IgG purified from patients with AF shortened action potentials and enhanced the constitutive form of <i>I</i>_KACh, both key mediators of AF. To establish a causal relationship, we developed a mouse model of K_ir3.4 autoimmunity. Electrophysiological study in K_ir3.4-immunized mice showed that K_ir3.4 autoantibodies significantly reduced atrial effective refractory period and predisposed animals to a 2.8-fold increased susceptibility to AF. To our knowledge, this is the first report of an autoimmune pathogenesis of AF with direct evidence of K_ir3.4 autoantibody-mediated AF.