Autoimmune Atrial Fibrillation

Author:

Maguy Ange1ORCID,Mahendran Yuvaraj2,Tardif Jean-Claude3ORCID,Busseuil David3,Li Jin45ORCID

Affiliation:

1. Institute of Physiology, University of Bern, Switzerland (A.M.).

2. PEPperPRINT GmbH, Heidelberg, Germany (Y.M.).

3. Montreal Heart Institute, Université de Montréal, Canada (J.-C.T., D.B.).

4. Department of Cardiology, University Heart Center, University Hospital Zurich, University of Zurich, Switzerland (J.L.).

5. Center for Translational and Experimental Cardiology, Department of Cardiology, University Hospital Zurich, University of Zurich, Schlieren, Switzerland (J.L.).

Abstract

BACKGROUND: 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. METHODS: 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. RESULTS: A common autoantibody response against K ir 3.4 protein was detected in patients with AF and even before the development of clinically apparent AF. K ir 3.4 protein forms a heterotetramer that underlies the cardiac acetylcholine-activated inwardly rectifying K + current, I KACh . Functional studies on human induced pluripotent stem cell–derived atrial cardiomyocytes showed that anti-K ir 3.4 IgG purified from patients with AF shortened action potentials and enhanced the constitutive form of I KACh , both key mediators of AF. To establish a causal relationship, we developed a mouse model of K ir 3.4 autoimmunity. Electrophysiological study in K ir 3.4-immunized mice showed that K ir 3.4 autoantibodies significantly reduced atrial effective refractory period and predisposed animals to a 2.8-fold increased susceptibility to AF. CONCLUSIONS: To our knowledge, this is the first report of an autoimmune pathogenesis of AF with direct evidence of K ir 3.4 autoantibody-mediated AF.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

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