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  • Review Article
  • Published:

Autoimmune channelopathies as a novel mechanism in cardiac arrhythmias

This article has been updated

Key Points

  • Nearly 70% of cases of life-threatening arrhythmias or sudden cardiac death (SCD) in individuals with a structurally normal heart are unexplained, even after molecular autopsy

  • Autoimmune cardiac channelopathies are a novel and increasingly recognized mechanism of cardiac arrhythmias, which are mediated by circulating autoantibodies interfering with the function of various cardiac ion channels

  • By targeting calcium, potassium, or sodium channels, arrhythmogenic autoantibodies induce substantial, but potentially reversible, electrophysiological changes predisposing to the development of conduction disturbances and life-threatening tachyarrhythmias

  • Pathogenic autoantibodies against ion channels are detectable in patients with manifest autoimmune diseases and apparently healthy individuals, and might have a causal role in a subset of unexplained arrhythmias or SCDs

  • Specific autoantibody testing in patients with 'idiopathic' rhythm disturbances could lead to novel treatment opportunities, primarily immunomodulatory therapies

Abstract

Cardiac arrhythmias confer a considerable burden of morbidity and mortality in industrialized countries. Although coronary artery disease and heart failure are the prevalent causes of cardiac arrest, in 5–15% of patients, structural abnormalities at autopsy are absent. In a proportion of these patients, mutations in genes encoding cardiac ion channels are documented (inherited channelopathies), but, to date, the molecular autopsy is negative in nearly 70% of patients. Emerging evidence indicates that autoimmunity is involved in the pathogenesis of cardiac arrhythmias. In particular, several arrhythmogenic autoantibodies targeting specific calcium, potassium, or sodium channels in the heart have been identified. Experimental and clinical studies demonstrate that these autoantibodies can promote conduction disturbances and life-threatening tachyarrhythmias by inducing substantial electrophysiological changes. In this Review, we propose the term 'autoimmune cardiac channelopathies' to define this novel pathogenic mechanism of cardiac arrhythmias, which could be more frequent and clinically relevant than previously appreciated. Indeed, pathogenic autoantibodies against ion channels are detectable not only in patients with manifest autoimmune disease, but also in apparently healthy individuals, which suggests a causal role in some cases of unexplained arrhythmias and cardiac arrest. Considering this possibility and performing specific testing in patients with 'idiopathic' rhythm disturbances could create novel treatment opportunities.

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Figure 1: Molecular targets and changes of ionic currents in autoimmune cardiac channelopathies.
Figure 2: Molecular and electrophysiological mechanisms of bradyarrhythmias induced by anti-ion channel autoantibodies.
Figure 3: Molecular and electrophysiological mechanisms of tachyarrhythmias induced by anti-ion channel autoantibodies.

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Change history

  • 06 July 2017

    The version of this article initially published online included the following errors. In Box 1, phase 3 of the action potential was described as involving 'depolarization' instead of 'repolarization'. In the legend for Figure 1, IKs was defined as the 'rapid' component instead of the 'slow' component of the delayed rectifier K+ current. In the study from reference 115, the rabbits were described as being immunized with a peptide 'against' instead of 'from' the KCNQ1 K+ channel. Finally, there were errors with the references at the end of Box 1, and in the main text on pages 10 and 12. All these errors have been corrected for the print, HTML, and PDF versions of the article.

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Acknowledgements

The authors were supported by award number I01BX002137 from Biomedical Laboratory Research and Development Service of Veterans Affairs Office of Research and Development to M.B., and by FAS-Salute ToRSADE project (FAS Salute 2014, Regione Toscana).

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P.E.L. researched data for the article and wrote the manuscript. All the authors discussed the content of the article and reviewed/edited the manuscript before submission. P.L.C., F.L.-P., and M.B. are co-senior authors of this manuscript

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Correspondence to Pietro Enea Lazzerini.

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Lazzerini, P., Capecchi, P., Laghi-Pasini, F. et al. Autoimmune channelopathies as a novel mechanism in cardiac arrhythmias. Nat Rev Cardiol 14, 521–535 (2017). https://doi.org/10.1038/nrcardio.2017.61

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