Abstract
Conduction disorders and arrhythmias remain difficult to treat and are increasingly prevalent owing to the increasing age and body mass of the general population, because both are risk factors for arrhythmia. Many of the underlying conditions that give rise to arrhythmia — including atrial fibrillation and ventricular arrhythmia, which frequently occur in patients with acute myocardial ischaemia or heart failure — can have an inflammatory component. In the past, inflammation was viewed mostly as an epiphenomenon associated with arrhythmia; however, the recently discovered inflammatory and non-canonical functions of cardiac immune cells indicate that leukocytes can be arrhythmogenic either by altering tissue composition or by interacting with cardiomyocytes; for example, by changing their phenotype or perhaps even by directly interfering with conduction. In this Review, we discuss the electrophysiological properties of leukocytes and how these cells relate to conduction in the heart. Given the thematic parallels, we also summarize the interactions between immune cells and neural systems that influence information transfer, extrapolating findings from the field of neuroscience to the heart and defining common themes. We aim to bridge the knowledge gap between electrophysiology and immunology, to promote conceptual connections between these two fields and to explore promising opportunities for future research.
Key points
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Immune cells express various ion channels that influence their phenotypes and functions.
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Numerous leukocytes reside in the normal myocardium; their numbers, phenotypes and electrophysiological properties change in pathologies that give rise to arrhythmia, including acute myocardial infarction, sepsis, heart failure and myocarditis.
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Macrophages are the most abundant leukocytes in the heart and electrotonically couple to cardiomyocytes via connexin 43-containing gap junctions; this sink–source relationship leads to rhythmic macrophage depolarization and modulates the resting membrane potential and action potential of cardiomyocytes.
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Leukocytes might contribute to rhythm disorders either directly through altered coupling or indirectly by influencing cardiomyocytes and their environment.
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Indirect pro-arrhythmic leukocyte actions include production of cytokines and antibodies, which act on cardiomyocytes and change tissue properties by instigating fibrosis.
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Immunotherapy is an emerging option for the treatment of rhythm disorders such as atrial fibrillation.
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Acknowledgements
The authors are funded in part by the NIH (HL139598 and HL142494), the MGH Research Scholar Program and the German Research Foundation (GR 5261/1-1). J.G. is also supported by DynAge FU Berlin, the German Society for Cardiology and the German Center for Cardiovascular Research. M.Y. is also supported by the Japan Heart Foundation/Bayer Yakuhin Research Grant Abroad. We acknowledge K. Joyes (Massachusetts General Hospital, Boston, MA, USA) for editing the manuscript before submission.
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J.G., M.Y. and M.N. contributed substantially to all aspects of preparing the manuscript.
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M.N. has received funds or material research support from Alnylam, Biotronik, CSL Behring, GlycoMimetics, GSK, Medtronic, Novartis and Pfizer, as well as consulting fees from Biogen, Gimv, IFM Therapeutics, Molecular Imaging, Sigilon, Takeda and Verseau Therapeutics. The other authors declare no competing interests.
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Grune, J., Yamazoe, M. & Nahrendorf, M. Electroimmunology and cardiac arrhythmia. Nat Rev Cardiol 18, 547–564 (2021). https://doi.org/10.1038/s41569-021-00520-9
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DOI: https://doi.org/10.1038/s41569-021-00520-9
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