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  • Review Article
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Inflammatory signalling in atrial cardiomyocytes: a novel unifying principle in atrial fibrillation pathophysiology

Nature Reviews Cardiology volume 20, pages 145–167 (2023)Cite this article

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Abstract

Inflammation has been implicated in atrial fibrillation (AF), a very common and clinically significant cardiac rhythm disturbance, but its precise role remains poorly understood. Work performed over the past 5 years suggests that atrial cardiomyocytes have inflammatory signalling machinery — in particular, components of the NLRP3 (NACHT-, LRR- and pyrin domain-containing 3) inflammasome — that is activated in animal models and patients with AF. Furthermore, work in animal models suggests that NLRP3 inflammasome activation in atrial cardiomyocytes might be a sufficient and necessary condition for AF occurrence. In this Review, we evaluate the evidence for the role and pathophysiological significance of cardiomyocyte NLRP3 signalling in AF. We first summarize the evidence for a role of inflammation in AF and review the biochemical properties of the NLRP3 inflammasome, as defined primarily in studies of classic inflammation. We then briefly consider the broader evidence for a role of inflammatory signalling in heart disease, particularly conditions that predispose individuals to develop AF. We provide a detailed discussion of the available information about atrial cardiomyocyte NLRP3 inflammasome signalling in AF and related conditions and evaluate the possibility that similar signalling might be important in non-myocyte cardiac cells. We then review the evidence on the role of active resolution of inflammation and its potential importance in suppressing AF-related inflammatory signalling. Finally, we consider the therapeutic potential and broader implications of this new knowledge and highlight crucial questions to be addressed in future research.

Key points

  • Atrial fibrillation is the most common cardiac arrhythmia, and new insights into the pathophysiological mechanisms are required to improve the available therapeutic options.

  • Although inflammation has been thought to have a role in atrial fibrillation for ≥20 years, the precise nature of the association has proved elusive.

  • Work over the past 5 years has revealed a key role for inflammatory signalling in cardiomyocytes in atrial fibrillation development, revealing the importance of non-leukocyte cardiac cells in mediating disease-promoting cardiac inflammation.

  • The NLRP3 inflammasome in particular has been implicated in cardiomyocyte-mediated inflammatory signalling in atrial fibrillation.

  • The active resolution of inflammation is thought to be mediated by endogenous bioactive agents, which can be administered as pharmaceutical products to attenuate the development of chronic conditions such as atrial fibrillation.

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Fig. 1: Pathways involved in NLRP3 inflammasome activation.
Fig. 2: Pathways leading to NLRP3 inflammasome activation induced by comorbidities and cardiovascular risk factors.
Fig. 3: Inflammation resolution concept.
Fig. 4: Cardiomyocyte–immune cell interactions promote and maintain atrial fibrillation.

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Acknowledgements

The authors thank T. Poppenborg (Institute of Pharmacology, University Duisburg-Essen, Germany) for help with preparing the figures for initial submission and A. Saljic (Institute of Pharmacology, University Duisburg-Essen, Germany) for critical review of the tables. The authors are supported by funding from the National Institutes of Health (R01HL136389, R01HL131517, R01HL089598 and R01HL163277 to D.D.; R01HL136389, R01HL147108 and R01HL163277 to N.L.), the German Research Foundation (DFG, Do 769/4-1 to D.D.), the European Union (large-scale integrative project MAESTRIA, no. 965286 to D.D.), the Netherlands Organization for Scientific Research (NWO/ZonMW Vidi 09150171910029 to J.H.), the Montreal Heart Institute Foundation (4800 to R.H.), the Canada Foundation for Innovation (42228 to S.N. and R.H.), the Canadian Institutes of Health Research (148401 to S.N.), and the AHA (Established Investigator Award 936111 to N.L).

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Author notes

  1. These authors contributed equally: Dobromir Dobrev, Stanley Nattel.

Authors and Affiliations

  1. Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Duisburg, Germany

    Dobromir Dobrev & Stanley Nattel

  2. Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montréal, Canada

    Dobromir Dobrev, Roddy Hiram & Stanley Nattel

  3. Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX, USA

    Dobromir Dobrev & Na Li

  4. Department of Cardiology, Cardiovascular Research Institute Maastricht, Faculty of Health, Medicine, and Life Sciences, Maastricht University, Maastricht, Netherlands

    Jordi Heijman

  5. Department of Medicine, Section of Cardiovascular Research, Baylor College of Medicine, Houston, TX, USA

    Na Li

  6. Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA

    Na Li

  7. IHU LIRYC and Fondation Bordeaux Université, Bordeaux, France

    Stanley Nattel

  8. Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada

    Stanley Nattel

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Dobrev, D., Heijman, J., Hiram, R. et al. Inflammatory signalling in atrial cardiomyocytes: a novel unifying principle in atrial fibrillation pathophysiology. Nat Rev Cardiol 20, 145–167 (2023). https://doi.org/10.1038/s41569-022-00759-w

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