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  • Review Article
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Translation of pathophysiological mechanisms of atrial fibrosis into new diagnostic and therapeutic approaches

Nature Reviews Cardiology volume 22, pages 225–240 (2025)Cite this article

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Abstract

Atrial fibrosis is one of the main manifestations of atrial cardiomyopathy, an array of electrical, mechanical and structural alterations associated with atrial fibrillation (AF), stroke and heart failure. Atrial fibrosis can be both a cause and a consequence of AF and, once present, it accelerates the progression of AF. The pathophysiological mechanisms leading to atrial fibrosis are diverse and include stretch-induced activation of fibroblasts, systemic inflammatory processes, activation of coagulation factors and fibrofatty infiltrations. Importantly, atrial fibrosis can occur in different forms, such as reactive and replacement fibrosis. The diversity of atrial fibrosis mechanisms and patterns depends on sex, age and comorbidity profile, hampering the development of therapeutic strategies. In addition, the presence and severity of comorbidities often change over time, potentially causing temporal changes in the mechanisms underlying atrial fibrosis development. This Review summarizes the latest knowledge on the molecular and cellular mechanisms of atrial fibrosis, its association with comorbidities and the sex-related differences. We describe how the various patterns of atrial fibrosis translate into electrophysiological mechanisms that promote AF, and critically appraise the clinical applicability and limitations of diagnostic tools to quantify atrial fibrosis. Finally, we provide an overview of the newest therapeutic interventions under development and discuss relevant knowledge gaps related to the association between clinical manifestations and pathological mechanisms of atrial fibrosis and to the translation of this knowledge to a clinical setting.

Key points

  • Atrial fibrosis occurs as reactive or reparative fibrosis, which differ in their underlying mechanisms; the epicardial layer of the atrium shows a higher degree of fibrosis than the endocardial bundle network.

  • Activated fibroblasts are the main cell type involved in collagen synthesis, but sensing of environmental factors that lead to atrial fibrosis involves other cell types, such as cardiomyocytes, adipocytes and immune cells.

  • Diffuse, reactive fibrosis on the millimetre scale results in discontinuous electrical conduction, longitudinal dissociation and endocardial–epicardial dissociation of electrical activity during atrial fibrillation; larger areas of patchy fibrosis (at the centimetre scale) are more likely to anchor macro re-entrant circuits.

  • Neither late gadolinium enhancement cardiac MRI nor low-voltage areas show a convincingly reliable and reproducible association with atrial fibrosis; therefore, the term ‘atrial fibrosis’ to refer to enhanced late gadolinium enhancement or low-voltage areas might lead to misinterpretation and should be avoided.

  • Angiotensin-converting enzyme inhibitors, angiotensin II receptor inhibitors and aldosterone receptor blockers are of limited use in preventing atrial collagen deposition, particularly if used independently from indications for cardiovascular diseases such as hypertension or heart failure.

  • MicroRNAs and mRNAs encapsulated in lipid nanoparticles are currently being explored as potential approaches for antifibrotic treatment; the advantage of these strategies is the high level of specificity for targeting molecular pathways.

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Fig. 1: Association between human atrial fibrotic phenotype and clinical traits in patients undergoing cardiac surgery.
Fig. 2: Spatial distribution of atrial fibrosis.
Fig. 3: Paracrine signalling regulating fibroblasts.
Fig. 4: Patterns of fibrosis and arrhythmogenicity.
Fig. 5: Potential therapeutic interventions for atrial fibrosis.

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Acknowledgements

The authors’ work was supported by the Netherlands Heart Foundation (CVON2014-09, RACE V (Reappraisal of Atrial Fibrillation: Interaction between hyperCoagulability, Electrical remodeling, and Vascular Destabilisation in the Progression of AF), and grant number 01-002-2022-0118, EmbRACE (Electro-Molecular Basis and the theRapeutic management of Atrial Cardiomyopathy, fibrillation and associated outcomEs)) and the European Union (ITN Network Personalize AF (Personalized Therapies for Atrial Fibrillation: a translational network), grant number 860974; CATCH ME (Characterizing Atrial fibrillation by Translating its Causes into Health Modifiers in the Elderly), grant number 633196; MAESTRIA (Machine Learning Artificial Intelligence Early Detection Stroke Atrial Fibrillation), grant number 965286; and REPAIR (Restoring cardiac mechanical function by polymeric artificial muscular tissue), grant number 952166).

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Authors and Affiliations

  1. Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands

    Ulrich Schotten & Sander Verheule

  2. Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, The Netherlands

    Ulrich Schotten

  3. Department of Cardiology and Intensive Care Medicine, St. Vincenz Hospital, Paderborn, Germany

    Andreas Goette

  4. Otto-von-Guericke University, Medical Faculty, Magdeburg, Germany

    Andreas Goette

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  1. Ulrich Schotten
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Correspondence to Ulrich Schotten.

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Competing interests

U.S. received consultancy fees or honoraria from Università della Svizzera Italiana (Switzerland), Roche Diagnostics, and YourRhythmics BV, a spin-off company of the Maastricht University (Netherlands); and is cofounder and shareholder of YourRhythmics BV. A.G. received speaker fees from Abbott, Astra Zeneca, Bayer Health Care, Berlin Chemie, Biotronik, Boehringer Ingelheim, BMS/Pfizer, Boston Scientific, Daiichi-Sankyo, Medtronic, Menarini, Omeicos, Sanofi-Aventis and Viofor. S.V. declares no competing interests.

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Schotten, U., Goette, A. & Verheule, S. Translation of pathophysiological mechanisms of atrial fibrosis into new diagnostic and therapeutic approaches. Nat Rev Cardiol 22, 225–240 (2025). https://doi.org/10.1038/s41569-024-01088-w

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