Selective blockade of microRNA-31-5p−calcitonin receptor interaction reverses established atrial fibrosis and atrial arrhythmia burden
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is promoted by atrial fibrosis, a form of structural remodelling for which effective therapies are lacking. MicroRNA-31-5p (miR-31-5p), an aging-associated, atrial-enriched microRNA, has been linked to AF, but its role in atrial fibrosis is unknown. Here we show that atrial fibroblasts from patients with persistent AF exhibit increased miR-31-5p expression and reduced expression of the calcitonin receptor (CTR, encoded by CALCR). MiR-31-5p directly represses CTR and promotes pro-fibrotic fibroblast responses, whereas its inhibition restores CTR expression. Fibroblast-specific overexpression of miR-31 in mice reduces atrial CTR expression, increases atrial fibrosis and enhances arrhythmia susceptibility. Selective disruption of miR-31-5p-CALCR binding using a locked nucleic acid target site blocker restores atrial CTR expression, prevents fibrosis progression and reduces arrhythmia burden. In mice with established atrial remodeling, this strategy promotes fibrosis regression, identifying the miR-31-5p-CTR axis as a potential therapeutic target in AF.
Authors
- Xander H.T. Wehrens (ORCID: https://orcid.org/0000-0001-5044-672X)
- Svetlana N. Reilly (ORCID: https://orcid.org/0000-0003-1231-1239)
- Craig A. Lygate (ORCID: https://orcid.org/0000-0001-6079-0284)
- Rana A Sayeed (ORCID: https://orcid.org/0000-0002-2887-1874)
- Keith M. Channon (ORCID: https://orcid.org/0000-0002-1043-4342)
- Antonios Kourliouros (ORCID: https://orcid.org/0000-0002-1032-379X)
- Chi Him Kendrick Yiu (ORCID: https://orcid.org/0000-0001-8070-972X)
- Nicholas Walcot (ORCID: https://orcid.org/0000-0002-2583-6467)
- Benjamin Davies (ORCID: https://orcid.org/0000-0003-3623-600X)
- David A. Menassa (ORCID: https://orcid.org/0000-0002-5984-8407)
- Priya Sastry (ORCID: https://orcid.org/0000-0002-1012-1434)
- Mohit M. Hulsurkar (ORCID: https://orcid.org/0000-0003-0595-6661)
- Robia G. Pautler (ORCID: https://orcid.org/0000-0001-7952-8526)
- Stanley Nattel (ORCID: https://orcid.org/0000-0002-5565-3311)
- Lucia M. Moreira (ORCID: https://orcid.org/0000-0001-8168-1538)
- Kathryn W. Aguilar‐Agon (ORCID: https://orcid.org/0000-0003-3840-0731)
- Satadru K. Lahiri (ORCID: https://orcid.org/0000-0001-9502-1530)
- Roddy Hiram (ORCID: https://orcid.org/0000-0003-4291-8314)
- Paul D. Robinson (ORCID: https://orcid.org/0000-0001-7397-105X)
- Vivek Kumar Srivastava (ORCID: https://orcid.org/0000-0003-0503-1108)
- Aaron M. Johnston (ORCID: https://orcid.org/0000-0002-7836-4221)
- Mozhdeh Mehdizadeh
- Shakil Farid
- Rita A. Schack
- Lorena Perez Carrillo
- Jasha Trompf*
- Shuai Zhao
- George Krasopoulos
Institutions
- Baylor College of Medicine (US)
- Montreal Heart Institute (CA)
- John Radcliffe Hospital (GB)
- British Heart Foundation (GB)
- University of Oxford (GB)
- Electrophysiology and Heart Modeling Institute (FR)
- West German Heart and Vascular Center Essen (DE)
- McGill University (CA)
- University of Duisburg-Essen (DE)
- Université de Montréal (CA)
- University of Glasgow (GB)
Publication Details
- Journal
- Nature Cardiovascular Research
- Published
- 2026-10-30
- DOI
- https://doi.org/10.1038/s44161-026-00897-1
- Primary Topic
- Cardiac Fibrosis and Remodeling
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- American Heart Association
- Heart and Stroke Foundation of Canada
- National Institute for Health and Care Research
- British Heart Foundation
- University of Oxford
- Universiteit Maastricht
- Queen's University
- BHF Centre of Research Excellence, Oxford
- National Institutes of Health
- Canadian Institutes of Health Research