Role of plakophilin-2 expression on exercise-related progression of arrhythmogenic right ventricular cardiomyopathy: a translational study
Open accessAbstract
Aims: Exercise increases arrhythmia risk and cardiomyopathy progression in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients, but the mechanisms remain unknown. We investigated transcriptomic changes caused by endurance training in mice deficient in plakophilin-2 (PKP2cKO), a desmosomal protein important for intercalated disc formation, commonly mutated in ARVC and controls. Methods and results: Exercise alone caused transcriptional downregulation of genes coding intercalated disk proteins. The changes converged with those in sedentary and in exercised PKP2cKO mice. PKP2 loss caused cardiac contractile deficit, decreased muscle mass and increased functional/transcriptomic signatures of apoptosis, despite increased fractional shortening and calcium transient amplitude in single myocytes. Exercise accelerated cardiac dysfunction, an effect dampened by pre-training animals prior to PKP2-KO. Consistent with PKP2-dependent muscle mass deficit, cardiac dimensions in human athletes carrying PKP2 mutations were reduced, compared to matched controls. Conclusions: We speculate that exercise challenges a cardiomyocyte “desmosomal reserve” which, if impaired genetically (e.g., PKP2 loss), accelerates progression of cardiomyopathy.
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Environmental modifiers such as endurance exercise, psychological stress, diet, alcohol, and metabolic dysregulation influence ACM disease penetrance and progression, in part through modulation of inflammatory processes.
“environmental modifiers such as endurance exercise [24,25,26,27,28,29,30], psychological stress [31,32,33], diet [34,35], alcohol [36], and metabolic dysregulation [37,38,39] have been shown to influence disease penetrance and progression, in part, through modulation of inflammatory processes.”
From A Paradigm Shift: Arrhythmogenic Cardiomyopathy Is an Inflammatory Disease (2026) · cites this paper as [30]
In Pkp2-cKO mice, exercise enhanced cardiac dysfunction, but its effect was attenuated by exercise pre-training.
“In Pkp2-cKO mice, exercise enhanced cardiac dysfunction, but its effect was attenuated by exercise pre-training [30].”
From A Paradigm Shift: Arrhythmogenic Cardiomyopathy Is an Inflammatory Disease (2026) · cites this paper as [30]
Perturbed calcium handling often precedes structural remodeling, suggesting this is a primary pathogenic event predisposing the heart to malignant VAs.
“Importantly, perturbed calcium handling often precedes structural remodeling, suggesting this is a primary pathogenic event predisposing the hearts to malignant VAs [30].”
From A Paradigm Shift: Arrhythmogenic Cardiomyopathy Is an Inflammatory Disease (2026) · cites this paper as [30]
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- Authors
- Cerrone, M., Marrón-Liñares, G. M., van Opbergen, C. J. M., Costa, S., Bourfiss, M., Pérez-Hernández, M., Schlamp, F., Sanchis-Gomar, F., Malkani, K., Drenkova, K., Zhang, M., Lin, X., Heguy, A., Velthuis, B. K., Prakken, N. H. J., LaGerche, A., Calkins, H., James, C. A., Te Riele, A. S. J. M., & Delmar, M.
- Affiliations
- New York University (US)
- The ‘Leon Charney’ Division of Cardiology, New York University Grossmann School of Medicine , 435 East 30th Street, NSB 707, New York, NY 10016,
- Division of Cardiology, University Heart Center Zurich , Rämistrasse 100, Zurich CH-8091,
- University Medical Center Utrecht (NL)
- Department of Physiology, Faculty of Medicine, University of Valencia and INCLIVA Biomedical Research Institute , C. de Menéndez y Pelayo, 4, 46010 Valencia,
- University Medical Center Groningen (NL)
- Clinical Research Domain, Baker Heart and Diabetes Institute, 75 Commercial Rd, Melbourne VIC 3004, Australia and National Centre for Sports Cardiology, St Vincent's Hospital Melbourne, Building C, 41 Victoria Parade , Fitzroy VIC 3065,
- Johns Hopkins University (US)
- Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht and The Netherlands Heart Institute , Heidelberglaan 100, 3584 CX Utrecht,
- Corresponding author
- Delmar, Mario
- ORCID
- Cerrone, Marina
- Marrón-Liñares, Grecia M
- van Opbergen, Chantal J M
- Costa, Sarah
- Bourfiss, Mimount
- Pérez-Hernández, Marta
- Schlamp, Florencia
- Sanchis-Gomar, Fabian
- Malkani, Kabir
- Drenkova, Kamelia
- Zhang, Mingliang
- Lin, Xianming
- Heguy, Adriana
- Velthuis, Birgitta K
- Prakken, Niek H J
- LaGerche, Andre
- Calkins, Hugh
- James, Cynthia A
- Te Riele, Anneline S J M
- Delmar, Mario
- Venue
- European Heart Journal
- Publisher
- Oxford University Press (OUP)
- Published
- 2021-11-19
- Volume
- 43
- Issue
- 12
- Pages
- 1251-1264
- ISSN
- 0195-668X (ISSN-L)
- 1522-9645
- PMC
- PMC8934688
- OpenAlex
- W4200527283
- Cited by
- 51
- References
- 27
- Citations by year
- 2026: 13 · 2025: 11 · 2024: 7 · 2023: 8 · 2022: 11 · 2021: 1
- FWCI
- 4.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- European Heart Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- Funders
- National Institutes of Health (RO1-HL134328, RO1-HL136179, RO1-HL145911 (M.D.))
- Leducq Foundation
- American Heart Association (18TPA34230006 (M.C.), 20POST35120519 (G.M.M.-L.))
- Heart Rhythm Society
- Dutch Heart Foundation (2018R008 (CvO))
- National Heart Foundation Future Leader Fellowship (102206 (A.L.G.))
- Netherlands Heart Foundation (2015T058)
- UMC Utrecht (2016T042)
- Leonie-Wild Foundation
- Leyla Erkan Family Fund for ARVD Research
- Dr Francis P. Chiramonte Private Foundation
- Johns Hopkins
- Bogle Foundation
- Healing Hearts Foundation
- Campanella family
- Patrick J. Harrison Family
- Peter French Memorial Foundation
- Wilmerding Endowments (UL1 TR003098)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Effects of Exercise
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- arrhythmogenic right ventricular cardiomyopathy, plakophilin-2, physical activity, endurance training, desmosomes, intercalated discs, cardiomyocyte apoptosis, cardiac contractile dysfunction, cardiomyocyte calcium transients, athletes
- MeSH terms
- Animals, Humans, Mutation, Myocardium, Physical Conditioning, Animal, Mice, Knockout, Arrhythmogenic Right Ventricular Dysplasia, Myocytes, Cardiac, Plakophilins, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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