Psychosocial Stress Hastens Disease Progression and Sudden Death in Mice with Arrhythmogenic Cardiomyopathy
Open accessAbstract
Physiological stressors, such as exercise, can precipitate sudden cardiac death or heart failure progression in patients with arrhythmogenic cardiomyopathy (ACM). Yet, whether and to what extent a highly prevalent and more elusive environmental factor, such as psychosocial stress (PSS), can also increase ACM disease progression is unexplored. Here, we first quantified perceived stress levels in patients with ACM and found these levels correlated with the extent of arrhythmias and cardiac dysfunction. To determine whether the observed correlation is due to causation, we inflicted PSS-via the resident-intruder (RI) paradigm—upon Desmoglein-2 mutant mice, a vigorously used mammalian model of ACM. We found that ACM mice succumbed to abnormally high in-trial, PSS mortality. Conversely, no sudden deaths occurred in wildtype (WT) counterparts. Desmoglein-2 mice that survived RI challenge manifested markedly worse cardiac dysfunction and remodeling, namely apoptosis and fibrosis. Furthermore, WT and ACM mice displayed similar behavior at baseline, but Desmoglein-2 mice exhibited heightened anxiety following RI-induced PSS. This outcome correlated with the worsening of cardiac phenotypes. Our mouse model demonstrates that in ACM-like subjects, PSS is incisive enough to deteriorate cardiac structure and function per se, i.e., in the absence of any pre-existing anxious behavior. Hence, PSS may represent a previously underappreciated risk factor in ACM disease penetrance.
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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 [31]
The citation is attached to psychological stress, not to the separately cited modifiers. The Results report an association between perceived stress and ACM severity in patients, while the mouse findings support a role for psychosocial stress in disease progression. The Discussion mentions heightened sensitivity to pro-inflammatory disorders in stressed rodents, but does not establish that inflammation mediates ACM progression in this study. (LLM, conf=0.85)
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- Authors
- Agrimi, J., Scalco, A., Agafonova, J., Williams III, L., Pansari, N., Keceli, G., Jun, S., Wang, N., Mastorci, F., Tichnell, C., Murray, B., James, C. A., Calkins, H., Zaglia, T., Paolocci, N., & Chelko, S. P.
- Affiliations
- Johns Hopkins University (US)
- University of Padua (IT)
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Istituto di Fisiologia Clinica (IT)
- Florida State University (US)
- Corresponding author
- Paolocci, Nazareno
- Chelko, Stephen P.
- ORCID
- Venue
- Journal of Clinical Medicine
- Publisher
- MDPI AG
- Published
- 2020-11-24
- Volume
- 9
- Issue
- 12
- Pages
- 3804
- ISSN
- 2077-0383 (ISSN-L)
- PMC
- PMC7761318
- OpenAlex
- W3106784138
- Cited by
- 29
- References
- 46
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 7 · 2023: 6 · 2022: 4 · 2021: 4
- FWCI
- 2.17
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Clinical Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Padua Research Archive (University of Padova) (submittedVersion, cc-by)
- Funders
- American Heart Association (19CDA34760185)
- National Heart, Lung, and Blood Institute (R01 HL136918, UL1 TR003098, T32AG058527)
- Fondation Leducq (16CVD02)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Effects of Exercise
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Keywords
- arrhythmogenic cardiomyopathy, psychosocial stress, sudden cardiac death, disease progression, resident-intruder paradigm, anxiety, cardiac remodeling, apoptosis, myocardial fibrosis, perceived stress, risk factors
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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