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Altered Desmosomal Proteins in Granulomatous Myocarditis and Potential Pathogenic Links to Arrhythmogenic Right Ventricular Cardiomyopathy

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Asimaki, Angeliki, Tandri, Harikrishna, Duffy, Elizabeth R., Winterfield, Jeffrey R., Mackey-Bojack, Shannon, Picken, Maria M., Cooper, Leslie T., Wilber, David J. +11 more·2011·Circulation: Arrhythmia and Electrophysiology
DOI 10.1161/circep.111.964890PMC PMC3203520
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Abstract

Background—: Immunoreactive signal for the desmosomal protein plakoglobin (γ-catenin) is reduced at cardiac intercalated disks in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), a highly arrhythmogenic condition caused by mutations in genes encoding desmosomal proteins. Previously, we observed a false-positive case in which plakoglobin signal was reduced in a patient initially believed to have ARVC but who actually had cardiac sarcoidosis. Sarcoidosis can masquerade clinically as ARVC but has not been previously associated with altered desmosomal proteins. Methods and Results—: We observed marked reduction in immunoreactive signal for plakoglobin at cardiac myocyte junctions in patients with sarcoidosis and giant cell myocarditis, both highly arrhythmogenic forms of myocarditis associated with granulomatous inflammation. In contrast, plakoglobin signal was not depressed in lymphocytic (nongranulomatous) myocarditis. To determine whether cytokines might promote dislocation of plakoglobin from desmosomes, we incubated cultures of neonatal rat ventricular myocytes with selected inflammatory mediators. Brief exposure to low concentrations of interleukin (IL)-17, tumor necrosis factor-α (TNF-α), and IL-6 (cytokines implicated in granulomatous myocarditis) caused translocation of plakoglobin from cell-cell junctions to intracellular sites, whereas other potent cytokines implicated in nongranulomatous myocarditis had no effect, even at much higher concentrations. We also observed myocardial expression of IL-17 and TNF-α and elevated levels of serum inflammatory mediators, including IL-6R, IL-8, monocyte chemoattractant protein 1, and macrophage inflammatory protein 1β, in patients with ARVC (all P <0.0001 compared with controls). Conclusions—: The results suggest novel disease mechanisms involving desmosomal proteins in granulomatous myocarditis and implicate cytokines, perhaps derived in part from the myocardium, in disruption of desmosomal proteins and arrhythmogenesis in ARVC.

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  • Elevated levels of circulating and myocardial inflammatory cytokines and chemokines from DGV-linked ACM subjects have been observed across disease phases and phenotypes.

    “Prior works have shown elevated levels of circulating [22] and myocardial inflammatory cytokines and chemokines from DGV-linked ACM subjects [11,23] that have been observed across disease phases and phenotypes”

    From A Paradigm Shift: Arrhythmogenic Cardiomyopathy Is an Inflammatory Disease (2026) · cites this paper as [22]

    The Results section, “Myocardial expression of cytokines in ARVC” (page unavailable), reports increased myocardial IL-17 and TNFα signals in ARVC cases, including five with documented desmosomal gene mutations. It does not establish that these elevations occur across disease phases or phenotypes. The paper also reports elevated circulating inflammatory mediators, but the citing sentence assigns the circulating finding to a different citation [22]. (LLM, conf=0.86)

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Authors
Asimaki, A., Tandri, H., Duffy, E. R., Winterfield, J. R., Mackey-Bojack, S., Picken, M. M., Cooper, L. T., Wilber, D. J., Marcus, F. I., Basso, C., Thiene, G., Tsatsopoulou, A., Protonotarios, N., Stevenson, W. G., McKenna, W. J., Gautam, S., Remick, D. G., Calkins, H., & Saffitz, J. E.
Affiliations
  • Boston University (US)
  • From the Department of Pathology (A.A., J.E.S.) and Department of Medicine (S.G.), Beth Israel Deaconess Medical Center and Harvard Medical School, the Department of Medicine (J.R.W., W.G.S.), Brigham and Women's Hospital and Harvard Medical School, and Department of Pathology, Boston University Medical Center (E.R.D., D.G.R.), Boston, MA; Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD (H.T., H.C.); Jesse E. Edwards Registry of Cardiovascular Diseases, St Paul, MN (S.M.-B....
ORCID
Venue
Circulation: Arrhythmia and Electrophysiology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2011-10
Volume
4
Issue
5
Pages
743-752
ISSN
  • 1941-3084 (ISSN-L)
  • 1941-3149
DOI
10.1161/circep.111.964890
PMC
PMC3203520
OpenAlex
W2127460971
Cited by
194
References
0
Citations by year
2026: 8 · 2025: 10 · 2024: 8 · 2023: 21 · 2022: 9 · 2021: 22 · 2020: 24 · 2019: 9 · 2018: 8 · 2017: 10 · 2016: 11 · 2015: 14 · 2014: 12 · 2013: 14 · 2012: 12
FWCI
8.80
Type
journal article
Language
en
Open access
Locations
  • Circulation Arrhythmia and Electrophysiology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Padua Research Archive (University of Padova) (submittedVersion)
Funders
  • Brigham and Women's Hospital
  • National Heart, Lung, and Blood Institute (K23HL093350, RC1HL100110, HL102361, R01HL102361)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Viral Infections and Immunology Research
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Effects of Exercise
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
Keywords
arrhythmogenic right ventricular cardiomyopathy, plakoglobin, desmosomal proteins, granulomatous myocarditis, sarcoidosis, giant cell myocarditis, cytokines, IL-17, TNF-α, interleukin-6, intercalated discs, arrhythmogenesis, inflammatory mediators
MeSH terms
Adolescent, Adult, Aged, Animals, Arrhythmias, Cardiac, Autopsy, Biopsy, Cells, Cultured, Child, Desmosomes, Female, Humans, Intercellular Junctions, Male, Middle Aged, Cardiomyopathies, Myocarditis, Sarcoidosis, Tumor Necrosis Factor-alpha, Signal Transduction, Interleukin-6, Case-Control Studies, Interleukin-8, Rats, Wistar, Ventricular Dysfunction, Right, Chemokine CCL2, Interleukin-17, Models, Animal, Myocytes, Cardiac, gamma Catenin, Rats, Chemokine CCL4, Young Adult

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