title: Altered desmosomal proteins in granulomatous myocarditis and potential pathogenic links to arrhythmogenic right ventricular cardiomyopathy.
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.
  
  
  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.
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Angeliki
authors.initials: A
authors.lastname: Asimaki
authors.forename: Harikrishna
authors.initials: H
authors.lastname: Tandri
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Duffy
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Winterfield
authors.forename: Shannon
authors.initials: S
authors.lastname: Mackey-Bojack
authors.forename: Maria M
authors.initials: MM
authors.lastname: Picken
authors.forename: Leslie T
authors.initials: LT
authors.lastname: Cooper
authors.forename: David J
authors.initials: DJ
authors.lastname: Wilber
authors.forename: Frank I
authors.initials: FI
authors.lastname: Marcus
authors.forename: Cristina
authors.initials: C
authors.lastname: Basso
authors.forename: Gaetano
authors.initials: G
authors.lastname: Thiene
authors.forename: Adalena
authors.initials: A
authors.lastname: Tsatsopoulou
authors.forename: Nikos
authors.initials: N
authors.lastname: Protonotarios
authors.forename: William G
authors.initials: WG
authors.lastname: Stevenson
authors.forename: William J
authors.initials: WJ
authors.lastname: McKenna
authors.forename: Shiva
authors.initials: S
authors.lastname: Gautam
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Remick
authors.forename: Hugh
authors.initials: H
authors.lastname: Calkins
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Saffitz
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000097:blood / Q000209:etiology / Q000503:physiopathology*; D001344:Autopsy; D001706:Biopsy; D009202:Cardiomyopathies / Q000097:blood / Q000209:etiology / Q000503:physiopathology*; D016022:Case-Control Studies; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000097:blood; D054407:Chemokine CCL4 / Q000097:blood; D002648:Child; D003896:Desmosomes / Q000378:metabolism*; D005260:Female; D006801:Humans; D007365:Intercellular Junctions / Q000187:drug effects / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology; D016209:Interleukin-8 / Q000097:blood; D008297:Male; D008875:Middle Aged; D023421:Models, Animal; D009205:Myocarditis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012507:Sarcoidosis / Q000378:metabolism / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D018497:Ventricular Dysfunction, Right / Q000097:blood / Q000209:etiology / Q000503:physiopathology*; D055815:Young Adult; D051185:gamma Catenin / Q000378:metabolism*
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D054407:Chemokine CCL4; D020381:Interleukin-17; D015850:Interleukin-6; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; D051185:gamma Catenin