title: Myocardial citrullination in rheumatoid arthritis: a correlative histopathologic study.
abstract: BACKGROUND
  The aim of this study was to explore the presence and localization of myocardial citrullination in samples from rheumatoid arthritis (RA) patients compared to rheumatic and non-rheumatic disease control groups.
  
  
  METHODS
  Archived myocardial samples obtained during autopsy from 1995 to 2009 were assembled into four groups: RA; scleroderma; fatal myocarditis; and non-rheumatic disease controls. Samples were examined by immunohistochemistry (IHC) for the presence and localization of citrullination and peptidyl arginine deiminase enzymes (PADs) by a single cardiovascular pathologist blinded to disease group and clinical characteristics.
  
  
  RESULTS
  Myocardial samples from seventeen RA patients were compared with those from fourteen controls, five fatal myocarditis patients, and ten scleroderma patients. Strong citrullination staining was detected exclusively in the myocardial interstitium in each of the groups. However, average and peak anti-citrulline staining was 59% and 44% higher, respectively, for the RA group compared to the combined non-RA groups (P < 0.05 for both comparisons). Myocardial fibrosis did not differ between the groups. In contrast to citrullination, PADs 1 to 3 and 6 were detected in cardiomyocytes (primarily PADs 1 and 3), resident inflammatory cells (primarily PADs 2 and 4), and, to a smaller extent, in endothelial cells and vascular smooth muscle cells. PAD staining did not co-localize with anti-citrulline staining in the interstitium and did not vary by disease state.
  
  
  CONCLUSIONS
  Staining for citrullination was higher in the myocardial interstitium of RA compared to other disease states, a finding that could link autoimmunity to the known increase in myocardial dysfunction and heart failure in RA.
authors.affiliation: Division of Rheumatology, Columbia University, College of Physicians & Surgeons, 630 W 168th St, New York, NY 10032 USA. jtg2122@columbia.edu
authors.forename: Jon T
authors.initials: JT
authors.lastname: Giles
authors.forename: Justyna
authors.initials: J
authors.lastname: Fert-Bober
authors.forename: Jin Kyun
authors.initials: JK
authors.lastname: Park
authors.forename: Clifton O
authors.initials: CO
authors.lastname: Bingham
authors.forename: Felipe
authors.initials: F
authors.lastname: Andrade
authors.forename: Karen
authors.initials: K
authors.lastname: Fox-Talbot
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Pappas
authors.forename: Antony
authors.initials: A
authors.lastname: Rosen
authors.forename: Jennifer
authors.initials: J
authors.lastname: van Eyk
authors.forename: Joan M
authors.initials: JM
authors.lastname: Bathon
authors.forename: Marc K
authors.initials: MK
authors.lastname: Halushka
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism; D001344:Autopsy; D002956:Citrulline / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005355:Fibrosis; D006801:Humans; D006867:Hydrolases / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009205:Myocarditis / Q000276:immunology / Q000378:metabolism; D009206:Myocardium / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D000080062:Protein-Arginine Deiminase Type 1; D000080063:Protein-Arginine Deiminase Type 3; D000080002:Protein-Arginine Deiminase Type 4; D000080065:Protein-Arginine Deiminase Type 6; D000076342:Protein-Arginine Deiminases; D012594:Scleroderma, Localized / Q000276:immunology / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000276:immunology / Q000378:metabolism
chemical_list: D002956:Citrulline; D006867:Hydrolases; C000629235:PADI4 protein, human; C488263:PADI6 protein, human; D000080062:Protein-Arginine Deiminase Type 1; D000080063:Protein-Arginine Deiminase Type 3; D000080002:Protein-Arginine Deiminase Type 4; D000080065:Protein-Arginine Deiminase Type 6; D000076342:Protein-Arginine Deiminases