Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Citrullination Is Present in the Perivascular Interstitium of the Myocardium and Is Increased in Rheumatoid Arthritis Compared to Controls.
Giles1, Jon T., Halushka4, Marc K., Mary4, Fox-Talbot K., Bingham2, Clifton O., Andrade5, Felipe, Park3, Jin Kyun, Rosen2, Antony
Myocardial dysfunction is increased among rheumatoid arthritis (RA) patients relative to controls. Autoimmunity against post-translationally modified (citrullinated) myocardial proteins may represent a pathophysiological link to both myocardial structural and functional abnormalities in RA patients.
Archived myocardial samples obtained during autopsy between 1995 and 2009 were assembled into four groups: RA; scleroderma; fatal myocarditis with no underlying rheumatic disease; and non-rheumatic disease controls. Records were adjudicated to confirm diagnosis. Samples were examined by immunohistochemistry for the presence and localization of citrullination using a commercial anti-modified citrulline antibody. A blinded cardiovascular pathologist graded average citrullination intensity, peak intensity, and average fibrosis for each case on a 03 scale. RA and control samples were further examined for the presence of peptidyl argenine deiminase enzymes (PADs 2 and 4) by immunohistochemistry.
Myocardial samples from 17 RA patients were compared to those from 14 controls, 5 fatal myocarditis patients, and 9 scleroderma patients. The RA and control groups did not significantly differ by age, gender, race, or post-mortem interval. Citrullination was detected in the perivascular myocardial interstitium in each of the groups. Citrullination was not detected in the cardiomyocytes or endothelium. Average and peak citrullination were significantly higher in the RA group compared to the other groups, among which citrullination was equivalent (Figure, panels A and B). Myocardial fibrosis did not differ between the groups (Figure, panel C).
Figure. Average semiquantitative scores for immunohistochemical assessments of average citrullination (A), peak citrullination (B), and average myocardial fibrosis (C), according to group. Means and 95% confidence intervals are depicted. P-values were calculated using the Kruskal-Wallis test.
Myocarditis did not differ between the RA and control groups, and did not co-localize with citrullination. Rare, scattered PAD2 and PAD4 staining leukocytes were observed in both the RA and control samples. PAD2 and PAD4 staining was negligible within the cardiomyocytes and endothelium in both groups.
These data provided evidence for the first time that: 1) Citrullinated proteins are present in the myocardium, in general, 2) Higher levels of myocardial interstitial citrullination appear to be specific to RA, 3) differences in demographics, post-mortem interval, and histologic features did not account for higher citrullination in RA, and 4) While myocardial leukocytes were potential sources of PAD2 and PAD4 within the myocardial interstitium, these cells were not increased in RA at the time of death. Further investigation is centered on identifying the specific myocardial proteins that are targets for citrullination, determining whether citrullinated myocardial proteins are recognized by RA sera, and elucidating the consequences of interstitial citrullination on myocardial structure and function in RA patients.
To cite this abstract, please use the following information:
Giles, Jon T., Halushka, Marc K., Mary, Fox-Talbot K., Bingham, Clifton O., Andrade, Felipe, Park, Jin Kyun, et al; Citrullination Is Present in the Perivascular Interstitium of the Myocardium and Is Increased in Rheumatoid Arthritis Compared to Controls. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :2167