Endothelial injury in rheumatoid arthritis: a crosstalk between dimethylarginines and systemic inflammation.
BACKGROUND
Symmetric (SDMA) and asymmetric (ADMA) dimethylarginines have emerged as novel biomarkers of cardiovascular disease (CVD) in several disease settings associated with atherosclerosis. Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by high CVD mortality and morbidity. ADMA and SDMA levels are abnormal in RA patients, but their correlation with assessments of endothelial function and structure remains unknown. We aimed to investigate whether SDMA and ADMA are associated with carotid intima media thickness (cIMT) and arterial stiffness as well as non-invasive assessments of in vivo micro- and macrovascular endothelial function in RA patients with high systemic inflammatory load.


METHODS
ADMA and SDMA levels were measured using immunoassays in 197 RA individuals. Twenty-six of these [23 (86.4%) females, median age 70, quartiles (60, 73)] were identified as having high inflammatory markers [erythrocyte sedimentation rate (ESR) >25 mm/hr and C-reactive protein (CRP) > 5 mg/L], and were compared to the remainder of the cohort. Patients underwent assessments of microvascular endothelium-dependent and endothelium-independent function [laser Doppler imaging with iontophoresis of acetylcholine (Ach) and sodium-nitroprusside (SNP) respectively], macrovascular endothelium-dependent and endothelium-independent function (flow-mediated dilatation and glyceryl-trinitrate-mediated dilation respectively), and vascular morphology [pulse wave analysis, and carotid intima media thickness (cIMT)].


RESULTS
Significant interactions with inflammation were detected in the associations between ACh and both SDMA (p = 0.014) and ADMA:SDMA ratio (p = 0.027), as well as between SNP and SDMA (p = 0.042) and between arterial stiffness and ADMA:SDMA (p = 0.036), with the associations being stronger in the patients with high inflammatory markers in each case.


CONCLUSIONS
Besides their emerging role as markers of endothelial dysfunction SDMA and ADMA may promote endothelial injury in RA as mediators of the adverse effects of systemic inflammation on micro- and macrovasculature respectively in patients with active disease.
4th Department of Internal Medicine, Hippokration Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece. dimitroul@hotmail.com.|Department of Rheumatology, Russells Hall Hospital, Dudley Group NHS FT, Pensnett Road, DY1 2HQ, Dudley, UK. dimitroul@hotmail.com.
Theodoros
T
Dimitroulas
Institute of Translational Medicine, University Hospital Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, Mindelsohn Way, Birmingham, B15 2WB, UK.
James
J
Hodson
School of Sport, Health and Exercise Sciences, Bangor University, George Building, Bangor, Gwynedd, Wales, LL57 2PZ, UK.
Aamer
A
Sandoo
Department of Rheumatology, Russells Hall Hospital, Dudley Group NHS FT, Pensnett Road, DY1 2HQ, Dudley, UK.
Jacqueline
J
Smith
Arthritis Research UK Epidemiology Unit, University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
George D
GD
Kitas
D000368:Aged; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D001172:Arthritis, Rheumatoid / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D002340:Carotid Artery Diseases / Q000150:complications / Q000378:metabolism / Q000473:pathology; D059168:Carotid Intima-Media Thickness; D015331:Cohort Studies; D004730:Endothelium, Vascular / Q000293:injuries / Q000378:metabolism / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007118:Immunoassay; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D017078:Laser-Doppler Flowmetry; D008297:Male; D008875:Middle Aged; D063177:Pulse Wave Analysis; D020239:Receptor Cross-Talk; D059289:Vascular Stiffness
C487735:dimethylarginine; C024917:symmetric dimethylarginine; D001120:Arginine
ADMA; Inflammation; Rheumatoid arthritis; SDMA; cIMT