Omentin and subclinical cardiovascular disease in rheumatoid arthritis

Abstract

The enhanced cardiovascular disease (CVD) risk experienced by patients with rheumatoid arthritis (RA) remains largely unexplained. Traditional risk factors including hypertension, dyslipidemia, diabetes, smoking and altered adiposity states do not fully account for the increased CVD risk in RA. High grade systemic inflammation, as characteristically present in patients with RA, is associated with adverse metabolic risk factor profiles and can directly increase atherogenesis. Further, genetic polymorphisms are related to CVD in RA. Notably, the impact of cardiovascular risk factors on CVD is epidemiological health transition stage dependent within populations. Indeed, cardiovascular risk factor-CVD relations consistently differ amongst patients with RA from developed compared to developing populations. In line with these findings, adequate CVD risk stratification in RA currently eludes us. Adipose tissue derived adipokines are major determinants of systemic metabolism. Several recent studies revealed that adipokines are involved in RA activity and severity. Adipokines play key roles in interactions between obesity, metabolic cardiovascular risk factors and systemic inflammation, all of which contribute to cardiovascular pathology. These adipokine effects depend on pathophysiological context. Against this background, in the present study, we investigated the associations of omentin concentrations with subclinical CVD and whether population origin and RA activity and severity impacts on the respective relationships. Omentin concentrations were measured in 213 (104 black; 109 white) RA patients. Relationships of omentin levels with those of 6 endothelial activation markers, ultrasound determined carotid intima-media thickness and plaque, and matrix metalloproteinase (MMP)-2, -3 and -9 that mediate plaque stability, were identified in multivariate regression models. Omentin concentrations were inversely associated with MMP-3 levels (β=-364 (0.113), p=0.002). This relationship was influenced by population origin, RA activity and the erythrocyte sedimentation rate (ESR) and joint deformity count (interaction p value=0.009, 0.04, 0.04 and 0.007, respectively). Accordingly, in stratified analysis, the omentin-MMP-3 concentration relationship was reproduced in white (β (SE)=- 0.450 (0.153), p=0.0004) but not black patients (β (SE)=- 0.099 (0.195), p=0.6), in participants with disease remission or mild disease activity (β (SE)=-0.411 (0.139), p=0.004) but not with moderate or severe RA activity (β (SE)=-0.286 (0.202), p=0.2), and in those with a small (β (SE)=-0.534 (0.161), p=0.001) but not large erythrocyte sedimentation rate (ESR) (-0.212 (0.168), p=0.2) and without (β (SE)=-0.554 (0.165), p=0.0001) but not with large joint deformity counts (-0.110 (0.173), p=0.5). Omentin levels were unrelated to endothelial activation and atherosclerosis. Omentin concentrations do not represent endothelial activation and atherosclerosis extent in RA. However, omentin concentrations were inversely associated with those of MMP-3, a surrogate marker of plaque vulnerability to rupture, in white but not black Africans with RA. This inverse relationship was also absent RA patients with moderate or severe RA activity and large ESR values and joint deformity counts. A loss of beneficial effects of omentin on plaque instability may contribute to the link between severe disease and increased cardiovascular risk in RA.