In the present study, total and HMW adiponectin concentrations related to a similar extent to metabolic risk factors in RA, as was previously documented in the non-RA population . We found two similarities and three disparities in adiponectin-cardiovascular risk relations in black compared to white patients with RA. The former comprised positive adiponectin-blood pressure variable and inverse adiponectin-glucose concentration associations, and the latter positive adiponectin-favorable lipid profile and overall number of metabolic risk factors relationships in black but not white patients as well as positive adiponectin-endothelial activation associations in white but not black participants.
Numerous experimental studies have documented the protective effects of adiponectin on obesity induced pathological conditions, including insulin resistance and enhanced atherogenesis . Although an insulin sensitivity enhancing effect would be expected to reduce high blood pressure, direct effects of adiponectin on components of vascular tissue are considered more important in this context . These comprise the activating effects of adiponectin on endothelial nitric oxide (NO) synthase and cyclooxygenase-2 leading to the production of NO and prostaglandin-I2 production, respectively, and the ability of adiponectin to promote macrophage polarization toward the anti-inflammatory phenotype, which results in reduced interleukin-6, tumor necrosis factor (TNF)-α and MCP-1 and increased arginase-1, interleukin-1 and macrophage N-acetyl-galactosamine specific lectin-1 by M1 and M2 macrophages, respectively . Each of these processes improves endothelial function.
Patients with RA experience substantially increased risk for cardiovascular disease [67–72]. Over the recent past, paradoxical positive relations between adiponectin concentrations and cardiovascular risk were reported in non-RA populations at high risk of cardiovascular disease [14–17]. In this context, we recently also found for the first time a paradoxical positive association between total adiponectin concentrations and blood pressure parameters in African black RA but not non-RA subjects . In the present investigation we assessed total and HMW adiponectin concentrations and comprehensively adjusted for potential mediating and confounding characteristics in our analysis. Our current finding of positive relations between both total and HMW adiponectin concentrations and each of three blood pressure variables that were further present to a statistically similar extent in black and white patients argues against our previous result  being spurious and supports the notion that these relationships may be RA specific. Additionally, we found paradoxical positive associations between total and HMW adiponectin concentrations and endothelial activation in white patients only and indeed, in the respective models, the extent of effect of adiponectin concentrations on surrogate markers of enhanced early atherogenesis was significantly larger in white compared to black study participants. Thus, this relationship was ethnic specific among patients with RA.
Importantly in this regard, not only do genetic loci associated with adiponectin levels differ in black compared with whites but also, in the Health ABC study, adiponectin concentrations associated independently with prevalent and incident coronary heart disease in black but not white non-RA Americans . Taken together, the impact of ethnicity on the adiponectin-cardiovascular risk relation may be reversed in subjects with RA. Further, whereas white ethnicity associates with higher adiponectin concentrations among black and white non-RA Americans and this association is driven by visceral adiposity and metabolic risk factors [17, 39], ethnicity was not related to adiponectin levels both before and after adjustment for waist circumference and metabolic risk factors in the present RA cohort. Congruent with our previous findings , our current results suggest that findings on adiponectin metabolism and its associations with cardiovascular risk as reported in the non-RA population should not be merely translated to the RA population.
Potential mechanisms underlying the reported paradoxical adiponectin-cardiovascular risk relations were recently comprehensively and elegantly proposed by Sattar . Among six raised possibilities, an attractive option was that of reverse causality, whereby increased adiponectin concentrations represent a chronic or acute on chronic compensatory mechanism to counteract metabolic and vascular stress in subjects with acute coronary syndrome or heart failure . Recommendations for investigations aimed at elucidating paradoxical adiponectin-cardiovascular risk relations were also given.
Total and HMW adiponectin concentrations were strongly interrelated in the present RA investigation but the HMW-total adiponectin ratio was inconsistently associated with metabolic risk factors. The HMW-total adiponectin ratio was also not related to endothelial activation.
The previously alluded to paradoxical relation between total adiponectin and coronary heart disease among non-RA black Americans was postulated to result from a decreased production of HMW relative to other adiponectin isoforms in this population group [17, 39]. We indeed found that HMW adiponectin concentrations were lower in black compared to white patients and black ethnicity associated with a lower HMW-total adiponectin ratio in age and sex adjusted analysis. However, HMW adiponectin concentrations were also shown to be unrelated to incident coronary heart disease .
RA adipocytes and their surrounding macrophages produce adipokines that regulate systemic inflammation and the presence of a complex adipokine-mediated interaction among white adipose tissue, cardiovascular disease and chronic inflammatory disease like RA was previously proposed . In this regard, in a series of white patients with severe RA undergoing anti-TNF-α infliximab therapy, high grade inflammation showed an independent negative correlation with circulating adiponectin concentrations whereas low adiponectin levels clustered with metabolic syndrome features including dyslipidemia and high plasma glucose concentrations that reportedly contribute to atherogenesis in RA . However, adiponectin concentrations were not related to blood pressure in this study. In another series of non-diabetic and mostly non-obese patients with ankylosing spondylitis undergoing anti-TNF-α therapy, adiponectin concentrations related to insulin sensitivity and marginally to low BMI . Taken together, these findings support a role of hypoadiponectinemia in cardiometabolic risk in chronic inflammatory rheumatic diseases. The present study shows that in RA, ethnicity and presumably genetic factors may modulate metabolic risk through mechanisms that include an effect mediated by adipokines.
Our study has strengths and limitations. We assessed both total and HMW adiponectin concentrations and the production of four endothelial activation molecules, which reportedly mediates the initial stages of atherosclerosis [40–43] and is inhibited by adiponectin [9–11]. Endothelial activation is markedly enhanced and associated with disease characteristics that further are strongly implicated in increased cardiovascular risk, and hence constitutes a promising tool in the elucidation of atherogenic mechanisms in RA [44–47]. Importantly, endothelial activation was not associated with disease activity variables in the present cohort of patients with established and treated RA . The cross sectional design of the present investigation precludes drawing inferences on the direction of causality and our results need to be reproduced in a longitudinal study, preferably with the inclusion of cardiovascular event rates as an outcome variable. Alcohol intake and physical activity can associate with increased adiponectin concentrations . Only 15.3% of patients in the present study consumed alcohol with a median of three units per week, alcohol consumption was not related to total and HMW adiponectin concentrations (P = 0.4 and 0.5) and its inclusion as an additional confounder in the models in Tables 3, 4, 5 and 6 did not alter our findings (data not shown). The same lack of relationships was also present with regard to physical activity  (data not shown). Finally, the relative role of genetic  versus environmental factors, including socioeconomic characteristics  in the ethnicity-adiponectin and adiponectin-cardiovascular risk relationships among patients of different population origin in RA, were not determined and merit further study.