Towards the elucidation of the true impact of adipocytokines on cardiovascular risk
in rheumatoid arthritis |
| |
Authors: | Patrick H Dessein Ahmed Solomon |
| |
Institution: | 1.Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg 2193, South Africa;2.Department of Rheumatology, Charlotte Maxeke Johannesburg Academic Hospital, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg 2193, South Africa |
| |
Abstract: | Adipo(cyto)kines are mostly produced by adipose tissue and orchestrate the adverse
impact of excess adiposity on cardiovascular risk. Adipokines also contribute
importantly to the pathophysiology of rheumatoid arthritis. Congruent with data
reported in previous investigations, Kang and colleagues report in this issue of
Arthritis Research & Therapy that adipokine concentrations are
further associated with metabolic risk and inflammation and that the
leptin–adiponectin ratio associates with the carotid artery resistive index in
rheumatoid arthritis. Guided by evidence reported thus far on cardiovascular risk, we
discuss six reasons why careful elucidation of adipokine–cardiovascular risk
relations is needed in rheumatoid arthritis.In this issue of Arthritis Research & Therapy, Kang and colleagues
investigate whether adipokines could link inflammation, metabolic risk factors and
cardiovascular disease in rheumatoid arthritis (RA) 1]. Evidence in support of this paradigm was reported previously 2-6]. Patients with RA experience a markedly increased cardiovascular risk that is
driven by metabolic risk factors and by high-grade inflammation 7]. Kang and colleagues measured adiponectin, leptin, resistin, tumor necrosis
factor alpha and interleukin-6 concentrations and assessed the common carotid artery
intima-media thickness, resistive index (RI) and plaque presence by high-resolution
ultrasonography 1]. Concentrations of some of the adipokines related to inflammatory markers
including C-reactive protein levels and the erythrocyte sedimentation rate, and to
metabolic syndrome features.In a previous study by our group, leptin and adiponectin concentrations were not
associated with carotid intima-media thickness and plaque 3]. In addition, the leptin–adiponectin ratio and carotid RI as markers of
cardiovascular risk have not been reported in RA. For these reasons, besides the
abovementioned analyses, Kang and colleagues assessed (only) the relationship of the
leptin–adiponectin ratio with carotid RI. In univariate analysis, the
leptin–adiponectin ratio as well as age, homeostasis model assessment for insulin
resistance, waist circumference and body mass index were associated with the carotid RI.
Importantly, in multivariate analysis, only age and the leptin–adiponectin ratio
remained significantly related to the carotid RI. The leptin–adiponectin ratio may
thus provide information about the presence of subclinical cardiovascular disease beyond
that on insulin resistance as assessed by the homeostasis model of insulin resistance,
as well as adiposity extent as represented by body mass index and waist circumference in
RA.Adipo(cyto)kines comprise a vast range of disparate soluble bioactive proteins that are
mostly secreted by adipose tissue 8]. These molecules participate in biological processes that include
inflammatory responses and thereby orchestrate the adverse impact of excess adiposity on
cardiovascular risk and incident type 2 diabetes 8]. Adipokines represent both adiposity extent and biological activity. RA is a
prototypic inflammatory disease. In this context, ~200 recently reported investigations
substantiate an important involvement of adipokines in RA activity and severity 9]. By contrast, despite the contribution of adipokines to altered
cardiovascular risk in non-RA subjects and the enhanced cardiovascular risk in RA, there
is a striking paucity of reported studies on the potential role of adipokines in
atherogenesis in RA.A myriad of pertinent reasons exist why the role of adipokines in cardiovascular risk
amongst patients with RA requires thorough elucidation. First, RA can modify adipokine
production 3,9].Second, and presumably more important, the presence of autoimmunity can alter the
effects of adipokines on cardiovascular risk 3,4]. In non-RA subjects, adiponectin production decreases with increasing
adiposity and this adipokine has anti-inflammatory properties 8]. However, in RA adiponectin has marked proinflammatory properties 9]. In fact, in Kang and colleagues’ study the adiponectin concentrations
were paradoxically positively associated with the erythrocyte sedimentation rate 1]. Whereas in non-RA subjects adiponectin improves metabolic risk and also
directly inhibits atherogenesis, we reported recently that in RA, upon using
comprehensive potential confounder-adjusted analysis, adiponectin concentrations
associated paradoxically with high blood pressure 3,4] and in white but not black Africans with enhanced endothelial activation 4]. Endothelial activation mediates the very initial stages of atherosclerosis 3-6]. Whether such paradoxical relations represent altered effects mediated by RA
or a compensatory increase in adiponectin production in the presence of heightened
cardiovascular risk and in an attempt to reduce this risk needs further investigation 4].Third, conventional risk factors and disease characteristics can impact on
adipokine–atherogenesis relationships in RA 5]. Resistin concentrations thus associate independently with endothelial
activation in RA, but this relation is present only in those with, and not in those
without, traditional risk factors, abdominal obesity, joint damage as reflected by the
presence of deformed joints or prolonged disease duration 5]. This observation further supports the need for sensitivity analysis in the
present context. By contrast, interleukin-6 concentrations are more consistently
associated with endothelial activation in RA 6].Fourth, the effects of adipokines on cardiovascular risk require examination prior to
targeting the respective molecules in an attempt to reduce disease activity and severity
in RA 3]. Indeed, should the protective effect of adiponectin on cardiovascular risk
be preserved amongst patients with RA, then its blockade would be expected to further
enhance cardiovascular risk 3].Fifth, RA influences adiposity and its distribution, which also associates with
atherosclerosis in this disease 7,10].Finally, as illustrated by the disparity in adiponectin–endothelial activation
relations amongst Africans previously alluded to, population origin impacts on
adipokine–cardiovascular risk relations in RA 4].A caveat of Kang and colleagues’ study is that potential confounders were not
systematically identified. For example, gender, cardiovascular drug use, antirheumatic
agent use and the glomerular filtration rate can all influence both the concentrations
and effects of adipokines 3-6]. Nevertheless, this investigation reinforces previously reported evidence
that strongly suggests an intriguing and important involvement of adipokines in RA
atherogenesis. |
| |
Keywords: | |
|
|