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 Table of Contents  
Year : 2015  |  Volume : 43  |  Issue : 1  |  Page : 22-27

Biochemical markers for early detection of cardiovascular disorders in rheumatoid arthritis

1 Department of Medical Biochemistry, Faculty of Medicine, Tanta University, Tanta, Egypt
2 Department of Physiology, Faculty of Medicine, Tanta University, Tanta, Egypt
3 Department of Rheumatology and Rehabilitation, Faculty of Medicine, Tanta University, Tanta, Egypt

Date of Submission09-Jan-2015
Date of Acceptance17-Jan-2015
Date of Web Publication6-Apr-2015

Correspondence Address:
Abeer A Abo Zeid
Department of Physiology, Faculty of Medicine, Tanta University, Tanta
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DOI: 10.4103/1110-1415.154562

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The mechanism of accelerated atherosclerosis accompanied with rheumatoid arthritis (RA) remains unclear.
The aim of this study was to investigate the association between fetuin-A, asymmetric dimethylarginine (ADMA), advanced oxidation protein products (AOPPs), and accelerated atherosclerosis in patients with RA, for early detection of cardiovascular disorders.
Patients and methods
This study was carried out on 60 participants: 40 RA patients and 20 healthy volunteers of similar age and sex. Assessment of Disease Activity for 28-Joint Indices Score and ultrasonographic examinations of carotid intimal thickness and stiffness parameter β were carried out. In addition, lipid profile, serum high-sensitivity C-reactive protein, ADMA, fetuin-A, and AOPPs levels were measured in all participants.
There was a significant increase in serum ADMA and AOPP levels in RA patients compared with controls. Serum fetuin-A levels were lower in RA patients than in controls. There was a positive correlation between serum ADMA levels and serum erythrocyte sedimentation rate, high-sensitivity C-reactive protein, rheumatoid factor, Disease Activity for 28-Joint Indices Score, carotid intima-media thickness, stiffness index β, total cholesterol, low-density lipoprotein cholesterol, triglyceride levels, and total cholesterol/high-density lipoprotein cholesterol and low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratios.
Low levels of fetuin-A, in RA, suggest its possible contribution in the pathophysiology of endothelial dysfunctions, subsequently causing increase in arterial stiffness. An increase in ADMA and AOPPs in RA patients, together with dyslipidemia, suggests their possible involvement in the physiology and pathophysiology of vascular diseases in RA. These findings open new avenues for further studies on the physiology of cardiovascular diseases in RA that may lead to a better treatment of these diseases.

Keywords: advanced oxidation protein product, asymmetric dimethylarginine, fetuin-A, rheumatoid arthritis

How to cite this article:
Shafik NM, Gaballah HH, Abo Zeid AA, Hussein MS. Biochemical markers for early detection of cardiovascular disorders in rheumatoid arthritis. Tanta Med J 2015;43:22-7

How to cite this URL:
Shafik NM, Gaballah HH, Abo Zeid AA, Hussein MS. Biochemical markers for early detection of cardiovascular disorders in rheumatoid arthritis. Tanta Med J [serial online] 2015 [cited 2020 Aug 15];43:22-7. Available from: http://www.tdj.eg.net/text.asp?2015/43/1/22/154562

  Introduction Top

Rheumatoid arthritis (RA) is a systemic inflammatory disease associated with increased cardiovascular morbidity and mortality. Mortality related to cardiovascular disease (CVD) [1] . Therefore, prevention and treatment not only of joint damage but also of comorbidities is vital, particularly of CVD, which is the cause of 50% of the deaths in these populations [2] . Evidence of subclinical CVD has been demonstrated in patients with RA [3] . These patients have also been found to have a higher prevalence of atherosclerotic plaques, increased intima-media thickness (IMT) of the carotid arteries, and significantly impaired endothelial function [4] .

The availability of a marker of endothelial dysfunction would facilitate the stratification of patients with early RA based on their cardiovascular risk [5] . Asymmetric dimethylarginine (ADMA) is a recently recognized endogenous inhibitor of nitric oxide production, which acts by inhibiting nitric oxide synthase. Its role in CVD is emerging, and it appears to be an important causal factor in dysfunction of the vascular system [6] .

Fetuin-A is an anti-inflammatory glycoprotein mainly produced in the liver and inhibits synthesis of proinflammatory cytokines [7] . Fetuin-A is downregulated in response to inflammation and is known to be a negative acute phase reactant [8] . Low fetuin-A concentration is associated with cardiovascular death, and may play an important role in the prognosis of patients with acute coronary syndromes [9] . Furthermore, it has been reported that fetuin-A-deficient mice develop ectopic calcification of soft tissue [10] .

Antioxidant system is impaired in RA, and reactive oxygen species cannot be removed effectively because of impaired antioxidant system. Moreover, RA patients are exposed to lipid and protein peroxidation, which is one of the indicators of oxidative stress [11] . Human investigations support the oxidative stress hypothesis of atherosclerosis and its central role in CVD [12] . Advanced oxidation protein products (AOPPs) are new protein markers of oxidative stress with proinflammatory properties [13],[14] . Being the products of oxidative imbalance, AOPPs further participate in the potentiation of both oxidative stress and inflammation [15] . Therefore, the aim of the present work was to investigate the association between fetuin-A, ADMA, AOPPs, and accelerated atherosclerosis in patients with RA, for early detection of cardiovascular disorders in RA patients.

  Patients and methods Top

This study was carried out on 60 participants divided into two groups:

  1. Group I: this group included 40 RA patients collected randomly from the Outpatient Clinic of the Rheumatology and Rehabilitation Department, Tanta University Hospitals. They fulfilled the classification criteria for RA [16] .
  2. Group II: this group included 20 healthy volunteers matched in age and sex as controls.
  3. Written informed consent was obtained from each participant. This work was approved by the Ethical Committee of Faculty of Medicine, Tanta University (approval number: 2498 at April 2014).
Exclusion criteria

Exclusion criteria were as follows: RA patients who are hypertensive; individuals suffering from conditions that affect the lipid profile, such as diabetes mellitus, thyroid dysfunction, liver or kidney disease, Cushing syndrome, current smokers, obesity (BMI >30), and a history of familial dyslipidemia; patients receiving medications affecting lipid metabolism (lipid-lowering drugs, β-blockers, oral contraceptives, estrogen, progestin, thyroxin, and vitamin E); and individuals with a history of myocardial infarction during the last 6 months.

Clinical assessment

Disease activity in RA patients was assessed by measuring the Disease Activity for 28-Joint Indices Score (DAS-28) including erythrocyte sedimentation rate (ESR) [17] . Functional capacity was assessed on the basis of difficulty in performing daily activities using the Modified Health Assessment Questionnaire (MHAQ) [18] .

Laboratory investigations

Blood sampling

After 12 h of overnight fasting, blood samples were taken from controls and RA patients. Serum was separated. Lipid profile and rheumatoid factor (RF) were determined immediately, and aliquots of rest of the serum were immediately stored at -70°C until the time of analysis.

Both patients and controls were subjected to the following laboratory investigations:

(1) Routine laboratory investigations:

Complete blood count, ESR [19] , and RF were determined [20] . Lipid profile, including serum triglyceride (TG) levels, serum total cholesterol (TC) levels, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were analyzed using kits supplied by Bio Merieux Vitek Inc, USA.

(2) Specific laboratory investigations:

High-sensitivity C-reactive protein (hsCRP) assay concentrations were measured [21] . Serum ADMA levels [22] and serum fetuin-A levels were determined [23] . Serum AOPP levels were estimated [24] .

Radiological investigations

Carotid intima-media thickness

Common carotid arteries were assessed using a B-mode ultrasound [25] . Ultrasonographic examinations of the stiffness parameter β for the common carotid arteries were performed. The stiffness index β is an index of the elasticity of the arterial wall [26] .

Statistical analysis

All data were analyzed using SPSS software (version 11; SPSS Inc., Chicago, Illinois, USA). Baseline characteristics are presented as mean ± SD for the continuous variables and as frequency and percentage for the discrete ones. Comparisons between groups were made using Student's t-test. Correlation between variables was examined using Pearson's correlation coefficient. Multiple linear regression analysis was used to determine the independent predictors of serum ADMA, fetuin-A, and AOPP levels. A P value less than 0.05 was considered statistically significant.

  Results Top

The demographics and clinical, laboratory, and radiographic data for patients with RA and controls are summarized in [Table 1]. All patients and controls were female; there were no significant differences in age, sex, and mean BMI values between RA patients and controls.
Table 1: Demographic, b iochemical, and radiological characteristics of individuals with rheumatoid arthritis
and controls

Click here to view

RA patients exhibited a state of mild dyslipidemia characterized by a significantly higher baseline of TC, LDL-C, and TG, and lower levels of HDL-C. The atherogenic ratios of TC/HDL-C, as well as of LDL-C/HDL-C, were significantly higher in RA patients as compared with controls.

Moreover, serum levels of ESR, hsCRP, RF, AOPPs, and ADMA were significantly higher in RA patients than in controls (P < 0.05). However, serum fetuin-A and HDL-C levels were significantly lower in RA patients than in controls (P < 0.05).

As regards the radiological parameters, carotid intima-media thickness (cIMT) and stiffness index β revealed significantly higher levels in RA patients compared with controls (P < 0.05).

[Table 2] shows positive correlations between serum ADMA levels and serum ESR, hsCRP, RF, DAS-28, cIMT, stiffness index β, TC, LDL-C, TG, TC/HDL-C, as well as LDL-C/HDL-C. In contrast, significant negative correlations were found between serum ADMA levels and serum fetuin-A levels, as well as serum HDL-C levels. However, no significant correlation was demonstrated between serum ADMA levels and age, disease duration, and MHAQ. As regards serum fetuin-A levels in RA patients, there was a significant negative correlation between their levels and DAS-28, ESR, hsCRP, ADMA levels, cIMT, and stiffness index β. Moreover, there was a significant positive correlation with RF, TC, LDL-C, TG, TC/HDL-C, as well as LDL-C/HDL-C. However, no significant correlation was demonstrated between serum fetuin-A levels and age, disease duration, MHAQ, and serum HDL-C levels. Moreover, serum AOPP levels were positively correlated with DAS-28, ESR, hsCRP, RF, TC, LDL-C, TG, TC/HDL-C, LDL-C/HDL-C, serum levels of ADMA, cIMT, and stiffness index β. However, serum levels of AOPPs were negatively correlated with both serum fetuin-A and HDL-C levels. No significant correlation was found between AOPP levels, disease duration, BMI and age, and MHAQ.
Table 2: Correlations of serum asymmetric dimethylarginine asymmetric dimethylarginine, fetuin-A, and advanced oxidation protein products with clinical, laboratory, and radiological parameters

Click here to view

As regards multiple linear regression analysis, serum ADMA levels were positively and significantly associated with DAS-28 (β = 0.299; P < 0.05), hsCRP (β = 0.389; P < 0.05), LDL-C (β = 0.489; P < 0.05), and cIMT (β = 0.556; P < 0.05). However, serum fetuin-A levels were negatively and significantly associated with DAS-28 (β = −0.345; P < 0.05), hsCRP (β = −0.296; P < 0.05), cIMT (β = −0.565; P < 0.05), stiffness index β (β = -0.453; P < 0.05), serum ADMA levels (β = −0.542; P < 0.05), and AOPPs (β = −0.278; P < 0.05). In addition, serum AOPPs were positively associated with DAS-28 (β = 0.299; P < 0.05), hsCRP (β = 0; P < 0.05), LDL-C (β = 0.432; P < 0.05), and cIMT (β = 0.565; P < 0.05).

  Discussion Top

Autoimmune disorders are associated with significantly enhanced cardiovascular morbidity and mortality, which is not fully explained by traditional CVD risk factors. It has been suggested that interactions between high-grade systemic inflammation and the vasculature lead to endothelial dysfunction and atherosclerosis, which may account for the excess risk for CVD events in this population [27] . Diminished nitric oxide synthesis due to downregulation of endothelial nitric oxide synthase appears to play a prominent role in the imbalance between vasoactive factors and the early development of atherosclerosis [28] .

ADMA is one of the most potent endogenous inhibitors of the three isoforms of nitric oxide synthase, and it is a newly discovered risk factor in the setting of diseases associated with endothelial dysfunction and adverse cardiovascular events [29] .

In the present study, serum ADMA levels were significantly increased in patients with RA compared with controls; this is confirmed by other studies in which higher ADMA levels have been reported in patients with RA [30] . Elevated serum ADMA levels have been associated with several mechanisms proposed to explain endothelial dysfunction in various conditions linked with atherosclerosis, including downregulation of dimethylarginine and dimethylaminohydrolase activity secondary to oxidative stress induced by proinflammatory cytokines, with increased expression of protein arginine type I N-methyltransferase, which is responsible for ADMA synthesis and increased endothelial cell turnover with potential liberation of ADMA during cell catabolism [31] .

In the present study, there was a positive correlation between serum ADMA levels and TC, LDL-C, TG, TC/HDL-C, as well as LDL-C/HDL-C; however, there was a negative correlation between levels of serum ADMA and serum HDL-C levels. These results could be explained by the effects of cytokines on adipose tissue and liver to increase free fatty acid (FFA) release and triglyceride synthesis, and at the vascular endothelium to reduce lipoprotein lipase activity, the principal catabolic enzyme for triglyceride. High triglyceride levels reduce HDL-C by virtue of neutral lipid exchange, and this same process promotes synthesis of small, dense LDL [32] . These findings have been confirmed by previous findings, which reported that plasma ADMA may promote atherogenesis as it opposes the vasoprotective effects of nitric oxide [33] ; therefore, elevations in plasma ADMA may accelerate the progression of atherosclerosis and increase the risk of cardiovascular events.

Positive correlations were found also between serum ADMA levels and cIMT. These findings were in agreement with those of Husamettin et al. [34] , who reported a positive correlation between the increased concentrations of ADMA with markers of atherosclerosis, such as cIMT.

Fetuin-A is known to be a negative acute phase reactant. It is often considered as a mediator that links chronic inflammation to CVDs, including vascular calcification [8] .

Our results demonstrated significantly lower serum fetuin-A levels in RA patients that were significantly correlated with the disease activity markers and DAS-28. These findings could be explained by inhibition of proinflammatory cytokines by fetuin-A during inflammation. A decrease in the synthesis of fetuin-A in the liver affects and limits the activities of numerous anti-inflammatory mediators, enabling amplification of proinflammatory mediators [35] .

These results are confirmed by other studies, which estimated that the decreased serum fetuin-A levels may be considered as a promising marker of inflammatory activity among RA patients [9],[10] . In accordance with the results, Sato et al. [36] documented that the decreased serum fetuin-A levels observed in the RA patients inversely correlated with serum C-reactive protein concentration and ESR. In contrast, Koch et al. [37] reported a positive correlation between fetuin-A and hsCRP levels.

Moreover, our results showed a significant negative correlation between serum fetuin-A and ADMA levels, which had an important role in inflammation-induced endothelial dysfunction in healthy participants and in patients with coronary artery disease or RA [38] .

In addition, we found that low serum fetuin-A levels were associated with high IMT, an early marker of atherosclerosis. These results are in agreement with those of Szeberin et al. [39] , who reported that there is a negative correlation between IMT and serum fetuin-A levels in a number of patients with atherosclerotic vascular disease. In contrast to our results, the results of Ix et al. [40] found that lower fetuin-A levels were not related to peripheral artery diseases or common IMT.

The results of the present study demonstrated that serum AOPP levels were significantly increased in RA patients and that serum AOPP levels were positively correlated with cIMT. These results are in agreement with a previous study, which reported that AOPPs were found to be implicated in the expression of monocyte chemoattractant protein-1, promoting migration of monocytes into the vessel wall, thus contributing to the progression of atherosclerosis [41] . Moreover, there was a positive correlation between serum levels of AOPPs and levels of the ESR and hsCRP, which measure the acute phase response, indicating that AOPPs may be a useful marker for monitoring the progress and severity of RA. Oxidative stress resulting in the generation of free radicals in inflamed joints has been suggested to cause increased formation of AOPPs in RA [13] . This hypothesis seems to be in agreement with our results, which showed a positive correlation between DAS-28 and serum levels of AOPPs. Moreover, there was a positive correlation between serum AOPPs and serum ADMA levels. It was found that ADMA can profoundly increase superoxide generation and lipid and protein oxidations from uncoupled nitric oxide synthase [31] . Inhibition of the L-arginine-nitric oxide synthase pathway by ADMA and enhanced oxidative stress are associated with active inflammatory process in RA. Therefore, it might be speculated that elevated ADMA and oxidative stress are associated with an increased risk for cardiovascular events in RA [30] .

  Conclusion Top

On the basis of these results it could be concluded that low levels of fetuin-A, in RA, suggest its possible contribution in arterial stiffness, subsequently causing increase in endothelial dysfunctions. An increase in ADMA and AOPPs in RA patients, together with dyslipidemia, suggests their possible involvement in pathophysiology of vascular diseases in RA. These findings open new avenues for further studies on pathophysiology of CVDs in RA that may lead to a better treatment of these diseases.

  Acknowledgements Top

Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Table 1], [Table 2]


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