|Year : 2020 | Volume
| Issue : 1 | Page : 288-294
Chemerin levels in patients with coronary artery disease
Mohammed F Elnoamany1, Ashraf A Dawood2, Mahmoud A Aboelezz3
1 Department of Cardiology, Faculty of Medicine, Menoufia University, Menoufia, Cairo, Egypt
2 Department of Biochemistry, Faculty of Medicine, Menoufia University, Menoufia, Cairo, Egypt
3 Department of Cardiology, Ministry of Health, Cairo, Egypt
|Date of Submission||22-Mar-2019|
|Date of Decision||17-Apr-2019|
|Date of Acceptance||27-Apr-2019|
|Date of Web Publication||25-Mar-2020|
Mahmoud A Aboelezz
Mansoura, Dakahlia 35511
Source of Support: None, Conflict of Interest: None
To evaluate chemerin levels in patients with coronary artery disease and detect the correlation between these levels (if any) with the severity of coronary artery disease.
Recent evidence demonstrated that the circulating adipokines were associated with the onset of coronary artery disease (CAD). As a novel adipokine; chemerin has been related to atherosclerosis and the presence of coronary artery disease. However, the plasma levels of chemerin in patients with acute coronary syndrome (ACS) have yet to be investigated.
This study a prospective case-control study included 96 participates undergoing coronary angiography at cath lab, cardiology department-Menoufia University from January 2018 to September 2018. Serumchemerin levels weremeasured by an enzyme-linked immunosorbent assay (ELISA). Echocardiography, electrocardiography and routine laboratory investigations were done. The severity of coronary stenosis was estimated usingGensini, vessel and severity coronary scores.
Among the 96 patients, 4groups were described: group I included 24 Acute myocardial infarction (AMI) patients, 30 unstable angina (UA) patients in group II, 27 stable angina (SA) patients inGroup III, 15 patients with normal coronary artery findings (control group) in Group IV. Serumchemerin levels were significantly higher in AMI and UA groups than SAand control groups P < 0.001. Also there was a high significant positive correlation between serum chemerin levels and severity of CAD as regard to Gensiniscore P < 0.001, severity score P < 0.001 and vessel score P = 0.005.
Chemerin is a novel biomarker for CAD and it was significantly correlated with various metabolic risk factors and atherosclerotic cardiovascular disease.
Keywords: acute coronary syndrome, enzyme.linked immunosorbent assay, serum chemerin levels
|How to cite this article:|
Elnoamany MF, Dawood AA, Aboelezz MA. Chemerin levels in patients with coronary artery disease. Menoufia Med J 2020;33:288-94
| Introduction|| |
Coronary artery disease (CAD) is typically divided into different clinical types including stable angina (SA) and acute coronary syndrome (ACS). ACS including unstable angina (UA) and acute myocardial infarction (AMI) is the clinical definition of the critical phase of CAD, which results primarily from a disruption of a coronary atherosclerotic plaque associated with partial or complete thrombotic vessel occlusion. In contrast, SA is the initial manifestation of ischemic heart disease in one-half of patients and becomes a recurrent symptom in survivors of ACS that is generally due to one or more significant obstructive, but more stable lesions, in coronary arteries. Although chronic inflammation is a characteristic shared between ACS and SA, inflammatory response is significantly more robust in ACS than in SA. In addition, the prognosis for ACS is poorer than for SA, and revascularization therapy must be performed promptly in ACS, but deliberately in those SA patients who had symptoms after optimal medial therapy or were performed by appropriate intracoronary assessment of hemodynamic relevance. Therefore, it is necessary and helpful to seek the biomarkers associated with the presence of ACS.
Adipose tissue serves not only as a mass of fat for storing energy but also as an active endocrine organ that secretes various bioactive adipokines. Most adipokines, such as tumor necrosis factor-α, interleukin-6, and visfatin and leptin are well-known pro-inflammatory cytokines that accelerate atherosclerosis in the experimental model, and contribute to the presence of ACS.
Chemerin, which is also known as tazarotene-induced gene 2 protein or retinoic acid receptor responder 2, is a novel adipokine that plays a pivotal role in adipose differentiation, maturation and metabolism, regulation of immune response, and insulin resistance. In addition, chemerin acts as an inflammatory mediator to promote the migration of macrophages and immature dendritic cells and the production of pro-inflammatory cytokines. However, chemerin was also demonstrated to play an anti-inflammatory role as chemerin significantly prevented tumor necrosis factor-α-induced VCAM-1 expression and monocyte adhesion by inhibiting the activation of nuclear factor-КB and p38in vitro. So, the authors intend to evaluate chemerin levels in patients with CAD and detect the correlation between these levels (if any) with the severity of CAD.
| Patients and Methods|| |
This study is a prospective case–control study which included 96 participates who were undergoing coronary angiography at Cath Lab, Cardiology Department, Menoufia University from January 2018 to September 2018.
The patients were divided into four groups: 24 of them with AMI confirmed by a significant increase of troponin I and creatine kinase MB levels; 30 UA patients who were expressing chest pain at rest with definite ischemic ECG changes (ST-segment changes and/or T-wave inversions); 27 SA patients complaining of typical exertional chest discomfort that was associated with effort and relived with rest, and 15 control group patients with normal coronary artery findings. Patients with the following diseases were excluded from the study: valvular heart disease, thromboembolism, collagen disease, disseminated intravascular coagulation, advanced liver disease, renal failure, malignant disease, septicemia, other inflammatory disease, or current steroid therapy.
A complete history was taken including the history of smoking, hypertension, dyslipidemia, previous cardiovascular disease, and family history of CAD. Blood pressure and heart rate were measured. Neck veins, chest examination, abdominal examination, and local cardiac examination were done. All patients underwent ECG and echocardiography.
Diabetes mellitus was diagnosed according to WHO and the American Diabetes Association as fasting blood glucose more than or equal to 126 mg/dl (≥7 mmol/l) or 2 h postprandial blood glucose more than or equal to 200 mg/dl (≥11.1 mmol/l), or random blood glucose more than or equal to 200 mg/dl and presence of diabetes symptoms, or glycated hemoglobin more than or equal to 6.5 g/dl.
Serum urea and creatinine, fasting and postprandial blood sugars, glycated hemoglobin, lipid profile, creatine kinase MB, troponin and serum chemerin levels by enzyme-linked immunosorbent assay (ELISA).
Five milliliters of fasting (12–14 h) venous blood was withdrawn from the cubital vein of every patient just before coronary angiography. A measure of 2 ml was transferred slowly into a vacutainer EDTA tube and centrifuged for 5 min at 4000 rpm, the plasma obtained for determination of plasma glucose was frozen at −20°C till analysis. A measure of 3 ml was transferred slowly into a plain tube for determination of serum total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol and was left for 30 min for clotting and centrifuged for 10 min at 4000 rpm. The serum obtained was frozen at −20°C till analysis. Blood glucose, serum cholesterol, triglycerides, and HDL cholesterol were determined by enzymatic colorimetric test. Low-density lipoprotein (LDL) cholesterol was estimated by the Friedewald formula.
Lipid profile measurement
Serum cholesterol and triglycerides were determined by enzymatic colorimetric test, using kits supplied by Spinreact (Vall D'En Bas (la), Girona, Spain).
Serum HDL cholesterol was determined by colorimetric method, using Human ELISA kit supplied by Spinreact (Spain).
Serum chemerin measurement
Human Chemerin ELISA kit (Chongqing Biospes Co. Ltd, Paradise Walk, Jiangbei District, Chongqing, China):
Diagnostic coronary angiography was carried out in all patients and a scoring of CAD was done by:
- Gensini score: it grades narrowing of the lumen of the coronary artery and scores it as: 1 for 1–25% narrowing, 2 for 26–50% narrowing, 4 for 51–75% narrowing, 8 for 76–90% narrowing, 16 for 91–99% narrowing, and 32 for a completely occluded artery. The score is then multiplied by a factor according to the importance of the coronary artery as follows: left main stem lesion is 5, proximal left anterior descending artery (LAD) is 2.5, proximal left circumflex artery (LCX) is 2.5, mid LAD lesion is 1.5, distal LAD, mid and distal LCX and right coronary artery lesions have a score of 1. Any branch is 0.5
- Vessel score the one in which severity is assessed as no vessel disease, one vessel disease, two-vessel disease, and multi-vessel disease
- Severity score: the coronary circulation was divided into eight proximal segments. Disease in the distal segments was not considered because of difficulty in quantitating the severity of lesions in these areas. The eight proximal segments scored included the left main coronary artery, LAD up to the junction of the middle and distal third of the vessel, the proximal third of the major septal branch of the LAD, the proximal third of the major diagonal branch of the LAD, the LCX up to the junction of the middle and distal thirds of the vessel, the proximal third of the major obtuse marginal branch of the LCX, the right coronary artery up to and including the origin of the posterior descending coronary artery, and the proximal third of the posterior descending coronary artery.
The study was approved by Cardiology Department (Menoufia University), Ethics Committee, and all patients and controls gave a written informed consent.
Data were analyzed using the Statistical Program for the Social Sciences (SPSS), version 23.0 for Windows (SPSS Inc., Chicago, Illinois, USA), NCSS 12 for Windows (NCSS LCC., Kaysville, Utah, USA), and MedCalc 15.4 for Windows (MedCalc Software BVBA, Ostend, Belgium). Quantitative data were expressed as mean ± SD. Qualitative data were expressed as frequency and percentage. The sample size included 96 participants.
| Results|| |
Clinical characteristics of the study population
The baseline characteristics of the four groups are shown in [Table 1]. In the control group (n = 15), six were men, and the mean age was 57.1 ± 11.6 years. In the SAP group (n = 27), 21 were men, and the mean age was 57.2 ± 6.7 years. In the unstable angina patients (UAP) group (n = 30), 22 were men, and the mean age was 56.5 ± 10.5 years. In the AMI group (n = 24), 20 were men, and the mean age was 55.5 ± 11.0 years.
|Table 1: Comparison between the studied groups regarding demographic data and risk factors|
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No significant differences in age, history of hypertension, diabetes, or BMI were observed among the four groups. History of smoking and male sex score were significantly higher in the UA and AMI groups than in the control group.
As shown in [Table 2] and [Figure 1], the plasma chemerin levels in patients with CAD (SA, UA, and AMI groups) were significantly increased compared with those of the control group. In addition, the plasma chemerin levels in AMI and UA groups were significantly increased compared with those in the SA group.
|Table 2: Comparison between the studied groups regarding serum chemerin levels|
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|Figure 1: Comparison between the studied groups regarding the serum chemerin level.|
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As shown in [Table 3], analyzing the correlation of chemerin and other variables within all study groups showed that the circulating chemerin level exhibited no significant differences with age, BMI, total cholesterol level, triglycerides, HDL, LDL, and serum creatinine. In addition, the plasma chemerin levels showed significant differences with ejection fraction, CK-MB, Gensini and severity and vessel scores.
|Table 3: Correlation analysis of chemerin and other variables within all study groups (n=96)|
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In our study, receiver-operating characteristics curve showed that the cutoff value of serum chemerin levels for detection of CAD was more than or equal to 48.2 ng/ml with a sensitivity of 83.3%, specificity of 88.1%, accuracy of 85.4%, positive predictive value of 90.0%, and negative predictive value of 80.4% [Table 4] and [Figure 2].
|Table 4: Acute coronary syndrome diagnostic performance of chemerin (ng/ml); receiver-operating characteristic curve analysis|
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|Figure 2: ACS diagnostic performance of chemerin (ng/ml). ACS, acute coronary syndrome.|
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| Discussion|| |
Atherosclerosis causes cardiovascular disease by atherosclerotic plaques developing on the endothelium of medium to large arteries. Atherosclerosis generally develops in vessels of all dimensions from weak to hard. Atherosclerosis is a chronic inflammatory response of the arterial wall to endothelial injury and the inflammation cascade. Risk factors for cardiovascular diseases cause structural and functional endothelial dysfunctions. Among other factors, chemerin is known to be responsible for CAD development. Chemerin affects adipose tissue differentiation, maturation and function through its autocrine and its paracrine actions. Chemerin also shows some important endocrine roles in immunity and metabolism. Chemerin was initially described in 2003 as a novel chemoattractant protein.
Chemerin undergoes enzymatic proteolysis and performs its functions through several G protein receptors such as CMKLR1, GPR1, and CCRL2. In 2007, the role of chemerin as a novel adipokine was discovered and its effects on adipogenesis, metabolism, and sustained inflammation were then established.
This study was designed to investigate the relationship between chemerin levels and the presence, extent, and severity of CAD. In this study, the mean ± SD for age of all patients were 56.5 ± 9.8 years, and the men represented about 71.9% of patients with 55.2% of all patients being smokers, 52.1% had hypertension, and 36.5% had diabetes mellitus. In this study, 25% of all patients had myocardial infarction, 31.3% had UA, 28.1% had SA while the control group were 15.6%. Our study showed no significant difference concerning age in all groups; this might be due to the limited number of patients included.
In our study, we found out that male sex was higher in the whole study population (71.9%), mostly because men are more prone to ischemic heart disease; it is assumed that the exposure to endogenous estrogen during the fertile period of life delays the manifestation of atherosclerotic disease in women.
In our study, smoking has specific significance with CAD groups. There was no specific significance of hypertension in our study; this may be explained by the fact that they included a very large sample size in this study. There was no statistically significant difference regarding BMI mostly because our study population were all overweight. There was no statistically significant correlation between serum chemerin and the lipid profile parameters, including total serum cholesterol, LDL cholesterol, HDL cholesterol, and serum triglycerides.
In our study, there were highly significant statistical differences between ACS, SA, and control group as regards serum chemerin levels, where the mean serum chemerin level in the ACS group (MI and UA patients) was 57.18 ± 14.37 ng/ml with the mean serum chemerin levels in MI and UA groups being 63.29 ± 16.34 and 52.30 ± 10.48, respectively. The mean serum chemerin level in the SA group was 42.10 ± 6.59 ng/ml and the mean serum chemerin level in the control group was 38.23 ± 5.90 ng/ml. This suggests that there is a direct relation between serum chemerin levels and coronary atherosclerosis. Also, there was a high significant positive correlation between serum chemerin levels and severity of CAD as regards Gensini and severity scores.
These values are in agreement with the results of two studies by Xiaotao et al. on a total of 132 Chinese patients with CAD and 56 patients without CAD who underwent coronary angiography for the evaluation of CAD and had their serum chemerin levels measured, where serum chemerin levels were significantly elevated in the group with CAD, compared with those without CAD, suggesting that increased chemerin levels are associated with the presence of CAD and that serum chemerin levels may reflect the extent of coronary atherosclerosis.
Although significantly high serum chemerin levels were found in CAD, it is not clearly known if this increased level represents a predictor for CAD or is a result of atherosclerotic plaque morphology. Also, these values are in agreement with the results of studies by Yoo et al. and Aksan et al., which demonstrated that in metabolic syndrome patients (the metabolic syndrome is a cluster of coronary heart disease risk factors including high blood pressure, dyslipidemia, hyperglycemia and insulin resistance), chemerin levels were higher in patients with CAD than those in patients without CAD and showed a significant positive correlation with CAD severity. Analysis of results indicated that serum chemerin levels were a significant and independent predictor for determining the presence of angiographic CAD.
Also Kostopoulos et al. evaluated the contributions of chemerin in the development of coronary atherosclerotic lesions, and detected high levels of chemerin in periadventitial adipose tissues, foam cells, vascular smooth-muscle cells in the regions of atherosclerotic lesions, and found a significant correlation between the level of chemerin released from these cells and the severity of atherosclerotic lesions. Cross-sectional studies of human autopsy specimens have demonstrated that aortic and coronary atherosclerosis is positively correlated with chemerin expression in perivascular fat.
Gensini et al. showed that chemerin mRNA expression in the epicardial adipose tissue is significantly higher in patients with CAD compared with healthy controls. They also added that the severity of coronary atherosclerosis is positively correlated with the level of chemerin mRNA in the epicardial adipose tissue rather than its circulating level.
Dong et al. have conducted a study including a total of 112 patients with metabolic syndrome (66 patients with CAD and 46 without CAD) and 52 healthy participants, all of whom underwent coronary angiography for the evaluation of CAD and serum levels of chemerin had been measured for all patients. Serum chemerin levels were significantly elevated in metabolic syndrome patients with CAD compared with those without CAD and healthy participants. Metabolic syndrome patients without CAD also had higher serum chemerin levels compared with healthy participants. They concluded that elevated serum chemerin levels could be considered as an independent predictive marker of the presence of CAD in patients with metabolic syndrome.
Similar results were shown by Yan et al., who conducted a study including a total of 430 participants from a Chinese population (239 with CAD and 191 without CAD) who underwent coronary angiography. Their results showed that serum chemerin levels were associated with CAD independent of other cardiovascular risk factors but they also showed that serum chemerin levels were significantly increased as the number of diseased coronary artery vessel increased and were positively related to the used Gensini score, which was contradictory to our results as regards the positive correlation between serum chemerin and Gensini score.
These studies have attempted to determine the relationship between chemerin levels and development of coronary atherosclerosis.
On the other hand, Lehrke and colleagues in a cross-sectional study of 303 patients with stable typical or atypical chest pain who underwent dual-source multislice computed tomography angiography demonstrated that chemerin levels had a weak positive correlation with coronary plaque burden and the number of noncalcified plaques. These associations were lost after adjusting for established cardiovascular risk factors for coronary plaque burden. They concluded that although serum chemerin is strongly associated with markers of inflammation and components of the metabolic syndrome, however, chemerin could not predict coronary atherosclerosis.
Several reasons can explain the conflicting results, such as the use of multislice computed tomography angiography to evaluate coronary atherosclerosis index and enrollment of patient populations with different ethical backgrounds and basal characteristics. Variability could also arise when measuring total chemerin levels, because chemerin ELISA kits can detect prochemerin as well as some proteolytically processed short forms of chemerin in their study.
Also Becker et al. was not able to show a significant increase in the area of atherosclerosis with long-term chemerin expression in their in-vivo study and Aronis et al. has found similar ACS group and control group results in their case–control study. They were not able to show chemerin as a predictor of ACS in their logistic regression analysis.
| Conclusion|| |
Chemerin is a novel biomarker for CAD and it was significantly correlated with various metabolic risk factors and atherosclerotic cardiovascular disease. So, chemerin could be used as a biomarker to identify high-risk patients, such as MetS or diabetic patients, who could develop atherosclerotic heart disease.
It is correlated with the presence and severity of CAD according to Gensini and severity scores. As serum chemerin levels also correlate with the extent of the disease, it may also be helpful in guiding the treatment strategy.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]