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 Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 31  |  Issue : 4  |  Page : 416-422

Cyclophilin A: a novel biomarker for cardiovascular disease in patients with type 2 diabetes


1 Department of Clinical Pathology, Ain Shams University, Cairo, Egypt
2 Department of Internal Medicine, Ain Shams University, Cairo, Egypt

Date of Submission17-Nov-2019
Date of Decision30-Nov-2019
Date of Acceptance19-Dec-2019
Date of Web Publication18-Aug-2020

Correspondence Address:
MBBCH, MSc, PhD Emad A.M. Abdel Hady Mohammed
Ass. Professor of Internal Medicine, Ain Shams University, 10 Ahmed Saman St. Infront of Serag Mall, Nasr City, Cairo, 1199
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ejim.ejim_147_19

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  Abstract 


Background and aims Type 2 diabetes mellitus (DM) is a strong independent risk factor for coronary heart disease. Cyclophilin A (CyPA) is a protein secreted from vascular smooth muscle cells in response to reactive oxygen species. It is suggested that CyPA plays an important role in later stages of atherosclerosis and plaque rupture. It was demonstrated that plasma levels of CyPA are significantly higher in patients with coronary artery disease (CAD) in proportion to severity of disorder. Moreover, several studies have demonstrated a role of CyPA as a biomarker of CADs. Indeed studies revealed significantly higher plasma levels of CyPA in patients with CAD with type 2 DM.
Objective To assess the severity of CAD among diabetic and prediabetic patients and predict future cardiovascular events.
Patients and methods The study was conducted on 65 patients with CAD diagnosed by coronary angiography, stratified according to GRACE score into low/intermediate/high death risk categories and subdivided into diabetic, prediabetic, and nondiabetic, and 20 age-matched and sex-matched patients, who had normal angiography as a control group. Blood samples were collected for determination of glycated hemoglobin (HbA1c), serum creatinine, cardiac troponin, and CyPA level using double-antibody sandwich enzyme-linked immunosorbent assay technique.
Results There were significantly higher levels of CyPA among patient group than control group (P<0.001). Moreover, significantly higher CyPA levels were detected in diabetic group when compared with normal and prediabetic groups (P<0.029). CyPA was positively correlated with HbA1c in all patients and with diabetic patients. HbA1c was negatively correlated with serum creatinine and positively with estimated glomerular filtration rate in prediabetic group and with systolic blood pressure in diabetic group. The number of occluded vessels was positively correlated with both CyPA and HbA1c. The diagnostic sensitivity and specificity of CyPA were 76.92 and 95%, respectively, at a cutoff value of more than 13 ng/ml.
Conclusion CyPA can be used as an early predictor of CAD in patients with type 2 DM and also in prediabetic patients.

Keywords: coronary heart disease, cyclophilin A, type 2 diabetes


How to cite this article:
Hussain MM, Mohammed EA, El-Sherbeny AA, Shehata AR. Cyclophilin A: a novel biomarker for cardiovascular disease in patients with type 2 diabetes. Egypt J Intern Med 2019;31:416-22

How to cite this URL:
Hussain MM, Mohammed EA, El-Sherbeny AA, Shehata AR. Cyclophilin A: a novel biomarker for cardiovascular disease in patients with type 2 diabetes. Egypt J Intern Med [serial online] 2019 [cited 2020 Sep 20];31:416-22. Available from: http://www.esim.eg.net/text.asp?2019/31/4/416/292207




  Introduction Top


Type 2 diabetes mellitus (DM) is a strong and independent risk factor for coronary artery disease (CAD) [1]. This association is so strong that a diagnosis of DM could be considered a CAD risk equivalent. Individuals with DM have between two and eight times higher rates of cardiovascular events, compared with nondiabetic controls [2]. More than 75% of all mortality in diabetic patients is the result of CAD [3].

During calorie excess, adipocytes undergo hypertrophy and their stromal vascular fraction becomes infiltrated with macrophages. These macrophages around dead adipocytes form ‘crown-like structures,’ associated with expression of cytokines, including tumor necrosis factor-α and interleukin-6 [4]. These changes have been shown to coincide with the onset of insulin resistance and provide a pathophysiological link between metabolic and vascular disease [5]. These pro-inflammatory and metabolic consequences of obesity and insulin resistance result in endothelial dysfunction [6].

It has been reported that the plasma levels of high-sensitivity C-reactive protein, brain natriuretic peptide, D-dimer, and fibrinogen can predict the occurrence of cardiovascular events and progression. However, the plasma levels of these biomarkers are increased in inflammatory diseases, in addition to arteriosclerotic diseases. Thus, the search for a useful biomarker that can effectively predict the risk of future progression to more serious cardiovascular events still remains to be developed [7].

Cyclophilin A (CyPA) belongs to a group of proteins collectively known as immunophilins, which play vital roles in many biological conditions, including protein folding, T-cell activation, and cell signaling [8].

Various cell types have been described to secrete CyPA into the extracellular space. For example, CyPA is released by macrophages upon stimulation with high levels of glucose [9]. Moreover, the release of CyPA by vascular smooth muscle cells appears to highly promote the pathophysiology of vascular inflammation in abdominal aortic aneurysms, vascular restenosis, and atherosclerosis [10]. In addition, both activated platelets and hypoxic cardiomyocytes have been shown to secrete CyPA into the extracellular space [11].

It was demonstrated that the plasma levels of CyPA are significantly higher in patients with CAD in proportion to the severity of the disorder [12]. It was previously reported that the plasma levels of CyPA are significantly higher in patients with CAD with type 2 DM [13]. Indeed, several studies have demonstrated the role of CyPA as a biomarker of CADs [14],[15],[16],[17],[18]. Huang et al. [14] reported that the plasma levels of CyPA 1 month after AMI predict the prognosis of the patients.

In the present study, we aimed to investigate the effect of hyperglycemia on CyPA level in patients suspected to have CAD in comparison with age-matched and sex-matched normoglycemic individuals not suspected to have CAD.


  Patients and methods Top


Study participants

This is a case–control study that was conducted on 65 patients undergoing coronary angiography for suspected CAD (being subdivided according to their GRACE score into low-risk, intermediate-risk, and high-risk patients); their ages ranged from 45 to 65 years. Patients were subdivided into three subgroups [normoglycemic (n=15), prediabetic (n=25), and diabetic (n=25)] according to the American Diabetes Association [19] guidelines, stating to consider DM when glycated hemoglobin (HbA1c) is more than or equal to 6.5%, consider prediabetes when HbA1c is more than or equal to 5.7% but less than or equal 6.4%, and consider being normal when HbA1c is below 5.7%. The patients were selected from the Cardiology Department in Ain Shams University Hospitals during the period from January to March 2019, in addition to 20 age-matched and sex-matched controls. The study was approved by the Ethics Committee for medical research.

All patients with valvular or congenital heart disease, or recent myocardial infarction were excluded from the study. Diabetes was assessed by recording HbA1c, whereas CAD was diagnosed by GRACE score and coronary angiography.

Methods

After an informed verbal consent, all individuals in this study were subjected to comprehensive history taking; physical examination; standard 12-lead ECG; coronary angiography; laboratory investigations assigned in GRACE score, including serum creatinine, HbA1c, and serum troponin; and serum CyPA using enzyme-linked immunosorbent assay (ELISA) technique.

Serum creatinine was performed using Beckman coulter AU 480 system by a modified rate Jaffé method. Estimated glomerular filtration rate (eGFR) was calculated using MDRD equation. Troponin I was assayed using two-step assay chemiluminescent microparticle immunoassay using Architect I 1000. HbA1c was assayed on the D10 dual program based on chromatographic separation of the analytes by ion exchange high-performance liquid chromatography. CyPA concentrations were measured using a double-antibody sandwich ELISA using a commercially available ELISA kit supplied by Korain Biotech Co. Ltd. (Shanghai, China).

Statistical analysis

IBM SPSS statistics (V. 25.0, 2018; IBM Corp., Chicago, Illinois, USA) was used for data analysis. Data were expressed descriptively as median and interquartile range for quantitative skewed data. Comparison between each two groups was done using Wilcoxon rank sum test for skewed data for dependent samples. P value less than 0.05 was considered significant, P value less than 0.01 was considered highly significant, and P value more than 0.05 was considered nonsignificant. Furthermore, the diagnostic performance of the studied parameters was evaluated using receiver operating characteristic curve analysis, in which sensitivity % was plotted on the y-axis and 100-specificity on the x-axis. The best cutoff value (the point nearest to the upper left corner of the curve) was determined.


  Results Top


Description of both clinical and laboratory data are shown in [Table 1] and [Table 2], whereas the number of occluded vessels in all studied groups and the management are shown in [Table 3].
Table 1 Demographic and clinical data and laboratory results of patients and control

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Table 2 Description of laboratory data of patients and control groups

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Table 3 Number of occluded vessels in all studied patient groups

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The most important findings were that HbA1c was significantly higher in all patient groups (mean, 6.238±1.117), with P value less than 0.001.

Moreover, regarding CyPA level, it was significantly higher in patients than control, with mean of 29.515±24.883 and 7.1±3.547, respectively, with P value less than 0.001 ([Table 2]). Moreover, it was significantly higher in diabetic group compared with prediabetic one and normal participants, with P value 0.029, as shown in [Table 4] and [Figure 1] as well.
Table 4 Comparison between cyclophilin A levels among all groups

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Figure 1 Distribution of cyclophylin A level among the 3 studied groups.

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Correlations between both CyPA and HbA1c and all studied parameters are shown in [Table 5]. The most important findings were that CyPA levels were positively correlated with HbA1c in diabetic group (r=0.536, P=0.006). Moreover, HbA1c was significantly positively correlated with systolic blood pressure in diabetic group (r=0.562, P=0.003).
Table 5 Correlation between cyclophilin A and clinical and laboratory results, in addition to correlation between glycated hemoglobin and clinical and laboratory results

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However, in the prediabetic group, there was a significant positive correlation between HbA1c and eGFR (r=0.443, P=0.026), whereas HbA1c was negatively correlated with serum creatinine in the same group. In [Table 6], a significant positive correlation was found between number of occluded vessels and both CyPA levels and HbA1c, with P values of 0.003 and 0.015, respectively, among all groups.
Table 6 Correlation between no. of occluded vessels and cyclophilin A and glycated hemoglobin

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In [Table 7], it was shown that CyPA has 95% specificity and 76.92% sensitivity at cutoff value of more than 13, as shown also in [Figure 2].
Table 7 Receiver operating characteristic for sensitivity and specificity of cyclophilin A

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Figure 2 Sensetivity and specificity of cyclophylin A level.

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  Discussion Top


Importantly, plasma CyPA is significantly increased in patients with inflammatory diseases such as rheumatoid arthritis [20]. Furthermore, it was found that CyPA expression in mice is closely associated with the development of intimal thickening, aortic aneurysms, and atherosclerosis [21],[22],[23]. The secretion of CyPA is regulated by activation of Rho-kinase [24], which plays a crucial role in inflammation, vascular contraction, and the development of atherosclerosis [25],[26]. Thus, it seems plausible that the plasma levels of CyPA may discriminate between patients at high or low risk for CAD.

The present study is a case–control study conducted on 65 patients undergoing coronary angiography for suspected CAD, who were subdivided according to their GRACE score into low-risk, intermediate-risk, and high-risk patients; their ages ranged from 45 to 65 years. Patients were subdivided into three subgroups: normoglycemic (n=15), prediabetic (n=25), and diabetic (n=25). They were selected from the Cardiology Department in Ain Shams University Hospitals. In addition, 20 age-matched and sex-matched individuals were included as a control group.

In the current study, we found that CyPA level was statistically significantly higher in patients proven to have CAD by angiography (29.515±24.883) than control (7.100±3.597), with a P value less than 0.001

This was similar to a study done by Satoh et al. [27], who found that patients with high CyPA levels had a significantly higher prevalence of CAD by coronary angiography than those with low levels of CyPA.

We found that CyPA level was statistically significant higher in diabetic group in comparison with normoglycemic and prediabetic groups (P<0.029). In agreement with our results, Yossef et al. [28] found that there was a statistically highly significant increase in the median CypA concentration in all patient groups in comparison with the control group (P<0.001). Moreover, there was a statistically highly significant increase in the median CypA concentration in diabetic patients with CAD when compared with only diabetic patients group (P<0.001) and in patient with only CAD when compared with diabetic patients with or without CAD (P<0.001).

Ramachandran et al. [13] agreed with us and reported that patients with type 2 DM have higher circulating levels of CypA than the normal population. Plasma CypA levels were increased in patients with DM and CAD, suggesting a role of this protein in accelerating vascular disease in type 2 DM.

Yan et al. [29] also found that serum concentration of CypA in patients with acute coronary syndrome (UA and AMI) was significantly higher than those with stable angina and controls (P<0.05). Hence, increased concentrations of CypA may be a valuable marker for predicting the severity of acute coronary syndrome.

A possible role for CyPA in atherosclerosis is becoming increasingly apparent. It was shown that knockdown of CyPA in EC reduced apoptosis, induced in vitro by tumor necrosis factor-α, and that CyPA deficiency was associated with a marked decrease in EC apoptosis in the early stages of atherosclerosis.

Our study revealed that CyPA level was significantly positively correlated with HbA1c, especially in the diabetic group. Other parameters such as age, systolic blood pressure, diastolic blood pressure, heart rate, serum creatinine, GRACE score, and eGFR had no significant correlation with CyPA among the studied groups.

On the contrary, Ramachandran et al. [13] reported that age was positively associated with increased plasma CypA level, whereas sex, serum levels of cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides were not associated with increase in CypA levels. In contrast, Satoh et al. [27] found that age, diabetes, and dyslipidemia correlated with plasma CypA levels in their patients with stenotic coronary arteries. Moreover, Ramachandran et al. [13] found that fasting blood glucose and HbA1c were positively associated with plasma CypA levels, indicating a specific relation of plasma CypA levels with hyperglycemia.In our study, we found that patients with 3-vessel disease were higher among diabetic patients in comparison with those with prediabetes and normoglycemic patients with CAD. We also found that CyPA level has a statistical significant positive correlation with the number of occluded vessels in patients with CAD (P=0.003). The findings of Satoh and colleagues go in line with our results, when they found that CyPA is a prognostic marker for requirement of cardiovascular intervention such as percutaneous coronary intervention and coronary artery bypass grafting. The increased severity of CAD observed among patients with elevated CyPA may be a consequence of a higher frequency of risk factors for atherosclerosis, all of which promote reactive oxygen species production and CyPA secretion. All these mechanisms, while promoting an environment of oxidative stress, are likely to contribute to the increased plasma levels of CyPA in patients with severe CAD [27].


  Conclusion Top


It was demonstrated that CyPA level is increased in diabetic patients with CAD, and this could be of importance in both prevention and follow-up of type 2 diabetic patients with high cardiovascular risks.

Limitation

The small sample size has some limitation.

Acknowledgements

The authors are grateful to the Cardiology Department and Clinical Pathology Department for their support and help during this work all the time.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  [Full text]  
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