| BackgroundIn recent years, with the rapid development of national economy, change of people’s life style, the incidence of cardiovascular disease has increasing rapidly, and the trend is becoming younger. Coronary atherosclerosis (CAS) is the main fundamental pathology of variety cardiovascular diseases. With the progression of the disease, it can cause stable angina pectoris (SAP) and unstable angina (UA), and when the further development of the disease it can lead to acute myocardial infarction (AMI) and other severe cardiovascular disease. Coronary atherosclerosis heart disease referred as "coronary heart disease (CHD)" is the serious public health hazard and lethal disease in present. Early detection, early diagnosis and early intervention of CHD disease progression is the basic and vital measures to delay and control the cardiovascular events.Atherosclerosis (AS) is a vascular endothelial cell injury pathological process characterized by lipid infiltration and vascular wall inflammation. Vascular endothelial cell can damaged by various factors, thus initiating the inflammatory reaction, inducing serum lipid protein into the vascular intima, leading to accumulation of inflammatory cells, facilitating to generation of foam cells and formation of the necrotic lipid core of atherosclerosis plaque. The inflammation responses induce fiber cell and smooth muscle cell proliferation, the artery vascular wall thickening and luminal stenosis finally.In method of diagnosis of coronary heart disease, coronary angiography is the "golden standard" currently. It is difficult to be used in some severe cardiovascular patients and some patients who allergic to contrast medium, also it can not predict the risk of acute coronary syndrome (ACS). With the forward of prevention of atherosclerosis disease, researchers begin to pay attention to the occurrence and development related mechanisms of atherosclerosis disease, hope to find non-interventional prognosis biomarkers of CHD or ACS, in order to take effective method to treat or cure atherosclerosis diseases in the early stage by these factors. Consequently, reduce the mortality and morbidity of the lethal cardiovascular diseases.Increasing evidence suggests that the inflammation play vital role almost in the entireprocess of initial and development of atherosclerosis and plaque rupture in CHD. Thus, inflammation factors may serve as serum biomarkers of prediction of early stage of CHD or ACS, such as C reaction protein(CRP), interleukin-6(IL-6), interleukin-8(IL-8) and acute phrase serum amyliod(A-SAA) etc. On the other side, chemokines may induce the inflammation through regulation the expression of adhesion molecule or recruiting inflammatory cells directly. Chemokines can induce smooth muscle cell (SMC) proliferation and activation. Therefore, the formation and the progression of CHD may have a closely relationship with the level of chemokines. A large number of clinical studied and epidemiological investigations confirm that homocysteine(Hcy) is a novel independent risk factor for CHD. Hcy may through oxidative stress injury, low methylation reaction, protein homocysteinylation or endothelial progenitor cell dysfunction and finally lead to vascular endothelial injury and formation of atherosclerosis plaque.Recent studies have found matrix metalloproteinase (MMPs) play an important role in the formation and development of atherosclerosis. MMPs specifically combine with extracellular matrix components and degrade it. Researches show that MMPs participate in inflammatory reaction, hypoxic ischemia injury and some other physiological or pathological processes of cardiovascular. MMPs mainly derived from macrophages, fibroblasts, vascular endothelial cells, SMC and foam cells. The composition of fibrous cap determines the stability of the plaque. Atherosclerosis lesions are rich in type Ⅰ collagen. After invasive into the lesions, macrophages secrete MMPs which result in destruction of plaque structure and degradation of type Ⅰ collagen, subsequently produce carboxy-terminal telopeptide of type Ⅰ collagen(ICTP). Currently, ICTP is a marker of metastatic bone tumor index. Compared with other metastatic bone tumor index, ICTP is not influenced by the cathepsin k and osteoclastic bone resorption. A recent research shows that serum ICTP is correlated with necrotic core area of coronary plaque lesions in patients with coronary heart disease,and can be used as a non-invasive surrogate marker for vulnerable plaque lesions in atherosclerotic patients. Therefore the correlation between the serum ICTP and the instability plaque and its relationship with CHD is worth to be clarified.Under normal conditions, the activity of MMPs is not detected, but in atherosclerosis, the activity of MMPs increased significantly. MMP-2 and MMP-9 belong to gelatinases, the main function of gelatinases are to degradation type Ⅳ, Ⅴ, Ⅶ, Ⅹ collagen and elastin and type Ⅰ, Ⅱ, Ⅲ collagen after the proteolytic reaction of collagenase. MMP-2 is highly active in coronary atherosclerosis plaque, and its activation is associated with plaque calcification. The secretion of MMP-2 will degrade of the plaque fibrous cap, leading to formation of unstable plaque. In an animal model of MMP-9 knock out mice, researchers found that the deficiency of MMP-9 will significantly reduce the atherosclerosis lesions, luminal loss and increase of extracellular matrix. Thus it is presumably that inhibition of MMP-9 will strengthen the vascular wall and reduce the number and the volume of the plaque. Relative studies show elevated level of MMP-2 and MM-9 suggest the formation of unstable plaque, and the serum level of MMP-2 and MMP-9 has correlation with the severity of CHD. According to the production mechanism of ICTP, the serum ICTP may closely related to the level of MMPs. Understanding the relationship between ICTP and MMP-2, MMP-9 helps to clear the origination sources of ICTP. Thus the correlation between ICTP and MMP-2, MMP-9 needs to be explored.Objective:1. To investigate the serum level of ICTP in patients with CHD and its clinical value.2. Explore ICTP correlation to MMP-2, MMP-9 and clinical values.Methods:1. Subjects and MethodsFrom October 2013 to May 2014,103 CHD patients were collected as CHD group, including 39 SAP patients,39 UA patients and 25 AMI patients. Within it there are 11 SAP patients,12 UA patients and 6 AMI patients were underwent intravascular ultrasound (IVUS) detection.38 non-CHD volunteers were recruited in control group. The diagnosis of SAP reference in 2006 European Society of Cardiology (ESC) diagnostic criteria. Diagnosis of UA references in the American Heart Association diagnostic criteria. Diagnostic criteria for AMI referenced in ESC diagnosis standard. Exclusion criteria (excluded if one below standard match), (1)Patients with malignant disease history, (2)Patients with severe hepatic and renal dysfunction, (3)Patients with Blood system diseases, (4)Patients with specific immune disease or inflammatory disease, (5)Patients with hyperthyroidism and other kinds of thyroid diseases, (6)Patients with other kinds of disease may cause chest pain diseases, such as pulmonary embolism, aortic aneurysm, cardiomyopathy, valvular heart disease and congestive heart failure, (7)Patients with the upper respiratory tract, liver, kidney and other infectious diseases.2. Experimental methods(1) All patients were evaluated for coronary risk factors including dyslipidemia (triglyceride and low density lipoprotein), sex, age, current smoking, hypertension. The serum levels of ICTP, MMP-2, MMP-9, IL-6 and CRP were detected by enzyme-linked immunosorbent assay (ELISA).(2) IVUS displays the reconstructed color-coded tissue map of plaque composition superimposed on cross-sectional images of the coronary artery (iLab, Boston Scientific, Guangzhou, Guangdong). After baseline angiography, a 3.0-F,40-MHz Ultrasound Imaging catheter was placed distal to the target lesion. The catheter tip was subsequently pulled back using a motorized pullback system, back at the speed of 1mm/s. IVUS of the coronary plaque was performed at the most severe stenosis in each patient. Image data were archived onto a CD-ROM. Using this technology, coronary artery plaques at the section of most severe luminal obstruction were divided into fibrotic tissue, fibro-fatty tissue, necrotic core and dense calcium. Necrotic core area is composed of a mixture of lipidlike dead cells, foam cells and trapped blood cells. In this area, most of any real structure is lost, with some areas containing microcalcification as a byproduct from the dead cells, and friable areas next to sharp calcification become sites of gross instability and rupture. The cross-sectional area (CSA) of the extravascular elastic membrane(EEM) was measured by tracing the leading edge of the adventitia. Plaque plus media CSA was calculated as (EEM_lumen CSA). The percent plaque area was defined as:[(EEM area-lumen area)/EEM area] ×100.3. Statistical analysisAll the data was analyzed with software SPSS 13.0. Statistical chart was drawn by GraphPad Prism 5.01. Summary descriptive statistics for continuous parameters are presented as means±SD.Categorical variables were compared among study groups by using the chi-square test. Student’s t-test (for comparison of continuous parameters between two groups) or 1-way analysis of variance (for comparison of continuous parameters among 3 or more groups), followed by a Tukey post hoc test, was used to test significant differences. If the homogeneity of variance assumption was violated, the nonparametric Kruskale-Wallis test was used instead. The factors that were related at the P< 0.05 level were selected by invariable analyses as independent variable candidates for multiple logistic regression analysis, which were used to evaluate the independent contribution of clinical parameters to CHD. Correlation coefficients were calculated using linear regression analysis. P values of less than 0.05 were considered statistically significant.Results:(1)general clinical data of patients in different groups.In SAP group, there are 17 male patients and 22 female patients with average age of 59.3 years old. In this group, the average BMI is 24.7 kg/m2, the average triglyceride is 4.2 mmol/L and the average low density lipoprotein is 3.4 mmol/L. In SAP group, here are 9 cases of hypertension and 16 cases of smoking. Within UA group, there are 17 male patients and 22 female patients with an average age of 61.2 years old. In UA group, the average BMI is 24.2 kg/m2, the average triglyceride is 4.5 mmol/L and the average low density lipoprotein is 3.5 mmol/L. There are 10 cases of hypertension and 15 smoking cases. In AMI group, here are 11 male patients and 14 female patients. The average age is 59.5 years old. In this group, the average BMI is 25.4 kg/m2, the average triglyceride is 4.9 mmol/L and the average low density lipoprotein is 3.8 mmol/L. In AMI group, there are 6 cases of hypertension and 9 cases of smoking. In healthy control group, here are 16 males and 22 females with the average age of 61 years old. The average BMI in control group is 23.5 kg/m2, the average triglyceride is 4.1 mmol/L and the average low density lipoprotein of 3.2 mmol/L. Among this control group, here are 7 cases of hypertension and 14 cases of smoking. Thus, Age, gender, BMI, the blood pressure, blood lipid levels and the smoking cases, hypertension cases, the number of patients were comparable with no statistical significance, P> 0.05.(2)Comparison of serum levels of ICTP in different groups.The serum level of ICTP in C group is 3.78±1.31 ng/mL, in SAP group the level is 4.11±1.25 ng/mL. Simultaneously, in UA group the serum level of ICTP is 5.25±2.51 ng/mL and 5.46±2.84 ng/mL in AMI group. There was no significant difference between control group and SAP group in the serum levels of ICTP (P> 0.05),the difference between UA and AMI group is not significantly either(P>0.05), however the serum levels of ICTP in UA and AMI group were significant higher than those in SAP and control groups (P<0.05).(3)Comparison of plaque datum analysis by IVUS between SAP and UAP-AMI groupand regression analysis of the relationship between serum ICTP and plaque datum.The average of minimum luminal area (MLA) of SAP group is 6.21±3.50 mm2 and 5.15±2.81 mm2 in UA-AMI group, but there was no significant difference in the MLA, P>0.5. The average plaque area of MLA in SAP group is 6.34±2.42 mm2 and 9.25±2.41 mm2 in UA-AMI group with significant difference, P=0.004. The average plaque stress of SAP group is 51.90±16.30% and 64.94±6.70% in UA-AMI group with significant difference, P=0.004.The average fibrous area of MLA of SAP group is 79.64±6.44% and 70.94±8.33% in UA-AMI group with significant difference, P=0.006.The average lipid area of MLA in SAP group is 7.45±2.91% and 10.83±3.03% in UA-AMI group with significant difference, P=0.006.The average necrosis area of MLA in SAP group is 10.45±4.32% and 17.566.86% in UA-AMI group with significant difference, P=0.005.The average calcium area of MLA in SAP group is 2.18±3.14% and 0.61±1.50% in UA-AMI group, but without significant difference, P=0.16.Negative correlation was observed between serum ICTP and fibrotic area and positive correlation between serum ICTP and lipidic area (P< 0.05).(4)Comparison of serum levels of MMP-2、MMP-9、CRP、IL-6 in different groups.The serum level of MMP-2 in C group is 1.36±0.89 ng/mL, in SAP group the level is 1.45±1.02 ng/mL. Differently, in UA group the serum level of MMP-2 is 2.34±1.47 ng/mL and 3.44±1.89 ng/mL in AMI group. The serum level of MMP-9 in C group is 302.15±84.33 ng/mL, in SAP group the level is 317.53±89.17 ng/mL. Simultaneously, in UA group the serum level of MMP-9 is 393.04±185.46 ng/mL and 463.18±222.09 ng/mL in AMI group. There is no significant difference between control group and SAP group in the serum levels of MMP-2 and MMP-9 (P> 0.05),the difference between UA and AMI group is not significantly either(P>0.05), however the serum levels of MMP-2 and MMP-9 in UA and AMI group are significant higher than those in SAP and control groups (P<0.05).The serum level of CRP in C group is 2.63±1.19 mg/L, in SAP group the level is 3.78±1.38 mg/L. Differently, in UA group the serum level of CRP is 4.69±1.59 mg/L and 5.39±1.95 mg/L in AMI group. The serum level of IL-6 in C group is 67.39±49.34 mg/L, in SAP group the level is 116.00±48.20 mg/L. While, in UA group the serum level of IL-6 is 164.78±51.41 mg/L and 196.45±59.85 in AMI group. There is significant difference between control group and SAP group in the serum levels of CRP and IL-6 (P<0.05), the serum levels of CRP and IL-6 in UA and AMI group are significant higher than those in SAP and control groups (P< 0.05). The difference between UA and AMI group is not significantly higher in the serum level of CRP (P>0.05), however there is significant difference in the serum IL-6 between UA and AMI group.(5)There was a significant positive correlation between serum ICTP and MMP-2, and between ICTP and MMP-9 by regression analysis(P<0.05).Conclusions1. It is possible that serum ICTP can be used as a non-invasive marker for the presence and severity of vulnerable plaques in ACS patients without cancer metastasis to bone, and the level of ICTP is more correlated to MMP-2 than MMP-9.2. Increased serum level of MMP-2 and MMP-9 may become a biomarker to prognosis the formation of atherosclerosis instability plaque, while MMP-2 and MMP-9 can’t be used as the risk factor to predict early coronary heart disease. |
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