| BackgroundAtherosclerosis is clearly an inflammatory disease and does not result simply from the accumulation of lipids. The discovery and functional assessment of cytokines and cytokine networks involved in the inflammatory cascade are receiving growing emphasis.Interleukin 18 (IL-18) is a pleiotropic proinflammatory cytokine that has immunomodulatory effects on both the innate and the adaptive immune systems. Originally identified as an interferon-gamma inducing factor, it stimulates interferon-gamma production in T lymphocytes and natural killer cells, both of which are essential for atherosclerotic plaque progression and stability. IL-18 plays a critical role for in neointimal formation, induces endothelial cell apoptosis via activating p38MAPK-NF-kappaB-PTEN signal transduction pathway and human coronary artery smooth muscle cell migration in matrix metalloproteinase-9-dependent manner, and accelerates atherosclerosis and plaque vulnerability. Plasma IL-18 concentrations are increased in patients with acute coronary syndromes and correlate with the severity of myocardial dysfunction, and plasma IL-18 levels are an independent predictor of coronary events, which suggest that IL-18 mediates later events in plaque unstability and eventual disruption. IL-18 is not an independent risk factors for atherosclerosis in asymptomatic individuals, but IL-18 mRNA is expressed at higher levels in unstable human carotid plaques compared with stable plaques.Among the risk factors for coronary artery disease, diabetes mellitus has a privileged position. Cardiovascular complications are the leading cause of mortality in patients with diabetes mellitus. Diabetes mellitus is a strong independent predictor for both death and myocardial infarction (MI).Increased carotid artery intima-media thickness is a marker of coronary vascular disease which can be measured non-invasively and may be used as a biological marker of coronary artery disease. In addition, an increased carotid artery intima-media thickness may have considerable importance as a screening tool for coronary atheroma.Recently, variations within the IL-18 gene have been shown to influence circulating levels of IL-18 and clinical outcome in subjects with coronary artery disease and play an active role in age-related functional impairment, as well as to affect IL-18 production capability by monocytes. It has been identified single nucleotide polymorphisms (SNPs) in the promoter of IL-18 gene at the position-137G/C (RS187238) can influence the expression of IL-18 and also potentially of IFN-gamma. However, the relationship between the functional promoter polymorphism and coronary artery disease has not been clearly defined.Objectives1 To study the relations of the levels of serum interleukin-18, tumor necrosis factor-a and interleukin 10 with acute coronary syndrome and their clinical significance.2 To investigate the expression and significance of interleukin-18 in coronary heart disease patients with type 2 diabetes mellitus.3 To investigate the clinical relationship of carotid artery intima-media thickness, atherosclerotic plaque and serum interleukin-18 levels in patients with coronary heart diseases.4 To investigate the changes of serum interleukin-18 before and after percutaneous coronary intervention therapy for exploring the Clinical significance.5 To investigate the clinical significance of the single nucleotide polymorphisms (SNPs) in promoter of IL-18 gene at the position-137G/C (RS187238) in patients with coronary artery disease, using the ligase detection reaction-polymerase chain reaction (LDR-PCR) method. Subjects studied in this research are Chinese Han population in Xiangfan region.Methods1 Patient:Cases of coronary artery disease and Control Cases were identified by coronary angiography. Assessment of coronary stenosis requires in at least two orthogonal projections. Lesion severity was then assessed in the projection revealing the greatest extent of narrowing. The diameter of the narrowed segment and reference vessel may be measured by digital and stenosis severity calculated as: %stenosis= (lumen diameter at stenosis site/reference diameter)×100. Diameter narrowing of more than 50% was considered to be Patients Group. The degree of severity is commonly classified into one of the following categories:(1), Normal coronary arteries; (2), Irregularities; (3),< 50% stenosis; (4),50%-69% stenosis; (5),70%-89% stenosis; (6),> or= 90% stenosis; (7), Occlusion. Categories (1), (2), and (3) were belonged to the Control Cases; Category 4) defined as Patients Group 1 (50%～69%stenosis); Category (5) defined as Patients Group 2 (70%～89% stenosis); Categories (6) and (7) were defined as Patients Group 3 (> or= 90% stenosis and Occlusion). Blood was collected from the arteriae femoralis for detection of the serum levels of IL-18 before selective coronary angiography. The concentration of serum IL-18, TNFaand IL-10 was measured with ELISA in patients with acute coronary syndrome (including unstable angina pectoris and acute myocardial infarction), patients with stable angina pectoris and control cases. The relations of the levels of serum interleukin-18, tumor necrosis factor-a and interleukin 10 between groups were analyzed.2 Patients with coronary heart disease were divided in two groups based on the presence or absence of type 2 diabetes mellitus. Diabetes mellitus was considered present if the fasting glucose level was at least 7 mmol/L, or if the patient had been informed of the diagnosis and treatment had been prescribed with a special diet, oral antidiabetic drugs or insulin. The concentration of serum IL-18 was measured with ELISA. The relations of the levels of serum interleukin-18 between groups were analyzed.3 Ultrasonography was performed to measure the carotid artery intima-media thickness and to observe the incidence rate of carotid atheromatous plaque in patients who had been examined by selective coronary angiography. The concentration of serum IL-18 was measured.4 The levels of serum IL-18 in patients with coronary artery disease before percutaneous coronary intervention (PCI) and 12 hours and 2 weeks after percutaneous coronary intervention therapy were measured, changes of IL-18 were analyzed. The cardiovascular events were followed up 12 months after therapy.5 The functional-137 G/C polymorphism (rs187238) in the promoter region of IL-18 gene was genotyped using the ligase detection reaction-polymerase chain reaction. Case patients of coronary artery disease and control patients were identified by coronary angiography and the plasma IL-18 concentrations were measured. Correlation between plasma IL-18 protein levels and genotypes of IL-18 polymorphism in studied population were analyzed.Results1 The serum levels of IL-18 and TNF-awere higher, and level of IL-10 was lower in than patients with coronary heart disease than those in control cases (P< 0.01). The levels of IL-18 and TNF-awere higher, and level of IL-10 was lower in acute coronary syndrome (including unstable angina pectoris and acute myocardial infarction) than patients with stable angina pectoris (P< 0.01). The level of IL-18 in Patients Group 2 (70%～90%stenosis) and Patients Group 3 (> 90% stenosis and Occlusion) was higher than Patients Group 1 (50%～70% stenosis) respectively. There were no significant differences in the levels of TNF-αand IL-10 between these groups.2 The coronary heart disease patients with type 2 diabetes mellitus were similar to the non-diabetic coronary heart disease patients with respect to age, BMI and lipid (P> 0.05). The serum level of IL-18 in patients with coronary heart disease was higher than that with control patients (P< 0.01). Concentration of IL-18 was higher in patients with diabetes mellitus than patients with non-diabetes mellitus. 3 Carotid artery intima-media thickness in coronary disease group was significantly greater than control group (0.93mm±0.26mm vs 0.65mm±0.13mm, P< 0.01). The incidence rate of an carotid atherosclerotic plaques in coronary disease group was significantly higher than control group (97.65% vs 6.9%, P< 0.01). The serum level of IL-18 was in coronary disease group was higher than control group (316.5 pg/ml±94.2 pg/ml vs 36.38 pg/ml±18.99 pg/ml, P< 0.01).4 The concentration of IL-18 12 hours after percutaneous coronary intervention therapy in patients with coronary artery disease was significantly increased than that before therapy (423.5 pg/ml±298.7 pg/ml vs.316.5 pg/ml±274.2 pg/ml, P<0.01), but 2 weeks later it was decreased significantly than that before therapy (286.7 pg/ml±256.9 pg/ml vs.316.5 pg/ml±274.2 pg/ml, P<0.01).5 A significant increase of G allele or GG-genotype was observed in 241 case patients compared to 145 control individuals (frequency of G allele= 0.90 vs 0.83, P=0.004; frequency of GG-genotype= 0.81 vs 0.68, P= 0.005). In case patients, G allele carriers in multi-vessel disease patients had a higher occurrence rate when compared to single-vessel disease patients, but no significant difference was detected (frequency of G allele= 0.92 vs 0.88, P=0.107; frequency of GG-genotype = 0.84 vs 0.75, P= 0.089). IL-18 protein concentration of the-137GG genotype was much higher than concentration of CG and CC genotype (case patients:229.1±131.5 vs 122.7±73.6 pg/ml, P< 0.001; control patients:65.9±31.6 vs 42.4±19.5 pg/ml, P< 0.001).ConclusionsIL-18 and TNF-a are suggested to play a role in atherogenesis and atheromatous plaque rupture leading to the coronary artery disease. Conversely, the anti-inflammatory cytokine IL-10 seems to have an atheroprotective role. Patients of type 2 diabetes mellitus predispose to a higher serum level of IL-18, which may explain their vulnerability to fatal cardiovascular events. Carotid artery intima-media thickness, the incidence rate of carotid atheromatous plaque and the serum levels of IL-18 can be used as a satisfactory index to quantitatively detect carotid artery atherosclerosis, and further to judge the risk factors of coronary heart disease. There is inflammation after percutaneous coronary intervention therapy. IL-18 are sensitive to reflect early inflammation and the changing degree of IL-18 may be one of predictors for cardiovascular events after coronary intervention therapy. IL-18 promoter-137G/C polymorphism influences IL-18 levels and the occurrence of coronary artery disease, suggesting that IL-18 is causally involved in the development of atherosclerosis. In summary, IL-18 and Coronary Artery Disease are closely related.
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