Interleukin-18, matrix metalloproteinase-22 and -29 are independent risk factors of human coronary heart disease.

BACKGROUND: Coronary heart disease (CHD) is characterized by arterial wall inflammation and matrix degradation. Matrix metalloproteinase (MMP)-22 and -29 and pro-inflammatory cytokine interleukin-18 (IL18) are present in human hearts. IL18 may regulate MMP-22 and -29 expression, which may correlate with CHD progression. METHODS AND RESULTS: Immunoblot analysis showed that IL18 induced MMP-22 expression in human aortic smooth muscle cells. The Mann Whitney test from a prospective study of 194 CHD patients and 68 non-CHD controls demonstrated higher plasma levels of IL18, MMP-22 and -29 in CHD patients than in the controls. A logistic regression test suggested that plasma IL18 (odds ratio (OR)=1.131, P=0.007), MMP-22 (OR=1.213, P=0.040), and MMP-29 (OR=1.198, P=0.033) were independent risk factors of CHD. Pearson's correlation test showed that IL18 (coefficient (r)=0.214, P=0.045; r=0.246, P=0.031) and MMP-22 (r=0.273, P=0.006; r=0.286, P=0.012) were associated with the Gensini score before and after adjusting for potential confounding factors. The multivariate Pearson's correlation test showed that plasma MMP-22 levels correlated positively with high-sensitive-C-reactive protein (hs-CRP) (r=0.167, P=0.023), and MMP-29 levels correlated negatively with triglyceride (r=-0.169, P=0.018). Spearman's correlation test indicated that plasma IL18 levels associated positively with plasma MMP-22 (r=0.845, P<0.001) and MMP-29 (r=0.548, P<0.001). CONCLUSIONS: Our observations suggest that IL18, MMP-22 and -29 serve as biomarkers and independent risk factors of CHD. Increased systemic IL18 in CHD patients may contribute to elevated plasma MMP-22 and -29 levels in these patients.

Clinical Value of CYP2C19 Genetic Testing for Guiding the Antiplatelet Therapy in a Chinese Population.

OBJECTIVE: To compare the clinical effects between individual antiplatelet therapy guided by CYP2C19 genetic testing and conventional dual antiplatelet therapy in patients with coronary artery disease after percutaneous coronary intervention. METHODS: In total of 628 coronary artery disease patients who had undergone successful percutaneous coronary intervention were included in this study. Patients were consecutively divided into routine group (n = 319) and individual group (n = 309) because of weather received CYP2C19 genetic testing. The individual group was divided again into extensive metabolizer group, intermediate metabolizer group, and poor metabolizer group according to CYP2C19 genotype. Then extensive metabolizer group received 75 mg daily of clopidogrel, intermediate metabolizer group received 150 mg daily of clopidogrel, and poor metabolizer group received ticagrelor 90 mg twice daily. Routine group was treated with clopidogrel 75 mg daily conventionally. The primary end points were defined as major adverse cardiovascular events (MACE), namely a composite of death from any cause, myocardial infarction, or target vessel revascularization. Safety end points were bleeding events classified by GUSTO. RESULTS: All the 628 patients were followed for an average of 12 months and clinical outcomes were analyzed at 1, 6, and 12 months after discharge. The morbidity rates of MACE in individual group were all lower than those in routine group at 1, 6, and 12 months (1.3% vs. 5.6%, P = 0.003; 3.2% vs. 7.8%, P = 0.012; 4.2% vs. 9.4%, P = 0.010). No significant difference in the rates of bleeding was found between the 2 groups (P > 0.05). Even performed a multivariate logistic regression analysis, the benefit of individual antiplatelet therapy remained. CONCLUSION: Individual antiplatelet therapy guided by CYP2C19 genetic testing significantly reduced the rate of MACE without an increase in the rate of bleeding in the near term in this Chinese population.

Prognostic value of total bilirubin in patients with angina pectoris undergoing percutaneous coronary intervention.

BACKGROUND: Bilirubin is a potent antioxidant and previous studies have reported the relationship between low serum bilirubin concentration and atherosclerosis. OBJECTIVE: To evaluate the prognostic value of serum total bilirubin (STB) in patients with angina pectoris undergoing percutaneous coronary intervention (PCI). METHODS: In total of 1419 patients (931 men, mean age 60.9±10.5 years) with angina pectoris who had undergone successfully percutaneous coronary intervention (PCI) were included in this study. Patients were divided into 2 groups according to the median baseline STB (0.49 mg/dL in this cohort), which was measured before the PCI. Patients with a STB ≥0.49 mg/dL were classified into the high STB group and those with a STB <0.49 mg/dL were classified into the low STB group. RESULTS: The incidence of in-hospital mortality and myocardial infraction was similar in the two groups. After a mean follow-up of 29.0±7.6 months, the incidence of death/myocardial infarction/stroke was significantly higher in low STB group compared with high STB group. Multivariate Cox regression analysis showed that low STB was an independent predictor of death/myocardial infarction/stroke (hazard ratio (HR) = 1.59, 95% confidence interval (CI) = 1.04-2.41, P = 0.031). The cumulative survival rate free from death/myocardial infarction/stroke was lower in low STB group than in high STB group (P = 0.002). CONCLUSION: Low STB levels before PCI is an independent predictor of long-term adverse clinical outcomes in patients with angina pectoris.

Effects of high glucose on human umbilical vein endothelial cell permeability and myosin light chain phosphorylation.

BACKGROUND: Diabetes mellitus is one of the most important risk factors for atherosclerosis. However, the mechanisms underlying high-glucose-induced atherosclerosis remain unclear. This study was designed to observe the effects of high-glucose stimulation on the permeability of cultured human umbilical vein endothelial cells (HUVECs), and to explore the effects of RhoA-Rho-associated protein kinase (ROCK) signal transduction pathway activation and myosin light chain (MLC) phosphorylation. METHODS: HUVECs were cultured in conventional M199 medium to produce endothelial cell monolayers, and stimulated with high-glucose-M199 medium. The transmembrane transport of dextran and THP-1 cells and levels of MLC phosphorylation were measured. The effects of blocking the RhoA-ROCK pathway using dnRhoA or the ROCK inhibitor Y27632 on dextran and THP-1 transport and MLC phosphorylation were observed. RESULTS: Transendothelial migration of dextran and THP-1 cells were significantly increased by stimulation of HUVEC monolayers with high glucose (P < 0.05). This effect was attenuated by treatment with dnRhoA or Y27632. CONCLUSION: High-glucose stimulation upregulated MLC phosphorylation and increased endothelial permeability by activating the RhoA-ROCK signaling pathway in HUVECs in vitro.

Plasma levels of C1q/TNF-related protein 1 and interleukin 6 in patients with acute coronary syndrome or stable angina pectoris.

BACKGROUND: C1q/TNF-related protein 1 (CTRP-1), a novel adipocyte factor, may participate in the mechanisms of metabolism and inflammation. Interleukin 6 (IL-6) is a proinflammatory cytokine that is correlated with the severity of coronary heart disease (CHD). In this study, we focused on the levels of CTRP-1 and IL-6 in patients with CHD. METHODS: Circulating CTRP-1 and IL-6 levels were measured using enzyme-linked immunosorbent assay in 81 patients with acute coronary syndrome (n=41) or stable angina pectoris (n=40). CTRP-1 and IL-6 levels were also examined in 30 healthy individuals (control group). We examined the correlations between the levels of CTRP-1 and IL-6 and cardiac risk factors in CHD. Logistic regression analysis was performed to screen for factors that predict CHD. RESULTS: Both CTRP-1 and IL-6 concentrations were increased in the acute coronary syndrome or stable angina pectoris group compared with the control group (P<0.01). Both plasma levels of CTRP-1 and IL-6 in the single-, double- and triple-vessel lesion group were higher compared with the control group (P<0.01). CTRP-1 levels were positively correlated with IL-6 (r=0.667, P<0.01) and high-sensitivity C-reactive protein levels (r=0.520, P<0.01) and negatively correlated with HDL-C (r=-0.432, P<0.01). The logistic regression analysis showed that increases in CTRP-1 and IL-6 levels may be powerful predictors of CHD. CONCLUSIONS: The variation of plasma CTRP-1 and IL-6 concentrations may play an important role in reflecting the degree of inflammation in CHD and the severity of coronary arterial atherosclerosis. This potential suggests that evaluating CTRP-1 and IL-6 in combination may aid in predicting the occurrence of CHD.

Domestic versus imported drug-eluting stents for the treatment of patients with acute coronary syndrome.

BACKGROUND: The application of coronary stents, especially drug-eluting stents (DESs), has made percutaneous coronary intervention (PCI) one of important therapeutic methods for CHD. DES has reduced the in-stent restenosis to 5%-9% and significantly improved the long-term prognosis of patients with CHD. The study aimed to investigate the long-term efficacy and safety of domestic drug-eluting stents (DESs) in patients with acute coronary syndrome (ACS). METHODS: All patients with ACS who had undergone successful percutaneous coronary intervention (PCI) in the First Affiliated Hospital of Zhengzhou University from July 2009 to December 2010 were included in this study. Patients were excluded from the study if they were implanted with bare metal stents or different stents (domestic and imported DESs) simultaneously. The included patients were divided into two groups according to different stents implanted: domestic DESs and imported DESs. RESULTS: In the 1 683 patients of this study, 1 558 (92.6%) patients were followed up successfully for an average of (29.1±5.9) months. 130 (8.3%) patients had major adverse cardiovascular events (MACEs), including cardiac death in 32 (2.1%) patients, recurrent myocardial infarction in 16 (1%), and revascularization in 94 (6%). The rates of cardiac death, recurrent myocardial infarction, revascularization, in-stent restenosis, stent thrombosis and other MACEs were not significantly different between the two groups (all P>0.05). Multivarite logistic regression revealed that diabetes mellitus (OR=1.75, 95%CI: 1.09-2.82, P=0.021), vascular numbers of PCI (OR=2.16, 95%CI: 1.22-3.83, P=0.09) and PCI with left main lesion (OR=9.47, 95%CI: 2.96-30.26, P=0.01) were independent prognostic factors of MACEs. The Kaplan-Meier method revealed that there was no significant difference in cumulative survival rates and survival rates free from clinical events between the two groups (all P>0.05). CONCLUSIONS: The incidences of clinical events and cumulative survival rates are not statistically different between domestic DESs and imported DESs. Domestic DES is effective and safe in the treatment of patients with ACS.

Long-term follow-up results in patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stents: results from a single high-volume PCI centre.

OBJECTIVE: To assess both short-term and long-term prognosis in consecutive patients with coronary heart disease treated with drug-eluting stents in a high-volume percutaneous coronary intervention (PCI) centre. DESIGN: Observational cohort study. SETTING: A hospital in the Henan province, China, between 2009 and 2011. PARTICIPANTS: A total of 2533 patients were enrolled. Patients with ST-elevation myocardial infarction (STEMI) treated with urgent PCI accounted for 3.9% of cases; patients with STEMI treated with delayed PCI accounted for 20.5% of cases; patients with stable angina accounted for 16.5% of cases; and patients with non-ST elevation acute coronary syndrome (NSTE-ACS) accounted for 58.6% of cases. PRIMARY OUTCOMES: Death, major adverse cardiac and cerebrovascular events (MACCE: death/myocardial infarction/stroke), and target vessel revascularisation. RESULTS: Follow-up after a median of 29.8 months was obtained for 2533 patients (92.6%). The mortality rate during hospitalisation was highest in the urgent PCI group (p<0.001). During follow-up, although the incidences of death and MACCE were highest in the urgent PCI group, no significant differences were observed among the different groups. The incidences of cardiac death and myocardial infarction were significantly higher in the paclitaxel-eluting stent (PES) group than in the sirolimus-eluting stent (SES) group. Independent predictors of death during follow-up were age, left ventricular ejection function <40%, diabetes mellitus, prior coronary artery bypass graft and chronic total occlusion. CONCLUSIONS: PCI patients with STEMI had the worst hospital and long-term prognosis. The mortality rate after hospital increased markedly in patients with NSTE-ACS. SESs seem to be more effective than PESs.

Characterization of interleukin-33 and matrix metalloproteinase-28 in serum and their association with disease severity in patients with coronary heart disease.

OBJECTIVE: To investigate serum levels of interleukin (IL)-33 and matrix metalloproteinase-28 (MMP-28) in patients with coronary heart disease (CHD) and to evaluate their association with disease severity. METHODS: A total of 103 patients with CHD, including 27 cases of acute myocardial infarction (AMI), 33 cases of unstable angina pectoris (UAP) and 43 cases of stable angina pectoris were enrolled to detect serum levels of IL-33 and MMP-28 by enzyme-linked immunosorbent assays. Forty volunteers without CHD served as the control group. RESULTS: Compared with stable angina pectoris and control groups, serum levels of IL-33 were significantly lower (P<0.01) and serum concentrations of MMP-28 were higher (P<0.05) in AMI and UAP groups. Serum levels of IL-33 in single-vessel, double-vessel and triple-vessel lesion groups were lower than that in the control group (P<0.05), and the differences among the three groups were not significant (P>0.05), whereas only levels of MMP-28 in double-vessel and triple-vessel lesion groups were higher than in the control group (P<0.05). Spearman's correlation analyses showed a negative correlation between serum levels of IL-33 and MMP-28 in AMI and UAP groups (r=-0.596, P<0.05 and r=-0.750, P<0.01). A binary logistic regression analysis showed that IL-33, low-density lipoprotein cholesterol, and MMP-28 may be independent predictors of the occurrence of acute coronary syndrome. CONCLUSION: A decreased level of IL-33 and an elevated concentration of MMP-28 were found in CHD patients and correlated with disease severity. IL-33 and MMP-28 may play important roles in the development of CHD or as markers of disease severity.

Red blood cell distribution width and long-term outcome in patients undergoing percutaneous coronary intervention in the drug-eluting stenting era: a two-year cohort study.

BACKGROUND: Previous studies suggest the higher the red blood cell distribution width (RDW) the greater the risk of mortality in patients with coronary artery disease (CAD). However, the relationship between RDW and long-term outcome in CAD patients undergoing percutaneous coronary intervention (PCI) with a drug-eluting stent (DES) remains unclear. This study was designed to evaluate the long-term effect of RDW in patients treated with drug-eluting stent for CAD. METHODS: In total of 2169 non-anemic patients (1468 men, mean age 60.2 ± 10.9 years) with CAD who had undergone successful PCI and had at least one drug-eluting stent were included in this study. Patients were grouped according to their baseline RDW: Quartile 1 (RDW<12.27%), Quartile 2 (12.27% ≤ RDW <13%), Quartile 3 (13% ≤ RDW<13.5%), and Quartile 4 (RDW ≥ 13.5). RESULTS: The incidence of in-hospital mortality and death or myocardial infarction was significantly higher in Quartiles 3 and 4 compared with Quartile 1 (P<0.05). After a follow-up of 29 months, the incidence of all-cause death and stent thrombosis in Quartile 4 was higher than in Quartiles 1, 2, and 3 (P<0.05). The incidence of death/myocardial infarction/stroke and cardiac death in Quartile 4 was higher than in Quartiles 1 and 2 (P<0.05). Multivariate Cox regression analysis showed that RDW was an independent predictor of all-cause death (hazard ratio (HR) = 1.37, 95% confidence interval (CI) = 1.15-1.62, P<0.001) and outcomes of death/myocardial infarction/stroke (HR = 1.21, 95% CI = 1.04-1.39, P = 0.013). The cumulative survival rate of Quartile 4 was lower than that of Quartiles 1, 2, and 3 (P<0.05). CONCLUSION: High RDW is an independent predictor of long-term adverse clinical outcomes in non-anemic patients with CAD treated with DES.

Levels of interleukin-33 and interleukin-6 in patients with acute coronary syndrome or stable angina.

PURPOSE: The purpose of this study was to investigate the levels of interleukin-33 (IL-33) and interleukin-6 (IL-6) in patients with acute coronary syndrome or stable angina. METHODS: Serum IL-33 and IL-6 were measured with Enzyme Linked Immuosorbent Assay (ELISA) in patients with acute coronary syndrome (ACS, n=40), and stable angina pectoris (SAP, n=43). IL-33 and IL-6 were also determined in 30 healthy subjects (control group). RESULTS: The serum level of IL-33 in the ACS group (78.60±44.84 ng/L) was lower than in the SAP (102.58±37.21 ng/L, P<0.01) or control groups (130.24±10.17 ng/L, P<0.01). The serum level of IL-6 in the ACS group (39.90±12.64 ng/L) was higher than in the SAP (18.68±11.89 ng/L, P<0.05) or control groups (6.28±17.72 ng/L, P<0.05). There were no differences in serum levels of IL-33 and IL-6 among the single-, double- and triple-vessel lesion groups. IL-33 and IL-6 levels were negatively correlated with each other in the ACS (r=-0.871, P<0.01) and SAP groups (r=-0.788, P<0.01). CONCLUSION: The serum level of IL-33 was lower in patients with ACS or SAP and was negatively correlated with the serum level of IL-6. Thus, IL-33 and IL-6 may be used as biomarkers for evaluating inflammatory response and severity of coronary heart disease in patients with ACS or SAP.

Oral everolimus inhibits intimal proliferation in injured carotid artery in rats.

BACKGROUND: Everolimus, a derivative of sirolimus, is a potent immunosuppressant that has important anti-proliferative properties. In the present study, we demonstrated the inhibiting neointimal hyperplasia in injured carotid arteries in rats by using two different doses of everolimus administrated via the oral route for a long time. METHODS: A rat model of carotid artery injury was established by balloon inflation. Eighty rats were randomly divided into the sham-operated group (n = 20), injury group (n = 20), low dosage of everolimus group (n = 20), and high dosage of everolimus group (n = 20). The low dose of everolimus (1.5 mg/kg) was given one day before injuring the carotid artery by balloon, followed by 0.75 mg/kg per day for 28 days via intragastric gavage. High dose everolimus (2.5 mg/kg) was given one day before injuring the carotid artery by balloon, followed by 1 mg/kg per day for 28 days. Expression of eukaryotic translation initiation factor 4E (eIF-4E) and phosphorylation of ribosomal protein S6 kinase 1 (P70S6K) were determined by reverse transcription-polymerase chain reaction and Western blotting analysis. RESULTS: In the injured carotid artery, neointimal hyperplasia was normally observed four weeks after injury. Everolimus inhibited neointimal hyperplasia after balloon injury in a dose dependent manner. At the same time, the study demonstrated that everolimus reduced the expression of P-P70S6K, eIF-4E, transforming growth factor (TGF)-ß1 and of proliferating cell nuclear antigen (PCNA). CONCLUSIONS: Everolimus significantly inhibited neointimal hyperplasia of the injured carotid artery. The effect depended on dosage and was associated with the reduction of phosphorylation of P70S6K and the eIF-4E expression level.

Amelioration of atherosclerosis in apolipoprotein E-deficient mice by inhibition of lipoprotein-associated phospholipase A2.

PURPOSE: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is involved in the pathogenesis of atherosclerosis, especially in advanced plaques. In the present study, the abilities of darapladib, a selective Lp-PLA(2) inhibitor, and lentivirus-mediated Lp-PLA(2) silencing on inflammation and atherosclerosis in apolipoprotein E-deficient mice were compared. METHODS: Apolipoprotein E-deficient mice were fed on a high-fat diet and a constrictive collar was placed around the left carotid artery to induce plaque formation. The mice were randomly divided into control, negative control (NC), darapladib and RNA interference (RNAi) groups. Eight weeks after surgery, lentivirus-mediated RNAi construct or darapladib were used to decrease the expression of Lp-PLA(2). Plaques were collected five weeks later for histological analysis. Inflammatory gene expression in the atherosclerotic lesions were then determined at the mRNA and protein level. RESULTS: The expression of pro-inflammatory cytokines was significantly reduced in the treatment group, compared to nontreatment group, whereas the plasma concentration of anti-inflammatory cytokines increased markedly. Moreover, our results demonstrated a significant reduction in plaque lipid content, as well as a rise in collagen content following Lp-PLA(2) inhibition. Interestingly, when comparing the two methods of Lp-PLA(2) inhibition, animals treated with Lp-PLA(2) RNAi were found to exhibit lower plaque areas and enhanced improvement of plaque stability as compared with animals treated with darapladib. Darapladib had no attenuating effect on atherosclerotic plaque area. These therapeutic effects were independent of plasma lipoprotein levels. CONCLUSIONS: Lp-PLA(2) inhibition by darapladib or lentivirus-mediated RNAi ameliorated inflammation and atherosclerosis in apolipoprotein E-deficient mice. The effect was more prominent in the RNAi group.