不同炎性标志物对冠状动脉病变的预测价值

目的 探讨可溶性CD40L、单核细胞趋化蛋白1、白细胞介素8和白细胞介素6等炎性标志物对冠状动脉病变严重程度和稳定性的预测价值.方法 应用流式细胞术检测129例冠心病患者血浆可溶性CD40L、单核细胞趋化蛋白1、白细胞介素8和白细胞介素6水平,计算各类型冠心病患者冠状动脉病变的Gensini积分,分析上述炎性标志物与Gensini积分的相关关系以及对急性冠状动脉综合征的预测价值.结果 四种炎性标志物血浆浓度在冠心病组均显著高于对照组(P均<0.01),其中可溶性CD40L、单核细胞趋化蛋白1和白细胞介素6的浓度在急性心肌梗死组高于稳定型心绞痛组(P=0.001、P=0.009和P=0.011).血浆单核细胞趋化蛋白1和白细胞介素6水平与冠状动脉Gensini积分呈正相关关系(r=0.322, P<0.00001;r=0.203,P=0.026);多因素Logistic回归分析显示白细胞介素6对急性冠状动脉综合征有预测价值(OR=1.275,P=0.037).结论 血浆可溶性CD40L、单核细胞趋化蛋白1、白细胞介素8和白细胞介素6等炎性标志物与冠状动脉粥样硬化病变有关;血浆单核细胞趋化蛋白1和白细胞介素6能反映冠状动脉病变的严重程度;白细胞介素6对预测冠状动脉病变不稳定的冠心病急性冠状动脉综合征有一定价值.     

Lack of association between soluble CD40L and risk in a large cohort of patients with acute coronary syndrome in OPUS TIMI-16

Background Previous studies have suggested that elevated soluble CD40 ligand (sCD40L) levels predict adverse cardiovascular outcomes in patients with acute coronary syndromes (ACS). Recently, questions have been raised regarding the influence of pre-analytical and analytical conditions on measurement of sCD40L, and additional studies have had conflicting findings regarding the prognostic value of this marker. Methods and Results We measured levels of sCD40L in citrated plasma using an analytically validated automated immunoassay (Roche Diagnostics) in a large cohort of ACS patients (n = 2403) from the placebo arm of the OPUS TIMI-16 trial. No association was observed between elevated sCD40L levels and risk of death or myocardial infarction (MI) (Quartile 1, 8.0%; Quartile 2, 11.7%; Quartile 3, 8.2%; Quartile 4, 6.8%; P = 0.54) or risk of death, MI or heart failure at 10 months (Quartile 1, 9.9%; Quartile 2, 14.2%; Quartile 3, 10.9%; Quartile 4, 8.3%; P = 0.55). A comparison of plasma vs. serum measurements of sCD40L was performed on samples from a nested case–control analysis (n = 42) from within this cohort. Median sCD40L levels did not differ between cases and controls using plasma (0.23 ng/ml vs. 0.27 ng/ml, respectively; P = 0.82) or serum samples (0.64 vs. 0.77, respectively; P = 0.85). Serum samples consistently yielded elevated sCD40L measurements compared to plasma samples (median value 0.72 ng/ml vs. 0.25 ng/ml, respectively, P < 0.001). Conclusions The absence of an association between sCD40L and cardiovascular outcomes in a large cohort of patients with ACS raises concern regarding the reproducibility of clinical results with this novel biomarker. Despite a plausibly important role in the pathobiology of atherothrombosis, pre-analytic sources of variability may limit the practical clinical application of sCD40L.     

Does anti-tnf therapy cause any change in platelet activation in ankylosing spondylitis patients?

Recently, it has been reported that ankylosing spondylitis (AS) was characterised by endothelial dysfunction and the development of atherosclerotic complications. In this study, we evaluated platelet and endothelial activation parameters in AS patients. Fiftynine AS patients and 22 healthy controls were included. The clinical features and acute phase parameters were evaluated. In all patients and healthy controls, platelet-monocyte complexes (PMC), platelet-neutrophil complexes, basal and ADP-stimulated P-selectin (CD62P) expression were determined by flow cytometry; soluble E-selectin (sE-selectin) and soluble CD40L (sCD40L) were determined by ELISA. AS patients were divided into two groups as active and inactive by using BASDAI. In 15 AS patients, the evaluated parameters were assessed before and after 12 weeks of anti-TNF therapy. PMC and sCD40L levels in AS patients were significantly higher than in the control group (P values 0.013 and 0.016). The evaluated variables were similar in active and inactive AS groups (P > 0.05). There were no significant changes in platelet and endothelial activation parameters in AS patients after anti-TNF therapy (P > 0.05). Platelet activation which is reflected by high levels of PMC and sCD40L might be responsible for the increased frequency of atherosclerosis in AS. The platelet activation in our AS patients was not associated with disease activity and did not improve after anti-TNF therapy.     

Soluble CD40 ligand,interleukin (IL)-6, and hemostatic parameters in metabolic syndrome patients with and without overt ischemic heart disease

Background and aimSoluble CD40 ligand (sCD40L, also known as CD154) is a marker for platelet activation which could increase coagulation and inflammation. In this case-control study, we aimed to assess the levels of plasma sCD40L, IL-6, and some hemostatic parameters in patients with metabolic syndrome (MetS) whether or not associated with overt ischemic heart disease (IHD).Subjects and methodsWe measured plasma sCD40L (an index of platelet activation), interleukin (IL)-6 (a proinflammatory cytokine), and some hemostatic parameters (tissue factor [TF], thrombin–antithrombin [TAT] and D-dimer) in 47 patients with metabolic syndrome (21 with and 26 without overt IHD) versus 25 comparable healthy control subjects.ResultsSignificantly higher levels of sCD40L, IL-6, and thrombotic markers (TF, D-dimer and TAT) were found in patients with metabolic syndrome compared to healthy controls. The levels of IL-6 and sCD40 were highest in patients with overt IHD. Strong positive correlations existed between sCD40L and IL-6 (r = 0.67, p = 0.003), TF (r = 0.59, p = 0.008), and platelets count (r = 0.64, p = 0.005).ConclusionHigher levels of sCD40L, IL-6, and thrombotic markers exist in MetS patients, particularly those with IHD. The strong positive correlations between sCD40L and IL-6, TF, and platelets count support a link between the CD40–CD40L system and the underlying inflammatory and hypercoagulable state in MetS patients.     

Inverse correlation between soluble CD40 ligand and soluble CD40 is absent in patients with unstable angina

The CD40/CD40 ligand (CD40L) system mediates inflammatory processes important in atherogenesis and plaque instability. The expression of CD40L on activated T cells was suppressed by soluble CD40 (sCD40) in vitro. However, the relationship between soluble CD40L (sCD40L) and sCD40 in unstable angina (UA) is still unknown. Thirty-seven consecutive patients with recent chest pain or discomfort were recruited. Patients with both Braunwald's class IB–IIIB and with coronary stenosis (or stenoses) of >75% were assigned to the UA group (n = 19, aged 67.2 ± 8.2 years), and the rest to the control group (n = 18, aged 63.4 ± 8.7 years). The serum levels of sCD40L and sCD40, and the plasma levels of matrix metalloproteinase (MMP)-9, were measured by enzyme-linked immunosorbent assays. A significantly inverse correlation between sCD40L and sCD40 was shown in the controls (r = −0.72, P = 0.0007), but was absent in the UA group (r = −0.16, P not significant), although there was no statistical significance between these groups in terms of serum levels of sCD40L or sCD40. The difference of the regression slopes of these regression lines was statistically significant (P < 0.01). Additionally, there was a significant correlation between sCD40 and plasma levels of MMP-9 in the patients with and without UA (r = 0.58, P = 0.0096), but no significant correlation between sCD40L and MMP-9 levels (r = 0.00, P not significant). The balance between CD40 and CD40L may be lost in patients with UA. Soluble CD40 expression may also be related to MMP-9 expression in atherosclerotic tissues.     

Enhanced soluble CD40 ligand contributes to endothelial cell dysfunction in vitro and monocyte activation in patients with diabetes mellitus: effect of improved metabolic control

Aims/hypothesis Inflammation plays a pathogenic role in the development of accelerated atherosclerosis in diabetes. Soluble CD40 ligand (sCD40L) is enhanced in diabetes; however, the molecular mechanisms linking sCD40L to accelerated atherosclerosis in diabetes are still unclear. We tested the hypothesis that sCD40L may be involved in the vascular complications in diabetes and exerts its effect by triggering inflammatory reactions on mononuclear and endothelial cells (ECs).Methods We studied 70 patients, 40 with type 2 and 30 with type 1 diabetes, with a history or physical examination negative for cardiovascular disease, and 40 non-diabetic and 30 healthy subjects, matched with the type 2 and type 1 diabetic patients, respectively. Plasma and serum sCD40L, and plasma soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, E-selectin and monocyte chemo-attractant protein-1 (MCP-1) were measured. Adhesion molecules and MCP-1 release, the ability to repair an injury in ECs, and O₂^– generation in monocytes were analysed in vitro after stimulation with serum from patients or controls.Results Type 2 and type 1 diabetic patients had significantly higher sCD40L levels than controls. Furthermore, high sCD40L was associated with in vitro adhesion molecules and MCP-1 release, impaired migration in ECs and enhanced O₂^– generation in monocytes. Improved metabolic control was associated with a reduction of plasma sCD40L by 37.5% in 12 type 1 diabetic patients. Furthermore, elevated sCD40L in diabetic patients was significantly correlated with HbA₁c levels.Conclusions/interpretation Upregulation of sCD40L as a consequence of persistent hyperglycaemia in diabetic patients results in EC activation and monocyte recruitment to the arterial wall, possibly contributing to accelerated atherosclerosis development in diabetes.     

Elevated circulating soluble CD40 ligand in patients with mixed connective tissue disease

 Abnormalities of CD40 ligand have been demonstrated in various kinds of diseases. Our objective was to determine serum soluble CD40 ligand (sCD40L) levels in patients with mixed connective tissue disease (MCTD). Serum sCD40L levels of 23 patients with MCTD and 21 healthy individuals were measured with specific enzyme-linked immunosorbent assays. Serum levels of sCD40L were significantly higher in patients with MCTD than in healthy individuals (median 0.179 ng/ml vs 0.99 ng/ml, 25th–75th percentile; 0.117–0.296 ng/ml vs 0.82–1.70 ng/ml, P<0.005), whereas there were no significant correlation between elevated serum sCD40L levels and clinical or serological features in patients with MCTD. These results suggest that sCD40L plays a role in the pathogenesis of MCTD. Further studies are needed to clarify this. Received: 29 March 2002 / Accepted: 28 August 2002     

Impact of nasal continuous positive airway pressure therapy on markers of platelet activation in patients with obstructive sleep apnea

BACKGROUND: Considerable evidence implicates CD40 signaling in the pathogenesis of atheromas. Exposure to CD40 ligand induces platelet-leukocyte conjugation, a heightened expression of inflammatory cytokines, matrix-degrading enzymes, and procoagulant factors. OBJECTIVES: To investigate the association between plasma soluble CD40 ligand (sCD40L) and platelet-monocyte aggregates in patients with obstructive sleep apnea (OSA) and to determine whether treatment of OSA with nasal continuous positive airway pressure (nCPAP) alters this relationship. METHODS: Twelve patients with OSA who were free of other diseases and 12 healthy controls matched for age, gender, and body mass index had blood drawn for sCD40L and platelet-monocyte aggregate measurements. A repeat assessment was obtained following 8 weeks of nCPAP therapy. RESULTS: Subjects with OSA had significantly higher plasma sCD40L levels and exhibited elevated platelet-monocyte aggregates compared to nonapneic subjects (7.6 +/- 4.3 versus 1.7 +/- 1.1, p = 0.004; and 41.3 +/- 23.7 versus 6.7 +/- 4.9, p = 0.001, respectively). Both parameters correlated positively with the percentage of time spent with SpO(2) <90% (r = 0.69, p = 0.01 and r = 0.6, p = 0.03, respectively). After 8 weeks of nCPAP treatment, sCD40 levels declined by 47% (p = 0.003) and platelet-monocyte aggregates by 42% (p = 0.002). None of the controls showed any changes in either sCD40L or platelet- monocyte aggregates after nCPAP therapy. CONCLUSIONS: OSA is associated with upregulation of circulating sCD40L levels and platelet-monocyte aggregation that may account for the increased incidence of cardiovascular events in this population. Treatment with nCPAP may alleviate this risk.     

Increased soluble CD44 concentrations are associated with larger tumor size and lymph node metastasis in breast cancer patients

Purpose  CD44 is a cell surface glycoprotein involved in cell–cell and cell–substrate interactions, which may be shed or released into circulation by proteolytic enzymatic mechanisms. Alternative splicing of CD44 and aberrant levels of soluble CD44 variants in the serum of cancer patients have been correlated to tumor progression and metastasis in different tumors including breast cancer. In this study we evaluated the clinical value of CD44 serum levels (sCD44) in patients with primary breast cancer. Methods  Concentrations of soluble isoforms sCD44std, sCD44v5 and sCD44v6 were determined with a sensitive ELISA and normalized against the total protein concentration (TP). Pre-operative serum samples from 82 patients and 67 age-matched healthy blood donors were analyzed. The results were correlated to clinico-pathological parameters (tumor size, grading, lymph node metastasis, etc.). Results  In sera of breast cancer patients, we detected elevated concentrations of sCD44v6 (P = 0.0001) and total protein TP (P = 0.0001) in comparison to healthy controls, whereas overall sCD44 (sCD44std) and sCD44v5 did not differ. Patients with sCD44v6-concentrations above the 75%-percentile showed an increased T stage (2.9 cm vs. 1.8 cm) as well as a higher risk for lymph node metastasis (55% vs. 35%). In breast cancer patients with lymph node metastasis the median value of sCD44v6 was significantly higher (P = 0.025) in comparison to patients without lymph node metastasis and healthy controls. Conclusions  Our data suggest an upregulated expression of alternatively spliced soluble CD44 isoforms in breast cancer patients. The specific alterations of certain CD44 isoform concentrations (especially sCD44v6) may reflect disturbances of the nuclear splicing machinery in tumor cells. The clinical significance of our findings are underlined by the positive correlation of elevated sCD44v6 concentrations and lymph node metastases (r _s = 0.25).     

Association of soluble CD40 ligand with carotid atherosclerosis in Japanese type 1 diabetic patients

Aims/hypothesis It has recently been shown that the soluble form of CD40 ligand (sCD40L) interacts with CD40 on vascular cells, leading to a variety of proinflammatory responses, and that serum sCD40L levels can be a predictive marker of cardiovascular events. The aim of this study was to estimate sCD40L levels in type 1 diabetic patients to examine a possible association with carotid atherosclerosis.Subjects and methods Human sCD40L levels in serum and intima–media thickness (IMT) of carotid artery were examined in 80 Japanese type 1 diabetic patients (27 men and 53 women, age 22.8±3.4 years (mean±SD), duration of diabetes 13.2±6.1 years) and 20 healthy age-matched non-diabetic individuals.Results Serum sCD40L levels were significantly (p=0.0185) higher in subjects with type 1 diabetes (2.10±1.33 ng/ml) compared with non-diabetic subjects (1.35±0.88 ng/ml). The greatest IMT (Max-IMT) and averaged IMT (Mean-IMT) were also significantly greater in patients with type 1 diabetes than in control subjects (0.73±0.14 vs 0.64±0.07 mm, p=0.0041, 0.63±0.09 vs 0.57±0.06 mm, p=0.0066, respectively). Levels of sCD40L were statistically significantly associated with Max-IMT (r=0.383, p<0.001) and Mean-IMT (r=0.275, p=0.0058). Furthermore, stepwise multivariate regression analyses demonstrated that sCD40L is a determinant of both Max- and Mean-IMT, independently of conventional risk factors.Conclusions/interpretation It is suggested that increased levels of serum sCD40L are associated with accelerated atherosclerotic change observed in young patients with type 1 diabetes.     

Relationship between soluble CD40 ligand and γ‐glutamyltransferase concentrations in non‐drinking,young Type 1 diabetic individuals

Aims To assess the association between circulating levels of soluble CD40 ligand (sCD40L), an emerging cardiovascular risk factor, and γ‐glutamyltransferase (GGT) activity concentrations in Type 1 diabetic subjects. Methods Plasma concentrations of sCD40L and GGT activity, a marker of liver dysfunction, were measured in 54 non‐smoking, non‐drinking, young Type 1 diabetic patients, who were free of diagnosed cardiovascular disease. Results When participants were grouped according to tertiles of GGT, plasma sCD40L concentrations steadily increased across GGT tertiles (P = 0.007 for trend). Similarly, plasma sCD40L concentrations were positively correlated with plasma GGT levels in the whole group of participants (r = 0.532; P < 0.0001). In multivariate linear regression analysis, plasma GGT activity levels were positively associated with sCD40L (standardized beta coefficient = 0.342; P = 0.027) independently of age, gender, diabetes duration, glycated haemoglobin, total cholesterol and systolic blood pressure. Further adjustment for the presence of diabetic retinopathy and microalbuminuria did not appreciably attenuate this association. Conclusions Our findings suggest that there is a strong, graded, relationship between plasma GGT activity and sCD40L concentrations in non‐smoking, non‐drinking, young Type 1 diabetic individuals. This association appears to be independent of numerous confounding factors. Further studies are required to confirm the reproducibility of these results.     

Relationships between vascular factors and plaque morphology in patients with acute coronary syndrome

Objective To investigate the relationships between vascular factors and plaque morphology in the patients with acute coronary syndrome（ACS）. Methods Intravascular ultrasound（lVUS） was performed on 56 consecutively enrolled patients with ACS. Cytometric bead array for seven vascular factors（sPE,t-PA, MCP-1, IL-8,1L-6,sVCAM-1, and sCD40L） was measured by cytometry. The others biomarkers were tested by ELISA or biochemistry. Differences in bio-factors were compared between vulnerable plaque and non- vulnerable plaque groups, accte myocardial infarction （AMI） and ustable angina （UA） patients, and occurring plaque rupture. The relationship between the parameters of morphology and vascular factors was analyzed. Results There were positive correlations between sVCAM-lsPE, sVCAM-I-sCD40L, sCD40L-sPE, IL-6-ILS,ILS-MCP1, and MCPI-sVCAM-1; CRP （18.868±4.907mg/L vs 5.806±3.553 mg/L）and IL-6 （19.5 pg/ml [9.2 - 44.6 pg/ml]vs 5.3 pg/ml [2.3- 13.4 pg/ml]）were elevated in the vulnerable plaque group（P 〈0.05）. sCD40L（473.82± 126.11 vs 237.94± 34.78 pg/ml）,sPE （107.21±39.90 vs 49.06 ±5.61ug/L） and MCP-1（132.42 ± 17.85 vs 127.17±13.27 pg/ml） were increased in the plaque rupture group（P 〈 0.05）;There was correlation between tPA and plaque morphology（P 〈 0.05）. Increases in sCD40L, MCP-1, sPE, and TC were independent factors for plaque rupture. Conclusions IL-6 and CRP may be biomarkers for vulnerable plaque and for diagnosis ofAMI, sCD40L, MCP-1 and sPE are potential markers when for plaque rupture patient present with severe ACS.     

急性冠状动脉综合征患者血管因子与冠状动脉斑块特征的相关性研究

目的探讨急性冠状动脉综合征（ACS）患者血管因子与冠状动脉斑块特征的相关性。方法选择56例ACS患者,年龄（60±11）岁,男37例,女19例,发病时取血,应用液相蛋白芯片结合流式细胞分析方法测定7种血管因子：可溶的P选择素（sPE）、组织血纤维蛋白溶酶原激活物（tPA）、单核细胞趋化蛋白1（MCP-1）、白细胞介素（IL）-8、IL-6、可溶的血管细胞间黏附分子1（sVCAM-1）和可溶的黏附分子40配体（sCD40L）,以及相应的炎症因子;常规冠状动脉造影,并用血管内超声（IVUS）检测56个靶病变处动脉粥样斑块形态学及性质特征。分析急性心肌梗死（AMI）与不稳定性心绞痛（UA）患者、易损斑块与非易损斑块组发生斑块破裂时的血管因子改变以及斑块形态学指标与血管因子的相关性。结果存在密切相关的血管因子有sVCAM-1和sPE、sVCAM-1和sCIMOL、sCD40L和sPE、IL-6和IL-8、IL-8和MCP1、以及MCP1和sVCAM-1;易损斑块组的高敏C反应蛋白（hs-CRP）为（18．9±4．9）mg／L,IL-6为[19.5ng／L（9．2—44．6ng／L）],明显高于非易损斑块组[hs-CRP：（5.8±3．6）mg／L,IL-6：5.3ng／L（2．3—13．4ng／L）,均P〈0．05];与非斑块破裂组比较,斑块破裂组的sCD40L[（474±126）ng／L比（238±35）ng／L],sPE[（107．2±39．9）ng／L比（49．1±5．6）μg／L]和MCP-1[（132±18）ng／L比（127±13）ng／L]明显升高（均P〈0．05）;tPA与斑块形态之间存在一定的相关性（均P〈0．05）。sCIMOL、MCP—1,sPE和TC水平升高是发生斑块破裂的独立危险因素（均P〈0．05）。结论炎症反应作为中间过程,IL-6和CRP标志易损斑块的生物特点,对AMI可能有一定的诊断意义,而sCIMOL、MCP-1和sPE可能是另一个潜在的反映ACS严重发作的标志。     

Circulating soluble CD40 ligand mediates the interaction between neutrophils and platelets in acute coronary syndrome

Following plaque rupture, activated platelet will induce subsequent inflammatory process including neutrophil recruitment. In vitro study demonstrated an interaction between neutrophils and platelets via a mechanism involving CD40-CD40 ligand. However, whether this mechanism exists in the clinical setting remains unknown. Fifty-four patients with acute myocardial infarction (AMI) and 25 with unstable angina of pain onset of ≤24 h were enrolled consecutively. Acute myocardial infarction was diagnosed from three diagnostic criteria, i.e., anginal pain, electrocardiogram ST-T changes, and cardiac enzyme elevation. Unstable angina was diagnosed in patients without elevated cardiac enzymes. Peripheral venous blood was drawn at admission for routine blood count and soluble CD40 ligand (sCD40L) measurement. Neutrophil count was determined by an automated blood cell counter. Circulating sCD40L was measured using a standard enzyme-linked immunosorbent assay. Neutrophil count was significantly higher in AMI as compared with unstable angina (P < 0.001), whereas circulating sCD40L did not significantly differ. Despite marked elevation, no correlation was observed between neutrophil count and circulating sCD40L in AMI. Interestingly, we observed a strong and positive significant correlation between neutrophil count and circulating sCD40L level (r = 0.607, P = 0.002) in unstable angina. Circulating sCD40L is associated with neutrophil count and may mediate interaction between neutrophils and platelets in acute coronary syndrome, particularly in unstable angina.     

Increased platelet activation markers in rheumatoid arthritis: Are they related with subclinical atherosclerosis?

Atherosclerotic cardiovascular mortality is increased in rheumatoid arthritis (RA) patients. We evaluated the association of inflammatory response with platelet, endothelial, coagulation activation parameters; and subclinical atherosclerosis in RA patients. We included 27 RA patients (21 female; six male) and 19 healthy subjects (14 female; five male). Disease activity score (DAS28) in RA patients was calculated; and patients were divided into two groups as active and inactive. Flow cytometry was used to determine platelet CD62P expression, platelet microparticles (PMP), platelet-monocyte (PMC) and platelet-neutrophil complexes (PNC). Plasma E-selectin, thrombin-antithrombin (TAT) complex, and serum sCD40L levels were determined by ELISA. The intima-media thickness (IMT) of carotid arteries was determined by B-mode ultrasonography. In RA patients, platelet CD62P expression (p < 0.001), PMC (p = 0.037) and sCD40L (p < 0.001) levels were increased when compared to the control group. PNC (p = 0.07) and TAT levels (p = 0.1) were non-significantly higher, and PMP level (p = 0.075) was nonsignificantly lower in RA patients. Soluble E-selectin level was significantly higher in the active RA group than in the inactive RA group (p = 0.009). There was no correlation between carotid IMT and activity markers, the evaluated parameters (p > 0.05).The increase in markers of active platelets, CD62P and sCD40L, and PMC levels might be associated with the increased cardiovascular mortality in RA. Nevertheless, none of these parameters were associated with carotid IMT: this suggests that one cross-sectional value might not be a good marker for atherosclerosis.     

Enhanced soluble CD40L in patients with the metabolic syndrome: relationship with in vivo thrombin generation

Aims/hypothesis The metabolic syndrome is associated with proinflammatory and prothrombotic states. This study was designed to assess the behaviour of soluble CD40 ligand (sCD40L) and prothrombin fragment F ₁₊₂, a marker of thrombin generation, in patients with the metabolic syndrome.Methods We investigated 106 patients with the metabolic syndrome, diagnosed according to the ATPIII report, and 104 subjects without the metabolic syndrome.Results Plasma values of sCD40L and F ₁₊₂ were higher in patients with the metabolic syndrome (4.11±1.64 vs 2.61±0.89 ng/ml and 1.54±0.49 vs 0.87±0.21 nmol/l, respectively; p<0.001) and were significantly correlated (r=0.925, p<0.001). Stepwise multiple linear regression analysis showed that sCD40L was significantly associated with F ₁₊₂, female sex and waist circumference.Conclusions/interpretation Patients with the metabolic syndrome have enhanced values of plasma sCD40L and F ₁₊₂. The study provides further insight into the relationship between metabolic syndrome, inflammation and thrombosis.     

Prognostic value of interleukin-6 during a 3-year follow-up in patients with acute ST-segment elevation myocardial infarction

Accumulating evidence suggests that inflammation plays an essential role in the pathogenesis of atherosclerosis. This recognition has stimulated the evaluation of different inflammatory markers as potential predictors of cardiovascular risk. However, the existing data are limited and controversial. This study was designed to simultaneously measure serum levels of interleukin-6 (IL-6), soluble CD40 ligand (sCD40L), metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinase-1 (TIMP-1) in patients with acute ST segment elevation myocardial infarction (STEMI) and to evaluate their ability to predict prognosis. A prospective cohort study was conducted with 263 patients with first STEMI who were admitted to our institute within 6 h of symptoms onset. Clinical data were recorded and serum admission levels of IL-6, sCD40L, MMP-9, and TIMP-1 were measured by sandwich enzyme-linked immunosorbent assay. The patients were then followed prospectively for the occurrence of cardiovascular mortality for 3 years. Follow-up information was available for 228 patients (86.7%) from the 263 STEMI patients; 34 patients died from cardiovascular causes during the 3-year follow-up period. Kaplan-Meier plots demonstrated a significant increase in cardiovascular mortality with increasing IL-6 levels (χ² = 14.13, P = 0.0002, by log-rank test). Logistic regression analysis revealed that IL-6 was an independent predictor for cardiovascular mortality. The present study indicates that elevated admission level of IL-6 could provide valuable information for long-term risk stratification in patients with STEMI.     

Soluble CD40 ligand and interleukin-6 in the coronary circulation after acute myocardial infarction

BACKGROUND: Inflammation, operated by blood, vascular and immune cells interaction, is implicated in plaque disruption and CD40 ligand (CD40L) was identified on activated T cells and platelets. We sought to investigate the roles of local inflammation in acute myocardial infarction (AMI). METHODS: Coronary sinus (CS) and arterial (A) levels of interleukin (IL)-6 and soluble CD40L (sCD40L) and matrix metalloproteinase (MMP)-9 activity in serial blood samples obtained until 48 h after percutaneous coronary intervention (PCI) were determined. In tissue specimens obtained by aspirating thrombectomy and directional coronary atherectomy, CD40L was immunohistochemically stained. RESULTS: Trans-cardiac gradient (CS-A) of IL-6, indicating cardiac release into the coronary circulation, significantly increased at 24 h after PCI in patients with AMI (group MI, n=17) in contrast with angina pectoris (n=10). Soluble CD40L levels in CS showed earlier peak, yielding trans-cardiac gradient, at 9 h in both groups. The maximum (max) release of IL-6 in MI, but not sCD40L, positively correlated with end-diastolic volume index (R=0.84) and negatively with ejection fraction (R=-0.66) by contrast ventriculography at 6-month follow up. Immunohistological study revealed the expression of CD40L in intra-coronary occlusive and mural thrombi. Aspirating thrombectomy significantly reduced the increase in both sCD40L levels and MMP-9 activity, but not max IL-6 release in MI. CONCLUSIONS: In contrast with myocardial injury represented by IL-6 release, acute rise in sCD40L levels with the MMP-9 activation in the coronary circulation may possibly reflect local inflammation with platelet activation and be a novel marker of plaque damage by PCI.     

The inflammatory receptor CD40 is expressed on human adipocytes: contribution to crosstalk between lymphocytes and adipocytes

Aims/hypothesis  Obesity is associated with adipose tissue inflammation. The CD40 molecule, TNF receptor superfamily member 5 (CD40)/CD40 ligand (CD40L) pathway plays a role in the onset and maintenance of the inflammatory reaction, but has not been studied in human adipose tissue. Our aim was to examine CD40 expression by human adipocytes and its participation in adipose tissue inflammation. Methods   CD40 expression was investigated in human whole adipose tissue and during adipocyte differentiation by real-time PCR, Western blot and immunohistochemistry. The CD40/CD40L pathway was studied using recombinant CD40L (rCD40L) in adipocyte culture and neutralising antibodies in lymphocyte/adipocyte co-culture. Results   CD40 mRNA levels in subcutaneous adipose tissue were higher in the adipocyte than in the stromal–vascular fraction. CD40 expression was upregulated during adipocyte differentiation. Addition of rCD40L to adipocytes induced mitogen activated protein kinase (MAPK) activation, stimulated inflammatory adipocytokine production, and decreased insulin-induced glucose transport in parallel with a downregulation of IRS1 and GLUT4 (also known as SCL2A4). rCD40L decreased the expression of lipogenic genes and increased lipolysis. CD40 mRNA levels were significantly higher in subcutaneous adipose tissue than in visceral adipose tissue of obese patients and were positively correlated with BMI, and with IL6 and leptin mRNA levels. Lymphocyte/adipocyte co-culture led to an upregulation of proinflammatory adipocytokines and a downregulation of leptin and adiponectin. Physical separation of the two cell types attenuated these effects, suggesting the involvement of a cell–cell contact. Blocking the CD40/CD40L interaction with neutralising antibodies reduced IL-6 secretion from adipocytes. Conclusions/interpretation  Adipocyte CD40 may contribute to obesity-related inflammation and insulin resistance. T lymphocytes regulate adipocytokine production through both the release of soluble factor(s) and heterotypic contact with adipocytes involving CD40.     

Elevated levels of platelet-monocyte aggregates and related circulating biomarkers in patients with acute coronary syndrome

AimsTo investigate whether patients with acute coronary syndrome (ACS) possessed high levels of platelet–monocyte aggregates (PMAs) and related circulating biomarkers.Methods74 ACS patients, 58 stable angina pectoris (SAP) patients and 46 control patients without coronary artery disease were selected and their PMAs were measured by flow cytometry. Their plasma IL-6, IL-8, MCP-1, soluble CD40L and soluble P-selectin were also measured simultaneously by flow cytometry.ResultsPatients with ACS exhibited higher level of PMAs compared with SAP patients and the control. Furthermore, the levels of IL-6, IL-8, MCP-1, soluble CD40L, soluble P-selectin and CRP were also significantly higher in ACS patients than in SAP patients and the control group. However, there were no significant difference in the levels of IL-8, sCD40L, sP-selectin and CRP between SAP patients and the control group. Correlation analysis showed that high levels of IL-6 and sP-selectin were significantly correlated with PMAs. Logistic analysis further demonstrated that the presence of elevated CRP, IL-6 and PMAs level each confers an increased risk of ACS.ConclusionElevated levels of PMAs and related circulating biomarkers might indicate the unstable coronary syndrome in ACS patients, and the levels of PMAs, CRP and IL-6 could be used for monitoring and guiding the early intervention of ACS patients.