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.     

Clinically apparent atherosclerotic disease in diabetes is associated with an increase in platelet microparticle levels.

BACKGROUND: The commonest cause of mortality in patients with Type 2 diabetes is atherothrombosis, which can be related to abnormalities in the coagulation and fibrinolytic pathways, as well as in platelet function. Platelet microparticles (PMPs) may contribute to the prothrombotic state and may promote the progression of atherosclerosis. We hypothesized that PMPs are elevated in Type 2 diabetes and that patients with Type 2 diabetes and clinically apparent atherosclerosis would have the highest levels. Similarly, we hypothesized that soluble plasma P-selectin (sPsel) and CD40L (both molecules which are released by activated platelets), as well as %CD62P (P-selectin) and %CD63 positivity on platelets quantified by flow cytometry, would be highest in patients with Type 2 diabetes and clinically apparent atherosclerotic disease, and might be correlated to PMP levels. METHODS: Venous blood was obtained from 21 Type 2 diabetic patients without atherosclerotic complications, 18 diabetic patients with clinically apparent atherosclerotic disease and 21 non-diabetic control subjects. PMPs, as well as %CD62P and %CD63 positivity on platelets, were quantified by flow cytometry. sPsel and CD40L were measured using ELISA. RESULTS: Patients with Type 2 diabetes and clinically apparent atherosclerotic disease had the highest PMP (P=0.045) and sPsel (P=0.046) levels, compared with patients without complications (who had intermediate PMP levels) and control subjects. Control subjects had the lowest CD40L levels (P<0.001) when compared with patients with Type 2 diabetes, with no difference in sCD40L levels between the two diabetic subgroups. %CD62P and %CD63 positivity did not differ between the groups. PMP levels correlated with %CD62P positivity (P=0.026) but not to %CD63 positivity (P=0.089), sCD40L (P=0.407) or sP-sel (P=0.163); sCD40L levels did not correlate with any other marker of platelet activation. CONCLUSION: PMPs are elevated in Type 2 diabetes. In addition, patients with clinically apparent atherosclerosis had the highest levels of PMPs and sPsel. Thus, PMPs may be a marker of symptomatic atherosclerotic vascular disease in Type 2 diabetes, and may both represent a useful risk stratification tool as well as a novel therapeutic target for anti-thrombotic drugs.     

The effects of simvastatin, losartan, and combined therapy on soluble CD40 ligand in hypercholesterolemic, hypertensive patients

The proinflammatory mediator CD40 ligand plays an important role in atherogenesis. Biological mechanisms underlying statin and angiotensin II type 1 receptor blocker therapies differ. Therefore, we compared the effects of these therapies either alone or in combination on plasma soluble CD40 ligand (sCD40L). This was a randomized, double-blind, placebo-controlled cross-over trial with three treatment arms (each 2 months) and two washout periods (each 2 months). Forty-seven hypertensive, hypercholesterolemic patients were given simvastatin 20mg and placebo, simvastatin 20mg and losartan 100mg, or losartan 100mg and placebo daily during each 2 month treatment period. Simvastatin alone did not significantly reduce sCD40L levels relative to baseline measurements when the entire cohort was analyzed. However, simvastatin significantly reduced sCD40L levels from 5.10+/-0.34 to 3.07+/-0.43ng/ml (P=0.002) in a subgroup of 18 patients with high baseline sCD40L levels >2.95ng/ml. Combined therapy or losartan alone significantly decreased plasma sCD40L levels relative to baseline measurements by 14+/-7% (P=0.001) and 13+/-10% (P=0.001), respectively. These decreases were significantly greater than those observed with simvastatin alone (P=0.023 by ANOVA). Significant inverse correlations between baseline sCD40L levels and percent changes in sCD40L levels were observed (r=-0.456, P=0.001 after simvastatin alone; r=-0.476, P<0.001 after combined therapy; r=-0.451, P=0.002 after losartan alone). Losartan alone or combined therapy significantly reduced plasma sCD40L levels more than simvastatin alone in our subjects. Simvastatin, losartan and combined therapy significantly reduced sCD40L to the greatest extent in patients with high baseline sCD40L levels.     

急性冠状动脉综合征患者sCD40L的变化及他汀类药物的影响

目的探讨急性冠状动脉综合征(ACS)患者血清可溶性CD40L(sCD40L)水平的变化及他汀类药物对其的影响。方法102例ACS患者随机分为2组:安慰剂组,辛伐他汀和普伐他汀组(他汀组)。用间接免疫荧光流式细胞术和酶联免疫吸附法(ELISA)及常规酶法分别测定2组患者用药前和用药2、4、6周后血清sCD40L水平及总胆固醇(TC)水平。结果(1)他汀组患者服药2,4及6周后血清sCD40L水平明显低于安慰剂组(均P<0.05)。(2)他汀组患者服药2、4、6周后血清sCD40L水平呈逐渐下降趋势,同用药前相比差异均有统计学意义(均P<0.05)。(3)他汀组患者服药2、4、6周后血浆TC水平与用药前相比差异均有统计学意义(均P<0.05)。(4)他汀组患者血清sCD40L水平的降低与血浆TC水平的降低无明显相关性(r=0.014,P>0.05)。结论他汀类药物能明显降低ACS患者体内sCD40L水平,对减轻炎症反应、稳定斑块有一定作用。     

Effects of switching statins on lipid and apolipoprotein ratios in the MERCURY I study

BACKGROUND: Lipid ratios are clinically useful markers of coronary artery disease (CAD) risk. The effects of rosuvastatin, atorvastatin, simvastatin, and pravastatin on lipid ratios were investigated in the Measuring Effective Reductions in Cholesterol Using Rosuvastatin TherapY (MERCURY) I trial. METHODS: This trial was conducted in 3140 hypercholesterolemic patients with CAD, atherosclerosis, type 2 diabetes mellitus, or a 20% 10-year risk for CAD. Patients were randomized to rosuvastatin 10 mg, atorvastatin 10 or 20 mg, simvastatin 20 mg, or pravastatin 40 mg for 8 weeks; all patients except those receiving rosuvastatin 10 mg either were switched to rosuvastatin 10 or 20 mg or remained on initial treatment for 8 more weeks. RESULTS: At 8 weeks, reductions in total cholesterol (TC):high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol:HDL-C, non-HDL-C:HDL-C, and apolipoprotein (apo) B:apo A-I ratios with rosuvastatin 10 mg were significantly greater than those with atorvastatin 10 mg, atorvastatin 20 mg, simvastatin 20 mg, and pravastatin 40 mg (P<0.0001 for all). At week 16, switching to rosuvastatin 10 mg from atorvastatin 10 mg, simvastatin 20 mg, and pravastatin 40 mg and to rosuvastatin 20 mg from atorvastatin 20 mg produced significantly greater reductions in all lipid ratios (P< or =0.0001 for all). Switching to rosuvastatin 10 mg from atorvastatin 20 mg produced significantly greater reductions in TC:HDL-C (P<0.025) and apo B:apo A-I (P<0.01). CONCLUSIONS: Rosuvastatin 10 mg reduces lipid ratios more than equivalent and higher doses of other statins; switching to equal or lower doses of rosuvastatin produces significantly improved reductions in lipid ratios.     

罗格列酮对兔动脉粥样硬化MMP-2、TIMP-2表达的影响

目的:通过比较罗格列酮和辛伐他汀对兔动脉粥样硬化基质金属蛋白酶-2(MMP-2)、基质金属蛋白酶抑制因子-2(TIMP-2)表达的影响,探讨罗格列酮抗动脉粥样硬化的作用机制。方法:将36只雄性新西兰兔随机分为对照组、模型组、辛伐他汀组和罗格列酮组;采用皮下注射同型半胱氨酸硫内酯及高脂饲养的方法建立兔动脉粥样硬化模型。检测血清氧化低密度脂蛋白(ox-LDL)、sCD40L水平和主动脉粥样硬化组织中MMP-2和TIMP-2的表达。结果:与对照组相比,其他3组MMP-2蛋白表达显著升高,而TIMP-2蛋白表达显著降低;与模型组比较,辛伐他汀和罗格列酮组MMP-2表达显著降低,TIMP-2表达显著增加,血清ox-LDL、sCD40L水平显著降低。辛伐他汀组和罗格列酮组比较,差异无统计学意义。结论:罗格列酮可通过下调兔主动脉粥样硬化组织中MMP-2、上调TIMP-2的表达,降低血清ox-LDL和sCD40L水平,减轻大动脉内膜的炎性反应,发挥抗动脉粥样硬化的作用。     

Effects of rosiglitazone alone and in combination with atorvastatin on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus

Combination therapy of rosiglitazone and atorvastatin has been shown to have beneficial effects on glycemic control and lipid profiles in patients with type 2 diabetes mellitus. This study investigated the effects of the combination of rosiglitazone and atorvastatin on vascular inflammation by studying their effects on levels of biomarkers in patients with type 2 diabetes mellitus. Thirty patients with type 2 diabetes mellitus and hyperlipidemia were enrolled to receive rosiglitazone monotherapy at 4 mg/day for 3 months and then atorvastatin at 10 mg/day was added for 3 more months as combined therapy. Inflammatory biomarkers, including high-sensitivity C-reactive protein (hs-CRP), matrix metalloproteinase-9 (MMP-9), soluble CD40 ligand (sCD40L), and adiponectin, and lipid profiles were measured at the time of initiation, after rosiglitazone monotherapy and after combination therapy with rosiglitazone and atorvastatin. With treatment of rosiglitazone at 4 mg/day monotherapy for 3 months, hs-CRP levels decreased significantly by 26% (p <0.05) and adiponectin levels increased significantly by 192% (p <0.05), but no significant changes in levels of MMP-9 and sCD40L were demonstrated. After combination therapy, hs-CRP levels further significantly decreased by another 23% (p <0.05) and adiponectin further increased by another 124%. In addition, serum levels of MMP-9, sCD40L, total cholesterol, and low-density lipoprotein cholesterol decreased significantly compared with baseline levels. In conclusion, combination therapy with rosiglitazone and atorvastatin not only significantly improved lipid profiles but also decreased levels of vascular biomarkers, such as hs-CRP, MMP-9, and sCD40L, and increased serum adiponectin levels in patients with type 2 diabetes mellitus.     

Activated platelet and oxidized LDL induce endothelial membrane vesiculation: clinical significance of endothelial cell-derived microparticles in patients with type 2 diabetes.

Endothelial cells, platelets, and oxidized LDL could play very important roles in the development of atherosclerosis in diabetes patients. The levels of plasma endothelial cell-derived microparticles (EDMP), platelet-derived microparticles (PDMP), platelet-P-selectin (plt-PS), soluble CD40 ligand (sCD40L), and anti-oxidized LDL antibody were measured and compared to develop a better understanding of their potential contribution to diabetic vascular complications. The concentrations of EDMP, PDMP, plt-PS, and sCD40L in diabetic patients were significantly higher than those in normal subjects. The number of EDMPs in patients with diabetes complicated by nephropathy was significantly higher than that in those without complications. Levels of anti-oxidized LDL antibody were also higher in type 2 diabetic patients than in control subjects. In addition, anti-oxidized LDL antibody levels correlated with EDMP, PDMP, plt-PS, and sCD40L levels in nephropathy patients. In the nephropathy group treated with sarpogrelate hydrochrolide, a 5-HT(2A) receptor antagonist, EDMP, PDMP, plt-PS, and sCD40L levels were decreased significantly. Oxidized LDL increased expression of plt-PS, and also promoted shedding of PDMP. Furthermore, oxidized LDL promoted a dose-dependent release of 5-hydroxytriptamine. On the other hand, activated platelets and PDMP promoted endothelial cells and THP-1 (monocytic cell line) interaction, and membrane vesiculation occurred in the presence of oxidized LDL. These findings suggest that activated platelets and oxidized LDL induce EDMP generation, and that elevated EDMPs may be a sign of vascular complications in type 2 diabetic patients, particularly those who suffer from diabetes-associated nephropathy.     

不同剂量辛伐他汀对急性心肌梗死患者炎性因子和血脂的影响

目的观察不同剂量辛伐他汀早期治疗急性心肌梗死患者对血清炎性因子、血脂水平及动脉粥样硬化病变消退程度的影响。方法43例急性心肌梗死患者分为A、B两组。A组(22例)口服辛伐他汀20mg/d,B组(21例)口服辛伐他汀40mg/d,治疗前后分别测定高敏C反应蛋白(hs-CRP)、可溶性白细胞分化抗原40配体(sCD40L)、基质金属蛋白酶-9(MMP-9)和血脂水平,随访12周和24周,颈动脉超声检查随访24周和48周。结果A组和B组患者血清hs-CRP、sCD40L、MMP-9和血脂水平在治疗后12周和24周时均有明显下降(P<0.05),且B组较A组作用更明显(P<0.05)。颈动脉内膜中层厚度、斑块积分随访48周后均有一定程度的下降,且以B组明显(P<0.05)。结论急性心肌梗死患者早期使用辛伐他汀治疗可显著降低血清炎性因子和血脂水平,并在一定程度上可阻止动脉粥样硬化病变的进展,且以大剂量为优。     

血糖水平对急性脑梗死患者血清可溶性CD40配体水平的影响

目的 对比不同血糖水平急性脑梗死患者外周血清中可溶性CD40配体（sCD40 L）水平,并探讨其与血糖水平的相关性.方法 选择急性脑梗死患者98例,根据血糖水平将其分为：糖耐量正常组、糖耐量异常组和2型糖尿病组.经超声检测颈动脉内中膜厚度及斑块情况并行Crouse斑块积分,酶联免疫吸附法检测外周血清中sCD 40L水平.结果 3组间血清sCD40L、IMT、Crouse积分比较差异有显著性（P＜0.05）.相关分析显示,血清sCD40L与血糖水平（r=0.272,P＜0.05）、IMT（r=0.651,P＜0.01）、Crouse积分（r=0.733,P＜0.01）均呈显著正相关.结论 糖尿病患者CD40L表达明显增高,血清sCD40L促进2型糖尿病患者颈动脉粥样硬化,其水平升高可能反应颈动脉粥样斑块的不稳定性.继发脑血管病的过程中可能启动或者介导了CD40/CD40L信号途径.     

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.     

Raised serum levels of soluble CD40 ligand in patients with familial hypercholesterolemia: downregulatory effect of statin therapy

OBJECTIVES: In the present study, we investigated the effects of statins on serum levels of soluble CD40 ligand (sCD40L) in patients with familial hypercholesterolemia (FH). BACKGROUND: Atherosclerotic disease seems to involve inflammatory and immunologic mechanisms, and sCD40L has recently been identified as one of the key players in the atherosclerotic process. HMG-Co A reductase inhibitors, statins, have been recognized as immunomodulators and reduce cardiovascular events and mortality, but the effects of statins on sCD40L has not been clarified. METHODS: In a randomized, double-blind, clinical trial, as part of the Atorvastatin versus Simvastatin on Atherosclerosis Progression (ASAP) trial, 110 patients with FH were given atorvastatin 80 mg/daily (n = 57) or simvastatin 40 mg/daily (n = 53) for two years. RESULTS: Our main findings were: 1) at baseline patients with FH had significantly higher (approximately 27-fold) serum levels of sCD40L than healthy controls; 2) statin therapy markedly decreased serum levels of sCD40L (approximately 40% reduction); 3) this decrease in sCD40L was found during both "aggressive" (i.e., atorvastatin) and "conventional" (i.e., simvastatin) statin therapy and was not correlated with the degree of reduction in cholesterol levels. CONCLUSIONS: Our findings may suggest enhanced CD40L-CD40 interaction in FH and that this inflammatory response may be downregulated by statins.     

Increased soluble CD40L levels are reduced by long-term simvastatin treatment in peritoneally dialyzed patients.

BACKGROUND: Dyslipidemia and increased mortality due to cardiovascular events are common in peritoneally dialyzed patients [continuous ambulatory peritoneal dialysis (CAPD)]. Statins show beneficial effects on serum lipids and reduce cardiovascular mortality. The CD40-CD40 ligand (CD40L) system has proved critical for the activation of tissue structural cells that include endothelial cells, epithelial cells and fibroblasts. It has been reported that enhanced CD40L-CD40 interaction in familial hypercholesterolemia may be downregulated by statins, but prospective studies on CAPD patients are lacking. AIM: To determine the effects of 6 months treatment with simvastatin on platelet aggregation, markers of endothelial cell injury, and sCD40L in 15 hyperlipidemic CAPD patients. METHODS: Simvastatin (Zocor, Merck Sharp & Dohme) was given in a dose of 10 mg at bedtime. RESULTS: CD40L decreased significantly after 6 months of the therapy. Thrombomodulin decreased significantly after 3 months of the therapy, whereas von Willebrand factor, E-selectin and P-selectin did not change significantly during the study. CONCLUSION: Simvastatin reduced enhanced sCD40L levels together with amelioration of endothelial dysfunction. Treatment with simvastatin might downregulate enhanced CD40L-CD40 interactions in CAPD patients.     

Enhanced levels of soluble CD40 ligand and C-reactive protein in a total of 312 patients with metabolic syndrome

The metabolic syndrome (MS) is associated with a systemic inflammatory response that plays an important pathogenetic role in atherothrombotic disease. Increasing evidence indicates that CD40-CD40 ligand interactions constitute an important mediator for vascular inflammation. The purpose of this study was to assess whether high-sensitivity C-reactive protein (hs-CRP) and soluble CD40 ligand (sCD40L) levels were increased in patients with MS. During the study period from January 2004 to August 2004, 312 patients with MS and 98 control subjects were included. Anthropometric measurements, blood pressure assessment, electrocardiography, and blood measurements including fasting blood glucose, postprandial blood glucose, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, glycated hemoglobin, white blood cell (WBC), platelets, hs-CRP, and sCD40L were performed. Patients with MS were divided into 3 groups based upon their glucose tolerance (group 1, normal glucose tolerance; group 2, prediabetic group; and group 3, diabetes mellitus). Patients with MS showed a significant increase of WBC, hs-CRP, and sCD40L levels compared with control subjects. The levels of both hs-CRP and sCD40L were positively correlated with body mass index (BMI). High-sensitivity CRP levels were also positively correlated with waist circumferences, fasting blood glucose, postprandial blood glucose, and glycated hemoglobin, and negatively correlated with high-density lipoprotein cholesterol. In patients with MS, both hs-CRP and sCD40L levels were positively correlated with WBC count. We found a positive correlation between sCD40L and platelets. Among the subgroups of patients with MS, the mean levels of WBC, hs-CRP, and sCD40L did not show any significant differences. In conclusion, elevated levels of WBC, hs-CRP, and sCD40L in MS patients provide further insight into the relationship between MS and inflammation. In our study, positive correlations between BMI and both hs-CRP and sCD40L levels suggest that BMI is an important determinant of a chronic inflammatory state in patients with MS. Moreover, this study reports significantly increased levels of WBC, hs-CRP, and sCD40L not only in diabetic subjects with MS but also in prediabetic subjects and nondiabetic subjects with MS compared with control subjects. Our data suggest that MS patients have proinflammatory state independent of their glucose tolerance status. In our study, the positive correlation between the levels of sCD40L and platelets in patients with MS supports previous reports indicating that sCD40L are derived predominantly from platelets.     

Usefulness of preprocedural soluble CD40 ligand for predicting restenosis after percutaneous coronary intervention in patients with stable coronary artery disease

CD40-CD40 ligand interaction is involved in the inflammatory pathogenesis of atherosclerosis but clinical data about its role in stent restenosis are still limited. We investigated the effect of preprocedural CD40 ligand (sCD40L) on stent restenosis. We enrolled 36 patients (mean age 61.4 +/- 8.5 years) with stable angina who underwent successful stent implantation. Control angiograms were performed in all patients after 6 months. Plasma sCD40L and high-sensitive C-reactive protein levels were measured before stent implantation and at 1 and 6 months after the procedure. Angiographically proven restenosis rate was 27.8%. Plasma sCD40L levels were significantly higher (preprocedural 0.74 +/- 0.79) and more prolonged in patients with stent restenosis compared with patients without stent restenosis (0.02 +/- 0.22 ng/ml, p < 0.001). According to receiver-operator characteristic analysis, sCD40L > 0.41 ng/ml was the best distinguished parameter between patients with and without restenosis. At the multivariate logistic regression analysis, preprocedural sCD40L was an independent predictor (RR 39.4, 95% confidence interval 4.05 to 383.8, p = 0.002) of stent restenosis after adjusting for confounding variables, including diabetes, reference vessel diameter, lesion length, stent diameter, stent length, and baseline high-sensitive C-reactive protein. Sensitivity, specificity, and positive and negative predictive values and likelihood ratio of preprocedural sCD40L levels in stent restenosis were 78%, 92%, 78%, 92%, and 9.37%, respectively. In conclusion, enhanced inflammation of plaque (increased sCD40L) before percutaneous coronary intervention may increase the rate of stent restenosis. Increased preprocedural sCD40L level is an independent predictor of stent restenosis. We can use this marker for the assessment of risk stratification before planning stent implantation.     

调脂治疗对急性脑梗死患者血清炎性因子水平的影响

目的探讨阿托伐他汀调脂治疗对急性脑梗死患者血清炎性因子水平的影响。方法选择急性脑梗死患者120例,根据颈动脉超声检查结果分为稳定斑块组60例和易损斑块组60例,2组又随机各选30例分别服用阿托伐他汀10mg/晚(小剂量)和阿托伐他汀40 mg/晚(大剂量)治疗。所有患者治疗前和治疗后2周,检测血脂及血清高敏C反应蛋白(hs-CRP)、可溶性细胞间黏附因子1(sICAM-1)、可溶性血管细胞黏附分子1(sVCAM-1)和可溶性CD40配体(sCD40L)及基质金属蛋白酶3(MMP-3)。结果治疗前,易损斑块组sCD40L、sVCAM-1和MMP-3水平明显高于稳定斑块组(P<0.05,P<0.01)。治疗后2周,2组大剂量治疗患者血清LDL-C、hs-CRP、sICAM-1、sVCAM-1、sCD40L和MMP-3水平明显低于小剂量治疗患者(P<0.01)。结论大剂量阿托伐他汀调脂治疗,能降低患者血清炎性因子的水平,具有抑制炎症和稳定斑块作用。     

阿司匹林对2型糖尿病患者血清可溶性CD40配体水平的影响

目的观察2型糖尿病（T2DM）患者血清可溶性CD40配体（sCD40L）水平的变化，以及阿司匹林（ASP）对其水平的影响。方法T2DM患者55例按是否服用阿司匹林（ASP）分为DM不服用ASP（DMwithoutASP）组24例和DM服用ASP组（DMwithASP）31例，设对照组33例。采用ELISA法测定血清sCD40L水平。结果DM-ASP组较对照组的sCD40L水平升高（2．14±0．74VS1．89±1．07，P〉0．05），DM＋ASP组CD40L较DM组下降（1．19±0．76，P〈0．01），较对照组下降（P〈0．01）。结论DM患者血清sCD40L升高；服用ASP可降低DM患者sCD40L水平。     

Enhanced P-selectin expression and increased soluble CD40 Ligand in patients with Type 1 diabetes mellitus and microangiopathy: evidence for platelet hyperactivity and chronic inflammation

Aims/hypothesis Platelet activation, endothelial dysfunction and inflammation may be involved in early stages of diabetic microangiopathy. We therefore investigated patients with Type 1 diabetes mellitus, without (n=19) and with (n=20) microangiopathy, matched for glycaemic control and duration of disease, and matched with healthy control subjects (n=27).Methods Platelet activation was measured as platelet P-selectin expression using whole blood flow cytometry and as soluble P-selectin by immunoassay. Von Willebrand factor antigen in plasma, serum soluble E-selectin, CD40 ligand (sCD40L) and C-reactive protein (CRP) served as markers for endothelial function and inflammation.Results Thrombin-induced platelet P-selectin expression was enhanced, and soluble P-selectin and sCD40L concentrations were increased in patients with microangiopathy compared with the control subjects (p<0.01 for both) and with patients without microangiopathy (p<0.05 for P-selectin expression and sP-selectin), whereas all three parameters were similar in patients without microangiopathy and in the control subjects. CRP and soluble E-selectin were increased in patients with microangiopathy, compared with the control subjects (p<0.01 and p<0.05), whereas von Willebrand factor did not differ between the groups.Conclusions/interpretation Microangiopathy in Type 1 diabetes is associated with platelet hyperactivity, endothelial dysfunction and low-grade inflammation, indicating an increased risk for cardiovascular disease.Abbreviations sP-selectin Soluble P-selectin - sCD40L soluble CD40 Ligand - CRP C-reactive protein     

可溶性CD40L对不稳定型心绞痛近期预后的影响

目的探讨sCD40L对不稳定型心绞痛（UA）近期预后的影响。方法采用酶联免疫吸附法对uA患者49例、稳定型心绞痛（SA）患者20例及对照组20例入院时血浆sCD40L水平进行检测,并对UA患者住院期间及出院后30d的急性不良心血管事件进行随访。结果①UA组患者入院时血浆sCD40L水平[（9．39±1．89）ng／ml]显著高于SA组[（5．92±2．06）ng／ml]（P〈0．01）和正常对照组[（4．91±1．97）ng／ml]（P〈0．01）,SA组略高于对照组,但差异无统计学意义。②UA患者中血浆sCD40L增高组住院期间和出院后30d急性不良心血管事件发生率显著高于血浆sCD40L正常组（P〈0．01）。结论UA患者血浆sCD40L显著增高。sCD40L可以作为冠心病易损斑块的血清学标记物,其水平对uA的近期预后有很好的预测价值。     

Abnormal soluble CD40 ligand and C-reactive protein concentrations in hypertension: relationship to indices of angiogenesis

BACKGROUND: Abnormal inflammation, platelets and angiogenesis are involved in the pathophysiology of cardiovascular disease (CVD). OBJECTIVE: To test the hypothesis that concentrations of high sensitive C-reactive protein (CRP, an index of inflammation) and soluble CD40 ligand (sCD40L, an index of platelet activation) would be abnormal in hypertension, and in turn, be related to plasma indices of angiogenesis, the angiopoietins-1 and -2, and vascular endothelial growth factor (VEGF), in addition to the presence or absence of CVD. METHODS: Using a cross-sectional approach, we measured plasma concentrations of CRP, sCD40L, VEGF, and angiopoietins-1 and -2 in 147 patients with hypertension (85 with a history of CVD event/s, 62 CVD event-free) and 68 age- and sex-matched healthy controls. RESULTS: Concentrations of sCD40L (P = 0.039), CRP (P < 0.001), angiopoietin-1 (P < 0.001), angiopoietin-2 (P = 0.003) and VEGF (P < 0.001) were all greater amongst hypertensive patients than in controls. There were no significant differences in sCD40L and VEGF concentrations between hypertensive individuals with and without CVD events, but CRP and angiopoietin-1 concentrations were significantly greater amongst those with CVD events. On multiple regression analysis, sCD40L was associated with angiopoietin-2 (P = 0.01) and VEGF (P = 0.007) in hypertensive individuals, but no such associations were found within the healthy control group. CONCLUSION: In patients with hypertension, sCD40L was associated with increased circulating markers of abnormal angiogenesis (angiopoietin-2, VEGF). The interaction between sCD40L and angiogenesis may contribute to the pathophysiology of CVD in hypertension.