Inhibitory Effect of Clopidogrel on Release of Soluble CD40 Ligand by ADP-activated Platelet in Patients With Non-ST-segment-elevation Acute Coronary Syndromes

Objectives To investigate the inhibitory effect of clopidogrel on release of soluble CD40 ligand （sCD40L） by ADP-activated platelet in patients with non-ST-segment elevation acute coronary syndromes（NSTEACS）. Methods Forty-two patients with NSTEACS were treated with clopidogrel for 6 - 8 days. In order to obtain platelet rich plasma （PRP） samples, the venous blood was drawn before and after treatment, respectively. The platelets were activated by adenosine diphosphate （ADP） , thus releasing sCD40L, sCD40L levels were determined by en- zyme-linked immunosorbent assay （ELISA） at different time of the reaction. Results Plasma sCD40L concentration before treatment was （0. 199 ± 0. 155 ） ng/mL, and （0. 190 ± 0. 176） ng/mL after treatment （ P 〉 0.05 ）. Before treatment the PRP sCD40L level at 20-minute of platelet activation was （4.34 ± 2.51 ） ng/mL, and decreased to （2.79 ±1.93 ） ng/mL after treatment （ P 〈 0. 001 ）. The corresponding level at 40 - minute of platelet activation was （5.29 ± 3. 13 ） ng/mL before treatment and （ 2.87 ± 1.59 ） ng/mL after treatment（ P 〈 0. 001 ）. Conclusions Short-term clopidogrel administration might inhibit the release of sCD40L by ADP-activated platelet in patients with NSTEACS, suggesting that, in addition to its antiplatelet potency, clopidogrel may still have an anti-inflammatory effect.     

可溶性CD40配体与心血管事件

可溶性CD40配体是肿瘤坏死因子超家族中的一种跨膜糖蛋白。可溶性CD40配体与心血管事件之间的关系是目前研究的热点。可溶性CD40配体可促使冠状动脉粥样硬化的发生发展;与急性冠脉综合征和心房纤颤关系密切;与心血管事件的危险因素相关。     

可溶性白细胞分化抗原40配体对急性冠脉综合征预后评价的意义

可溶性白细胞分化抗原40配体作为急性冠脉综合征时血小板活化的指标,较肌钙蛋白而言,能提供动脉粥样斑块破裂和血小板激活的更为直接的信息.具有重要的早期诊断和预测意义.大量的研究已经证实了可溶性白细胞分化抗原40配体与急性冠脉综合征的密切关系.因此,临床上,将可溶性白细胞分化抗原40配体用于对急性冠脉综合征预后的预测与评估具有重要意义.本综述阐述可溶性白细胞分化抗原40配体的来源,可溶性白细胞分化抗原40配体与急性冠脉综合征关系,以及可溶性白细胞分化抗原40配体对急性冠脉综合征预后的预测价值.     

Assessment of mean platelet volume and soluble CD40 ligand levels in patients with non-dipper hypertension,dippers and normotensives

Abstract

Objective: Patients with a lack of nocturnal decline in blood pressure (BP) are at an increased risk for cardiovascular events. Mean platelet volume (MPV) and soluble CD40 ligand (sCD40L) are accepted biomarkers of platelet activation and considered as a risk factor for cardiovascular disease. The aim of this study was to determine whether MPV and sCD40L levels are higher in non-dipper hypertensive (NDHT) patients than in dipper hypertensive (DHT) patients and healthy controls.

Methods: 124 consecutive patients were included to this study. Patients were divided into three groups: NDHT patient group [n?=?43; mean age 51.8?±?6.6; 31?males (72.1%)]; DHT patient group [n?=?41; mean age 50.2?±?7.3; 22?males (53.7%)]; and normotensive group [n?=?40; mean age 49.9?±?6.7; 22?males (55%)]. Physical examination, laboratory work-up and 24-h ABPM were performed for all participants.

Results: The sCD40L and MPV levels were significantly higher in the NDHT group than in the DHT and normotensive groups (p?<?0.05). In correlation analysis, MPV, 24-h systolic blood pressure (SBP), 24-h diastolic blood pressure (DBP), night-time SBP and night-time DBP were positively correlated with sCD40L.

Conclusion: Our study demonstrated that MPV and sCD40L levels were significantly higher in NDHT patients compared to DHT and normotensive patients. sCD40L levels were positively correlated with MPV, 24-h SBP, 24-h DBP, night-time SBP and night-time DBP.     

血清可溶性CD40L在冠心病患者中的价值

目的 观察sCD40L在不同类型冠心病患者血清中的水平变化,明确sCD40L能否作为易损斑块的血清标志物,同时探讨它和冠心病传统危险因素的关系及其诊断急性冠状动脉综合征的临床价值.方法 研究对象分四组:急性心肌梗死组(34例)、不稳定型心绞痛组(31例)、稳定型心绞痛组(30例)和非冠心病组(40例).采用双抗体夹心酶标免疫分析法测定标本中sCD40L水平.结果 (1)sCIM40L水平:急性心肌梗死组(8.02±4.03μg/L)和不稳定型心绞痛组(8.35±3.89μg/L)明显高于稳定型心绞痛组(4.86±2.23μg/L)和非冠心病组(4.35±1.83μg/L)(均P<0.01);稳定型心绞痛组略高于非冠心病组,不稳定型心绞痛组略高于急性心肌梗死组,但差异均无显著性(均P0.05).(2)四组中男性sCD40L水平均高于女性,但差异均无统计学意叉(P0.05).吸烟、冠心病家族史、高血压病和糖尿病不影响各组sCD40L水平;sCD40L与年龄、体质指数和血压无相关性(P0.05);在冠心病患者中,sCIMOL与脂蛋白(a)呈正相关(r=0.567,P=0.001),与高密度脂蛋白胆固醇呈负相关(r=-0.365,P=0.0001).(3)以血清sCD40L、脂蛋白(a)和肌酸激酶同工酶作为诊断指标判断急性冠状动脉综合征,ROC曲线分析结果显示以sCD40L诊断价值最大,曲线下面积达0.872(P<0.05),最佳临界值为4.58μg/L,对应的灵敏度、特异度和准确率分别为82.8%、61.9%和85.7%.结论 血清sCD40L在判定冠状动脉粥样硬化斑块易损性方面具有一定临床价值.sCD40L可能是冠心病的独立危险因素,sCD40L对急性冠状动脉综合征诊断的灵敏度、特异度、准确率较高,是诊断急性冠状动脉综合征的较理想指标.     

CD40 Ligand Deficiency

CD40 ligand deficiency (CD40L), currently classified as an inborn error of immunity affecting cellular and humoral immunity, prevalently emerges in boys within the first two years of life. It manifests itself as a decrease in serum IgG, IgA and IgE, with normal or high IgM, defects in T cell proliferation, and decrease in soluble CD40L. These accompany sinopulmonary and/or gastrointestinal infections, and there may be infections caused by pyogenic bacteria, opportunistic infections, autoimmune diseases, and neoplasms. Mild and moderate cases of this deficiency may respond well to prophylactic antibiotic therapy or to human immunoglobulin replacement therapy, in addition to the early treatment of infections. Severe cases can be treated with hematopoietic stem cell transplantation, which allows the healing of such patients, rather than sequelae and a poor progression. Thus, its differential diagnosis with other inborn errors of immunity is essential, especially CD40 deficiency and variable common immunodeficiency; the reason why we have proposed the present literature review.     

Elevated levels of biologically active soluble CD40 ligand in the serum of patients with chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia (CLL) is an indolent lymphoproliferative disorder manifested by low growth fraction and prolonged survival of the malignant cells. The mechanisms that enable CLL cells to live longer and to resist apoptosis remain unclear. Because the malignant CLL cells express CD40 and Fas receptors, which can transduce cell-survival and cell-death signals, we examined the role of CD40 in the growth regulation of CLL cells and its interaction with Fas-mediated and fludarabine-induced apoptosis in vitro . Primary CLL cells underwent spontaneous apoptosis in culture, which was enhanced by exogenous human Fas ligand (FasL) or fludarabine. Exogenous CD40L rescued CLL cells from spontaneous apoptosis in a dose-dependent manner, and caused CLL cells to resist apoptosis induced by FasL or fludarabine. Patients' autologous plasma rescued CLL cells from spontaneous apoptosis, an effect that could be reversed with anti-CD40 ligand (CD40L) antibodies. The levels of soluble CD40 ligand in the sera of 51 CLL patients and 55 healthy donors were determined by enzyme-linked immunosorbent assay. The mean soluble CD40L level in normal donors was 0.29 ng/ml compared to a mean value of 0.80 ng/ml in CLL patients ( P  < 0.001). CD40L up-regulated bcl-X_L mRNA but not bcl-2 in CLL cells within 3–6 h in culture. Our results demonstrated that serum of patients with CLL contained elevated levels of biologically active soluble CD40L, and that CD40L can prolong survival of CLL cells and mediate their resistance to FasL and fludarabine in vitro .     

降解药物涂层支架对冠心病患者血浆可溶性CD40配体的影响

目的 研究冠心病患者血浆可溶性CD40配体变化及降解涂层药物洗脱支架(EXCEL支架)对血浆可溶性CD40配体的影响.方法 选择接受裸支架(BMS)或EXCEL支架治疗,并且行冠状动脉造影随诊的80例冠心病患者,根据患者所接受支架不同分为BMS组和EXCEL支架组,每组40例,测定术后1个月、3个月和6个月时血浆可溶性CD40配体的水平.结果 80例患者(男48例,女32例)120个靶病变接受治疗并完成冠状动脉造影随诊.术后1个月和3个月时血浆可溶性CD40配体水平EXCEL支架组显著低于BMS组(P<0.01),于6个月时,血浆可溶性CD40配体水平两组相比差异无显著性(P>0.05).结论 EXCEL支架可降低血浆可溶性CD40配体,适度内皮化,减少再狭窄.减少迟发性血栓形成.     

Effect of Clopidogrel on Platelet Membrane CD40 Ligand in Coronary Artery Disease Patients Undertaking Percutaneous Coronary Intervention

Objectives To investigate the change and clinical significance of clopidogrel on platelet membrane CD40L in coronary artery disease patients before and after percutaneous coronary intervention(PCI). Methods 30 cases who were diagnosis coronary artery diseases(CAD) by coronary angiography, mean age 56±9 years old. All the patients who had no antiplatelet aggregation contraindication, were treated with standard anti angina pectoris drugs. Before PCI, all the patients took clopidogrel 75 mg per day. Activated platelet membrane CD40L express rate was measured by flow cytometry before and after PCI 6 hours. Results Activated platelet membrane CD40L express rate were 3.73±2.15 and 2.46±0.90, respectively in 30 patients before and after PCI 6 hours. Activated platelet membrane CD40L express rate was significantly decrease after PCI 6 hours than that before PCI(P<0.01). Conclusions Clopidogrel has significance effect on platelet membrane CD40L in coronary artery disease patients undergoing PCI. Clopidogrel can suppression platelet activation and prevent thromboembolism event occurrence.     

Coexpression of CD40 and CD40 ligand in B-cell lymphoma cells

CD40 ligand (CD40L) is involved in the T-cell-dependent regulation of B-cell growth and survival and can rescue normal germinal centre B cells and several types of malignant B cells from apoptosis in vitro . We have previously reported that serum of patients with chronic lymphocytic leukaemia contained elevated levels of biologically active soluble CD40L (sCD40L). Whether an augmented CD40L pathway exists in patients with other types of B-cell lymphoid malignancies and the source of native sCD40L in these patients is currently unknown. Using a sensitive ELISA assay, soluble CD40L (sCD40L) was detected in the sera of both healthy individuals and patients with haematological malignancies; however, its level was significantly elevated only in patients with B-cell lymphomas ( P   < 0.0001). Several types of malignant B cells coexpressed CD40 and CD40L proteins, and CD40L mRNA was detected in purified resting malignant B cells. The dual expression of CD40 and CD40L in B cells and the presence of native sCD40L in human serum suggest that a direct T–B-cell contact may not be required for CD40L delivery to B cells. This data raises the possibility that an autocrine cytokine loop involving CD40L may contribute to the growth regulation of benign and malignant B cells in vivo .     

炎性因子CD40配体在急性冠脉综合征患者中的作用

目的探讨急性冠脉综合征（ACS）患者血清可溶性CD40配体（sCD40L）和超敏C反应蛋白（hs-CRP）的水平及临床意义。方法按照诊断标准入选研究对象137例,分为两组：冠状动脉造影无异常者为对照组,21例,ACS组116例,男86例,30例,年龄35～77（56.9±12.6）岁,包括不稳定型心绞痛88例,急性心肌梗死28例。采集患者空腹肘静脉血,采用酶联免疫吸附（ELISA）方法测定血清sCD40L浓度和hs-CRP浓度。所有患者入院第2～4天行冠状动脉造影检查,用直径法测定冠状动脉狭窄的程度,用Gensini评分系统进行评分,累计积分。结果 ACS组sCD40L与hs-CRP水平均高于对照组（P＜0.05）。sCD40L水平与Gensini积分呈正相关关系（r＝0.328,P＝0.000）,hs-CRP水平与Gensini积分呈正相关关系（r＝0.748,P＝0.000）,sCD40L与hs-CRP之间呈正相关关系（r＝0.192,P＝0.039）。结论 ACS患者外周血清sCD40L和hs-CRP水平明显升高,提示CD40/CD40L系统与ACS的发生有关。     

可溶性CD40配体与急性冠状动脉综合征的关系

观察急性冠状动脉综合征、稳定型冠心病患者可溶性CD4 0配体变化及其与血脂水平的关系 ,采用酶联免疫吸附法测定血清可溶性CD4 0配体浓度。结果发现急性冠状动脉综合征患者可溶性CD4 0配体水平 (3.17± 2 .84 μg L)显著高于正常对照者 (1.19± 1.0 5 μg L ,P <0 .0 1)和稳定型冠心病患者 (1.6 1± 1.4 6 μg L ,P <0 .0 5 )。可溶性CD4 0配体水平受甘油三酯 (r=0 .2 3,P <0 .0 5 )、载脂蛋白B(r=0 .2 4 8,P <0 .0 5 )及高密度脂蛋白胆固醇等因素的影响 (r=- 0 .2 5 3,P <0 .0 5 )。以上提示可溶性CD4 0配体水平的升高可能与急性冠状动脉综合征的发生有关 ,是动脉粥样硬化斑块不稳定的标志     

CD40/CD40L系统与动脉粥样硬化和脑梗死的关系

脑动脉粥样硬化是导致脑梗死的主要原因.CD40/CD40L的过度表达会激发免疫和炎症反应,导致粥样斑块内局部炎症细胞浸润,促发斑块破裂,进而发生脑梗死.近年来的研究表明,CD40L与脑梗死体积和严重程度相关.因此,检测CD40L可作为判断脑梗死严重程度的一项指标,用以指导临床治疗.     

CD40配体预测急性冠状动脉综合征的临床价值

目的 观察不同类型冠心病患者可溶性CD40配体(sCD40L)的变化,探讨其在急性冠状动脉综合征(ACS)诊断中的价值.方法 选择2006年1月至6月在哈尔滨医科大学第一临床医学院心内科住院的冠心病患者66例和健康对照者20名.冠心病组包括ACS患者和稳定型心绞痛(SA)患者两组,采用酶联免疫吸附试验(ELISA)方法统一测定入选人群血清中sCD40L的质量浓度,采用t检验及评价不同试验方法临床准确性的受试者工作特征曲线(ROC curve)等统计学方法进行分析.结果 ACS患者的sCD40L[(2.39±0.37)μg/L]显著高于对照组[(1.76±0.17)μg/L,P＜0.01]和SA组[(1.89±0.16)μg/L,P＜0.01].SA患者与对照组比较差异无显著性意义,P＞0.05.ROC曲线显示,将sCD40L质量浓度2.01 μg/L作为临界值诊断ACS的灵敏度为91%,特异度为80%,曲线下面积(AUC)为0.907.结论 sCD40L质量浓度大于2.01μg/L对于ACS的诊断有重要临床意义.     

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.     

2型糖尿病合并冠心病患者血小板表面CD62P和CD40L的表达水平

目的 探讨2型糖尿病合并冠心病患者血小板表面CD62P和CD40L的表达水平及其和血清高敏C反应蛋白的关系.方法 选择单纯冠心病患者34例、单纯2型糖尿病患者33例、2型糖尿病合并冠心病患者30例及对照者30例,采用流式细胞术分别检测血小板表面CD62P和CD40L的表达水平,并与血清高敏C反应蛋白作相关分析.结果 2型糖尿病合并冠心病组血小板CD62P、CD40L和高敏C反应蛋白水平较对照组、单纯冠心病组及单纯2型糖尿病组显著升高(P<0.01),血小板CD62P和CD40L与血清高敏C反应蛋白水平呈正相关(r分别为0.343和0.495,P均<0.05).结论 2型糖尿病合并冠心病患者的血小板表面CD62P和CD40L表达水平明显升高,并与血清高敏C反应蛋白明显正相关.血小板表面CD62P和CD40L的表达水平可能是预示糖尿病患者合并冠状动脉粥样硬化的重要指标.     

氨基端脑钠肽原与细胞分化抗原40配体联合预测急性冠脉综合征近期预后

目的探讨联合血浆氨基端（N端）脑钠肽原（NT-proBNP）与可溶性细胞分化抗原40配体（sCD40L）共同预测急性冠脉综合征（ACS）患者的近期预后的价值。方法研究134例ACS患者,其中ST段抬高心肌梗死70例,非ST段抬高心肌梗死8例,不稳定型心绞痛56例,应用ELISA法分别在发病12～24h之内测定血浆NT-proBNP和scD40L浓度,根据NTproBNP浓度的ROc曲线确定分界值（1163．89pmol／L）,分为高NT-proBNP组和低NT-proBNP组,根据测得sCD40L浓度的ROC曲线确定分界值（915ug／L）,分为高sCD40L组和低sCD40L组,再将NT-proBNP与sCD40L联合分组,分为阳性组（NT-proBNP和sCD40L均为高浓度组）,弱阳性组（NT-proBNP和sCD40L仅有一项为高浓度组）,阴性组（NT-proBNP和sCD40L均为低浓度组）,并随访[平均（96．62土9．08）d]主要不良心脏事件（MACE）。结果高NT～proBNP组41例,MACE发生率48．8％（20例）,低NT-proBNP组93例,MACE发生率4．3％（4例）,两组间MACE的发生率有统计学显著性差异;高sCD40L组57例,MACE发生率28．1％（16例）,低sCD40L组77例,MACE发生率10．4％（8例）,两组间统计学差异有显著性意义;联合NT-proBNP与sCD40L共同预测ACS预后,阳性组23例,MACE发生率为56．5％（13／23）,弱阳性组52例,MACE发生率19．2％（10／52）,阴性组59例,MACE发生率为1．7％（1／59）,3组之间统计学差异有显著性意义。结论联合血浆NT-proBNP与sCD40L提高了对ACS患者近期预后的预测价值。     

Analysis of serum soluble CD40 ligand (sCD40L) in the patients undergoing allogeneic stem cell transplantation: platelet is a major source of serum sCD40L

CD40 ligand (CD40L) is expressed not only on activated T cells but also on activated platelets. A soluble CD40 ligand (sCD40L) is released from the activated T cells and platelets by ill-defined proteolytic process in vitro. It has been reported that sCD40L is elevated in the serum of patients with systemic lupus erythematosus, unstable angina, essential thrombocythemia, and autoimmune thrombocytopenic purupura. However, source of sCD40L in vivo remains to be elucidated. We investigated the serial sCD40L in the serum in patients undergoing allogeneic stem cell transplantation and compared with the platelets number and soluble IL2R, which is a marker of activated T cells. The value of sCD40L was well correlated with platelet number or thrombopoiesis. In cases of severe graft vs. host disease with markedly increased sIL2R, sCD40L was not increased in vivo. These results indicate that sCD40L in vivo is released mainly from the platelets or in the process of platelet production but not from the activated T cells.     

CD40/CD40L在毛细支气管炎发病机制中的作用

CD40/CD40L是T、B细胞表达的重要膜表面蛋白质分子,它们之间的相互作用对T、B细胞具有重要的影响,在炎症反应、免疫紊乱等方面具有重要的作用.它们之间的交联反应促进气道炎症反应和气道高反应性.目前认为CD40/CD40L在毛细支气管炎发病的多个环节中发挥作用,本文就其与毛细支气管炎的关系进行综述.     

Soluble CD40 ligand in acute and chronic heart failure.

AIMS: Inflammatory cytokines may play a pathogenic role in heart failure (HF). CD40-CD40 ligand (CD40L) interactions are important in atherogenesis and based on its role in inflammation we sought to evaluate the role of CD40L in human HF. METHODS AND RESULTS: Serum levels of soluble (s) CD40L were measured in 236 patients with acute HF following myocardial infarction, treated with either angiotensin-converting enzyme (ACE)-inhibition or angiotensin II blockade and followed for 2 years, and in 116 patients with chronic HF. Our main findings were: (i) patients with acute HF had increased sCD40L levels, particularly those with severe HF, diabetes, or hypertension; (ii) when these patients were followed longitudinally, persistently raised sCD40L levels were found throughout the observation period with no effect of captopril or losartan; (iii) the increase in sCD40L during follow-up was not seen in patients receiving warfarin therapy; (iv) patients with chronic HF also had raised sCD40L, significantly correlated with clinical severity, neurohormonal dysregulation, and left ventricular dysfunction; (v) studies from different blood compartments suggest that the vasculature of lower extremities and the failing myocardium itself may produce and secrete sCD40L in chronic HF. CONCLUSION: Our findings may suggest a pathogenic role for enhanced CD40-CD40L interactions in human HF.