Soluble CD40 Ligand In Patients Research Articles

Evaluation of plasma levels of neopterin and soluble CD40 ligand in patients with acute ischemic stroke in upper Egypt: can they surrogate the severity and functional outcome?

Inflammation constitutes a major component of ischemic stroke pathology. The prognostic value of "neopterin" and soluble CD40 ligand (sCD40L), as a potential biomarker of ischemic stroke, has been less extensively studied. This study aims at assessing the serum levels of neopterin and sCD40L in acute ischemic stroke (AIS), to clarify its association with the severity, etiology, and risk factors of stroke, and to evaluate their relationship with the stroke functional outcome in our study sample within 90 days of follow-up. This case-control study was conducted on 100 patients with first-ever acute onset ischemic stroke and 25 control subjects. Participants were subjected to full history taking and detailed clinical and neurological examination. Brain imaging was performed after hospital admission. Blood tests were drawn for assessment of neopterin and sCD40L on the first day of admission. High levels of neopterin and sCD40L was reported. Their levels were significantly higher in relation with survival status. There was a relationship between AIS and sCD40L levels and the severity of the stroke. Within 3 months of follow-up, these biomarkers were associated significantly with poor functional outcome, within a 90-day follow-up period, and mortality. These biomarkers were highly associated in patients with small vessel occlusion as an etiology for AIS. Neopterin and sCD40L levels increased after AIS. Both biomarkers were strong and independent predictors of 90-day unfavorable clinical outcome and death in patients after AIS.

Predictive value of elevated soluble CD40 ligand in patients undergoing primary angioplasty for ST-segment elevation myocardial infarction.

The aim of this study was to evaluate the prognostic value of soluble CD40 ligand (sCD40L) in patients with ST-segment elevation myocardial infarction (STEMI) undergoing a primary percutaneous coronary intervention (PCI). The prognostic value of sCD40L has been documented in patients with acute coronary syndrome; however, its value in acute STEMI remains unclear. We prospectively enrolled 499 consecutive STEMI patients (397 men, 102 women) undergoing primary PCI. The study population was divided into tertiles on the basis of admission sCD40L values. The high sCD40L group (n=168) included patients with a value in the third tertile (≥0.947 mg/l) and the low sCD40L group (n=331) included patients with a value in the lower two tertiles (<0.947 mg/l). Clinical characteristics and in-hospital and 1-year primary PCI outcomes were analyzed. The patients in the high sCD40L group were older (mean age 57.3±12.7 vs. 54.8±11.9, P=0.029). Higher in-hospital and 1-year all-cause mortality rates were observed in the high sCD40L group (7.7 vs. 3.3%, P=0.029; 16.1 vs. 4.8%, P<0.001, respectively). The results of Cox multivariate analysis indicated that a high sCD40L value at admission (>0.947 mg/l) is a powerful independent predictor of 1-year all-cause mortality (odds ratio: 3.68; 95% confidence interval: 1.54-8.77; P=0.003). The results of this study suggest that a high sCD40L level at admission is associated with increased in-hospital and 1-year all-cause mortality rates in patients with STEMI undergoing primary PCI.

Serum concentrations and clinical significance of soluble CD40 ligand in patients with multiple myeloma

Multiple myeloma (MM) is a disease of plasma cells that express the CD40 receptor. Binding of the CD40 by its natural ligand, CD40 ligand (CD40L), produces growth arrest and/or apoptosis in MM. To evaluate serum levels of soluble CD40L (sCD40L) in MM patients and to correlate them with markers of disease activity and angiogenesis, such as vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), interleukin-6 (IL-6), proliferation marker Ki-67 proliferation index (Ki-67 PI) and bone marrow plasma cell infiltration, fifty-eight MM patients were studied in diagnosis and 43 of them after completion of treatment. Serum levels of sCD40L, VEGF, HGF and IL-6 were measured by ELISA, whereas Ki-67 PI and bone marrow plasma cell infiltration were measured by immunohistochemistry. Pre-treatment levels of sCD40L in MM patients were higher compared to controls and to their levels after effective treatment. Treatment regimen did not affect the degree of reduction of sCD40L levels, whereas patient in partial remission had increased levels compared to those with better response. Significant differences were found among disease stages. There were also positive correlations between CD40L with HGF, VEGF, IL-6 and Ki-67 PI. Elevated serum sCD40L is found in patients with advanced MM stage and can be reduced after effective treatment. Increased levels of this mediator are correlated with angiogenic cytokines, providing evidences that CD40L/CD40 interactions play a significant role in the mechanisms of angiogenesis in MM patients.

Elevations in soluble CD40 ligand in patients with high platelet aggregability undergoing percutaneous coronary intervention

High aggregatory responses despite antiplatelet treatment is associated with an increased risk of thrombotic complications following percutaneous coronary intervention (PCI). In the present study, we investigated the relationship between platelet aggregatory responses to ADP and the release of CD40L (sCD40L): an immunomodulatory compound involved in atherothrombosis - in patients undergoing PCI. ADP-induced platelet aggregation, sCD40L and soluble P-selectin (sP-selectin) were determined before and 24 h after PCI, in samples from 52 patients receiving aspirin and thienopyridines. Platelet aggregation to ADP above the median was defined as 'high aggregation', and aggregation below the median as 'low aggregation'. Data below are medians and interquartile ranges. Patients with 'high platelet aggregability' had a significantly higher increase in both sCD40L (Delta-values: 0.78 (-0.19-3.18) vs. -0.65 (-2.10-0.00) ng/ml, P = 0.002) and sP-selectin (Delta-values: 8.0 (-2.00-16.00) vs. 4.50 (-13.00-0.50) ng/ml, P = 0.001) compared with patients with 'low platelet aggregability'. In a multivariate linear regression analysis adjusted for clinical characteristics and type of preintervention therapy, the only independent predictors of sCD40L and sP-selectin were platelet aggregation to ADP before PCI (P < 0.001) and the combination of platelet aggregation to ADP before PCI and urgency of PCI (P < 0.001). Circulating CD40L is more markedly increased after PCI in patients with high ADP-induced platelet aggregation.

P-323 Elevated Levels of Soluble CD40 Ligand in Patients with Cardiac Syndrome X

P-323 Elevated Levels of Soluble CD40 Ligand in Patients with Cardiac Syndrome X

Increased Plasma Levels of Asymmetric Dimethylarginine and Soluble CD40 Ligand in Patients with Sleep Apnea

Background: Cardiovascular (CV) diseases are a leading cause of mortality and they are frequent in patients with the obstructive sleep apnea syndrome (OSAS). Objectives: In this study we investigated if OSAS influences CV function independently of other CV risk factors frequently present in these patients (e.g. obesity, high blood pressure). Methods: We compared plasma markers of endothelial dysfunction, asymmetric dimethylarginine (ADMA) and endothelin-1 (ET-1), and atherosclerosis progression (soluble fraction of the CD40 ligand, sCD40L) in OSAS patients with (n = 23) and without (n = 18) concurrent CV risk factors, as well as in healthy subjects (n = 23). Results: Plasma ADMA (p < 0.01) and sCD40L (p < 0.05) were abnormally increased in patients with OSAS versus healthy controls, but they were not influenced by the presence or absence of CV risk factors in OSAS. ET-1 levels were not different between the three groups of subjects studied. Conclusions: OSAS is associated with endothelial injury and atherosclerosis progression independently of other CV risk factors.

Diurnal variation of soluble CD40 ligand in patients with acute coronary syndrome. Soluble CD40 ligand and diurnal variation

Introduction We sought to investigate whether day-night variations occur in the concentration of circulating soluble CD40 ligand in patients with acute coronary syndrome, as this may have practical implications. Materials and Methods We assessed 70 consecutive ST-segment elevation myocardial infarction patients admitted into the Coronary Care Unit and 50 control subjects. Each subject was studied under strictly controlled light/dark conditions. Blood samples were drawn at 09:00 h (light phase) and 02:00 h (dark phase). Nocturnal blood samples were drawn by a trained nurse, with the help of a minute torch with a dim red light in order to avoid any direct lighting on the patient during sleep. The soluble CD40 ligand was measured using a commercially available ELISA. Results Soluble CD40 ligand levels showed no diurnal variations in control subjects. In the ST-segment elevation myocardial infarction group, however, soluble CD40 ligand concentration (pg/mL) in the light phase was significantly higher than that in the dark phase (167.3 ± 63.2 vs 118.9 ± 48.3 pg/mL, p < 0.001). Conclusions The study shows for the first time the existence of diurnal variations in soluble CD40 ligand levels in ST-segment elevation myocardial infarction patients, which indicates the need for standardizing the time of blood sampling for the assessment of this molecule, at least in studies involving ST-segment elevation myocardial infarction patients.

Prognostic value of plasma soluble CD40 ligand in patients with chronic non-valvular atrial fibrillation

We aimed to clarify whether determination of levels of soluble CD40 ligand (sCD40L) could predict subsequent thrombo-embolic events in patients with non-valvular atrial fibrillation (NVAF). Forty-four consecutive outpatients (mean age: 58 +/- 6 years, 20 male) with chronic NVAF who were not receiving aspirin and had no thrombus or spontaneous echo contrast (SEC) on left atrium (LA) or left atrial appendage (LAA) were included in the study. The patients had no history of an embolic event and were followed up 24 +/- 2 months for thrombo-embolic events. sCD40L was determined at the enrollment. All patients were evaluated by means of SEC and thrombus formation by transoesophageal echocardiography at the end of follow-up period. Twelve (27%) patients had SEC and 2 (5%) patients had thrombus on LAA. Ischaemic stroke occurred in 2 (4.5%) patients and transient ischaemic attack developed in 4 (9%) patients during follow-up. sCD40L was significantly higher in patients with LASEC (0.41 +/- 0.05 vs. 0.16 +/- 0.04 ng/mL, P = 0.02) and embolic events (0.74 +/- 0.05 vs. 0.19 +/- 0.03 ng/mL, P = 0.001) than in those without. sCD40L levels were significantly related to the LASEC grade (R = 0.377, P = 0.02). In multivariable analysis, while independent variables for SEC or thrombus formation were LA diameter, sCD40L levels, and the duration of AF, independent variables for cerebrovascular events were the existence of SEC or thrombus formation on LAA, and sCD40L level. Plasma sCD40L may prospectively predict stroke in AF. sCD40L may provide useful marker to identify patients at high thrombo-embolic risk with NVAF.

Effect of Continuous Positive Airway Pressure on Soluble CD40 Ligand in Patients With Obstructive Sleep Apnea Syndrome

Obstructive sleep apnea syndrome (OSAS) is an independent risk factor for atherosclerosis. CD40-CD40 ligand interaction promotes several proinflammatory mediators and plays a pivotal role in the various stages of atherosclerotic diseases. The present study examines whether CD40 ligation contributes to outcomes in patients with OSAS. The study population comprised OSAS patients with an apnea hypopnea index (AHI) > or = 30 (n = 35) and control subjects (AHI < 5; n = 16). We measured serum levels of soluble CD40 ligand (sCD40L), tumor necrosis factor (TNF)-alpha, and hypersensitive C-reactive protein (hsCRP) before and after nasal continuous positive airway pressure (nCPAP) therapy for 3 months. Baseline levels of sCD40L were significantly higher in patients with OSAS (6.93 +/- 4.64 ng/mL) [mean +/- SD] than in control subjects (3.43 +/- 2.11 ng/mL, p < 0.01). Baseline levels of sCD40L positively correlated with TNF-alpha but not with hsCRP. The elevation of sCD40L was improved for 1 night after nCPAP therapy (3.83 +/- 2.78 ng/mL, p < 0.001). Even though patients with severe OSAS did not receive any other medication to control atherosclerotic risk factors for 3 months, nCPAP was continued to reduce the levels of sCD40L. The present study suggested that sCD40L is a key factor that links OSAS and atherosclerotic progression.

Effect of atorvastatin on circulating proinflammatory T-lymphocyte subsets and soluble CD40 ligand in patients with stable coronary artery disease—A randomized, placebo-controlled study

Coronary atherosclerosis includes an activation of circulating T lymphocytes. Statins exert anti-inflammatory effects beyond lipid lowering. Whether these properties influence systemic T lymphocytes is unclear. To investigate the effect of atorvastatin on circulating T-lymphocyte subsets producing proinflammatory and anti-inflammatory cytokines (interferon gamma [IFN-gamma(+)], interleukin 2 [IL-2(+)], IL-4(+), and IL-10(+)) and on the T-cell-activating soluble CD40 ligand (sCD40L), 30 hypercholesterolemic patients with angiographically documented stable coronary artery disease (CAD) were randomized to placebo or atorvastatin (20 mg/d) for 3 months. Eight healthy volunteers served as controls. Levels of peripheral cytokine-producing CD4+ and CD8+ T cells and their CD28- subsets were determined by FACS. Serum soluble CD40L was measured with ELISA. IL-2(+) T lymphocytes and sCD40L levels were higher in patients with CAD compared with controls, whereas IFN-gamma(+) and anti-inflammatory IL-4(+) and IL-10(+) T lymphocytes were similar. Levels of IL-2(+), IFN-gamma(+), IL-4(+), and IL-10(+) T-cell subsets as well as CD28- T lymphocytes were neither changed by atorvastatin nor by placebo, whereas sCD40L was lowered only in atorvastatin-treated patients (P < .01). Circulating IL-2(+) T lymphocytes are increased in patients with stable CAD reflecting an activation of the global immune system, but are not influenced by atorvastatin therapy. The elevated levels of platelet-derived T-lymphocyte-stimulating sCD40L are decreased by atorvastatin probably reflecting an atheroprotective effect. Hence, sCD40L may be an additional biomarker to be considered when evaluating the treatment effects of statins in patients with stable CAD.

Impact of Clopidogrel on Suppression of Circulating Levels of Soluble CD40 Ligand in Patients With Unstable Angina Undergoing Coronary Stenting

This study investigated whether a regimen that comprised a loading dose of 300 mg of clopidogrel followed by 75 mg/day could significantly suppress circulating levels of soluble CD40 ligand (sCD40L) in patients who had unstable angina and underwent coronary stenting. Study results showed that the clopidogrel loading dose substantially decreased the circulating level of sCD40L at 24 hours after stenting (p <0.0001). Combined with aspirin, 75 mg/day of clopidogrel continuously decreased sCD40L levels after coronary stenting.

Analysis of serum soluble CD40 ligand in patients with influenza virus-associated encephalopathy

CD40 ligand (CD40L) is mainly expressed on activated platelets and CD4 + T cells, and it can be cleaved from the cell surface, releasing a soluble CD40L (sCD40L). Most sCD40L is derived from activated platelets. A previous paper revealed that the platelet number of patients with influenza virus-associated encephalopathy (IE) was correlated with the outcome. We determined the utility of sCD40L as a predictor for the prognosis of IE. We measured the serum concentration of sCD40L and the platelet number on the day of hospitalization in 34 patients with IE, 16 with influenza virus-associated febrile seizures (IFS), 19 with influenza virus infection without complications (Flu), and 7 with Epstein–Barr virus (EBV) infection. The serum sCD40L concentrations in IE and IFS were significantly lower than those in controls, Flu, and EBV infections. Serum sCD40L concentrations in the IE group were 0.70 ± 0.43 ng/ml for deceased patients, 1.73 ± 1.36 ng/ml for those with sequelae, and 3.85 ± 2.91 ng/ml for those without sequelae. There was no significant difference in platelet number between IE patients with and without sequelae, while the platelet number of deceased patients with IE was significantly lower than in controls, Flu, and IFS. Serum sCD40L concentration on the day of hospitalization was more correlated with the outcome of IE than platelet number. Our findings suggest that the serum sCD40L concentration during acute IE is important for predicting the prognosis at an early stage.

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.

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

ObjectivesIn the present study, we investigated the effects of statins on serum levels of soluble CD40 ligand (sCD40L) in patients with familial hypercholesterolemia (FH). BackgroundAtherosclerotic 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. MethodsIn 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. ResultsOur 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. ConclusionsOur findings may suggest enhanced CD40L-CD40 interaction in FH and that this inflammatory response may be downregulated by statins.

Significance of chemokines and soluble CD40 ligand in patients with autoimmune thrombocytopenic purpura

We investigated the levels of various chemokines and soluble CD40L (sCD40L) in ITP patients, in order to determine the influence of CD40-CD40L interaction on the pathogenesis of ITP. We found increases in MCP-1 and RANTES levels in ITP patients compared with those in healthy individuals. Thirty-eight of the 65 ITP patients (58.5%) had elevated levels of sCD40L. We found significant decreases in platelet counts in sCD40L-positive ITP patients. Although the sCD40L level did not differ significantly between the control and nonimmune thrombocytopenia groups, but among ITP patients. sCD40L level was significantly higher in those with untreated ITP than in those with treated ITP. In addition, significant increases in RANTES, MCP-1, sCD14, and sP-selectin levels were observed in sCD40L-positive ITP patients, although sE-selectin levels were not increased in such patients. For other factors examined, however, there were no differences in level between sCD40L-positive and -negative ITP patients. These findings suggests that there are two groups of ITP patients, one with elevated and one with normal of sCD40L. ITP cases in which sCD40L was increased appeared to involve changes in platelet counts and monocyte activation. The pathogenesis of ITP may in some patients include alterations of the CD40/CD40L pathway.