Serum CD40 Ligand Research Articles

Determinants of post-operative atrial fibrillation in 1613 patients undergoing coronary artery bypass grafting in the Statin Therapy In Cardiac Surgery (STICS) trial

Abstract Introduction Post-operative atrial fibrillation (POAF) occurs in 20–40% of patients in the first week after cardiac surgery, and is associated with longer hospital stay, higher stroke risk, and worse overall prognosis. The surgery-related inflammatory response has been strongly implicated in POAF pathogenesis; however, lower CRP levels resulting from perioperative rosuvastatin therapy in the Statin Therapy In Cardiac Surgery (STICS) randomized trial were not associated with a reduced incidence of POAF. Furthermore, POAF independently predicts subsequent clinical AF and as such may reflect the presence of a subclinical cardiomyopathic substrate. We tested this hypothesis by investigating determinants of POAF in 1613 patients who underwent isolated coronary artery bypass grafting in China in the STICS trial. Methods Clinical data included age, sex, body mass index, medical history, medications, and type of surgery (on-pump vs off-pump). Blood taken prior to surgery was assayed for troponin I, N-terminal pro–brain natriuretic peptide (NT-proBNP), creatinine, low-density lipoprotein (LDL) cholesterol, and serum CD40 ligand. The biomarkers growth differentiation factor 15, interleukin-6, procalcitonin, and placental growth factor were measured at baseline and at 6 hours after surgery. Echocardiography evaluated left ventricular ejection fraction (LVEF) and left atrial (LA) size. POAF was detected by continuous Holter electrocardiographic monitoring for 5 days after surgery. Results POAF occurred in 314 of 1613 patients (19%). As expected, age was the single strongest predictor of POAF (C-statistic 0.66 [95% CI 0.62–0.70]). After adjustment for age, NT-proBNP, LA size, Troponin, LVEF, sex, calcium-channel blocker use, and prior myocardial infarction were all significantly associated with POAF when assessed individually (all P<0.05). In multivariate analysis, a basic model incorporating only age, NT-proBNP, and LA size had a C-statistic of 0.69 (95% CI 0.66–0.73). This performance was not significantly different to that of models including all available variables, irrespective of whether baseline or post-surgery biomarker results were used (all C-statistics 0.71 [95% CI 0.68–0.75]; Table 1). The basic model numerically outperformed more complex risk prediction scores including CHARGE-AF (0.66, 95% CI 0.63–0.70; Figure 1), POAF score (0.64, 95% CI 0.61–0.68), CHA2DS2-VASc (0.60, 95% CI 0.57–0.63), and AF risk index (0.57, 95% CI 0.54–0.60). Conclusions A basic model requiring only age, NT-proBNP, and LA size has good predictive value for POAF in this population, comparing well to more complex risk prediction scores. More broadly, these results suggest that systemic inflammation and perioperative myocardial injury may be less relevant to the pathogenesis of POAF than the effects of aging and cardiac structural and functional changes. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): British Heart Foundation

Evaluation of Soluble Serum cd40 Ligand Level as a Significant Marker of Unstable Angina

Evaluation of Soluble Serum cd40 Ligand Level as a Significant Marker of Unstable Angina

Serum CD40L, ST2, IL-6, and CRP serving as biomarkers for acute coronary syndrome

To analyze the diagnostic value of CD40 ligand (CD40L), soluble growth stimulating expression gene 2 protein (ST2), interleukin-6 (IL-6), and C-reactive protein (CRP) are used in patients with acute coronary syndrome (ACS). Serum samples were collected from 259 ACS patients admitted to our hospital. Additionally, 119 healthy individuals who received physical examination in the hospital at the same time period were included as normal control. The levels of CD40L, ST2, IL-6, and CRP in 259 patients with ACS and 119 healthy subjects were detected by ELISA. The levels of CD40L, ST2, IL-6, and CRP were significantly increased in unstable angina (UA) patients, while ST2, CRP, and IL-6 were significantly elevated in acute myocardial infarction (AMI) patients. Pearson correlation analysis showed that ST2 was also closely related to CRP in ACS patients, while ST2 was positively correlated with creatine kinase (CK), creatine kinase isoenzyme (CK-MB), and troponin I (cTnI) in AMI patients. The levels of glucose (GLU) and low-density lipoprotein cholesterol (LDL-c) were significantly decreased, while the levels of high-density lipoprotein cholesterol (HDL-c) were significantly increased in AMI patients treated with stent implantation. Furthermore, the level of serum CD40 L was significantly elevated in coronary heart disease (CHD) patients treated with stent implantation, while the levels of ST2 and IL-6 in AMI patients treated with the stent implantation decreased significantly. The levels of inflammatory factors significantly changed in patients with ACS. These inflammatory factors may involve in the pathological progression of ACS and can be used as diagnostic indexes for ACS.

Inhibition of the RANKL with denosumab has no effect on circulating markers of atherosclerosis in women with postmenopausal osteoporosis: a pilot study

We evaluated the early effect of denosumab on circulating markers of atherosclerosis in women with postmenopausal osteoporosis. Denosumab (60 mg) was administered subcutaneously every 6 months (m) in 27 women (mean age 75 ± 5 years) with postmenopausal osteoporosis and high cardiovascular risk for a total of 24 m. Zoledronic acid was administered in 6 age-matched women as a single intravenous dose. Serum levels of vascular cell adhesion protein 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), E and P selectin, CD-40 ligand (CD40L), interleukin-6 (IL-6), matrix metalloproteinase (MMP) 1 and 9, monocyte chemoattractant protein-1 (MCP-1), fibrinogen (FBG), and high sensitivity C-reactive protein (hs-CRP) were measured at baseline, 15 days (d), 2, 6 and 12 m after dosing. In the denosumab group, observation was extended to 24 m as secondary endpoint. Serum ICAM-1 levels showed significant increase in the zoledronic acid group (+18 ± 0.1%; p < 0.01) at 12 m. In the denosumab group, we observed a significant increase in serum CD40L (+2 ± 0.8%; p < 0.001), MMP-1 (+11 ± 0.4%, p < 0.02), and MMP-9 (+39.4 ± 0.8%, p < 0.01) at 24 m. There was a significant increase in serum FBG and hs-CRP in both groups at 12 m (denosumab:+2.2 ± 0.2% and +50.3 ± 1.6%; zoledronic acid: +9.4 ± 0.1 and +81.8 ± 0.8%; p < 0.01). No significant between-group differences were found. 24-m treatment with denosumab has no effect on the circulating markers of atherosclerosis in women with postmenopausal osteoporosis. Fluctuation of serum ICAM-1, CD40L, MMPs, FBG and hs-CRP can be ascribed to perturbation of immunological mechanisms stimulated by denosumab and zoledronic acid.

Platelet-related biomarkers and their response to inhibition with aspirin and p2y12-receptor antagonists in patients with acute coronary syndrome.

The PLATelet inhibition and patient Outcomes (PLATO) trial showed that treatment with ticagrelor reduced the rate of death due to vascular causes, myocardial infarction and stroke when compared to clopidogrel in patients with ST-elevation or non-ST-elevation acute coronary syndrome (ACS). While the comparative benefit of ticagrelor over clopidogrel increased over time, event rates accrued in both groups during the study period. The purpose of our biomarker-based exploratory analysis was to determine whether long-term platelet inhibition may be associated with platelet adaptation. A sample of 4000 participants from the PLATO trial also consented to participate in a prospectively designed biomarker substudy. Blood samples were procured at baseline, immediately prior to hospital discharge and at 1 and 6months. Markers of platelet activity, including platelet count, serum CD40-ligand and soluble P-selectin were analyzed. Mean levels were compared at discharge, 1 and 6months following study drug initiation-first for all patients and subsequently stratified by treatment group. A linear mixed model was used to estimate the short-term change rate (baseline to 1month) and long-term change rate (1-6months) for each biomarker. A Cox proportional hazards model was used to calculate hazard ratios for each change in biomarker over the two time periods examined: baseline to 1month and 1 to 6months. Prior to randomized treatment (baseline), sCD40 ligand and sP-selectin levels were elevated above the normal range of the assay (0.39 and 33.5µg/L, respectively). The mean level of each biomarker was significantly different at 1month compared to baseline (p < 0.0001). When stratified by treatment group, at 1month patients treated with ticagrelor had a larger increase in platelet count compared to those treated with clopidogrel (p < 0.0001). Similarly, when comparing biomarker levels for all patients at 6months with those at 1month, each differed significantly (p < 0.05). There was no significant difference between treatment groups during this time period. The rate of change for both platelet count and sP-selectin were significantly different between baseline and 1month when compared to the 1 to 6-month time period (p < 0.0001). When comparing treatment groups, the rate of increase in platelets from baseline to 1month was greater for patients treated with ticagrelor (p < 0.0001). This was no longer observed in the 1 to 6-month interval. Using a Cox proportional hazard model, the increase in platelet count from 1 to 6months was associated with ischemic-thrombotic events, while sCD40 ligand decrease from 1 to 6months was associated with hemorrhagic events. There were no differences between treatment groups for the associations with clinical endpoints. Dynamic changes in platelet count, sCD-40 ligand and sP-selectin occur over time among patients with ACS. Platelet-directed therapy with a P2Y12 receptor inhibitor in combination with aspirin modestly impacts the expression of these biomarkers. Platelet count and sCD40 ligand may offer modest overall predictive value for future ischemic-thrombotic or hemorrhagic clinical events, respectively. The existence of a platelet adaptome and its overall clinical significance among patients at risk for thrombotic events will require a more in-depth and platelet-biology specific investigation.

Relationship between serum level of CD40 ligand and persistent lone atrial fibrillation

Inflammation is thought to play a role in the pathogenesis of atrial fibrillation. The relationship between CD40 ligand (CD40L), a prothrombotic and proinflammatory molecule, and lone atrial fibrillation was presently investigated for the first time. Levels of serum CD40L were also tested, regarding potential to distinguish patients with lone atrial fibrillation from healthy individuals. Presently included were 35 patients with lone persistent atrial fibrillation and a control group of 30 healthy individuals. Serum levels of CD40L and high-sensitive C-reactive protein (hs-CRP) were measured, and transthoracic echocardiography was performed. Mean serum CD40L, hs-CRP, left ventricular end-diastolic diameter, and left atrial diameter values were significantly higher in the group with lone persistent atrial fibrillation than in the control group (7.4±3.5 ng/mL vs 4.3±1.2 ng/mL, p<0.0001; 3.7±1.6 mg/L vs 1.7±0.8 mg/L, p<0.0001; 53.0±4.2 mm vs 46.0±3.8, p<0.0001; 43.5±3.5 mm vs 33.7±3.5, p<0.0001, respectively). Serum CD40L levels were positively correlated with left atrial diameter (r=0.81, p<0.0001) and hs-CRP (r=0.72, p<0.0001). Receiver operating characteristic curve analysis revealed that serum CD40L at the optimal cut-off level of >4.5 ng/mL successfully discriminated patients with lone atrial fibrillation from controls (area under the curve: 0.847; 95% confidence interval: 0.759-0.934; p<0.0001). The present findings suggest that CD40L levels play a crucial role in the development of lone atrial fibrillation. In addition, results support that regular clinical follow-up of these patients is necessary, due to increased cardiovascular disease risk, determined by elevated CD40L levels.

Prospective study of circulating soluble CD40 ligand concentrations and the incidence of cardiovascular disease in a nested prospective case–control study of older men and women

CD40 ligand(CD40L) is implicated in atherosclerotic plaque formation. We investigated prospective associations between circulating soluble CD40L and myocardial infraction (MI) or stroke in an older general population cohort, accounting for established and novel cardiovascular risk factors. Baseline serum CD40L (sCD40L) was measured in incident MI (n = 368) and stroke (n = 304) cases and two controls per case, 'nested' in prospective UK studies of 4252 men and 4286 women aged 60-79 years, sampled from general practices in Britain in 1998-2000, with 7-year follow-up for fatal and non-fatal MI and stroke. sCD40L was higher in smokers and negatively associated with lung function and positively associated with total cholesterol and markers of inflammation, but not with other established cardiovascular disease (CVD) risk factors. Geometric mean sCD40L levels did not differ between MI cases and controls (5.94 ng mL(-1) vs. 5.82 ng mL(-1); P = 0.5) or between stroke cases and controls (5.61 ng mL(-1) vs. 5.28 ng mL(-1), P = 0.1). There was no strong evidence for elevated risk of MI or stroke in multivariable models comparing participants in the top to those in the bottom third of sCD40L. Age-adjusted odds ratios (ORs) were 1.39 [95% confidence interval (CI) 0.98, 1.96] for MI and 1.16 (0.78, 1.73) for stroke. These attenuated to 1.24 (95% CI 0.86, 1.79) and 1.18 (0.78, 1.78), respectively, after adjustment for established and novel CVD risk factors. sCD40L is associated with other inflammatory markers but is not itself a strong independent risk marker for either stroke or MI.

The effect of hormone therapy and tibolone on serum CD40L and ADAM-8 in healthy post-menopausal women

The role of neutrophils and platelets in atherothrombotic disease is well established. The aim of our study was to investigate the effect of HT and tibolone on the soluble markers of neutrophil and platelet activation, "a disentigrin and metalloproteinase domain" (ADAM-8) and CD40 ligand (CD40L) respectively, in healthy post-menopausal women. One hundred and six healthy post-menopausal women were randomly allocated to: estradiol plus drospirenone (E₂/DSP), E₂ hemihydrate 1 mg plus norethisterone acetate (E₂/NETA) 0.5 mg, and tibolone 2.5 mg. Serum ADAM-8 and CD40L were measured at baseline and at 6 months. Baseline values of ADAM-8 and CD40L were similar between groups. No significant correlation was revealed between ADAM-8 or CD40L and parameters related to cardiovascular risk factors in each group. No significant changes were observed between baseline values and values at 6 months (E₂/DSP group: ADAM-8: 267.4±71.3 pg/ml vs 270.7±42.8 pg/ml, p=0.86, CD40L: 6.43±3.13 vs 6.79±2.70 ng/ml, p=0.67), (E₂/NETA group: ADAM-8: 308.3±64.3 vs 294.7±57.7 pg/ml, p=0.40, CD40L: 9.68±2.81 vs 8.59±5.13 ng/ml, p=0.51), (tibolone group: ADAM-8: 307.5±87.5 vs 289±48.1 pg/ml, p=0.48, CD40L: 9.46±4.30 vs 9.26±4.60 ng/ml, p=0.99). Our study has not revealed an association between estrogen plus progestin treatment or tibolone on serum ADAM-8 and CD40L levels in healthy post-menopausal women. Larger prospective studies are needed to further investigate the effect of low-dose HT or tibolone on serum markers of neutrophil and platelet activation.

Effects of Labetalol on Hemodynamic Parameters and Soluble Biomarkers of Inflammation in Acute Coronary Syndrome in Patients With Active Cocaine Use

Cocaine use is associated with increased cardiovascular mortality and can promote acute coronary syndrome (ACS). Use of beta-blockers is controversial in patients who use cocaine, and the safety and efficacy of these medications in ACS in patients actively using cocaine is unknown. We enrolled 90 patients with ACS and positive urine drug screen for cocaine. Patients received standard ACS therapy plus either labetalol (n = 60) or diltiazem (n = 30). Blood pressure and heart rate were measured at baseline and 48 hours. Levels of serum CD40 ligand, interleukin (IL)-6, and choline at baseline and 48 hours were determined. There were no baseline differences in hemodynamics or serum levels of inflammatory markers between the labetalol and diltiazem groups. Both groups experienced a significant and equivalent decrease in BP and HR at 48 hours compared with baseline. At 48 hours of treatment, there were significant decreases of 17% in CD40 ligand (P < .005) and 16% in IL-6 (P < .005) but no change in choline in the diltiazem group. Furthermore, in the labetalol group, there were significant differences of 30% in CD40 ligand (P < .005 time and group comparison), 22% in IL-6 (P < .005 time and group comparison), and 18% in choline (P < .005 time and group comparison). There were no adverse events during hospitalization in any patients who received labetalol. In conclusion, labetalol appears to be safe in cocaine-associated ACS. Furthermore, labetalol provides a beneficial hemodynamic response and, in comparison to diltiazem, potentiates an anti-inflammatory vascular response in this setting.

A Novel Role of CD40/CD40Ligand Dyad in Regulation of Bone Marrow Granulopoiesis.

Abstract 4556Members of the tumor necrosis factor / tumor necrosis factor receptor (TNF/TNFR) superfamily are involved in bone marrow (BM) homeostasis by regulating the survival, apoptosis, proliferation, and differentiation of hematopoietic progenitor and precursor cells. The CD40 Ligand (CD40L)/CD40 molecules belong to the TNF/TNFR superfamily; we have recently showed that the CD40/CD40L interaction on BM CD34+ cells accelerates the apoptotic cell death. The aim of the present study is to investigate the distribution and function of the CD40/CD40L molecules in the BM granulocytic progenitor and precursor cell populations as well as the effect of their interactions on the stromal release of cytokines related to granulopoiesis. BM samples were obtained from posterior iliac crest aspirates from 19 hematologically healthy subjects after informed consent. We evaluated: (a) the surface expression of CD40 and CD40L on immunomagnetically sorted CD34+, CD34-/CD33+, CD34-/CD33-/CD15+ cells representing sequential stages of the granulocytic development, using flow cytometry in steady state conditions and following 20-hour incubation with 25ng/ml recombinant-human (rh) TNFα; (b) the proportion of apoptotic cells and the level of caspase-3 activation following CD40 engagement in the above cell populations using flow cytometry and a chromo-enzymatic method, respectively; (c) the production of granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) by long-term BM culture (LTBMC) stromal cells upon induction with rhCD40L (1μg/ml), using an enzyme-linked immunoabsorbent assay (ELISA) in culture supernatants. We found that the basal expression of CD40 and CD40L on the CD34+, CD34-/CD33+, CD34-/CD33-/CD15+ cells was 3.34%±3.90% and 1.8%±1.03%, 16.74%±14.69% and 6.96%±4.68%, 3.22%±3.36% and 2.26%±2.71%, respectively. Following incubation with rhTNFα a substantial increase was obtained in the expression of CD40 in all the above cell populations compared to baseline (37.18%±12.51%, 29.25%±14.81%, 15.84%±6.28%, respectively) (p<0.0001, p=0.0003, p=0.0002 respectively). Upon engagement of the TNF-induced CD40 in the CD34+, CD34-/CD33+, CD34-/CD33-/CD15+ cells, a significant increase was obtained in the proportion of apoptotic cells (13.98%±10.43%, 27.24%±19.30%, 25.64%±14.82%, respectively) in comparison to TNF-induced cells without CD40 ligation (5.25%±4.04%, 11.6%±9.04%, 12.42%±5.22%, respectively) (p=0.0071, p=0.0296, p=0.0169, respectively). In keeping with this finding was the significant increase in the caspase-3 activation in all the above populations upon ligation of CD40 compared to baseline (p<0.0001, p=0.0281, p=0.0046, respectively). CD40 was expressed in both CD45+ (8.25%±8.31%) and CD45- (8.46%±4.93%) adherent cell populations (hematopoietic and non hematopoietic, respectively) of confluent LTBMCs (week-3). Following 48-hour incubation of confluent LTBMC stromal layers with rhCD40L, a significant increase was obtained in the production of G-CSF and GM-CSF (2171±2161 pg/ml and 84.10±84.25 pg/ml, respectively) compared to unstimulated cultures (885±1099 pg/ml and 26.57±28.25 pg/ml, respectively) (p=0.0041 and p=0.0074, respectively). These data suggest that the CD40/CD40L interactions, although minimal under steady state conditions, display a dual role in regulation of granulopoiesis under inflammatory conditions by affecting both the BM granylocytic progenitor/precursor cells and the BM microenvironmental cells. More specifically, the expression of CD40 is upregulated in all stages of granulocytic development under the influence of TNFα and upon ligation with CD40L results in acceleration of the apoptotic cell death. The induction of G-CSF and GM-CSF production by BM stroma may represent a compensatory mechanism to rescue granulocytic progenitor/precursor cells from apoptosis. These mechanisms may have a role in the pathogenesis of chronic idiopathic neutropenia where there is evidence for both increased BM TNFα and serum CD40L levels. Disclosures:No relevant conflicts of interest to declare.

Relation of smoking status to a panel of inflammatory markers: The Framingham offspring

Aims We sought to investigate the hypothesis that smoking is accompanied by systemic inflammation. Methods and results We examined the relation of smoking to 11 systemic inflammatory markers in Framingham Study participants ( n = 2944, mean age 60 years, 55% women, 12% ethnic minorities) examined from 1998–2001. The cohort was divided into never ( n = 1149), former ( n = 1424), and current smokers with last cigarette >6 h ( n = 134) or ≤6 h ( n = 237) prior to phlebotomy. In multivariable-adjusted models there were significant overall between-smoking group differences (defined as p < 0.0045 to account for multiple testing) for every inflammatory marker tested, except for serum CD40 ligand (CD40L), myeloperoxidase (MPO) and tumor necrosis factor receptor-2 (TNFR2). With multivariable-adjustment, pair-wise comparisons with never smokers revealed that former smokers had significantly lower concentrations of plasma CD40L ( p < 0.0001) and higher concentrations of (CRP) C-reactive protein ( p = 0.002). Conclusions As opposed to never smokers, those with acute cigarette smoke exposure (≤6 h) had significantly higher concentrations of all markers ( p < 0.0001) except serum CD40L, MPO, and TNFR2; plasma CD40L were significantly lower. Compared with never smokers, cigarette smokers have significantly elevated concentrations of most circulating inflammatory markers, consistent with the hypothesis that smoking is associated with a systemic inflammatory state.

Early Improvements in insulin sensitivity and inflammatory markers are induced by pravastatin in nondiabetic subjects with hypercholesterolemia

Background Statins may improve lipid profiles and inflammation-associated biomarkers, but the effect on insulin sensitivity is controversial. We investigated the effects of 2 doses of pravastatin (40 and 10 mg/day) on insulin sensitivity and serum inflammatory markers in nondiabetic hypercholesterolemic patients. Methods This was a randomized, parallel, comparative design study. A total of 40 nondiabetic subjects with elevated low-density lipoprotein (LDL) cholesterol were randomized to either the 40 mg pravastatin/day group ( n = 21) or the 10 mg pravastatin/day group ( n = 19) for 8 weeks. The fasting serum lipid profile, homeostasis model assessment (HOMA), glucose and insulin response of the two-hour glucose tolerance test (2 h-OGTT), and several inflammatory markers were determined. Results Eight weeks of pravastatin treatment in both dose groups led to a significant reduction in serum LDL cholesterol, total cholesterol, triglycerides, and total cholesterol/ high-density lipoprotein (HDL) cholesterol ratios (all p < 0.01 in 40 mg group and all p < 0.05 in 10 mg group), though the 40 mg group had greater effects. Although the fasting HOMA insulin resistance did not change significantly in either group, glucose and insulin areas under the curve of 2 h-OGTT were significantly decreased, suggesting improvement in insulin sensitivity post glucose challenge. Serum CD-40 ligand concentration was significantly reduced in the 40 mg pravastatin/day group and soluble P-selectin significantly reduced in both groups. Conclusions Pravastatin treatment, at 10 mg or 40 mg daily for 8 weeks, reduced serum lipids and some inflammatory markers in nondiabetic hypercholesterolemic subjects. Furthermore, insulin resistance was improved even in short-term treatment by pravastatin.

Atorvastatin Effect on Circulating and Leukocyte‐Produced CD40 Ligand Concentrations in People with Normal Cholesterol Levels: A Pilot Study

To investigate whether atorvastatin decreases serum or leukocyte-produced CD40 ligand (CD40L) levels and whether these effects are dependent on reduction in low-density lipoprotein cholesterol (LDL) levels in people without overt dyslipidemia. Prospective pilot study. University research center. Twenty-five normocholesterolemic volunteers (mean age 32 +/- 11 yrs; 15 women, 10 men) without cardiovascular disease. After a 2-week drug-free run-in period, subjects received atorvastatin 80 mg/day orally for 16 weeks. All lipoprotein level measurements were performed with the subject in the fasting state. The CD40L concentrations were measured by immunofluorescence detection in serum and leukocyte culture supernates after 24-hour incubation, and treatment effect was analyzed. Baseline mean +/- SD total cholesterol, LDL, high-density lipoprotein cholesterol, and triglyceride levels were 179 +/- 33, 97 +/- 29, 62 +/- 20, and 102 +/- 69 mg/dl, respectively. Mean changes in each of these levels, respectively, after 16 weeks of atorvastatin were -34%, -59%, +3%, and -23%. The median serum CD40L level was lower at 16 weeks (2.3 ng/ml, interquartile range [IQR] 1.2-5.0 ng/ml) than at baseline (3.0 ng/ml, IQR 2.1-3.7 ng/ml), but the change was not significant (p=0.24). However, atorvastatin significantly lowered CD40L produced from leukocytes by 57% (21 pg/mg of protein [IQR 10-38 pg/mg] vs 49 pg/mg [IQR 21-149 pg/mg], p=0.045). Effects were independent of reduction in cholesterol levels. Although atorvastatin did not significantly lower serum CD40L levels, significant reduction in leukocyte production was seen independent of degree of LDL reduction. These pilot data suggest a potential benefit in normocholesterolemic individuals that should be further investigated, and that leukocyte CD40L concentrations should be considered in the drug response.

Soluble CD40 Ligand Levels during Controlled Ovarian Hyperstimulation – A Possible Culprit of Systemic Inflammation

To investigate the behavior and association of serum sex-steroids and serum CD40 ligand in patients undergoing controlled ovarian hyperstimulation (COH) for in vitro fertilization (IVF). Prospective, observational study. The IVF unit of an academic medical center. Blood was drawn three times during the COH cycle from 17 patients undergoing the long gonadotropin-releasing hormone-analog protocol: (i) day on which adequate suppression was obtained (Day-S); (ii) day of or prior to administration of human chorionic gonadotropin (Day-hCG); and (iii) day of ovum pick-up (Day-OPU). Levels of sex steroids and serum CD40 ligand were compared among the three time points. During gonadotropin treatment, serum ovarian sex steroids (estradiol, progesterone, free testosterone and androstenedione) significantly increased while CD40 ligand levels nonsignificantly decreased. After hCG administration, there was a significant increase in the levels of serum CD40 ligand, ovarian androgens, and progesterone, with a significant decrease in estradiol levels. No correlations were observed between CD40 ligand and ovarian sex-steroid levels or other treatment variables. The administration of hCG leads to activation of systemic inflammation, as reflected by CD40 ligand levels. This, in turn, may lead to the development of ovarian hyperstimulation syndrome via several mechanisms, including an increase in several angiogenic factors.

The presence of metabolic syndrome is independently associated with elevated serum CD40 ligand and disease severity in patients with symptomatic coronary artery disease

Nontraditional atherosclerotic risk factors have become the focus of attention in recent years. In addition, metabolic syndrome is gaining recognition as another multiplex cardiovascular risk factor. However, to date, no studies have investigated the effect of metabolic syndrome on circulating soluble CD40 ligand (sCD40L), monocyte chemoattractant protein 1, cellular adhesion molecules, and disease severity in patients with symptomatic coronary artery diseases. This study was conducted to address this issue. Patients with stable angina who received percutaneous coronary interventions for significant (≥70% diameter stenosis) de novo lesions between January 1999 and January 2004 and had preprocedural serum samples were enrolled. Metabolic syndrome was defined by the National Cholesterol Education Program criteria with waist criterion modified into body mass index of more than 25 kg/m 2. The serum samples were thawed and analyzed for circulating sCD40L, monocyte chemoattractant protein 1, adhesion molecules, and high sensitivity C-reactive protein (hs-CRP). Coronary severity was assessed by a modified version of Gensini scoring system. A total of 313 patients, 248 males and 65 females, were studied. Among them, 222 (70.9%, 170 males and 52 females) had metabolic syndrome. Patients with metabolic syndrome had higher serum creatinine level and lower low-density lipoprotein cholesterol despite higher triglyceride concentration. In multivariate analysis, patients with metabolic syndrome had higher sCD40L (6057 ± 275 vs. 5051 ± 423 pg/mL, P = .037) and more hs-CRP in higher tertiles ( P = .005) than patients without, but similar levels of intercellular adhesion molecule 1, vascular cell adhesion molecule 1, and P selectin. Metabolic syndrome was also significantly associated with multiple coronary vessel involvements with 70% or higher diameter stenosis (36.5% double-vessel and 14% triple-vessel diseases vs 30.8% double-vessel and 5.5% triple-vessel diseases, P = .026) and multiple coronary segment involvements with 50% or higher diameter stenosis ( P = .014) in multivariate analysis. In conclusion, the presence of metabolic syndrome is independently associated with elevated sCD40L, hs-CRP, and coronary disease severity in patients with coronary artery disease requiring interventional treatment of stable angina.

Female hyper IgM syndrome type 1 with a chromosomal translocation disrupting CD40LG

Hyper-IgM syndrome type 1 (HIGM1) is a primary immunodeficiency characterized by recurrent bacterial and opportunistic infections, associated with normal or high serum level of IgM and decreased serum levels of IgG, IgA and IgE due to the defect of class switch recombination. CD40LG, located in Xq26, has been reported to be mutated in male HIGM1 patients. Here, we report the second case of a female HIGM1 with the defect of CD40 ligand (CD40L) expression and of soluble serum CD40L. Clinical course and HIGM phenotype was indistinguishable from that of male HIGM1 including severe neutropenia. High-resolution chromosome banding revealed that this patient's karyotype is 46, X, t(X;14)(q26.3;q13.1), and FISH analysis demonstrated that the break point of the chromosomal translocation is within CD40LG. Using four chimeric cDNA clones obtained by 3' RACE method, the break point was identified within the intron 4 of CD40LG on X chromosome and non-coding region of chromosome 14. We also found an extremely skewed X-chromosome inactivation pattern by methylation-specific PCR. Thus, the reciprocal translocation caused the disruption of CD40LG, resulting in defective CD40L expression in the female patient with an extremely skewed X-inactivation pattern in T cells leading to the HIGM1 phenotype.