Soluble E-selectin Concentrations Research Articles

Adiponectin Resistance in Obesity: Adiponectin Leptin/Insulin Interaction.

The adiponectin (APN) levels in obesity are negatively correlated with chronic subclinical inflammation markers. The hypertrophic adipocytes cause obesity-linked insulin resistance and metabolic syndrome. Furthermore, macrophage polarization is a key determinant regulating adiponectin receptor (AdipoR1/R2) expression and differential adiponectin-mediated macrophage inflammatory responses in obese individuals. In addition to decrease in adiponectin concentrations, the decline in AdipoR1/R2 messenger ribonucleic acid (mRNA) expression leads to a decrement in adiponectin binding to cell membrane, and this turns into attenuation in the adiponectin effects. This is defined as APN resistance, and it is linked with insulin resistance in high-fat diet-fed subjects. The insulin-resistant group has a significantly higher leptin-to-APN ratio. The leptin-to-APN ratio is more than twofold higher in obese individuals. An increase in expression of AdipoRs restores insulin sensitivity and β-oxidation of fatty acids via triggering intracellular signal cascades. The ratio of high molecular weight to total APN is defined as the APN sensitivity index (ASI). This index is correlated to insulin sensitivity. Homeostasis model of assessment (HOMA)-APN and HOMA-estimated insulin resistance (HOMA-IR) are the most suitable methods to estimate the metabolic risk in metabolic syndrome. While morbidly obese patients display a significantly higher plasma leptin and soluble (s)E-selectin concentrations, leptin-to-APN ratio, there is a significant negative correlation between leptin-to-APN ratio and sP-selectin in obese patients. When comparing the metabolic dysregulated obese group with the metabolically healthy obese group, postprandial triglyceride clearance, insulin resistance, and leptin resistance are significantly delayed following the oral fat tolerance test in the first group. A neuropeptide, Spexin (SPX), is positively correlated with the quantitative insulin sensitivity check index (QUICKI) and APN. APN resistance together with insulin resistance forms a vicious cycle. Despite normal or high APN levels, an impaired post-receptor signaling due to adaptor protein-containing pleckstrin homology domain, phosphotyrosine-binding domain, and leucine zipper motif 1 (APPL1)/APPL2 may alter APN efficiency and activity. However, APPL2 blocks adiponectin signaling through AdipoR1 and AdipoR2 because of the competitive inhibition of APPL1. APPL1, the intracellular binding partner of AdipoRs, is also an important mediator of adiponectin-dependent insulin sensitization. The elevated adiponectin levels with adiponectin resistance are compensatory responses in the condition of an unusual discordance between insulin resistance and APN unresponsiveness. Hypothalamic recombinant adeno-associated virus (rAAV)-leptin (Lep) gene therapy reduces serum APN levels, and it is a more efficient strategy for long-term weight maintenance.

Endothelial Dysfunction and Parenchymal Hematoma in Ischemic Stroke Patients after Endovascular Thrombectomy

Introduction: Endothelial dysfunction (ED) may result in parenchymal injury and therefore worsen the outcomes of ischemic stroke. This study aimed to determine whether ED could predict parenchymal hematoma (PH) in ischemic stroke patients treated with endovascular thrombectomy (EVT). Methods: Patients with large artery occlusion in the anterior circulation and treated with EVT were prospectively enrolled from 2 stroke centers. Serum soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, soluble E-selectin, and von Willebrand factor (vWF) were tested and summed to a standardized score to reflect the levels of ED. PH was diagnosed according to the Heidelberg Bleeding Classification. Results: Of the 325 enrolled patients (mean age, 68.6 years; 207 men), 41 (12.6%) developed PH. Patients with PH had higher concentrations of soluble E-selectin, vWF, and ED sum score. After adjusting for demographic characteristics, National Institutes of Health Stroke Scale score, pretreatment Alberta stroke program early computed tomography score, and other potential confounders, the increased ED burden was associated with PH (odds ratio, 1.432; 95% confidence interval, 1.031−1.988; p = 0.032). Similar significant results were found in the sensitivity analysis. The multiple-adjusted spline regression model showed a linear association between the total ED score and PH (p = 0.001 for linearity). Adding the ED score to the conventional model significantly improved the risk prediction of PH (net reclassification improvement = 25.2%, p = 0.001; integrated discrimination index = 2.9%; p = 0.001). Conclusions: This study demonstrated that ED might be related to PH. Introducing the ED score could increase the reliability of the PH risk model for stroke patients treated with EVT.

Changes in plasma total saturated fatty acids and palmitic acid are related to pro-inflammatory molecule IL-6 concentrations after nutritional intervention for one year.

Systemic inflammation is associated with an increased risk of non-communicable diseases, such as cardiovascular diseases and diabetes. Circulating fatty acids (FA) are known to be related to these conditions, possibly through their role in inflammation, although different types of FAs can have opposite effects on inflammatory mediators. The aim of the present study was to analyze the association of plasma FAs with inflammatory biomarkers in a PREDIMED trial subsample after one year of intervention. In a one-year longitudinal study of 91 participants of the PREDIMED trial (Barcelona-Clinic center), plasma FAs and inflammatory biomarkers were analyzed using gas chromatography and ELISA, respectively. In baseline plasma, a multivariable-adjusted ordinary least squares regression model showed that n-3 polyunsaturated FAs concentrations were inversely associated with concentrations of soluble intercellular adhesion molecule-1 (sICAM-1) and E-selectin, whereas the level of the most abundant saturated FA, palmitic acid, was directly associated with concentrations of interleukin-6 (IL-6) (β=0.48pg/mL, 95% CI: 0.03, 0.93 per 1-SD increase, p-value = 0.037). After one year of nutritional intervention, changes of plasma diet-derived total saturated FAs and palmitic acid were directly associated with changes in IL-6 (β=0.59pg/mL [95% CI: 0.28, 0.89] per 1-SD, p-value = 0.001; β=0.64pg/mL, 95% CI: 0.31, 0.98, p-value = 0.001), respectively, after correction for multiple testing. Our findings suggest that saturated FAs of dietary origin, especially palmitic acid, are directly involved in the increase of IL-6 in plasma.

A preliminary study to assess neutrophil and endothelial response to knee arthroplasty with the use of a tourniquet : effects of spinal or sevoflurane anesthesia

Background : During orthopedic surgery, the use of a pneumatic tourniquet results in side effects secondary to ischemia-reperfusion phenomena. We tested the hypothesis that total knee arthroplasty with a tourniquet is associated with increase in plasma concentrations of biomarkers of neutrophil activation and endothelial injury. The second aim was to compare these changes during spinal or general inhalational anesthesia. Methods : 40 adult ASA I-II patients scheduled for total knee arthroplasty with a tourniquet under spinal or sevoflurane anesthesia were included. Venous blood samples were collected before surgery, 1 h, 3 h, and 24 h after tourniquet deflation. To assess neutrophil activation, plasma concentrations of total and active fractions of myeloperoxidase, as well as elastase concentrations and proteolytic activity were measured. Endothelial injury was assessed by measurement of plasma concentrations of syndecan-1, soluble thrombomodulin, soluble E-selectin, and vascular endothelial growth factor. Results were analyzed with a two-way analysis of variance. P< 0.05 was considered statistically significant. Results : Plasma concentrations of active but not total myeloperoxidase and elastase significantly increased following tourniquet deflation. The level of syndecan-1, soluble thrombomodulin, soluble E-selectin, but not vascular endothelial growth factor, significantly decreased postoperatively. These changes of biomarkers were similar during spinal and sevoflurane anesthesia. Conclusions : Total knee arthroplasty with pneumatic tourniquet is associated with systemic release of markers of neutrophil activation which was comparable during spinal or sevoflurane anesthesia. Systemic expression of endothelial injury was not detected in our clinical conditions.

The role of soluble E-selectin in HIV associated preeclampsia

ObjectiveTo determine the serum concentration of soluble E-selectin (sE-selectin) in HIV associated preeclampsia. Study DesignThe study population (n = 72) consisted of normotensive pregnant (n = 36) and preeclamptic (n = 36) women stratified by HIV status (negative vs. positive). Serum concentrations of sE-selectin were quantified using the MilliPlex multiplex immunoassay method. Statistical analyses were conducted using GraphPad Prism software. ResultsWhen stratified by pregnancy type and HIV status, serum sE-selectin levels were elevated in the preeclamptic HIV-negative group compared to the normotensive HIV-negative group (p = 0.0070**). Gestational age, systolic blood pressure, diastolic blood pressure and baby weight were statistically different across the study groups (p < 0.0001). ConclusionThis study demonstrates an elevation of sE-selectin in preeclamptic HIV-negative compared to the normotensive HIV-negative group. However, when stratified by HIV status, there was no significant difference observed in preeclamptic HIV-positive and normotensive HIV-positive groups. The findings of this small-scale study suggest that sE-selectin may be used as a biomarker or an early identifier of preeclampsia. Studies with large numbers should be considered to confirm our findings.

Inhibition of Protease-Activated Receptor (PAR1) Reduces Activation of the Endothelium, Coagulation, Fibrinolysis and Inflammation during Human Endotoxemia.

The protease-activated receptor-1 (PAR-1) is critically involved in the co-activation of coagulation and inflammatory responses. Vorapaxar is a reversible, orally active, low molecular weight, competitive antagonist of PAR-1.We investigated the effects of PAR-1 inhibition by vorapaxar on the inflammatory response, the activation of coagulation, fibrinolysis and endothelium during experimental endotoxemia. In this randomized, double blind, crossover trial, 16 healthy volunteers received a bolus infusion of 2 ng/kg lipopolysaccharide (LPS) ± placebo/vorapaxar with a washout period of 8 weeks. Vorapaxar dosing was guided by thrombin receptor-activating peptide-6-induced whole blood aggregometry. Participants received 10 mg vorapaxar or placebo as an initial dose and, depending on the aggregometry, potentially an additional 10 mg. Goal was > 80% inhibition of aggregation compared with baseline. Vorapaxar significantly reduced the LPS-induced increase in pro-thrombin fragments F1 + 2 by a median of 27% (quartiles: 11-49%), thrombin-anti-thrombin concentrations by 22% (-3 to 46%) and plasmin-anti-plasmin levels by 38% (23-53%). PAR-1 inhibition dampened peak concentrations of tumour necrosis factor -α, interleukin-6 and consequently C-reactive protein by 66% (-11-71%), 50% (15-79%) and 23% (16-38%), respectively. Vorapaxar decreased maximum von Willebrand factor levels by 29% (26-51%) and soluble E-selectin concentrations by 30% (25-38%) after LPS infusion. PAR-1 inhibition did not affect thrombomodulin, soluble P-selectin and platelet factor-4 concentrations.PAR-1 inhibition significantly reduced the activation of coagulation, fibrinolysis, the inflammatory response and endothelial activation during experimental human endotoxemia.

Preventive effect of rosiglitazone on liver injury in a mouse model of decompression sickness.

Severe decompression sickness (DCS) is a multi-organ injury. This study investigated the preventive effects of rosiglitazone on liver injury following rapid decompression in mice and examined the underlying mechanisms. Mice were randomly divided into four groups: a control group, vehicle group, and rosiglitazone (5 and 10 mg·kg⁻¹) groups, the latter three being exposed to a pressure of 911 kPa. Haematoxylin and eosin staining, plasma levels of alanine transaminase (ALT), aspartate transaminase (AST) and lactate dehydrogenase and blood cell counts were used to evaluate liver injury at 30 min after rapid decompression. The expression of endothelial and inducible nitric oxide synthase (iNOS) and its phosphorylation were measured to uncover the underlying molecular mechanisms. A significant increase in plasma ALT, red blood cells and platelets, and a decrease in neutrophils were observed in the vehicle group. Furthermore, the expression of iNOS, E-selectin and the total level of NO in hepatic tissue, and soluble E-selectin in the plasma were significantly elevated in the vehicle group. Rosiglitazone pre-treatment prevented the increases in ALT (and AST), soluble E-selectin concentration, red blood cells and platelet counts. Moreover, rosiglitazone reduced over-expression of iNOS and the NO level, prevented the fall in neutrophil count and promoted the phosphorylation of iNOS in the liver. Pre-treatment with rosiglitazone ameliorated liver injury from severe DCS. This preventive effect may be partly mediated by stimulating endothelial NO production, improving endothelial function and limiting inflammatory processes.

Level of serum soluble endothelial leukocyte adhesion molecule-1 in psoriatic patients after narrow-band ultraviolet-B and relation to disease activity: a case–control study

Context Endothelial leukocyte adhesion molecule-1 (E-selectin) is expressed on endothelial cells in psoriasis vulgaris (PV). Alteration in E-selectin is one of the influential proinflammatory cytokines in the pathogenesis of psoriasis. Aims This study aimed to assess the serum level of E-selectin and to determine the effect of narrow-band ultraviolet-B (UVB) therapy on serum E-selectin levels in patients with psoriasis and to assess the relationship between serum E-selectin levels and disease activity after this treatment. Settings and design This was a case–control study. Patients and methods Thirty-five patients with chronic plaque psoriasis and 35 age-matched and sex-matched healthy controls were included. The concentration of soluble E-selectin (sE-selectin), determined by enzyme-linked immunosorbent assay was studied in the sera of patients before and after narrow-band UVB treatment sessions (three times per week for 3 months) and compared with normal nonpsoriatic controls. The disease severity was established using the Psoriasis Area and Severity Index scoring system. Results Levels of sE-selectin were significantly increased in the sera of patients with atopic dermatitis and psoriasis (compared with the controls). Clinical improvement, after treatment, in patients with PV was associated with a significant decrease in the serum levels of sE-selectin. There was a significant correlation of sE-selectin and disease activity in PV patients. Conclusion E-selectin might be an indicator of treatment response and acts as a marker of psoriatic disease activity; it is also suggested to be a useful tool for evaluating the efficacy of treatment by narrow-band UVB in patients with psoriasis.

HAEMOSTASIS CHANGES AND ENDOTHELIUM ACTIVATION DURING PERCUTANEOUS TRANSCATHETER ISOLATION OF THE PULMONARY VEINS IN PATIENTS WITH ATRIAL FIBRILLATION

HAEMOSTASIS CHANGES AND ENDOTHELIUM ACTIVATION DURING PERCUTANEOUS TRANSCATHETER ISOLATION OF THE PULMONARY VEINS IN PATIENTS WITH ATRIAL FIBRILLATION

The role of selectins in alopecia areata.

IntroductionOne of the main histopathological features of alopecia areata (AA) is a lymphocytic infiltration that surrounds hair follicles. Soluble forms of E, L, P-selectins are known indicators of ongoing inflammation. There are no studies regarding the assessment of their contribution in AA.AimTo assess serum concentrations of selectins (E-selectin, L-selectin and P-selectin) in patients with AA in relation to selected clinical parameters, including disease severity and activity.Material and methodsSixty-four patients with AA were involved in the study. The diagnosis was based on physical examination and photodermoscopy. The control group consisted of 40 healthy subjects. The serum concentrations of soluble E-selectin, L-selectin and P-selectin were detected with ELISA method.ResultsStatistically significantly higher levels of E, P, L-selectins were found in AA patients as compared with the healthy group. Serum concentrations of soluble forms of E- and L-selectins correlated with the severity of the disease, while E-selectin with activity of AA.ConclusionsThis study shows that selectins may play an important role in the pathogenesis of AA and may be a target of future therapies in this disease.

Pan-Selectin Antagonist Rivipansel (GMI-1070) Reduces Soluble E-Selectin Levels While Improving Clinical Outcomes in SCD Vaso-Occlusive Crisis

Introduction: The pan-selectin antagonist rivipansel (GMI-1070) reduced intravascular arrest of red/white blood cell aggregates and improved blood flow and survival in a mouse model of sickle cell disease vaso-occlusive crisis (SCD VOC). In a Phase 1 study of GMI-1070 infusion in SCD adults at steady state (not in VOC), GMI-1070 decreased markers of cellular activation including neutrophil integrins, platelet/neutrophil aggregates, soluble adhesion molecule concentration; and markers of hemostatic activation. Furthermore, in a randomized Phase 2 study of SCD patients, treatment of VOC with GMI-1070 improved clinical outcomes such as time to resolution of crisis, time to discharge, and IV opioid use. Herein we report on the effect of GMI-1070 on biomarkers of cellular and hemostatic cascade activation from this Phase 2 trial.Methods: Patients in VOC enrolled in a prospective, randomized multi-center double-blind Phase 2 trial, ages 12-60 with HbSS or HbSB0thalassemia were treated with GMI-1070 q12h or placebo, in addition to standard treatment per institutional practice, until resolution of VOC. Clinical outcomes and pharmacokinetics have been previously reported (ASH 2013 Abstracts 775, 776, and 2206). Biomarker blood samples were drawn prior to study drug, and on a sparse sampling basis at times starting 30 minutes after initial dose and continuing until 36 hours after the last dose. Analytes measured included: soluble adhesion molecules E-selectin (sEsel), P-selectin, L-selectin, intercellular adhesion molecules 1 and 3, vascular cell adhesion molecule-1; and tissue factor and thrombin-antithrombin complexes by ELISA. At some sites, surface expression of monocyte b2 integrins MAC-1 & LFA-1 and platelet-monocyte aggregates were also measured by flow cytometry. Comparisons were made between the GMI-1070 and placebo groups, and serial expression levels were compared over time. Subgroup analyses were performed by hydroxyurea (HU) use, age group, baseline WBC, and 'responders’ based on clinical outcomes. A mixed effect model was used to test the LS means difference at each time point and ANCOVA model was used to analyze the nadir, peak, and last dose values.Results: ELISA and flow cytometry samples were collected from 70 and 15 subjects, respectively. Soluble E-selectin levels were reduced for the group on GMI-1070 compared to placebo throughout hospitalization, and the differences were statistically significant at some time-points (Figure 1). Baseline sEsel levels were similar; but the peak, nadir, and level at last dose were all lower in the GMI-1070 group (Figure 2). Exploratory subgroup analysis by HU use, age group, response as measured by visual analog scale or opiate use, frequency of VOC in the past, and baseline white blood cell count revealed consistently lower sEsel levels in the GMI-1070 group. Many, but not all, of these differences reached statistical significance.Conclusion: GMI-1070 use during VOC resulted in consistent and significant reductions of sEsel, overall and in sub-groups as compared to placebo. These findings are consistent with the hypothesized effect of GMI-1070 on endothelial activation and/or apoptosis, mediated by inhibition of E-selectin, although an effect on sEsel clearance cannot be excluded. A Phase 3 study is planned to evaluate efficacy and safety of GMI-1070 as treatment for VOC. Soluble E-selectin concentrations may be useful as a biomarker of pharmacodynamic effect. [Display omitted] [Display omitted] DisclosuresWun:GlycoMimetics: Research Funding; Pfizer: Steering Committee, Steering Committee Other; Emmaus Medical: Consultancy. Telen:GlycoMimetics: Research Funding; Pfizer: Consultancy; Dilaforette: Research Funding. Krishnamurti:GlycoMimetics: Research Funding. McCavit:GlycoMimetics: Research Funding; Pfizer: Consultancy. DeCastro:GlycoMimetics: Research Funding. Flanner:GlycoMimetics: Employment, Equity Ownership. Kuypers:GlycoMimetics: Research Funding. Larkin:GlycoMimetics: Research Funding. Rhee:GlycoMimetics: Consultancy. Magnani:GlycoMimetics Inc.: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees. Thackray:GlycoMimetics: Employment, Equity Ownership.

Relationship of late arteriovenous fistula stenosis with soluble E-selectin and soluble EPCR in chronic hemodialysis patients with arteriovenous fistula

Vascular access dysfunction caused by stenosis is a major complication for hemodialysis (HD) patients. However, physiopathology of late arteriovenous fistula (AVF) stenosis is still under investigation. The aim of the present study was to evaluate the association between plasma soluble EPCR (sEPCR) with serum soluble E-selectin (sE-selectin) concentration and late AVF stenosis in HD patients. Plasma sEPCR and serum sE-selectin concentrations were measured in 94 HD patients. Using these data, we studied the association of sEPCR and sE-selectin with the presence and degree of AVF stenosis using ultrasonography and fistulogram. Fifty-one patients have AVF stenosis, and the others (n = 43) have patent AVF. The degree of AVF stenosis was correlated with serum sE-selectin levels (r = 0.351, p = 0.01), but not sEPCR (r = 0.075, p = 0.702). The median level of sE-selectin was statistically higher in the group of AVF stenosis than in the group of patent AVF [463.2 pg/ml (275.4-671.4) vs. 162.5 pg/ml (96.7-285.3), p = 0.001]. Increased sE-selectin levels [OR (OR) = 6.356, p = 0.015] and high levels of LDL (OR = 4.321, p = 0.044) were independent predictors of late AVF stenosis in the multivariate model. sE-selectin and the LDL were the most important predictors of late AVF stenosis. In addition, sE-selectin correlated with the degree of AVF stenosis. We suggested that atherosclerosis might be contributing factor for development of late AVF stenosis.

Limited Impact of 2 g/day Omega-3 Fatty Acid Ethyl Esters (Omacor®) on Plasma Lipids and Inflammatory Markers in Patients Awaiting Carotid Endarterectomy

The objective of this study was to determine the effects of prescription omega-3 (n-3) fatty acid ethyl esters (Omacor®) on blood pressure, plasma lipids, and inflammatory marker concentrations in patients awaiting carotid endarterectomy. Patients awaiting carotid endarterectomy (n = 121) were randomised to Omacor® or olive oil as placebo (2 g/day) until surgery (median 21 days). Blood pressure, plasma lipids, and plasma inflammatory markers were determined. There were significant decreases in systolic and diastolic blood pressure and in plasma triglyceride, total cholesterol, low density lipoprotein-cholesterol, soluble vascular cellular adhesion molecule 1, and matrix metalloproteinase 2 concentrations, in both groups. The extent of triglyceride lowering was greater with Omacor® (25%) compared with placebo (9%). Soluble E-selectin concentration was significantly decreased in the Omacor® group but increased in the placebo group. At the end of the supplementation period there were no differences in blood pressure or in plasma lipid and inflammatory marker concentrations between the two groups. It is concluded that Omacor® given at 2 g/day for an average of 21 days to patients with advanced carotid atherosclerosis lowers triglycerides and soluble E-selectin concentrations, but has limited broad impact on the plasma lipid profile or on inflammatory markers. This may be because the duration of intervention was too short or the dose of n-3 fatty acids was too low.

Relationships of serum soluble E-selectin concentration with insulin sensitivity and metabolic flexibility in lean and obese women

The markers of endothelial dysfunction, including soluble E-selectin (sE-selectin), are related to insulin resistance, which is associated with metabolic inflexibility, i.e., impaired stimulation of carbohydrate oxidation and impaired inhibition of lipid oxidation by insulin. Endothelial dysfunction may also be important in the metabolic syndrome. The aim of our study was to analyze the association of sE-selectin with insulin sensitivity and metabolic flexibility in lean and obese women. We examined 22 lean women (BMI < 25 kg m−2) and 26 overweight or obese women (BMI > 25 kg m−2) with normal glucose tolerance. A hyperinsulinemic euglycemic clamp and indirect calorimetry were performed. An increase in the respiratory exchange ratio in response to insulin was used as a measure of metabolic flexibility. Obese women had lower insulin sensitivity (P < 0.01), higher plasma sE-selectin (P = 0.007), and higher the metabolic syndrome total Z-score (MS Z-score) (P < 0.0001). Insulin sensitivity was negatively correlated with sE-selectin level (r = −0.24, P = 0.04). sE-selectin was associated with the rate of carbohydrate oxidation at the baseline state (r = 0.31, P = 0.007) and was negatively correlated with metabolic flexibility (r = −0.34, P = 0.003). MS Z-score correlated positively with sE-selectin level and negatively with metabolic flexibility and insulin sensitivity (r = 0.49, P < 0.0001, r = −0.29, P = 0.04, r = −0.51, P < 0.0001, respectively). In multiple regression analysis we observed that the relationship between metabolic flexibility and sE-selectin (β = −0.36; P = 0.004) was independent of the other evaluated factors. Our data suggest that endothelial dysfunction as assessed by plasma sE-selectin is associated with metabolic flexibility, inversely and independently of the other estimated factors.

Adiponectin and endothelial markers in postmenopausal women taking oral or transdermal hormone therapy

To assess the concentration of adiponectin, soluble E-selectin, soluble thrombomodulin and tissue activator plasminogen antigen in postmenopausal women who received oral or transdermal hormone therapy. Case-control study. Polish university hospitals. Seventy-six healthy postmenopausal women. Forty-six women who received oral (n = 26) or transdermal (n = 20) hormone therapy and a control group without such medication (n = 30), all aged 44-58 years. Plasma concentrations of adiponectin, soluble E-selectin, soluble thrombomodulin and tissue activator plasminogen antigen by enzyme-linked immunosorbent assay. We found a significantly higher concentration of adiponectin in women on oral and transdermal therapy in comparison to the control group and a significantly lower concentration of soluble E-selectin in women who received oral hormone therapy vs. the control group. A significantly higher concentration of tissue activator plasminogen antigen was obtained in the group of women using transdermal menopausal hormone therapy compared with those receiving oral therapy and with the control group. Reduced levels of soluble E-selectin in women using menopausal hormone therapy could lead to reduction in the intensity of expression of the adhesion factors on the surface of the vascular endothelium. Menopausal hormone therapy might have advantageous effects on vascular endothelial function through adiponectin. Transdermal therapy may have adverse effects associated with elevated tissue activator plasminogen antigen levels and thereby the higher risk of ischemic heart disease.

Early pregnancy soluble E-selectin concentrations and risk of preeclampsia

Circulating biomarkers of endothelial dysfunction and inflammation are elevated in late pregnancy in women with preeclampsia. We examined plasma levels of inflammatory cytokines and adhesion molecules in early pregnancy, to assess their ability to predict preeclampsia. In a prospective longitudinal study, 2600 women with singleton pregnancies and no history of hypertension were recruited at their antenatal hospital (booking) visit at gestational week 12-16. Of these, 49 (1.9%) developed preeclampsia, whereas 74 women matched for age and BMI with uncomplicated pregnancies were selected as controls. A subset of women with risk factors for preeclampsia were sampled again at gestational weeks 16 and 28 (11 cases, 39 controls) and postnatally (six cases, 36 controls). From multiplex analysis, soluble E-selectin concentrations were higher at 12-16 weeks in women who subsequently developed preeclampsia (15.1 ± 4.9 versus 12.9 ± 4.5 ng/ml, P = 0.02). At gestational week 28, E-selectin concentrations were again higher in women who went on to develop preeclampsia compared with controls (14.4 ± 5.6 versus 10.7 ± 3.5 ng/ml, P = 0.010), whereas levels were not different between the two groups in postpartum samples. Changes in soluble E-selectin concentration in early pregnancy may reflect underlying pathophysiological processes, potentially providing mechanistic insights into preeclampsia.

Endothelial Cell Markers in Patients with Pseudoexfoliation Syndrome

The aim of the study was the assessment of the von Willebrand antigen (vWF Ag), E-selectin, and P-selectin concentration in blood plasma of patients with pseudoexfoliation syndrome (PEX). The group studied comprised 30 patients with PEX, aged from 50 to 86 years (mean 73, SD ± 8 years). Patients with cardiovascular and cerebrovascular diseases, diabetes mellitus, infectious disease, cancer, renal or liver insufficiency, connective tissue disease, current smoking, and hormone, antiplatelet, hypolipidemic, antioxidant, or antihypertensive drug therapy were excluded from the study. Each subject underwent a complete ophthalmological examination. Venous blood samples from the cubital vein were taken into sodium citrate solution. VWF Ag, sP-selectin, and sE-selectin concentration were determined by a commercially available enzyme-linked immunosorbent assay (MedSystems, Diagnostica Stago/Roche, R&D). Concentrations of vWF Ag, soluble E-selectin, and soluble P-selectin in blood plasma in the study group were compared with the levels in blood plasma in the control group. No significant differences were found between the groups. Our results indicate that there might be no correlation between PEX and such endothelial cell markers as vWF Ag, sP-selectin, and sE-selectin concentrations. Since the study size is limited, further investigations to confirm that there is no association between endothelial dysfunction in PEX and risk of future cardiovascular disease are necessary.

Limited Cutaneous and Diffuse Cutaneous Scleroderma: Circulating Biomarkers Differentiate Lung Involvement

Study background: Insufficient or absent angiogenesis are hallmarks of scleroderma (SSc). Microvascular change is an early manifestation of SSc followed by intimal proliferation and fibrosis of arterioles resulting in reduced blood flow and tissue ischemia. This ongoing vasculopathy in the lungs presents clinically as pulmonary hypertension and characteristically precedes lung fibrosis in patients. The purpose of this preliminary study is to elucidate possible interrelationships amongst circulating microparticles, angiogenic and angiostatic factors in SSc patients that are predictive of interstitial lung disease and high values of right ventricular systolic pressure (RVSP) by trans-thoracic Doppler-echocardiography (TTE). Methods: Nineteen cases with limited cutaneous SSc (lcSSc) and 11 cases with diffuse cutaneous SSc (dcSSc) were compared to 30 age- and sex-matched healthy controls. High resolution computed tomography was used to establish the diagnosis of interstitial lung disease and TTE was used to estimate RVSP and to diagnose putative pulmonary arterial hypertension (PAH). Plasma concentrations of circulating factors were assessed in patients and controls. Results: Angiopoetin-2, endostatin, E-selectin and platelet microparticles were higher in lcSSc cases compared to healthy controls (p<0.0001, p=0.0008, p=0.0003, p=0.0020, respectively). Only endostatin was higher in dcSSc cases (p=0.0020). In a classification tree analysis, concentrations of soluble E-selectin of at least 44.7 ng/ml and 37.2 ng/ml were predictive of ILD and PAH, respectively, in lcSSc cases, whereas, endothelial microparticle levels higher than 96 per μl were predictive of ILD in dcSSc cases. Conclusion: Scleroderma cases can be differentiated from healthy controls based on higher concentrations of the angiostatic factor endostatin. E-selectin was associated with lung involvement in lcSSc, whereas, high levels of endothelial microparticles were associated with ILD in dcSSc.

Endothelial Cell Function in Patients with Hereditary Angioedema: Elevated Soluble E-selectin Level During Inter-attack Periods

The bradykinin pathway in the pathomechanism of hereditary angioedema due to C1-inhibitor deficiency (henceforward "hereditary angioedema") has been thoroughly studied; however, much less is known about endothelial cell function. Enhanced endothelial cell permeability is obvious during edematous attacks, but not during inter-attack periods. Our knowledge about other endothelial characteristics is even more incomplete. Therefore the aim of this study was to characterize endothelial cell function in hereditary angioedema patients during symptom-free, inter-attack periods. We measured the serum levels of soluble E-selectin, endothelin-1, and von Willebrand factor along with collagen-binding activity in 49 hereditary angioedema patients and in 50 healthy controls. Endothelin-1 and von Willebrand factor level, as well as its collagen-binding activity, were similar in hereditary angioedema patients and in controls; however, we found elevated soluble E-selectin levels in the patients. Interestingly, soluble E-selectin concentration did not correlate with any of the inflammatory markers or smoking, and it is not the consequence of the known E-selectin/C1-inhibitor interaction (an analytical phenomenon). In a multiple logistic regression model, the difference in soluble E-selectin between hereditary angioedema patients and controls remained highly significant when adjusted for age, gender, smoking, C-reactive protein, and AB0 blood groups. These results demonstrate that in hereditary angioedema, the majority of endothelial functions are normal during inter-attack periods; however, soluble E-selectin levels are elevated. The higher soluble E-selectin plasma concentration is unlikely to result from inflammation; rather, it reflects enhanced shedding mechanisms.

Impact of biomarkers for endothelial dysfunction and procoagulant state on 10-year cardiovascular risk in Type 2 diabetes1

To estimate the coronary heart disease and cardiovascular disease risk associated with novel biomarkers in Type 2 diabetes mellitus. We measured baseline peripheral blood concentrations of soluble E-selectin, factor XIIa, thrombin-antithrombin III complex and plasminogen activator inhibitor-1 in 86 patients with Type 2 diabetes free of known coronary heart disease. We used Cox proportional hazard models to estimate multivariable-adjusted hazard ratios associated with biomarker levels for 10-year coronary heart disease risk (n = 33 events) or total cardiovascular disease risk (n = 45 events). At baseline, mean (sd) age was 62 years (7 years); 62 were men; and 43 had microalbuminuria. Soluble E-selectin demonstrated cross-sectional relationships with glucose and factor XIIa was related to plasminogen activator inhibitor-1 and triglycerides (all P < 0.05). Baseline log soluble E-selectin was significantly related to incident coronary heart disease and cardiovascular disease. Hazard ratios (95% CIs) associated with a 1-unit increase in log soluble E-selectin in age- and sex-adjusted models were: coronary heart disease : 4.6 (95% CI 1.9-11.3), P = 0.001; cardiovascular disease: 3.6 (95% CI 1.7-7.4, P = 0.001); and in multivariable-adjusted models were: coronary heart disease: 2.9 (95% CI 1.2-7.1, P = 0.02); cardiovascular disease: 2.3 (95% CI 1.1-4.8), P = 0.02. Factor XIIa was significantly related to incident cardiovascular disease. The hazard ratios associated with a 1-unit increase in factor XIIa in age- and sex-adjusted models was 1.5 (95% CI 1.1-1.9, P = 0.003) and in a multivariable-adjusted model was 1.3 (95% CI 1.0-1.6, P = 0.047). Plasminogen activator inhibitor-1 and thrombin-antithrombin III complex were not related to cardiovascular disease events. In our study, soluble E-selectin and factor XIIa were significantly related to 10-year incident macrovascular events in patients with Type 2 diabetes. These preliminary findings call for replication in larger studies.