Plasma profiles of peripheral monocyte-related inflammatory markers in patients with arterial hypertension. Correlations with plasma endothelin-1

BACKGROUND: This study investigates the plasma activity of inflammatory mediators such as granulocyte-macrophage colony-stimulating factor (GM-CSF), C-C chemokines and soluble adhesion molecules, produced by monocyte-endothelial cell adhesive interaction, in patients with arterial hypertension. METHODS: We studied 66 untreated patients with mild to moderate arterial hypertension (hypercholesterolemic: 34, normocholesterolemic: 32) and 30 sex- and age-matched normocholesterolemic normotensive controls. Plasma concentrations of GM-CSF, macrophage chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1alpha (MIP-1alpha), RANTES (regulated on activation normally T-cell expressed and secreted), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1), as well as plasma endothelin-1 (ET-1), were determined in study population by ELISA and RIA, respectively. RESULTS: Hypertensives exhibited significantly higher levels of GM-CSF (6.5+/-1.3 vs. 2.3+/-0.7 pg/ml, P=0.099), MCP-1 (175+/-31 vs. 120+/-24 pg/ml, P=0.0093), MIP-1alpha (23+/-4 vs. 15+/-2 pg/ml, P=0.0089), RANTES (17+/-4 vs. 14+/-3 ng/ml, P=0.047), sICAM-1 (235+/-39 vs. 187+/-21 ng/ml, P=0.0041), sVCAM-1 (684+/-42 vs. 589+/-23 ng/ml, P=0.0045) and ET-1 (6.1+/-1.5 vs. 2.4+/-0.3 pg/ml, P=0.0095) than those of normotensives. The normocholesterolemic hypertensives had significantly lower levels of GM-CSF, MCP-1, MIP-1alpha, sICAM-1 and sVCAM-1 than hypercholesterolemic hypertensives but higher than normotensives. In hypertensives, ET-1 levels were significantly correlated with mean arterial pressure (r=0.51, P=0.028), MCP-1 values (r=0.45, P=0.047) and sICAM-1 levels (r=0.64, P=0.0090). Significant correlations were also found between LDL cholesterol values and plasma inflammatory factors GM-CSF (r=0.58, P=0.0088), MCP-1 (r=0.49, P=0.040) and sICAM-1 (r=0.53, P=0.034) in the hypercholesterolemic sub-group of hypertensives. CONCLUSIONS: Inflammatory markers of monocyte-endothelial cell adhesive interaction are elevated in hypertensives in comparison to normotensives and may be related to plasma ET-1 activity. The coexistence of hypercholesterolemia may enhance this inflammatory process induced by arterial hypertension.     

Levels of soluble cell adhesion molecules in patients with angiographically defined coronary atherosclerosis

Adhesion molecules on the endothelial cell membrane play an important role in the pathogenesis of atherosclerosis. Levels of soluble forms of cell adhesion molecules are reportedly elevated in patients with peripheral artery vessel disease and in patients with an atherosclerotic aorta. The present study investigated the association of serum levels of soluble vascular cell adhesion molecule 1 (sVCAM-1), soluble intercellular adhesion molecule 1 (sICAM-1), and soluble P-selectin (sP-selectin) with coronary heart disease (CHD) and the extent of coronary atherosclerosis, and examined the influence of serum levels of lipids, lipoproteins and apolipoproteins (apo) in subjects with (n=52, M/F:43/9) and without (controls, n=40, M/F:25/15) angiographically proven coronary atherosclerosis. After controlling for age and gender, levels of sVCAM-1 (least squares mean +/- std error: 565+/-36 ng/ml vs 540+/-41 ng/ml, ns), sICAM-1 (261+/-17ng/ml vs 247+/-19ng/ml, ns), and sP-selectin (142+/-8ng/ml vs 149+/-10 ng/ml, ns) in patients with coronary atherosclerosis were not different from those in controls, as assessed by an analysis of covariance. After also adjusting for body mass index, hypertension, diabetes mellitus, and smoking by a multiple logistic function analysis, the association of sVCAM-1, sICAM-1, and sP-selectin with CHD was still not significant. Levels of sVCAM-1, sICAM-1, and sP-selectin were also not related to the extent of coronary atherosclerosis as judged by the number of stenosed vessels. However, inverse (p<0.05) relationships were observed between sVCAMs and serum levels of HDL3-cholesterol, apo A-II, and lipoprotein containing apo A-I and A-II, between sICAMs and levels of apo A-II and Lp A-I/A-II (Lp A-I/A-II), and between sP-selectin and lipoprotein containing only apo A-I. In conclusion, serum levels of soluble VCAM-1, ICAM-1, and P-selectin were not related to CHD or the extent of coronary atherosclerosis, but were inversely related to serum levels of high-density lipoprotein-related lipoproteins.     

Physical training reduces peripheral markers of inflammation in patients with chronic heart failure.

AIMS: Previous studies have shown an abnormal expression of cellular adhesion molecules and cytokines in chronic heart failure, which may be related to endothelial dysfunction characterizing this syndrome. Our study investigates the effects of physical training on serum activity of some peripheral inflammatory markers associated with endothelial dysfunction, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage chemoattractant protein-1 (MCP-1), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) in patients with chronic heart failure. METHODS AND RESULTS: Serum levels of GM-CSF, MCP-1, sICAM-1 and sVCAM-1 were determined in 12 patients with stable chronic heart failure (ischaemic heart failure: 6/12, dilated cardiomyopathy: 6/12, New York Heart Association: II-III, ejection fraction: 24+/-2%) before and after a 12-week programme of physical training in a randomized crossover design. In addition, the functional status of chronic heart failure patients was evaluated by using a cardiorespiratory exercise stress test to measure peak oxygen consumption. Physical training produced a significant reduction in serum GM-CSF (28+/-2 vs 21+/-2 pg. ml(-1), P<0.001), MCP-1 (192+/-5 vs 174+/-6 pg. ml(-1), P<0.001), sICAM-1 (367+/-31 vs 314+/-29 ng. ml(-1), P<0.01) and sVCAM-1 (1247+/-103 vs 1095+/-100 ng. ml(-1), P<0.01) as well as a significant increase in peak oxygen consumption (14.6+/-0.5 vs 16.5+/-0.5 ml. kg(-1)min(-1), P<0.005). A significant correlation was found between the training-induced improvement in peak oxygen consumption and percentage reduction in soluble adhesion molecules sICAM-1 (r=-0.72, P<0.01) and sVCAM-1 (r=-0.67, P<0.02). CONCLUSION: Physical training affects beneficially peripheral inflammatory markers reflecting monocyte/macrophage-endothelial cell interaction. Training-induced improvement in exercise tolerance is correlated with the attenuation of the inflammatory process, indicating that inflammation may contribute significantly to the impaired exercise capacity seen in chronic heart failure.     

Circulating adhesion molecules in patients with stable coronary artery disease

To evaluate platelet and endothelial function in patients with stable coronary artery disease (CAD), we investigated levels of the plasma-soluble (s) adhesion molecules E-selectin (sE-selectin), P-selectin (sP-selectin), and intercellular adhesion molecule-1 (sICAM-1) in 74 patients (mean age, 53 +/- 8 years) with angiographically documented coronary artery disease. Levels were compared to 27 matched healthy control subjects. Patients were excluded if they had recent cardiovascular events or any illness that might influence platelet and endothelial cell function. Concentrations of sP-selectin were significantly higher in patients with stable CAD (276 +/- 61 ng/mL) compared with control subjects (188 +/- 32 ng/mL) (P = .0001), whereas sE-selectin and sICAM-1 levels were similar between the 2 groups. Pooling both groups showed that sICAM-1 correlated weakly with triglycerides (r = 0.240, P = .01) and sP-selectin correlated weakly with low-density lipoprotein cholesterol (r = 0.204, P = .04). Although plasma sICAM-1 concentrations were significantly increased in hypercholesterolemic patients compared with those of normocholesterolemic patients (P = .04), sP-selectin and sE-selectin levels were similar between the 2 groups. In conclusion, significantly increased sP-selectin levels, indicating platelet activation, were found in patients with stable CAD. No other sign of endothelial cell activation in these patients could be detected. Moreover, sP-selectin levels seem to reflect the activation of platelets rather than of endothelial cells.     

Increased serum levels of granulocyte-macrophage colony-stimulating factor in hypercholesterolemic patients

Background: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine that may be implicated in multicellular events of the atherosclerotic inflammatory process. Methods: To investigate the impact of hypercholesterolemia on serum levels of GM-CSF, we determined circulating GM-CSF, soluble intercellular adhesion molecule-1 (sICAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1) in 25 hypercholesterolemic patients with no clinical evidence of cardiovascular disease and in 15 normocholesterolemic control subjects who were matched for age and sex to the hypercholesterolemic group. Results: Hypercholesterolemic patients had higher levels of GM-CSF than did controls (5.8±2.1 vs. 2.1±0.9 pg/ml, P<0.05). They also displayed increased serum levels of sICAM-1 (236.1±19.7 vs. 183.5±13.1, P<0.01) and of sVCAM-1 (673.8±27.3 vs. 591.3±23.4, P<0.01). A significant correlation was observed between GM-CSF levels and LDL-C values (r=0.58, P<0.01) as well as between GM-CSF and sICAM-1 levels (r=0.78, P<0.001). Conclusions: These results suggest that hypercholesterolemia is associated with elevated serum GM-CSF levels. The increased levels of circulating GM-CSF in hypercholesterolemic patients may be related to the monocyte/endothelial cell adhesive interaction and subsequent inflammatory process that accompany the hypercholesterolemia and characterize the early stages of atherogenesis.     

Soluble adhesion molecules (sICAM-1, sVCAM-1) and selectins (sE selectin, sP selectin, sL selectin) levels in children and adolescents with obesity, hypertension, and diabetes

The attachment of monocytes and lymphocytes to endothelial cells, which initiates atherosclerosis, arises under the influence of adhesion molecules. The preclinical phase of this disease lasts many decades, and this provides an opportunity for the presymptomatic detection of high-risk subjects. We evaluated levels of the adhesion molecules: sICAM-1 (soluble intercellular adhesion molecule 1), sVCAM-1 (soluble vascular adhesion molecule 1), sE selectin, sP selectin, and sL selectin in children with atherosclerosis risk factors (n = 123, mean age 15.1 years) (obese [n = 17], hypertensive [n = 25], obese with hypertension [n = 30], type 1 diabetic [n = 51]). Twenty-seven healthy children formed the control group, mean age 15.2 years. sICAM-1 was higher in the study group compared with control (314.1 +/- 61 vs 264.9 +/- 55 ng/mL, P < .01). The same was found for sVCAM-1 (513.7 +/- 187 vs 407.9 +/- 76 ng/mL, P < .05) and E selectin (86.04 +/- 33.6 vs 62.1 +/- 20.3 ng/mL, P < .01). sP-selectin and sL-selectin levels were not different compared with controls. E selectin correlated with body mass index (BMI; r = 0.18, P = .03), total cholesterol (r = 0.2, P = .016), and triglycerides (r = 0.22, P = .008). sICAM-1 correlated with BMI (r = 0.19, P = .019) and systolic blood pressure (r = 0.13, P = .045). In multiple linear regression analysis, sE selectin was found to be associated with triglycerides (R2 = 0.29, P = .045), sICAM-1 dependent on BMI (R2 = 0.58, P = .047), and sVCAM-1 dependent on total cholesterol (R2 = 0.51, P = .006). Elevated concentrations of sICAM-1, sVCAM-1, and E selectin were found in obese, hypertensive, and diabetic children. We conclude that endothelial activation appears in these children, and adhesion molecules are related to the earliest stages of atherosclerosis.     

Soluble adhesion molecules and marine n-3 fatty acids in patients referred for coronary angiography

OBJECTIVE: To investigate the relationship between soluble cellular adhesion molecules (sCAMs) and the extent of coronary artery disease (CAD) in patients with stable angina pectoris. METHODS AND RESULTS: Two hundred and ninety-one subjects had fasting levels of circulating intercellular adhesion molecule-1(sICAM-1), vascular cellular adhesion molecule-1 (sVCAM-1), sP-selectin and contents of n-3 polyunsaturated fatty acids (n-3 PUFA) in granulocyte membranes and adipose tissue determined before undergoing elective coronary angiography. Levels of soluble VCAM-1 (983+/-216 versus 893+/-196 ng/l, p<0.001), ICAM-1 (318+/-140 versus 290+/-75 ng/l, p<0.05) and P-selectin (90+/-27 versus 80+/-23 ng/l, p<0.01) were significantly increased in subjects with significant CAD compared to subjects with no significant stenoses. In a linear regression analysis, both sVCAM-1 and sP-selectin, but not sICAM-1, correlated to the presence and the severity of CAD. Both sICAM-1 and sP-selectin were significantly correlated to current smoking status and a history of myocardial infarction. The content of total n-3 PUFA and docosahexaenoic acid in adipose tissue was marginally, but significant positively correlated to VCAM-1. CONCLUSION: sVCAM-1 and sP-selectin may serve as markers of CAD in patients with stable angina pectoris. Only sVCAM-1 was weakly correlated to n-3 PUFA in adipose tissue.     

Serum levels of selected adhesion molecules in patients with coronary artery disease

BACKGROUND: Adhesion molecules have been suggested as mediators of atherosclerotic inflammatory process. They may contribute to the pathogenesis of stable and unstable angina. METHODS: The study group consisted of 59 patients with coronary artery disease: 27 patients with stable exertional angina (group A), 32 patients with unstable angina (group B). 20 healthy persons acted as controls (group C). Serum levels of soluble Intercellular Adhesion Molecule 1 (sICAM-1), Vascular Cell Adhesion Molecule 1 (sVCAM-1), sE-selectin, sP-selectin were measured both before and after the treadmill ECG stress test in groups A and C. In group B the measurements were carried out at 6, 24, and 48 hours following an episode of chest pain. RESULTS: There were no differences between the baseline serum levels of adhesion molecules as determined in groups A and C. In patients with stable angina, the post-exercise concentrations of sE-selectin were significantly higher (68.8+/-29 ng/ml) in comparison to both baseline- (38.7+/-15 ng/ml), and group C-values (pre-exercise: 35.1+/-16; post-exercise: 49.9+/-15 ng/ml). In unstable patients, serum sP-selectin (190.1+/-99 ng/ml) and sVCAM-1 levels (1359+/-299 ng/ml) were higher when compared to those found in groups A (142.3+/-24; 962+/-352 ng/ml, respectively) and C (136.4+/-33; 851+/-168 ng/ml, respectively). CONCLUSIONS: Serum levels of soluble adhesion molecules in patients with stable angina are comparable to those of healthy persons. Stress test-induced increase of sE-selectin concentration may reflect endothelial response to exercise. Unstable angina is characterized by significant elevation of sP-selectin and sVCAM-1 serum levels which seems to be related to enhanced platelets and leukocytes activation.     

Endothelial dysfunction and inflammatory process in transfusion-dependent patients with beta-thalassemia major

BACKGROUND: Beta-thalassemia major is associated with increased cardiovascular risk, although the underlying mechanisms remain unclear. We examined endothelial function and serum levels of inflammatory mediators in transfusion-dependent patients with beta-thalassemia major. METHODS: The study population consisted of 67 patients with homozygous beta-thalassemia major, (aged 24.6+/-0.7 years) and 71 healthy age and sex matched controls. Forearm blood flow was measured with gauge-strain plethysmography. Forearm vasodilatory response to reactive hyperemia (RH%) or to nitrate (NTG%) was expressed as the percentage change of forearm blood flow from baseline to the maximum flow during reactive hyperemia or sublingual nitroglycerin, respectively. Serum levels of interleukin 6 (IL-6), soluble vascular cell adhesion molecule (sVCAM-1) and soluble intercellular adhesion molecule (sICAM-1) were determined with ELISA. RESULTS: Patients had significantly lower levels of total cholesterol (125+/-4.5 vs. 207+/-7 mg/ml, p<0.01), ApoA1 (120+/-3 vs. 129+/-5 mg/ml, p<0.05), ApoB (60.5+/-2 vs. 95+/-4 mg/ml, p<0.01), ApoE (3+/-2 vs. 4+/-0.2 mg/ml, p<0.01) and Lp(a) (7.9+/-1.3 vs. 14.5+/-3.2 mg/ml, p<0.01) than controls. IL-6 levels were significantly higher in patients (3.03+/-0.31 pg/ml) than controls (1.15+/-0.15 pg/ml, p<0.01). Similarly, sVCAM-1 and sICAM-1 levels were significantly higher in patients (513+/-31 and 368+/-25.5 ng/ml, respectively) than controls (333+/-13.8 and 272+/-14.05 ng/ml, respectively, p<0.01 for both). Maximum hyperemic forearm blood flow and RH% were lower in patients (7.1+/-0.3 ml/100 ml tissue/min and 49+/-2.8%, respectively) than controls (8.26+/-0.32 ml/100 ml tissue/min and 86.3+/-5.57%, respectively, p<0.01 for both). CONCLUSIONS: Beta-thalassemia major is associated with impaired endothelial function and increased levels of IL-6, sVCAM-1 and sICAM-1, suggesting a potential role of inflammation and endothelial dysfunction in the complications of the disease.     

Elevated levels of circulating adhesion molecules in patients with active pulmonary tuberculosis

OBJECTIVE: Recent studies have indicated the importance of cell adhesion molecules in the pathogenesis of various inflammatory lung diseases. Our study was designed to determine whether five soluble adhesion molecules including soluble L-, E- and P-selectin (sL-, sE- and sP-selectin), intercellular adhesion molecule-1 (sICAM-1), and vascular cell adhesion molecule-1 (sVCAM-1) in serum reflect the severity of active pulmonary tuberculosis (TB), and whether there is a distinct profile of these soluble molecules in this disease. METHODOLOGY: Using enzyme-linked immunosorbent assays, we measured the serum levels of these five soluble adhesion molecules in 31 patients with active TB and 11 healthy volunteers. RESULTS: Serum levels of sE-selectin, sP-selectin and sICAM-1, but not sL-selectin or sVCAM-1, were significantly higher in patients with active TB than in the control subjects (P < 0.001, each). Significant correlations were detected only between serum levels of sE-selectin and sP-selectin, sE-selectin and sICAM-1, and sP-selectin and sICAM-1. There was a significant correlation between the Gaffky scale result (a scale assessing the number of mycobacteria bacilli present) and all of the above adhesion molecules, except for sL-selectin. Serum levels of sE-selectin, sL-selectin and sICAM-1 also correlated with the CXR radiological score. Higher levels of sL-selectin and sICAM-1 were detected in the serum of patients with radiological cavity formation compared to those without. The ESR, C-reactive protein and circulating neutrophil counts all correlated significantly with sE-selectin, sP-selectin, sICAM-1 and sVCAM-1. CONCLUSION: The results suggest that there is a distinct profile of soluble adhesion molecules in active pulmonary TB and that sE-selectin, sP-selectin, and especially sICAM-1 appear to be the most sensitive clinical measures of disease severity.     

Relationship between intracoronary and peripheral expression of soluble cell adhesion molecules

BACKGROUND: Elevated levels of soluble cell adhesion molecules (sCAMs) have been reported in various coronary artery disease processes. The principle stimulus for expression of sCAMs is believed to be an inflamed atherosclerotic plaque within the coronary vessel. The relationship between levels of sCAMs in the coronary circulation and the peripheral circulation has not been defined. The primary aim of this study was to define the relationship between levels of sCAMs sampled from the systemic circulation and from the coronary circulation. We also set out to document the acute expression of soluble CAMs following coronary angioplasty with or without stent implantation. METHODS: The coronary sinus was cannulated in patients undergoing LAD angioplasty. Samples were drawn from left coronary ostium (LCO) and coronary sinus (CS) and femoral vein simultaneously before, immediately after and 4 h after the PTCA procedure. Levels of sICAM-1, sVCAM-1, sE-selectin and sP-selectin were measured using ELISA technique. RESULTS: 10 patients (7 male/3 female, 61+/-11 y) entered the study. There was no significant difference in the levels of sICAM-1, sVCAM-1, sE-selectin and sPselectin whether sampled from left coronary ostium, coronary sinus or femoral vein at all time points. There was no significant change in the acute expression of sICAM-1, sVCAM-1 and sE-selectin following coronary angioplasty. Levels of sP-selectin fell significantly during the PTCA procedure (142+/-7 ng/ml to 64+/-6 ng/ml, P<0.001) but then rose again after 4 h and returned toward baseline levels at 24 h. CONCLUSION: Levels of soluble CAMs sampled in the systemic circulation directly reflect levels in the coronary circulation. Coronary angioplasty results in rapid fall in levels of sP-selectin which returns to normal within 24 h following the procedure.     

High serum concentrations of soluble E-selectin in patients with impaired glucose tolerance with hyperinsulinemia

High serum concentrations of soluble adhesion molecules are present in diabetics, but whether similar levels are present in patients with impaired glucose tolerance (IGT) is unclear. We measured serum concentrations of soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), and sE-selectin in 128 nondiabetic Japanese subjects. The concentrations of sICAM-1, sVCAM-1, and sE-selectin in IGT patients (n=47) were not different from those in subjects with normal glucose tolerance (NGT; n=81). IGT patients were subdivided into two groups by the results of 75 g OGTT, those with low- (hypoinsulinemia; n=23) or high-insulin (hyperinsulinemia; n=24). The levels of sICAM-1 and sVCAM-1 were not different among NGT and IGT with high-insulin or with low-insulin. However, sE-selectin concentrations were significantly higher in IGT patients with high-insulin than in NGT and IGT with low-insulin (61.1+/-3.4, 47.1+/-1.8 and 43.7+/-3.9 ng/ml, respectively, P<0.001). Adjustment for age and gender did not influence the results. Serum sE-selectin concentrations correlated significantly with the area under the curve of insulin (AUC(insulin)), AUC(glucose), diastolic blood pressure, and triglyceride levels (r=0.35, 0.26, 0.18 and 0.21, respectively), and negatively with HDL-cholesterol levels (r=-0.20). Multiple regression analysis showed that AUC(insulin) was the only independent factor that correlated with sE-selectin levels (P<0.001). Our results indicate that hyperinsulinemia/insulin resistance may be responsible for the elevation of sE-selectin levels.     

The effect of atorvastatin treatment on lipid profile and adhesion molecule levels in hypercholesterolemic patients: relation to low-density lipoprotein receptor gene polymorphism

Inflammation has been indicated to play a major role in the development of atherosclerosis. The beneficial effect of statins has been suggested to be related to their anti-inflammatory properties. We have studied plasma levels of soluble adhesion molecules in patients with hypercholesterolemia before and after 3 months of treatment with atorvastatin and evaluated possible relations to the mutations in low-density lipoprotein receptor (LDLR) gene. In patients with no LDLR gene polymorphism (group A), lower baseline levels of total cholesterol and LDL cholesterol were found than in patients with LDLR gene polymorphism (group B). The soluble adhesion molecules sICAM-1, sE-selectin and sP-selectin, but not sVCAM-1 and sL-selectin, were higher in group B than in group A. sICAM-1 levels decreased in group A by 7% (p = 0.007) and in group B by 21% (p = 0.039), whereas levels of sVCAM-1 decreased in group A by 12% (p = 0.001) and in group B patients by 19% (p = 0.039). Atorvastatin did not change sE-selectin nor sP-selectin levels in group A. However, in group B, the treatment reduced E-selectin and sP-selectin levels by 39% (p = 0.007) and 24% (p = 0.007), respectively. Atorvastatin attenuates the inflammatory reaction in hypercholesterolemic patients, but in patients with LDLR gene polymorphism, this effect is more profound.     

Cigarette smoking and inflammatory indices in coronary artery disease

BACKGROUND: Smoking-induced endothelial dysfunction may lead to inflammatory activation within a vascular wall mediated by cytokines and adhesion molecules. The aim of the study was to assess the relationship between the smoking status and serum levels of tumor necrosis factor (TNF) alpha, sTNFR 1 and 2 (soluble forms of TNF receptor), Interleukin (IL)-2, IL-10 and some selected adhesion molecules (AM): sE-selectin, sP-selectin, Vascular Cell AM-1 (sVCAM-1) and Intercellular AM-1 (sICAM-1) in patients with coronary artery disease (CAD). METHODS AND RESULTS: The study group consisted of 122 consecutive admissions with stable CAD (class II/III CCS): 31 current smokers (group I; mean age+/-S.E.M.: 53.8+/-1.6 years), 38 ex-smokers (group II; mean age+/-S.E.M.: 57.8+/-1.4 years) and 53 patients who have never smoked (group III; mean age+/-S.E.M.: 62.4+/-1.1 years). Serum concentration of IL-2 was higher in the group of active smokers (77.5+/-12.7 pg/ml) than in ex-smokers (40.0+/-10.6 pg/ml; P=0.017). AM determination also revealed differences between groups I and II-elevated serum sP-selectin levels in active smokers (174.7+/-17.1 ng/ml) than in ex-smokers (123.5+/-10.3 ng/ml; P=0.024). Serum sTNFR 2 level was higher in group III (2457.3+/-120.5 pg/ml) in comparison to group II (2018.4+/-121.5 pg/ml; P=0.006). There were no differences between TNF alpha, sTNFR 1, IL-10, sE-selectin, sICAM-1, sVCAM-1 levels in the groups examined. CONCLUSIONS: Cigarette smoking is associated with the elevation of IL-2 and sP-selectin serum levels in patients with stable CAD. CAD patients who have never smoked are characterized by delayed onset of angina and increased sTNFR 2 concentrations.     

Vitamin E supplementation reduces plasma vascular cell adhesion molecule-1 and von Willebrand factor levels and increases nitric oxide concentrations in hypercholesterolemic patients

Up-regulation of vascular cell adhesion molecule-1 (VCAM-1) and reduced nitric oxide (NO) availability represent early characteristics of atherosclerosis. To evaluate whether the antioxidant vitamin E affected the circulating levels of soluble VCAM-1 (sVCAM-1) and the plasma metabolite of NO (nitrite+nitrate) in hypercholesterolemic patients, either vitamin E (either 400 IU or 800 IU/d for 8 wk) or placebo were randomly, double-blindly given to 36 hypercholesterolemic patients and 22 age- and sex-matched controls. At baseline hypercholesterolemic patients showed higher plasma sVCAM-1 (microg.liter(-1)) (591.2 +/- 132.5 vs. 505.0 +/- 65.6, P < 0.007) and lower NO metabolite (microM) levels (15.9 +/- 3.4 vs. 29.2 +/- 5.1, P < 0.0001) than controls. In hypercholesterolemic patients, 8 wk vitamin E (but not placebo) treatment significantly decreased circulating sVCAM-1 levels (400 IU: -148.9 +/- 84.6, P < 0.009; 800 IU: -204.0 +/- 75.7, P < 0.0001; placebo: -4.7 +/- 22.6, NS), whereas it increased NO metabolite concentrations (400 IU: +4.0 +/- 1.7, P < 0.02; 800 IU: +5.5 +/- 0.8, P < 0.0001; placebo: +0.1 +/- 1.1, NS) without affecting circulating low- density lipoprotein levels. Changes in both plasma sVCAM-1 and NO metabolite levels showed a trend to significantly correlate (r = -0.515, P = 0.010; and r = 0.435, P = 0.034, respectively) with changes in vitamin E concentrations induced by vitamin E supplementation. In conclusion, isolated hypercholesterolemia both increased circulating sVCAM-1 and reduced NO metabolite concentrations. Vitamin E supplementation counteracts these alterations, thus representing a potential tool for endothelial protection in hypercholesterolemic patients.     

The role of soluble cell adhesion molecules in patients with suspected deep vein thrombosis.

Activation of the endothelium, platelets and leukocytes has been shown to play an important role in the aetiology of deep venous thrombosis (DVT) in in-vitro experiments, resulting in the release of soluble cell adhesion molecules (sCAMs). We therefore assessed the value of soluble intracellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin and soluble P-selectin for the diagnostic process in 69 consecutive patients with suspected DVT. Final diagnosis was based on the results of Duplex sonography or ascending venography. Thirty-seven patients (53.6%) finally suffered from DVT. Mean levels of sVCAM-1 were 589 +/- 530 ng/ml for controls and 587 +/- 328 ng/ml for patients. Corresponding levels concerning sICAM-1 were 316 +/- 161 and 342 +/- 186 ng/ml, those concerning soluble E-selectin were 54 +/- 38 and 42 +/- 18 ng/ml, and those concerning soluble P-selectin were 94 +/- 37 and 99 +/- 36 ng/ml (all P > 0.05). There was no significant correlation of the thrombus extension (all P > 0.05) or the duration of symptoms with sCAMs (all P > 0.05). In conclusion, we detected no significant differences concerning the concentration of four major sCAMs between patients with DVT and controls, so their assessment does not add any useful information for the diagnostic process of DVT.     

Early activation of vascular endothelial cells and platelets in obese children

Obesity in adulthood is combined with vascular endothelial cell and platelet activation. In this study we evaluated whether or not such activation is already present in obese children. Forty obese (10.3 +/- 2.5 yr) and 40 nonobese (10.3 +/- 2.3 yr) children were studied. Circulating levels of soluble (s) intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin, as indices of vascular endothelial cell activation, were assessed in both groups. Plasma concentrations of sP-selectin and sCD40 ligand, as indices of platelet activation, were also measured. Circulating levels of highly sensitive C-reactive protein (hs-CRP) and the lipid peroxidation product 8-iso-prostaglandin (PG)F(2alpha) were evaluated because of their ability to promote vascular endothelial cell and platelet activation. Circulating levels of all of the assessed markers were higher in obese than in nonobese children (sICAM-1, +38.8 +/- 13.3%; sVCAM-1, +26.5 +/- 13.7%; sE-selectin, +31.3 +/- 17.3%; sP-selectin, +31.7 +/- 16.9%; sCD40 ligand, +36.9 +/- 22.1%; total 8-iso-PGF(2alpha), +24.0 +/- 20.2%; hs-CRP, +76.6 +/- 12.9%; P < 0.0001). Significant correlations (P < 0.004) between plasma total 8-iso-PGF(2alpha) levels and circulating sICAM-1 (r = 0.485), sVCAM-1 (r = 0.506), sP-selectin (r = 0.449), sCD40 ligand (r = 0.498), and hs-CRP (r = 0.520) concentrations were found in obese children. In conclusion, an early activation of vascular endothelial cells and platelets was present in obese children. Increased lipid peroxidation was also present in these children and likely contributed to the observed proinflammatory phenotype.     

Impaired systemic cell-mediated immunity and increased susceptibility to acute respiratory tract infections in patients with COPD

Although it has been reported that chronic obstructive pulmonary disease (COPD) is frequently associated with systemic immune disturbances, negative impact of these disturbances on the increased prevalence of acute respiratory tract infections (aRTIs) has remained unclear. We evaluated circulating levels of interferon-gamma (IFN-gamma), soluble interleukin-2 receptor (sIL-2R), neopterin, and soluble intercellular adhesion molecule-1 (sICAM-1) in 35 clinically stable patients with COPD and in 22 age-matched healthy controls, since these molecules are considered to reflect the in vivo status of systemic cell-mediated immunity (CMI). We found that circulating levels of sIL-2R (1.52+/-1.25 vs. 0.97+/-0.48 ng/ml; P<0.05), neopterin (7.23+/-4.24 vs. 4.95+/-1.52 nmol/l; P<0.05), and sICAM-1 (665+/-302 vs. 328+/-164 ng/ml; P<0.0001), but not IFN-gamma (7.55+/-4.72 vs. 6.65+/-1.13 pg/ml; P=NS) were significantly higher in patients with COPD than in the controls. Importantly, follow-up study for 12 months demonstrated that patients in subgroup with relatively higher circulating levels of sIL-2R (2.20+/-1.44 ng/ml, n=18) had significantly higher risk of developing aRTIs (P=0.0204) than those in subgroup with relatively lower circulating levels of sIL-2R (0.80+/-0.23 ng/ml, n=17). These results may suggest that impaired systemic CMI observed in COPD patients is associated with the increased susceptibility to aRTIs in these patients.     

Diurnal variation of soluble E- and P-selectin, and intercellular adhesion molecule-1 in patients with and without coronary artery disease

BACKGROUND: The more frequent onset of acute coronary syndromes (ACS) in the morning has been known for a long time. Diurnal changes of fibrinolysis such as lower activity of tissue plasminogen activator and higher activity of plasminogen activator inhibitor-1 (PAI-1) in the morning has been demonstrated previously and correspond with the manifestation of ACS. Less is known about the diurnal variation of soluble adhesion molecules as markers of endothelial or platelet activity in patients with coronary artery disease (CAD). PATIENTS AND METHODS: 80 patients with a history of myocardial infarction and/or chest pain with positive exercise testing admitted for elective coronary angiography were studied. 10 had normal findings on coronary angiography (control group), 70 patients had at least one or more stenoses >/=50% of the diameter of an epicardial vessel. None of the patients suffered from acute inflammation, connective or tumor disease. Blood samples were drawn at 7:00 a.m. and at 7:00 p.m. at rest and plasma concentration of soluble P-selectin (sP-selectin), E-selectin (sE-selectin), intercellular adhesion molecule-1 (sICAM-1) and acute-phase proteins were measured by ELISA. RESULTS: In both groups, no diurnal variation was found in sE-selectin and sICAM-1. sP-selectin levels were significantly higher in the evening (CAD group: 149.8 +/- 54.5 vs. 172.2 +/- 68.8 ng/ml, p < 0.001; control: 148.7 +/- 75.5 vs. 187.5 +/- 96.3 ng/ml, p = 0.001, Wilcoxon test). CONCLUSION: We have demonstrated diurnal variation of sP-selectin in patients with CAD. We conclude that high sP-selectin values in the evening represent the shed forms of the morning membrane-bound P-selectin.     

Elevated soluble intercellular adhesion molecule-1 levels in patients with systemic lupus erythematosus: relation to insulin resistance

OBJECTIVE: Intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are members of the immunoglobulin supergene family and play a central role in cell-to-cell and in cell-to-extracellular matrix-mediated immune responses. Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by a wide variety of immunological abnormalities. The relationship between soluble adhesion molecules and insulin resistance has been observed in different populations. However, the association of circulating levels of soluble cell adhesion molecules with insulin resistance and/or hyperinsulinemia in patients with SLE has not been extensively established. METHODS: We evaluated the relationship of soluble ICAM-1 (sICAM-1) and VCAM-1 (sVCAM-1) to insulin resistance in 68 patients with SLE and 34 age-matched healthy controls. RESULTS: Patients with SLE had significantly higher fasting insulin levels, homeostasis model assessment insulin resistance (HOMA-IR), HOMA beta-cell, and plasma levels of sICAM-1 and sVCAM-1 than controls. SLE patients with HOMA-IR in the top quartile had the highest plasma levels of sICAM-1. However, there was no statistical difference in plasma levels of sVCAM-1 between patients in the respective quartiles of insulin sensitivity-related variables. Plasma levels of sICAM-1, but not sVCAM-1, were significantly correlated with fasting insulin (r = 0.327, p = 0.006), HOMA-IR (r = 0.278, p = 0.022), and HOMA beta-cell (r = 0.359, p = 0.003). In addition, fasting insulin was responsible for sICAM-1 variability in patients with SLE. CONCLUSION: The elevation of plasma levels of sICAM-1 was associated with a status of insulin resistance in patients with SLE.