Circulating soluble adhesion molecules in ANCA-associated vasculitis.

BACKGROUND: To evaluate whether changes in concentrations of soluble (s) E-selectin, sP-selectin, sL-selectin, intercellular adhesion molecule 1 (sICAM-1), and vascular cell adhesion molecule 1 (sVCAM-1) reflect disease activity in patients with ANCA-associated vasculitis and whether serum levels of these adhesion molecules are related to the degree of renal failure in patients with chronic renal failure (CRF). SUBJECTS AND METHODS: A sandwich ELISA was used to measure these soluble adhesion molecules in (i) sera from 20 patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (10 patients with Wegener's granulomatosis (WG) and 10 patients with microscopic polyangiitis (MPA)), obtained at the time of diagnosis and during the remission period; (ii) sera from 40 patients with CRF not undergoing haemodialysis. RESULTS: At the time of diagnosis, serum levels of sE-selectin, sICAM-1 and sVCAM-1 (88+/-42 ng/ml, 437+/-184 ng/ml, 1720+/-1174 ng/ml respectively) were significantly higher in patients with ANCA-associated vasculitis than in healthy controls (P<0.0001, P=0.002 and P=0.001 respectively). Serum sP-selectin values did not differ from those obtained in normal donors. In contrast, sL-selectin levels (940+/-349 ng/ml) were significantly lower in patients than those recorded in healthy controls (P<0.0001). A significant decrease in concentrations of sE-selectin, sP-selectin, sICAM-1, and sVCAM-1 was observed between active and remission phases (P<0.0001, P=0.002, P=0.001 and P=0.001 respectively). No significant differences were observed in sL-selectin levels between active and remission phases. sL-selectin concentrations (802+/-306 ng/ml) during the remission phase remained lower than those observed in healthy controls (P<0.0001). No correlation was observed between serum creatinine and sE-selectin, sP-selectin, sICAM-1 and sVCAM-1 in patients of the CRF group. A slight negative correlation was established between creatinine and sL-selectin concentration. CONCLUSIONS: Increased serum levels of sE-selectin, sICAM-1, and sVCAM-1 and decreased levels of sL-selectin in active ANCA-associated vasculitis, and the normalization of sE-selectin, sICAM-1, and sVCAM-1 during the remission phase suggest that the concentration of soluble levels of these adhesion molecules reflects disease activity. The decrease in sP-selectin levels between active and inactive phases also suggest that this receptor may reflect clinical activity. The lack of correlation between serum levels of sE-selectin, sP-selectin, sICAM-1, and sVCAM-1 and the degree of renal failure in patients with CRF suggests that the mechanism of clearance of these molecules is not renal.     

Comparison of novel risk factors for cardiovascular disease between hemodialysis patients with and without protein-energy wasting

Purpose

The present study was designed to compare novel risk factors for cardiovascular diseases (CVD) between hemodialysis (HD) patients with or without protein-energy wasting (PEW) for determining novel risk factors for CVD in HD patients with PEW.

Methods

In this cross-sectional study, 291 HD patients were randomly selected from among 2,302 adult HD patients in Tehran hemodialysis centers. The presence of PEW in HD patients was determined by subjective global assessment. In addition, 4 mL blood was obtained before dialysis and analyzed for serum concentrations of novel risk factors for CVD, including C-reactive protein (CRP), soluble intercellular adhesion molecule type 1 (sICAM-1), soluble vascular cell adhesion molecule type 1 (sVCAM-1), sE-selectin, malondialdehyde (MDA), nitric oxide (NO), endothelin-1 and lipoprotein (a) [Lp (a)].

Results

Serum CRP and sICAM-1 were significantly higher in HD patients with PEW as compared to those without PEW (P < 0.01), whereas there were no significant differences in serum sVCAM-1, sE-selectin, MDA, NO, endothelin-1 and Lp (a) between the two groups. Serum CRP and sICAM-1 were significantly higher in HD patients with PEW type IIa and IIb than in those with PEW type I (P < 0.01).

Conclusion

The present study indicates that serum CRP and sICAM-1, as two CVD risk factors, increase in HD patients with PEW as compared to those without PEW and these increases occur in HD patients with PEW type IIa and IIb who have inflammation.     

Effect of pravastatin on markers of endothelial activation in dialysis patients

AIM: The aim of this pilot study was to test the effect of pravastatin on serum levels of high-sensitivity CRP (hs-CRP), IL-6 and the soluble adhesion molecules sVCAM-1, sICAM-1 and sE-selectin in chronic dialysis patients. METHODS: At the commencement of the study, serum levels of lipids, liver function tests and endothelial markers (CRP, IL-6, sICAM-1, sVCAM-1, sE-selectin) were measured. Patients then commenced 1 month of 10 mg of pravastatin per day, and if tolerated, then 4 months of 40 mg of pravastatin per day. Serum levels of lipids, liver function tests and endothelial markers were repeated after the total of 5 months of pravastatin therapy. RESULTS: Thirty-nine patients were enrolled, and 25 (male/female 17/8; 21 haemodialysis, 4 peritoneal dialysis) patients completed the study. Pravastatin therapy significantly improved the patients' lipid profiles, but had no significant effect on the levels of CRP, IL-6, sICAM-1, sVCAM-1, or sE-selectin. CONCLUSION: Short-term (5 months) treatment with pravastatin in patients receiving chronic dialysis improved their lipid profile, but had no significant effect on surrogate markers of endothelial activation.     

Circulating soluble adhesion molecules in systemic vasculitis

The plasma levels of soluble intercellular adhesion molecule-1(sICAM-1), E-selectin (sE-selectin), and vascular cell adhesionmolecule-1 (sVCAM-1), might reflect endothelial activation andinjury and would therefore be useful markers of disease activityin vasculitis. To investigate this we measured the levels ofsICAM-1, sE-selectin, and sVCAM-1 by two-site ELISAs in theplasma of patients with (a) active vasculitis (n = 16), (b)vasculitis in remission (n = 15), (c) chronic renal failure(CRF) (n = 10), and (d) normal healthy controls (n = 10). PlasmasICAM-1 levels were significantly higher in patients with activevasculitis, 323 ng/ml (193–607) compared with patientswith inactive vasculitis, 199 ng/ml (131–297); P = 0.0006and healthy controls, 188 ng/ml (138–259); P =0.0002.Plasma sE-selectin levels were also significantly higher inthe patients with active vasculitis, 45 ng/ml (15–65)compared with patients with inactive vasculitis, 25 ng7sol;ml(15–55); P=0.027 but not when compared with healthy controls,35 ng/ml (20–55); P=0.16. There was no difference in plasmasVCAM-1 levels between patients with active vasculitis, OD 0.56(0.45–0.85) and inactive disease, OD 0.58 (0.47–0.79)(P=0.12) or with healthy controls OD 0.49 (0.42–0.68)(P=0.48). There were no significant differences between theplasma levels of any of the soluble adhe sion molecules betweenpatients with active vasculitis and patients with chronic failure.In patients with a vasculitis there was a significant correlationbetween sICAM-1 and plasma C-reactive protein (CRP) (r=0.60,P=<0.01) and plasma von Willebrand factor (vWF) (r=0.42,P<0.05). Likewise there was a cor relation between sE-selectinand CRP (r=0.45, P<0.02) but not with vWF. There was a significantcorrelation between sICAM-1 and sE-selectin (r=0.38, P<0.05),but not between sICAM-1 and sVCAM-1 or sE- selectin and sVCAM-1.No correlation was found between sVCAM-1 levels and CRP andvWF concentrations or between the levels of any of the solubleadhesion molecules and serum creatinine. Plasma levels of sICAM-iand of sE-selectin but not of sVCAM-1 reflect disease activityin vasculitis and may be markers of endothelial and or tissueinjury in these disorders.     

Soluble adhesion molecule profiling in preoperative infants with biliary atresia

Objective

Intercellular adhesion molecule (ICAM) expression in liver and bile duct remnant is a feature of the inflammatory component of biliary atresia (BA). Circulating levels of such soluble adhesion molecules (SAM) should reflect intrahepatic disease and would prove a useful adjunct in the evaluation of BA.

Study Design

Serum ICAM-1 (sICAM-1), serum vascular cell adhesion molecule (sVCAM-1), and serum E selectin (sE-selectin) were measured by enzyme-linked immunosorbent assay in infants with BA at the time of portoenterostomy and stratified by outcome. Results are quoted as medians (range). Binary logistic regression analysis and actuarial survival curves were used to investigate the relationship of SAM profile to outcome. Significance was assumed at P values of ≤.05.

Results

Sixty-one infants with BA were treated between 1996 and 2002 and at follow-up; 39 of these were alive and jaundice-free (good outcome, n = 39); 21 had been transplanted, and 1 died (poor outcome, n = 22). Preoperative values for sICAM-1 were 1233 (400-2000) ng/mL; sVCAM-1, 1204 (517-1921) ng/mL; and sE-selectin, 71 (26-192) ng/mL. sVCAM-1 (P < .0001) and sICAM-1 (P < .0001) significantly increased compared with normal control infants, although sE-selectin did not (P = .17). There was a significant correlation of age at surgery with sICAM-1 (r = 0.33, P = .01) but not with sVCAM-1 (r = 0.16, P = .23) or sE-selectin (r = 0.05, P = .70).Binary logistic regression analysis showed that the variables, sICAM-1, sE-selectin, or age at surgery, were not significant predictors of outcome, although sVCAM-1 approached significance (P = .069). A cutoff value for sVCAM-1 of 1380 ng/mL was defined by receiver operating characteristic curve analysis, and the cohort of patients with sVCAM-1 (>1380 ng/mL) showed a significantly worse actuarial survival (P = .05).

Conclusion

Levels of sICAM-1 and sVCAM-1 are grossly elevated in BA, whereas sE-selectin levels are normal. Only sVCAM-1 levels have prognostic significance. SAM profiling has the potential to monitor the inflammatory process of BA and may guide more novel forms of pharmacological intervention or immunomodulation.     

Soluble adhesion molecules in end-stage renal disease: a predictor of outcome.

BACKGROUND: Inflammation is thought to contribute to initiation and aggravation of atherosclerosis through a process predominantly mediated by adhesion molecules. The aims of this study were to investigate the association between the concentrations of circulating soluble intercellular (sICAM-1) and vascular cellular (sVCAM-1) adhesion molecules and clinical outcome, and to evaluate the effect of antihypertensive drugs on sICAM-1 and sVCAM-1 concentrations in end-stage renal disease (ESRD) patients. METHODS: We prospectively investigated 310 (191 males) incident ESRD patients, 53+/-12 years old, shortly before the start of renal replacement therapy. Glomerular filtration rate (GFR) was 6.4 (range 0.8-16.5) ml/min/1.73 m(2). Plasma sICAM-1 and sVCAM-1 were measured by enzyme-linked immunosorbent assay (ELISA) kits. Survival was determined from the day of examination, with a mean follow-up period of 39 (range 1-123) months. RESULTS: In non-adjusted analysis, high sICAM-1 and sVCAM-1 levels were associated with all-cause and cardiovascular (P<0.001) mortality. After adjusting for age, gender, diabetes mellitus, serum cholesterol, C-reactive protein (CRP), subjective global assessment and angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB), the association between high sICAM-1 and mortality remained significant for all-cause (HR 1.9; CI 1.2-2.9, P = 0.004) and cardiovascular (HR 1.8; CI 1.1-3.1, P = 0.02) mortality, and a high sVCAM-1 was associated with all-cause mortality (HR 1.7; CI 1.04-2.7, P = 0.03). Furthermore, the concentration of sICAM-1, but not sVCAM-1, was lower in patients receiving ACEI/ARB (254+/-83 vs 275+/-92 ng/ml; P<0.05) or patients receiving calcium channel blockers (CCB, 251+/-75 vs 273+/-95 ng/ml; P<0.05) than in non-users. CONCLUSIONS: In ESRD patients, sICAM-1 and sVCAM-1 are independent predictors of all cause and cardiovascular death. The use of ACEI/ARB or CCB was associated with decreased concentrations of soluble adhesion molecules.     

Systemic and vascular inflammation is elevated in early IgA and type 1 diabetic nephropathies and relates to vascular disease risk factors and renal function.

BACKGROUND: Inflammation is implicated in cardiovascular disease (CVD) and mortality in end-stage renal failure (ESRF). Its importance in early renal disease is yet to be defined. METHODS: Serum levels of systemic and vascular inflammatory markers in early IgA nephropathy (IgAN) and control subjects were measured and related to renal function and vascular risk factors. A parallel study in type 1 diabetes mellitus subjects with (T1DM Nx) and without nephropathy (T1DM No Nx) was performed. RESULTS: Fifty-one IgAN patients aged 46+/-2 years (mean+/-SEM), calculated creatinine clearance (CrCl) 88+/-5 ml/min, were compared with 51 matched control subjects. Forty-six T1DM Nx patients aged 40+/-2 years, CrCl 84+/-5 ml/min, and 73 T1DM No Nx patients aged 38+/-2 years were also compared. High sensitivity C-reactive protein (hsCRP) was elevated in IgAN, T1DM Nx and T1DM No Nx patients compared with controls [4.2+/-0.6 (P < 0.001), 4.1+/-0.6 (P < 0.001), 2.6+/-0.4 (P < 0.05) vs 1.6+/-0.3 mg/l]. Levels in T1DM Nx patients were higher than in T1DM No Nx patients (P < 0.05). Inflammation and vascular dysfunction as measured by pulse pressure (PP) were related. HsCRP correlated with PP in IgAN and T1DM Nx (r = 0.47, P = 0.001; r = 0.40, P < 0.05). PP was the strongest independent predictor of hsCRP in IgAN (T = 2.45, P < 0.001), while body mass index (T = 7.83, P < 0.001) was the strongest predictor in T1DM Nx. Endothelial cell adhesion molecules were increased in T1DM Nx > IgAN > T1DM No Nx vs controls: soluble vascular adhesion molecule-1 (sVCAM-1) 760+/-30 (P < 0.001) > 663+/-34 (P = 0.001) > 601+/-21 (P < 0.05) vs 536+/-15 ng/ml; soluble intracellular adhesion molecule-1 (sICAM-1) 320+/-8 (P < 0.001) > 313+/-13 (P < 0.001) > 307+/-8 (P < 0.001) vs 244+/-6 ng/ml. sVCAM-1 levels were higher in T1DM Nx than in T1DM No Nx, P < 0.001. In IgAN and T1DM Nx, hsCRP correlated with sICAM-1 (r = 0.33, P = 0.017; r = 0.37; P = 0.017). sVCAM-1 was related to renal function in IgAN and T1DM Nx: serum cystatin C (r = 0.63, P < 0.001: r = 0.425, P = 0.002), and urine protein:creatinine ratio in IgAN (r = 0.48; P = 0.001). CONCLUSIONS: Systemic and vascular markers of inflammation are increased in early renal disease and relate to renal dysfunction and cardiovascular risk factors. Inflammation may be a common process in various renal diseases and may link and accelerate renal dysfunction and CVD.     

Value of circulating adhesion molecules in assessing cardiac allograft vasculopathy.

Circulating adhesion molecules have been implicated in the development of spontaneous and transplant coronary artery disease. We analyzed soluble (s) intercellular adhesion molecule 1 (sICAM-1), vascular cell adhesion molecule 1 (sVCAM-1), and sE-selectin levels from the coronary sinuses of 25 cardiac allograft recipients, and we correlated these molecules with the degree of acute rejection detected in endomyocardial biopsy specimens and the presence of transplant vasculopathy assessed with coronary angiography. We found that sVCAM-1 significantly increased in patients with transplant vasculopathy compared with those without transplant vasculopathy, whereas sE-selectin and sICAM-1 did not. Therefore, increased coronary sinus levels of sVCAM-1 is a reliable marker in assessing cardiac transplant vasculopathy.     

Hemodialysis procedure does not affect the levels of sICAM-1 and sVCAM-1 in patients with end stage renal disease

Atherosclerosis is by far the leading cause of mortality and morbidity in patients with end stage renal disease undergoing chronic hemodialysis (HD). Vascular endothelial cell adhesion molecules like the intercellular adhesion molecule-1 (ICAM-1) and the vascular cell adhesion molecule-1 (VCAM-1) are involved in the pathogenesis of atherosclerosis. Their soluble forms (sICAM-1, sVCAM-1) are considered potential serum markers of endothelial activation and atherosclerosis. The aim of this study was to clarify the influence of the HD procedure on the levels of sICAM-1 and sVCAM-1 in patients with end stage renal disease. We evaluated 35 clinically stable patients (18 males, 17 females, mean age 61 +/- 12) on chronic HD treatment. Diabetes mellitus coexisted in eight patients and arterial hypertension in 23 patients. Blood was drawn before, every hour during, and after a single HD session in each patient. Low-flux cuprophane dialyzers (GFS 12, Gambro, Lund, Sweden) were used in 22 and high-flux polysulfone dialyzers (Hemoflow F 60S, Fresenius, Oberursel, Germany) in 13 cases. At 30 min into the HD session (n=31, 20 low-flux HD, 11 high-flux HD) blood was drawn simultaneously from the entrance and the exit line of the dialyzer. From all these samples, serum concentrations of sICAM-1 and sVCAM-1 were determined by commercially available enzyme immunoassays (ELISA, R&D Systems, Minneapolis, USA). Results were corrected according to hemoconcentration, where appropriate. Plasma levels of sVCAM-1 were elevated in patients with end stage renal disease before the beginning of the dialysis session when compared to healthy controls (1449 +/- 497 ng/mL vs. 691 +/- 118 ng/mL). On the contrary, such an elevation was not found in the case of sICAM-1 (231 +/- 58.5 ng/mL vs. 236.4 +/- 96.8 ng/mL in healthy controls). These levels remained stable in all measurements throughout the dialysis procedure. Furthermore, serum sICAM-1 and sVCAM-1 levels remained unaltered after the passage of the dialyzer. The levels of sICAM-1 and sVCAM-1 were not influenced by the existence of diabetes mellitus, hypertension, or by the utilization of biocompatible, high flux dialyzers. Our study confirms that in chronic HD patients serum levels for sVCAM-1 are elevated. The levels of adhesion molecules are not affected by the HD procedure. These findings probably can be attributed to a decreased renal clearance or catabolism of sICAM-1 and sVCAM-1 and to the different sources of the two molecules. Neither coexisting diabetes mellitus nor arterial hypertension influences the circulating levels of these adhesion molecules. The functional role of sVCAM-1 and sICAM-1, the exact renal contribution to their metabolism, and their role as markers of atherosclerosis in chronic renal disease need further evaluation.     

Serum concentration of adhesion molecules in postoperative biliary atresia patients: relationship to disease activity and cirrhosis

BACKGROUND/PURPOSE: Biliary atresia (BA) is associated with progressive liver fibrosis, which may be mediated by immunologic abnormalities involving adhesion molecules. This study investigates the relationship between serum intercellular adhesion molecule-1 (sICAM-1), serum vascular cell adhesion molecule-1 (sVCAM-1), and the clinical and histologic severity of BA. METHODS: Serum ICAM-1 and VCAM-1 levels were measured by enzyme-linked immunosorbent assay in 35 patients with BA and 20 healthy controls. Standard liver function tests (LFTs), and frozen section liver biopsy specimens were used to determine liver status. On the basis of LFT results, the BA patients were classified into group I (n = 10; normal LFTs), group II (n = 15; elevated LFTs, anicteric), and group III (n = 10; elevated LFTs, icteric). Eight subjects in group II, and all subjects in group III had portal hypertension (PH). RESULTS: sICAM-1 levels were significantly elevated in group III (1760.0 +/- 717.5 ng/mL) compared with group II (555.1 +/- 199.4 ng/mL), group I (272.1 +/- 59.9 ng/mL) and controls (256.3 +/- 71.6 ng/mL). Although sVCAM-1 levels were significantly elevated in group III (1932.9 +/- 282.6 ng/mL) compared with group II (1054.3 +/- 297.0 ng/mL), group I (605.4 +/- 112.4 ng/mL), and controls (616.0 +/- 112.0 ng/mL; P <.001), there was no statistically significant difference between groups I, II, or controls. sVCAM-1 levels were elevated significantly in BA subjects in group II with PH (1253.0 +/- 245.1 ng/mL) compared with those who did not have PH (827.3 +/- 151.7 ng/mL; P <.01). PH did not affect sICAM-1 levels. There was strong expression of ICAM-1 and VCAM-1 in proliferating bile ductules, endothelial cells, and liver cells in group III compared with group II and controls. CONCLUSIONS: In BA, sICAM-1 and sVCAM-1 levels could be useful as markers of end-stage liver disease, with sVCAM-1 being more specific for PH. Induction of ICAM-1 and VCAM-1 may be an important factor in the development of cirrhosis.     

Increased levels of soluble TNF-alpha receptors and cellular adhesion molecules in patients undergoing bioincompatible hemodialysis

BACKGROUND: The study aimed to differentiate the effects of hemodialysis (HD) and chronic renal failure (CRF) on the levels of circulating tumor necrosis factor-alpha (TNF-alpha) and TNF-alpha receptors p55 and p75, soluble vascular cell adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (sICAM-1), soluble endothelial-leukocyte adhesion molecule-1 (sE-selectin) and sP-selectin in 18 patients on regular HD treatment with cuprophane membrane in relation to 15 non-dialyzed CRF patients and 15 healthy controls. METHODS: The serum concentrations were determined with standard ELISA assays. RESULTS: Blood serum p75 and p55 were approximately tenfold increased in CRF (36.7 +/- 6.2 and 27.1 +/- 5.6 ng/ml) and HD patients (45.6 +/- 18.4 and 28.7 +/- 5.9 ng/ml) before the HD session (HD 0), during (HD 20) the session (45.7 +/- 18.4 and 28.5 +/- 7.3 ng/ml) and after (HD 240) the HD session (52.1 +/- 17.4 and 30.9 +/- 8.2 ng/ml) in comparison to control values (5.6 +/- 1.3 and 2.4 +/- 0.8 ng/ml, respectively) (p < 0.01). The highest increment of p75 at the end of HD session (HD 240) was also significantly higher than at preceding time points (HD 0 and 20) (p < 0.05). However, the remaining study parameters did not change during an HD session. Also, there were no relevant changes in TNF-alpha levels if (HD 0) 22.7 +/- 21.5 ng/ml and (HD 240) 21.1 +/- 18.9 ng/ml were compared. Chronic HD status was related to the increase of sVCAM-1 and sICAM-1 levels. Prior to HD, T0 sVCAM-1 and sICAM-1 concentrations were 2,180.4 +/- 761.8 and 567.3 +/- 218.8 ng/ml, during HD (T20): 2,172.7 +/- 759.2 and 602.3 +/- 379.9 ng/ml, and after HD (T240): 2,401.6 +/- 756.4 and 648.3 +/- 183.5 ng/ml, respectively (p < 0.05 vs. controls and CRF patients). sVCAM-1 and sICAM-1 serum levels (1,262.2 +/- 472.9 and 165.6 +/- 50.4 ng/ml) were similar in CRF patients and healthy controls (854.4 +/- 241.5 and 217.6 +/- 74.2 ng/ml, respectively). Even though serum sE- and sP-selectin in CRF patients did not differ from the control (39.8 +/- 21.3 vs. 42.1 +/- 18.9 ng/ml and 187.9 +/- 66.9 vs. 198.8 +/- 62.2 ng/ml, respectively), their levels were increased in HD patients up to 111.9 +/- 54.6 and 453.2 +/- 231.1 ng/ml in patients prior to HD, 118.7 +/- 66.2 and 350.8 +/- 114.8 ng/ml during the HD session and then 132.3 +/- 61.1 and 368.3 +/- 126.6 ng/ml, respectively, after its completion (p < 0.05 in comparison with CRF patients and controls). CONCLUSIONS: The increased circulating TNF-alpha receptors appear more associated with the uremic milieu than HD-related systemic inflammation, whereas increased soluble cellular adhesion molecules in patients undergoing bioincompatible HD may be related to the enhanced systemic inflammation specifically due to maintenance HD.     

Effect of upper- and lower-limb exercise training on circulating soluble adhesion molecules, hs-CRP and stress proteins in patients with intermittent claudication.

OBJECTIVES: To investigate the effects of exercise training on levels of circulating biomarkers associated with the progression of atherosclerosis and risk of cardiovascular events in patients with intermittent claudication. METHODS: Circulating levels of soluble adhesion molecules (sVCAM-1, sICAM-1, sE-selectin), high sensitivity C-reactive protein (hs-CRP) and stress proteins (Hsp60 and Hsp70) in patients randomised to a 24-week programme of arm- or leg-cranking exercise were compared with those in usual care controls. RESULTS: Arm and leg exercise similarly improved lower-limb aerobic exercise capacity (20% vs 19%, respectively; P<0.001) and maximum walking distance (30% vs 35%, respectively; P<0.001). Improvements in training limb-specific peak oxygen consumption were attenuated for patients in the highest vs lowest quartile for circulating sVCAM-1 levels at baseline (3% vs 25% respectively, P<0.001). Although circulating hs-CRP levels tended to be lower in the arm-cranking group (-1.55 [95% CI: -1.06 to -2.26]mgl(-1)), exercise training had no effect on circulating levels of soluble adhesion molecules or stress proteins. CONCLUSIONS: These findings suggest that high levels of circulating sVCAM-1 are associated with an attenuated exercise training response and that arm-cranking exercise may provide an effective stimulus for evoking systemic anti-inflammatory adaptations in patients with intermittent claudication.     

Association of mineral metabolism with an increase in cellular adhesion molecules: another link to cardiovascular risk in maintenance haemodialysis?

BACKGROUND: Abnormal mineral metabolism is associated with increased cardiovascular morbidity and mortality. The exact pathogenesis linking mineral metabolism to cardiovascular risk is unknown. This study was undertaken to investigate the association between serum phosphate and/or Ca x PO(4) product with serum levels of soluble E-selectin (sE-selectin), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 and the degree of carotid artery atherosclerosis in patients on haemodialysis. METHODS: Seventy-three patients (46 male, 27 female; mean age 48+/-13 years, on haemodialysis for 82+/-80 months) were included in the study. All patients were stable, had no evidence of vascular disease and/or active infection. Consecutive 6 months clinical and laboratory data were obtained for each patient from their medical records and mean values were used for analysis. Serum levels of soluble adhesion molecules were assayed by ELISA. All subjects underwent a detailed evaluation of the carotid arteries. RESULTS: The percentage of patients who met all three targets of NKF-K/DOQI for phosphate, calcium and Ca x PO(4) product was 27.1%, whereas those who did not achieve the target in one, two or three parameters was 28.1, 17.7 and 14.6%, respectively. The sICAM-1 levels were significantly higher in patients who had hyperphosphataemia (serum phosphate >5.5 mg/dl; P = 0.044) and hypercalcaemia (serum calcium >9.5 mg/dl; P = 0.014), both sE-selectin and sICAM-1 levels were significantly higher in patients with Ca x PO(4) product levels above 55 mg(2)/dl(2) (P = 0.002 and P = 0.000, respectively). Soluble E-selectin and sICAM levels demonstrated a near-linear increase in parallel to the degree of deviation from mineral metabolism targets. Soluble E-selectin and sICAM levels were correlated with serum phosphate and Ca x PO(4) product, but there were no correlations between adhesion molecules and carotid measurements. CONCLUSION: These findings suggest that in stable haemodialysis patients abnormal bone mineral metabolism was associated with increased soluble adhesion molecules. These alterations in adhesion molecules may favour the development of cardiovascular changes and contribute to high cardiovascular morbidity and mortality in patients with abnormal mineral metabolism.     

The relationship between the method of cardioplegia and vascular endothelial cell derived soluble adhesion molecules in myocardial ischemia-reperfusion injury

The relative role of different adhesion molecules in the ischemia-reperfusion injury after cardioplegic arrest in the clinical setting is unknown, because of protective effects of cardioplegia and hypothermia. The aim of this study is to determine the relationship between the method of the cardioplegia and endothelial derived soluble adhesion molecules; soluble vascular adhesion molecule-1 (sVCAM-1) and soluble intercellular adhesion molecule-1 (sICAM-1) in myocardial ischemia- reperfusion injury. Fourteen male patients who underwent aortocoronary bypass surgery with cardiopulmonary bypass were included in this study. They were randomised to be given blood or crystalloid cardioplegia for myocardial protection. Group I (n=7) received blood cardioplegia and group II (n=7) received crystalloid cardioplegia. The cross-clamp times were not significantly different between the two groups, 49.4+/-4.6 min for group I and 54.8+/-2.5 min for group II. Mean age of patients was 58+/-2.1 years for group I and 54+/-2.6 years for group II. Blood samples were taken from both the aorta and coronary sinuses of all patients before cross-clamp, after cross-clamping and at 30th min of reperfusion. Plasma were obtained from blood samples and then stored at -70 degrees C. sVCAM-1 and sICAM-1 levels were measured by ELISA in the samples. There were no significant differences in the levels of sICAM-1 and sVCAM-1 at the beginning of reperfusion and at 30th min of reperfusion in coronary sinus of group I patients. But, increased sICAM-1 and sVCAM-1 levels were observed at 30th min of reperfusion in blood taken from coronary sinuses of group II patients compared with beginning of reperfusion (respectively p=0.01, p=0.03). In conclusion, these results have shown that ischemia-reperfusion injury is more likely to occur in patients protected by crystalloid cardioplegia, and suggest that blood cardioplegia may be preferred especially in borderline myocardial functioned patients.     

Patient characteristics rather than the type of dialyser predict the variability of endothelial derived surface molecules in chronic haemodialysis patients.

BACKGROUND: Cardiovascular disease (CVD) is a frequent complication in chronic haemodialysis (HD) patients. Endothelial dysfunction, as measured by soluble cellular adhesion molecules (sCAM) and von Willebrand factor (vWf) in plasma, is an early manifestation of CVD. Today, it is unknown if, and to what extent, their levels are influenced by the type of dialyser. METHODS: Four dialysers, low-flux cuprammonium (CU); high-flux and low-flux polysulfone and super-flux polyethersulfone, were compared in 15 chronic HD patients in a randomized cross-over fashion. sCAM and vWf were measured at baseline as well as after 4 weeks, and both intra-dialytical and after 24 h (t24 h). Twenty healthy subjects served as controls. RESULTS: Baseline levels were considerably higher in chronic HD patients than in controls (soluble intercellular adhesion molecule-1: sICAM-1 732+/-216 vs 572+/-259 ng/ml, P = 0.06; soluble vascular cell adhesion molecule-1: sVCAM-1 1917+/-492 vs 1126+/-338 ng/ml, P<0.001; vWF: 205+/-55% vs 98+/-52%, P<0.001). After 4 weeks, no changes were observed. During and after HD, sCAM did not change, except in the case of CU (sICAM-1: 719+/-259 to 772+/-261 ng/ml, P = 0.04). CU induced a rise in vWF directly after HD (t4 h; from 188+/-48% to 255+/-92%, P<0.01), whereas all modalities induced a significant increase at t24 h (mean 228+/-54%, P = 0.02). The levels of sCAM and vWf appeared to be dependent on the individual patients rather than on the type of dialyser (explained variance by different patients: 66%-91%, P<0.001; by type of dialyser 0.4-1.2%). CONCLUSIONS: Baseline levels of sCAM and vWf were markedly higher in chronic HD patients than in controls and did not change after 4 weeks with any dialyser. All membranes induced a marked rise in vWf at t24 h, whereas sICAM-1 increased only in the case of CU at t4 h. As sCAM showed no marked changes during HD with any other modality, our study suggests activation of blood cells rather than endothelial cells. As pre-dialysis levels of sCAM and vWf varied noticeably between individual patients, endothelial dysfunction seems to be far more dependent on patient-related factors than on the HD treatment itself.     

Inflammation and outcome in end-stage renal failure: does female gender constitute a survival advantage?

BACKGROUND: Elevated C-reactive protein (CRP) is a strong predictor of cardiovascular events and all-cause mortality in end-stage renal disease (ESRD) patients. However, although sex hormones may influence serum levels of inflammatory proteins, gender has not been taken into consideration in previous studies of inflammation and outcome in ESRD patients. METHODS: We included 663 (374 males) ESRD patients (59 +/- 1 year) from three European renal centers (Sweden, Germany and Italy) in which CRP levels and outcome data (follow-up 33 +/- 1 months) were available. The relation between outcome and serum levels of the soluble intercellular adhesion molecule (sICAM-1) was evaluated in 312 of the patients. RESULTS: The present study shows that elevated CRP is a strong predictor of outcome, but whereas no difference in all-cause mortality was observed between non-inflamed (CRP 相似文献   

Expression of adhesion molecules and cytokines after coronary artery bypass grafting during normothermic and hypothermic cardiac arrest

Objective: Cardiac surgery with cardiopulmonary bypass (CPB) results in vascular injury and tissue damage which involves leukocyte-endothelial interactions mediated by cytokines and adhesion molecules. This study was designed to demonstrate the effect of normothermic and hypothermic CPB to cytokine and soluble adhesion molecule levels in adults and to determine whether these levels correlate to the patients postoperative course. Design and patients: In 25 patients after normothermic and in 25 patients after hypothermic coronary artery bypass grafting with cardiopulmonary bypass (CPB), blood samples for cytokine and soluble adhesion molecule analysis were taken preoperatively, 24, 36, 48 h, and 6 days postoperatively. Soluble adhesion molecules (sE-selectin, sICAM-1) were measured by ELISA and cytokines (TNF-, IL-6, IL-8) by chemilumenscent-immunoassay. Clinical data were collected prospectively. Results: Postoperatively, adhesion molecule and cytokine levels were significantly elevated after CPB. Mean plasma levels of sICAM-1 was 2.4-fold higher after 6 days. Mean plasma concentration of sE-selectin peaked after 48 h with a 2-fold increase compared to normothermic conditions. In the hypothermia group sICAM-1, sE-selectin, IL-6, and IL-8 showed significantly higher levels (P<0.0057, P<0.0012, P<0.0419, P<0.0145) after 24 h compared to the normothermia group. No clinical differences were seen. Conclusion: Adhesion molecules and cytokines are elevated after CPB. Patients after hypothermic CPB show significant higher sICAM-1, sE-selectin, IL-6, and IL-8 levels after 24 h compared to normothermic conditions. These results are mainly due to longer CPB and crossclamp times but do not alter the patient's postoperative course.     

Markers for endothelial activation during open heart surgery

BACKGROUND: Reliable markers for endothelial activation are needed when studying biocompatibility of cardiopulmonary bypass. METHODS: Blood samples from 21 patients undergoing combined valve and coronary artery bypass surgery were collected before anesthesia (T1), after re-transfusion of blood from the heart-lung machine (T2), and on the first postoperative morning (T3). Concentrations of soluble markers were determined using sandwich enzyme-linked immunoadsorbent assay for sICAM-1, sVCAM-1, and sE-selectin. The sera were also used to stimulate human umbilical vein endothelial cells (HUVEC) in culture for 6 hours, in which activation was measured using cell enzyme immunoassay for mICAM-1 and mVCAM-1. RESULTS: The concentrations of sICAM-1 and sVCAM-1 increased during both measurement intervals (p < 0.05). The sICAM-1 T1 was 311.0 ng/mL (range, 271.0 to 350.7 ng/mL); the sICAM-1 T2 was 341.6 ng/mL (range, 322.0 to 422.0 ng/mL), and the sICAM-1 T3 was 400.2 ng/mL (range, 348.0 to 556.4 ng/mL; the sVCAM-1 T1 was 607.5 ng/mL (range, 497.8 to 813.8 ng/mL), the sVCAM-1 T2 was 755.3 ng/mL (range, 660.6 to 834.4 ng/mL), and the sVCAM-1 T3 was 1149.0 ng/mL (946.0 to 1406.0 ng/mL); whereas the sE-selectin increased from T1 to T3 (p < 0.01). Both the mICAM-1 (p < 0.002) and the mVCAM-1 (p < 0.005) increased on the human umbilical vein endothelial cells in culture after stimulation with the patient sera. The amounts of soluble markers in vivo were not correlated with the degree of endothelial activation in vitro, but were correlated with various operative variables including age, medication, and time of aortic cross-clamping. CONCLUSIONS: Endothelial cells were activated during cardiopulmonary bypass. The soluble adhesion molecules sICAM-1, sVCAM-1, and sE-selectin displayed different kinetics, rendering it difficult to determine a simple expression for the degree of endothelial cell activation. Clinically, sVCAM-1 seemed to be the best-suited marker for endothelial cell activation, because it was only associated with aortic cross-clamping and heparin and protamine doses, and it also showed the largest numerical changes.     

High soluble vascular cell adhesion molecule-1 concentrations predict long-term mortality in hemodialysis patients

Purpose

Soluble vascular cell adhesion molecule-1 (sVCAM-1) has a strong association with cardiovascular deaths in patients with coronary artery disease. The aim of this study is to explore the association between sVCAM-1 and cardiovascular mortality in maintenance hemodialysis (MHD) patients.

Methods

Eighty-three clinically stable MHD patients (mean age of 59.4 ± 13.7 years) at a single hospital-based dialysis facility were included. sVCAM-1, soluble intercellular adhesion molecule-1 (sICAM-1), and soluble E-selectin (sE-selectin) were determined at study baseline. The study cohort was divided into higher and lower concentration groups by the median value. The all-cause and cardiovascular mortality of this cohort were followed for 7 years.

Results

The mean concentrations of sVCAM-1, sICAM-1, and sE-selectin were 1,393.08 ± 300.96, 230.16 ± 84.86, and 60.01 ± 42.00 ng/mL, respectively. The higher concentration groups of sVCAM-1 and sICAM-1 had higher all-cause mortality by Kaplan–Meier analysis (p = 0.002 and p = 0.030, respectively). Higher sVCAM-1 concentrations had a higher risk of all-cause and cardiovascular mortality (p = 0.006 p = 0.046, respectively) in Cox proportional hazards model analysis.

Conclusion

In MHD patients, higher sVCAM-1 concentrations independently predict all-cause and cardiovascular mortality. This biomarker may be used as a valid surrogate marker for predicting outcomes.     

The Effects of Vitamin E-Coated Membrane Dialyzer Compared to Simvastatin in Patients on Chronic Hemodialysis

Background: We investigated the effects of the use of vitamin E-coated membrane (VEM) dialyzer in comparison to simvastatin on markers of chronic inflammation, oxidative stress, and endothelial cell apoptosis in ten patients on chronic hemodialysis (HD), aiming at distinguishing the different treatment effects and their time sequence on these pathogenetic routes. Methods: Ten HD patients were sequentially submitted to a 6-month treatment with the use of VEM and 10 mg of simvastatin daily, interrupted by a 3-month washout period. At baseline, at 3, and 6 months of each trial, serum C-reactive protein (CRP), apolipoprotein (Apo) A1 and B, lipoprotein-a [Lp(a)], high-sensitivity interleukin-6 (hsIL-6), monocyte chemoattractant protein-1 (MCP-1), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin), soluble Fas (sFas), soluble Fas ligand (sFasL), and plasma oxidized low-density lipoproteins (oxLDL) levels were determined. Results: VEM treatment resulted in a significant decrease in CRP, IL-6, sICAM-1 at 3 months, and oxLDL at 6 months, compared to baseline. Simvastatin resulted in a significant decrease in CRP, which correlated with decreases in both total (r = 0.87, p < 0.05) and low-density lipoprotein cholesterol, IL-6, sICAM-1, sVCAM-1, oxLDL, and sFas at 6 months, compared to baseline. Simvastatin effects on sVCAM-1 (mean difference = 652 ng/mL; 95% CI = 294 to 2686; p < 0.05) and sFas (mean difference = 1284 pg/mL; 95% CI = 510 to 1910; p < 0.05) differed significantly from the corresponding VEM effects. Conclusions: The 6-month use of VEM resulted in more direct and immediate anti-inflammatory effects compared with those caused by the 6-month treatment with simvastatin. Simvastatin caused a more intense decrease in the markers of inflammation, which was in part correlated with its lipid-lowering effects.