Soluble adhesion molecules reflect endothelial cell activation in ischemic stroke and in carotid atherosclerosis

BACKGROUND AND PURPOSE: Activation of endothelial cells and platelets plays an important role in the development of atherosclerosis and thrombotic disorders. Soluble adhesion molecules originating from these cells can be demonstrated in plasma. We hypothesized that elevated plasma concentrations of soluble P-selectin (sP-selectin), soluble intercellular adhesion mole-cule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and soluble E-selectin (sE-selectin) can reflect activation of endothelial cells and/or platelets in acute ischemic stroke and in previously symptomatic internal carotid artery stenosis. METHODS: Plasma was sampled from patients within 2 days of acute ischemic stroke (n = 28), from patients with a previous (> 1 week) transient or persistent ischemic neurological deficit associated with stenosis of the internal carotid artery (n = 34), and from control patients without a history of vascular disease (n = 34). Concentrations of sP-selectin, sICAM-1, sVCAM-1, and sE-selectin were measured by means of an enzyme-linked immunosorbent assay. RESULTS: Compared with control subjects, sP-selectin and sE-selectin were significantly elevated in the acute stage of ischemic stroke (P < .0001 and P = .001, respectively) as well as in previously symptomatic carotid stenosis (P < .0001 and P = .0007). sICAM-1 and sVCAM-1 were not increased. CONCLUSIONS: The elevated levels of sE-selectin indicate that endothelial cell activation occurs both in the acute stage of ischemic stroke and in previously symptomatic carotid atherosclerosis. Increased sP-selectin concentrations reflect endothelial cell activation as well but may also be caused by platelet activation.     

Long-term follow-up of a patient with hepatocellular carcinoma associated with triple hepatitis virus (HBV, HDV, HCV) infection

OBJECTIVE: To determine the serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) and soluble E-selectin (sE-selectin) in patients with systemic sclerosis (SSc). METHOD: Serum samples from 80 patients with SSc and 20 healthy control subjects were examined by a sensitive enzyme-linked immunosorbent assay. RESULTS: The serum levels of sVCAM-1 and sE-selectin were significantly higher in the patients with SSc than in the healthy controls. The serum levels of sVCAM-1 were correlated with the presence of pulmonary fibrosis, joint involvement and elevated erythrocyte sedimentation rate levels. The serum levels of sE-selectin were correlated with the presence of pulmonary fibrosis. CONCLUSION: These results suggest that endothelial activation is involved in the development of this disease.     

Elevated concentrations of soluble E-selectin and vascular cell adhesion molecule-1 in NIDDM. Effect of intensive insulin treatment

OBJECTIVE: To evaluate the effects of a 14-day intensive insulin therapy and short-term improvement of glycemic control on serum levels of soluble forms of adhesion molecules, i.e., intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), and E-selectin (sE-selectin) in NIDDM patients with poor glycemic control. RESEARCH DESIGN AND METHODS: A total of 16 NIDDM patients were compared with 23 healthy subjects (control group) and investigated before and after intensive insulin treatment. RESULTS: On day 0, sE-selectin and sVCAM-1 levels were significantly higher in NIDDM patients than in nondiabetic control subjects (median 87, range 63-115; median 544, range 408-797 vs. 58, 43-80; 443, 395-573 ng/ml, respectively) (P < 0.008 in both cases). On day 15, the fall in sE-selectin levels was significant (P < 0.0001) and at a lesser extent in sVCAM-1 levels (64, 48-85; 506, 417-678 ng/ml, respectively); these levels reached values that no longer differed from those of control subjects (P = 0.23 and 0.15, respectively). Moreover, the fall in sE-selectin was positively associated with the change in LDL cholesterol and the improvement of glycemia. CONCLUSIONS: In poorly controlled NIDDM patients, sE-selectin levels are increased and significantly fall to normal after short-term improvement of glycemic control. This suggests that assaying sE-selectin makes it possible to detect endothelium activation and to follow its reversal with euglycemia.     

Vascular cell adhesion molecule--a new approach to detect endothelial cell activation in MS and encephalitis in vivo

INTRODUCTION: Leukocyte migration into inflammatory lesions is controlled by adhesion molecules on activated vascular endothelium. Pivotal among these are E-selectin and the vascular cell adhesion molecule-1 (VCAM-1), which are found on very few cell types other than activated endothelium. METHODS: We determined the presence of the soluble form of these adhesion molecules (sE-selectin and sVCAM-1) in serum and CSF of patients with multiple sclerosis (MS), viral encephalitis, and controls, using enzyme-linked immunosorbent assays. RESULTS: MS patients with active, Gadolinium-DTPA-enhancing lesions on magnetic resonance imaging had significantly higher sVCAM-1 serum levels than normal controls. Patients with viral encephalitis had significantly higher levels of sVCAM-1 in serum and cerebrospinal fluid than controls. sE-selectin levels showed no significant variations. CONCLUSION: Activated vascular endothelium controlling leukocyte migration may be demonstrated in MS patients in vivo by determining sVCAM-1 in serum. Furthermore, sVCAM-1 may be useful for monitoring inflammatory activity in central nervous system inflammatory disease.     

Neural development in the marsupial frog Gastrotheca riobambae

Hypertriglyceridemia may contribute to the development of atherosclerosis by increasing expression of cell adhesion molecules (CAMs). Although the cellular expression of CAMs is difficult to assess clinically, soluble forms of CAMs (sCAMs) are present in the circulation and may serve as markers for CAMs. In this study, we examined the association between sCAMs and other risk factors occurring with hypertriglyceridemia, the effect of triglyceride reduction on sCAM levels, and the role of soluble vascular cell adhesion molecule-1 (sVCAM-1) in monocyte adhesion in vitro. Compared with normal control subjects (n=20), patients with hypertriglyceridemia and low HDL (n=39) had significantly increased levels of soluble intercellular adhesion molecule-1 (sICAM-1) (316+/-28.8 versus 225+/-16.6 ng/mL), sVCAM-1 (743+/-52.2 versus 522+/-43.6 ng/mL), and soluble E-selectin (83+/-5.9 versus 49+/-3.6 ng/mL). ANCOVA showed that the higher sCAM levels in patients occurred independently of diabetes mellitus and other risk factors. In 27 patients who received purified n-3 fatty acid (Omacor) 4 g/d for > or =7 months, triglyceride level was reduced by 47+/-4.6%, sICAM-1 level was reduced by 9+/-3.4% (P=.02), and soluble E-selectin level was reduced by 16+/-3.2% (P<.0001), with the greatest reduction in diabetic patients. These results support previous in vitro data showing that disorders in triglyceride and HDL metabolism influence CAM expression and treatment with fish oils may alter vascular cell activation. In a parallel-plate flow chamber, recombinant sVCAM-1 at the concentration seen in patients significantly inhibited adhesion of monocytes to interleukin-1-stimulated cultured endothelial cells under conditions of flow by 27.5+/-7.2%. Thus, elevated sCAMs may negatively regulate monocyte adhesion.     

Kinetics of circulating adhesion molecules and chemokines after mechanical trauma and burns

OBJECTIVE: To assess the role of circulating adhesion molecules and chemotactic cytokines within different settings of major trauma. DESIGN: Retrospective study. SETTING: Teaching hospitals, USA and Germany. SUBJECTS: Two groups of patients with multiple injuries (group I n = 155 and group II n = 12) with mean (SEM) injury severity scores (ISS) of 35 (4) and 32 (4) points, respectively, and 18 burned patients with a mean of ISS 38 (9) points. INTERVENTIONS: Serum samples were collected at the site of the accident and on admission to the (Group I) as well as during the post-trauma course in the hospital (Group II: days 1, 3, 5, 7, 10; Group III; weekly, up to week 10). MAIN OUTCOME MEASURES: Measurement of concentrations of soluble (s) adhesion molecules (sE-selectin, sP-selectin), and chemotactic cytokines (interleukin-8 [IL-8], epithelial cell derived neutrophil activating peptide 78 [ENA-78]) in serum after major mechanical trauma and burns. RESULTS: High concentrations of ENA-78 and sP-selectin were already present at the site of accident as well as one hour after injury. During recovery from the injuries, persistently high concentrations of IL-8, ENA-78, and sP-selectin were found, but sE-selectin was increased only during the first week after major trauma. CONCLUSION: Massive tissue trauma causes immediate activation of selected chemokines and adhesion molecules within minutes of the injury which will then persist depending on the type and severity of the injury for a substantial length of time. There was, however, no correlation between serum concentrations of the mediators investigated and susceptibility to complications or outcome.     

Circulating cell adhesion molecules are correlated with ultrasound-based assessment of carotid atherosclerosis

Although cellular adhesion molecules (CAMs) are hypothesized to play an important role in atherogenesis, the relationship between CAMs and systemic atherosclerosis is uncertain. Among 92 outpatients (48 men; mean+/-SD age, 65+/-9 years), we evaluated the association of soluble vascular CAM-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1) with carotid intimal-medial thickness (IMT), an index of early atherosclerosis. All subjects underwent a 2-dimensional ultrasound examination of both carotid arteries at the distal common carotid arteries and bifurcation. sVCAM-1 and sICAM-1 levels measured by enzyme-linked immunosorbent assay were significantly correlated with mean IMT of the common carotid artery (r=0.34 and r=0.30, respectively; P<0.01) and carotid bifurcation (r=0.31 and r=0.26, respectively; P<0.05), whereas sVCAM-1 was also positively associated with maximal carotid IMT (r=0.35, P<0.01). Adjustment for age attenuated the association between sVCAM-1 and common (r=0.16, P=0.13) and bifurcation (r=0.18, P=0.07) carotid IMT but had minimal effect on the associations between sICAM-1 and carotid measurements (r=0.32, P<0.01; r=0.23, P<0.05; for common and bifurcation IMT, respectively). Age-adjusted sICAM-1 levels increased in a stepwise fashion across common carotid IMT tertiles (253+/-27 versus 275+/-24 versus 384+/-26 pg/mL for the lowest, intermediate, and highest IMT tertiles, respectively; P<0.01). A similar trend was also found between sVCAM-1 levels and common carotid IMT tertiles (625+/-60 versus 650+/-53 versus 714+/-58 pg/mL; P<0.15). These associations were minimally affected in analyses adjusting for hypertension, diabetes, smoking, low and high density lipoprotein cholesterol, lipoprotein(a), and homocysteine, or in a subgroup analysis limited to those with no prior history of atherothrombotic disease. These data demonstrate a positive association between serum CAMs with carotid IMT and further support the hypothesis that systemic inflammation may have a role in atherosclerotic lesion development.     

Effects of intravenous methylprednisolone therapy on leukocyte and soluble adhesion molecule expression in MS

Intravenous methylprednisolone (IVMP) may inhibit inflammatory cell recruitment to active MS lesions by effects on leukocyte or endothelial cell adhesion molecule expression. We investigated 15 MS patients in relapse receiving a 5-day course of IVMP (500 mg/day) and 15 normal subjects. Patients' blood samples were obtained pretreatment, at 6 and 24 hours after the first dose, and 48 hours after completion of therapy. Levels of L-selectin, leukocyte functional antigen 1 (LFA-1), Mac-1, and very late activation antigen 4 (VLA-4) expression were determined on alphabeta and gammadelta T cells and monocytes by dual-color immunofluorescent flow cytometry. Serum levels of soluble (s) L-selectin, sE-selectin, soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vascular cell adhesion molecule 1 (sVCAM-1) were measured by ELISA. There was a marked decrease in the T-cell and monocyte counts at 6 hours after therapy, with recovery to baseline at 24 to 48 hours. Adhesion molecule expression was normal on circulating T cells and monocytes in active MS. IVMP resulted in significant changes in the percent adhesion molecule expression on monocytes: increased L-selectin expression at 24 hours, decreased Mac-1 expression at 6 hours, and decreased VLA-4 expression at 6 hours and 24 hours following treatment. T-cell adhesion molecule expression was unaffected by the therapy. Serum sE-selectin was reduced at 6 hours and 24 hours following treatment. IVMP alters the distribution and kinetics of monocyte adhesion molecule expression and endothelial cell release of E-selectin, which may limit monocyte recruitment to areas of tissue destruction in MS.     

Modulation of circulating cellular adhesion molecules in postmenopausal women with coronary artery disease

OBJECTIVES: The present study examined the association of estrogen (E2) and the inflammatory response of endothelium in coronary artery disease (CAD) by measuring circulating cellular adhesion molecules (cCAMs) in subjects with atherosclerosis. BACKGROUND: Atherosclerotic plaque demonstrates features similar to inflammation. Endothelial cell activation by inflammatory cytokines induces expression of cellular adhesion molecules (CAMs), thereby perhaps augmenting leukocyte adhesion and recruitment and subsequent development of atherosclerosis. The incidence of CAD is lower in women; this may be due to the cardioprotective effects of E2. METHODS: Consecutive eligible subjects with CAD admitted for cardiac catheterization were studied. The groups evaluated were men, postmenopausal women receiving E2 replacement therapy (ERT), postmenopausal women not receiving ERT and premenopausal women. Control groups included men and women without CAD. Preprocedural blood samples were drawn from all groups. Measurements of cCAMs, E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 were performed by enzyme-linked immunoabsorbant assay. E2 levels were assessed by radioimmunoassay. RESULTS: We observed a statistically significant increase in all cCAMs in men with CAD and postmenopausal women with CAD not receiving ERT compared with postmenopausal women with CAD receiving ERT. Premenopausal women with CAD and postmenopausal women with CAD receiving ERT had a significant increase in VCAM-1 alone compared with the female control group. CONCLUSIONS: A possible mechanism by which E2 exerts one of its cardioprotective effects is by limiting the inflammatory response to injury by modulating the expression of CAMs from the endothelium.     

The influence of salmon calcitonin on the soluble form of VCAM-1 (CD 106) and E-selectin (CD 62E) in serum of patients with atopic bronchial asthma

The aim of the study was to evaluate the effect of salmon calcitonin (CT) on serum level of soluble form of VCAM-1 (sVCAM-1 = soluble vascular cell adhesion molecule-1) and E-selectin (sE-selectin = soluble E-selectin) in patients with atopic bronchial asthma. Twenty-four individuals divided into 4 groups (6 persons each) were investigated. The first group consisted of patients with chronic moderate bronchial asthma, the second and third groups consisted of patients with mild bronchial asthma and the fourth group K consisted of healthy individuals. The patients of the first and second group were treated with CT at a dose of 100 i.v./days s.c. for three days. The patients of the third group were given placebo (phychological saline) in similar way as CT. The indices were measured before the treatment with CT or placebo and on the 4th day of the treatment. It was found that CT treatment decreased sVCAM-1 in serum only in the patients of the first group (p < 0.05) but had no effect upon sE-selectin level. The obtained results suggest that CT interfered into mechanisms of inflammation involving adhesion molecules in patients with bronchial asthma.     

Circulating ICAM-1, E-selectin, IL-2 receptor, and HLA class I in human small bowel, liver, and small bowel-plus-liver transplant recipients

Recently, soluble(s) circulating isoforms of intercellular adhesion molecule-1 (sICAM-1) and sE-selectin (formerly endothelial leukocyte adhesion molecule-1) have been described in normal human serum. Elevated levels have been reported in acute and chronic inflammatory disorders, including allograft rejection. In this study, plasma levels of sICAM-1 and sE-selectin were determined in groups of tacrolimus (FK 506)-treated adult patients following either isolated small bowel (SB), liver, or combined SB plus liver (SB/L) transplantation. Each molecule was measured at 1, 2, 4, 6, 8, and 12 weeks (all patients) and at 6, 9, and 12 months after transplantation (SB and SB/L only) by enzyme linked immunosorbent assay. Levels were compared with those of soluble interleukin-2 receptor (sIL-2R; a marker of lymphocyte activation) and soluble HLA class I (which has been reported to be elevated in liver transplant-related complications). Elevations above normal in mean plasma levels of sICAM-1 (2.4-fold), sE-selectin (1.8-fold), sIL-2R (10.6-fold), and sHLA class I (1.3-fold) were found in patients with stable isolated SB grafts during the first 12 weeks posttransplant. Except for sHLA class I, levels of each protein were subsequently reduced, up to 1 year posttransplant. However, further increases in sICAM-1 and in sIL-2R and sE-selectin levels were observed during episodes of SB rejection compared with stable grafts. Mean levels of all molecules were higher in patients with isolated SB grafts compared with those given liver or combined (SB/L) transplants, either during stable SB graft function (up to 12 weeks posttransplant) or rejection. The data demonstrate increased adhesion molecule production/shedding following SB transplantation and are suggestive of a reduced overall level of immune activation in liver and SB/L compared with isolated SB transplantation.     

Elevated serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) closely reflect tumour burden in chronic B-lymphocytic leukaemia

The present study is the first to report elevated serum levels of soluble (s)VCAM-1 in B-cell chronic lymphocytic leukaemia (B-CLL). A large cohort of 106 untreated patients was studied. sVCAM-1 was compared to known prognostic serum markers (soluble (s)ICAM-1; lactate dehydrogenase, LDH; sCD23; thymidine kinase, TK; beta2microglobulin, beta2m). The serum levels of sVCAM-1 reflected tumour burden as expressed by Binet/Rai stages more closely than any other marker. sVCAM-1 also reflected the kinetics of the disease as revealed by lymphocyte doubling time. sVCAM-1 was the only one of the studied markers which showed elevated levels in smouldering disease compared to controls. sVCAM-1, sICAM-1 and sCD23 (but not LDH, TK, beta2m) separated smouldering from non-smouldering B-CLL. Only sICAM-1, sCD23 and TK added independent prognostic information for survival to that of stage and lymphocyte doubling time. The expression of both adhesion molecules was examined in lymph node and splenic specimens. VCAM-1 and ICAM-1 were overexpressed by vascular endothelium and stroma, but the intensity of expression correlated poorly with serum levels of the soluble molecules. In conclusion, serum levels of sVCAM-1 correlated with tumour burden and other prognostic markers in B-CLL. VCAM-1 was overexpressed in tumour tissue as was ICAM-1. sVCAM-1 could prove a valuable marker in younger early-stage patients eligible for therapeutic trials.     

A bioluminescent method of determining antibiotic sensitivity of microbial cells in septic blood]

Previous studies have shown that adhesion molecules play a crucial role in leukocyte-endothelium interactions that occur during myocardial ischemia and reperfusion. We assessed the plasma levels of the soluble form of E-selectin (sE-selectin) and intercellular adhesion molecule-1 (sICAM-1) in 15 patients with acute myocardial infarction (AMI) and in 15 controls with chronic stable angina. In patients with AMI, the levels of sE-selectin and sICAM-1 increased significantly during the first 8 h after infarction and subsequently decreased. Soluble E-selectin levels were inversely related to the peak plasma levels of creatine kinase-MB (CK-MB), and the time course of their appearance in plasma correlated with that of neutrophil count and plasma D-dimer. In individual patients, peak and mean sICAM-1 levels correlated respectively with plasma D-dimer concentrations and monocyte count, but no correlation were found when their time courses were analyzed. Eight hours after symptom onset, the mean plasma sE-selectin levels were higher in patients with AMI than in those with stable angina, whereas no significant differences were found in mean plasma sICAM-1 levels between the two groups at every time analyzed. In the acute phase of MI (a) sE-selectin and sICAM-1 levels increase during the first 8 h and subsequently decrease; (b) the increase in sE-selectin probably reflects activation of endothelial cells, correlates with other inflammatory and coagulation parameters, and is inversely related to the degree of myocardial damage; and (c) sICAM-1 plasma levels do not represent a good marker of "cell activation" because they reflect activation of different cells and may be affected by different conditions.     

The circulating adhesion molecules sICAM-1 and sP-selectin in patients with sepsis

AIM: The aim of this study was to investigate whether the plasma levels of the circulating adhesion molecules sICAM-1 and sE-selectin could serve as early predictors of developing sepsis and its severity. METHODS: Twenty-four patients admitted to an intensive care unit with a high risk of developing septic complications were enrolled in this study. Patients were divided into three groups: group I, with infection without systemic sepsis, n = 8; group II, surviving patients with severe sepsis and multi-organ failure (MOF), n = 8; and group III, nonsurviving patients with severe sepsis and MOF, n = 8. Classification of patients was performed according to the clinical criteria defined by the Sepsis Consensus Conference in 1992. Blood samples were taken at 7 a.m. starting from the day of admission until the 7th day after diagnosis of sepsis. Plasma levels of sICAM-1 and sE-selectin were determined in all samples taken between the 3rd pre-septic day and the 7th day after the diagnosis of sepsis was made. RESULTS: In group I, both sICAM-1 (354.21 +/- 128.60 ng/ml, 86 samples) and sE-selectin (30.41 +/- 7.20 ng/ml, 86 samples) levels remained within the reference range over the whole period of observation. The sICAM-1 levels of group II (between 550.82 +/- 275.67 ng/ml and 445.08 +/- 243.63 ng/ml) tended to show values above the reference range without being significant. Mean sICAM-1 levels in group II did not differ from those of group I. From the 2nd pre-septic day onwards the sICAM-1 levels of group III increased, but not significantly. Significant differences in sICAM-1 levels between group I and group III were observed, with peaks at the samples of the 2nd preseptic day and after the 3rd day of sepsis, respectively (P < 0.05). The sE-selectin levels in group II were elevated from the 3rd preseptic day onwards, with a peak value on the 2nd day of sepsis (P < 0.05). Afterwards, levels decreased to initial values despite ongoing sepsis. Mean values of sE-selectin levels of group I and II were significantly different with the onset of sepsis (P < 0.05). Plasma levels of sE-selectin in group III were significantly elevated (66.30 +/- 9.00 ng/ml on the 3rd pre-septic day), reaching their maximal values of 106.67 +/- 21.66 ng/ml at the end of the observation period. Significant differences between sE-selectin levels of groups I and III existed from the 3rd pre-septic day onwards, and between group II and III on the 7th and 8th day of sepsis. CONCLUSION: Our results show that sICAM-1 is a relatively non-specific indicator for sepsis. In contrast, sE-selectin seems to be a good and early predictor of the beginning of severe sepsis with MOF. Furthermore, sE-selectin levels seem to have a prognostic value for the severity, possible course, and outcome of developing sepsis.     

Bullous pemphigoid and pemphigus vulgaris: correlated behaviour of serum VEGF, sE-selectin and TNF-alpha levels

BACKGROUND: Recently, we reported that soluble E-selectin (sE-selectin), an isoform of the cell membrane E-selectin, an adhesion molecule synthesized only by endothelial cells, is significantly increased in sera of the patients with bullous pemphigoid (PB) or pemphigus vulgaris. A significant correlation was also found between the serum sE-selectin levels and the number of skin lesions, suggesting the possible use of this molecule to gauge disease intensity before therapy. One of the sE-selectin inducers is tumor nerosis factor-alpha (TNF-alpha), that is also able to enhance vascular endothelial growth factor (VEGF), a strong endothelium activator. OBJECTIVE: On the basis of these observations, the present study was conducted to analyze the serum levels of VEGF, sE-selectin, and TNF-alpha in 8 patients with BP (age: 82, range 54-87, 7 males, 1 female) and in 6 patients affected affected with PV (age: 55, range 44-65; 5 males, 1 female) and to verify possible correlations between these variables and the disease activity, In addition, serum sE-selectin levels were measured over time and compared with the serum anti-epithelium antibodies titers. METHODS: The sE-selectin, VEGF and TNF-alpha levels were measured in the samples by means of commercially available ELISA kit. The same samples were also employed to measure the anti-epithelium antibody titers. RESULTS: Serum VEGF, sE-selectin and TNF-alpha levels were significantly correlated each other (p at least < 0.01). All three variables were also significantly correlated with the number of lesions (p at least < 0.01). Serum VEGF levels were found increased (median = 178 pg/ml, range 37-595) as compared to 28 healthy controls (median = 135 pg/ml, range 18/269, p < 0.05). Also serum TNF-alpha levels were found increased (median = 5.5 pg/ml, range < 0.1-41.0) as compared to 28 healthy controls (median < 0.1 pg/ml, range < 0.1-5.3), p < 0.01). When the patients were observed over time, serum sE-selectin levels highly correlated with the disease intensity in both dermatoses, although with different regression curves. CONCLUSIONS: These data further underline the endothelium involvement in these bullous dermatoses and stress the possibility of employing sE-selectin as a non-specific follow-up marker of both BP and PV.     

Levels of circulating intercellular adhesion molecule 1 and E-selectin in serum and synovial fluid of juvenile chronic arthritis patients

OBJECTIVE: To measure the levels of two adhesion molecules (AM), soluble intercellular adhesion molecule 1 (sICAM-1) and soluble E-selectin (sE-selectin), in serum and synovial fluid (SF) of patients with juvenile chronic arthritis (JCA). METHODS: Both soluble AM levels were tested, in serum and synovial fluid (SF) samples, with an enzyme-linked immunosorbent assay (ELISA) method. RESULTS: Serum levels of sICAM-1 and sE-selectin in JCA patients were not significantly different from those of a control group. Synovial fluid levels of sICAM-1, but not of sE-selectin, assayed significantly higher (p < 0.05) in JCA patients than in controls. Moreover SF levels of both molecules correlated negatively with disease duration, being higher in the earliest phases. No significant correlations were found between JCA sICAM-1 and sE-selectin levels and leukocyte count or ESR. CONCLUSIONS: These observations may signify a more important role of ICAM-1 than E-selectin in the migration of inflammatory cells into JCA SF. The negative correlation of both AMSF levels in JCA patients with disease duration could reflect a higher expression of ICAM-1 and E-selectin during the earliest phases of the disease.     

Cardiac natriuretic peptides for diagnosis and risk stratification in heart failure: influences of left ventricular dysfunction and coronary artery disease on cardiac hormonal activation

BACKGROUND: Cardiac natriuretic peptides are activated in heart failure. However, their diagnostic and prognostic values have not been compared under the routine conditions of an outpatient practice. METHODS: We studied the diagnostic and prognostic value of plasma N- and C-terminal peptides of the atrial natriuretic factor prohormone (N-proANF and ANF respectively) and brain natriuretic peptide (BNP) to evaluate the severity of congestive heart failure (CHF) as reflected by the New York Heart Association (NYHA) classification and to predict its 2-year mortality. Peripheral plasma concentrations of the three natriuretic peptides were measured in 27 normal subjects (CTR), in 32 patients with coronary artery disease (CAD) and normal left ventricular ejection fraction and in 101 patients with chronic CHF in functional classes I and II (n = 61) or III and IV (n = 40). RESULTS: Plasma concentrations of the three peptides increased in the presence of CHF in relation to its severity (P < 0.01). BNP was unable to distinguish CTR from CAD, just as ANF could not differentiate CAD from CHF I-II; only N-proANF displayed a significant and continuous increase from CTR to CAD, CHF I-II and III-IV. Receiver-operating characteristic curves showed better evaluation of the degree of CHF by BNP than by ANF or ejection fraction (P < 0.05). Assessment of the 2-year prognosis revealed that N-proANF and BNP were the best independent predictors of outcome after the NYHA classification. These peptides identify a very high-mortality group. CONCLUSION: Plasma N-proANF and BNP concentrations are good indicators of the severity and prognosis of CHF in an outpatient practice. CAD does not stimulate BNP as long as ventricular dysfunction is not present, although increased N-proANF levels in this setting suggest an early humoral activation.     

Increased oxidative stress in patients with congestive heart failure

OBJECTIVES: We sought to study the markers of lipid peroxidation and defenses against oxidative stress in patients with varying degrees of heart failure. BACKGROUND: Despite advances in other areas of cardiovascular disease, the morbidity and mortality from congestive heart failure (CHF) are increasing. Data mainly from animal models suggest that free radical injury may promote myocardial decompensation. However, there are no studies in humans correlating the severity of heart failure with increased free radical injury and antioxidants. METHODS: Fifty-eight patients with CHF and 19 control subjects were studied. In addition to complete clinical and echocardiographic evaluations, the prognosis of these patients was established by measuring the levels of soluble tumor necrosis factor-alpha receptors 1 and 2 (sTNF-R1 and sTNF-R2). Oxidative stress was evaluated by measuring plasma lipid peroxides (LPO), malondialdehyde (MDA), glutathione peroxidase (GSHPx) and vitamin E and C levels. RESULTS: The patients' age range, cause of heart failure and drug intake were comparable across the different classes of heart failure. Heart failure resulted in a significant increase in LPO (p < 0.005), MDA (p < 0.005), sTNF-R1 (p < 0.005) and sTNF-R2 (p < 0.005). There was a significant positive correlation between the clinical class of heart failure and LPO, MDA, sTNF-R1 and sTNF-R2 levels. There was an inverse correlation between GSHPx and LPO. With increased lipid peroxidation in patients with CHF, the levels of vitamin C decreased, but vitamin E levels were maintained. CONCLUSIONS: These data demonstrate a progressive increase in free radical injury and encroachment on antioxidant reserves with the evolution of heart failure; they also suggest that oxidative stress may be an important determinant of prognosis. The therapeutic benefit of administering antioxidant supplements to patients with CHF should be evaluated.     

Angiotensin II receptor type 1 mRNA is upregulated in atria of patients with end-stage heart failure

There is increasing evidence that pathological changes in the myocardium during chronic heart failure (CHF) are partly regulated through the activation of the renin-angiotensin system (RAS), an effect mediated by the angiotensin II type 1 receptor (AT1R). We examined the expression of cardiac AT1R mRNA in normal (atria, n=7; ventricle, n=3) and end-stage CHF human hearts (atria, n=8; ventricle, n=14). Tissue was snap-frozen immediately after explantation during orthotopic cardiac transplantation; control specimens were obtained from healthy donor hearts rejected for technical reasons. Northern blots of purified total mRNA from each tissue were hybridized with a random primed radiolabeled probe for the coding sequence of AT1R. Stringent conditions were used for both hybridization (5X SSC, 65 degrees C) and washing (0.5X SSC, 0.1% SDS, 65 degrees C) of the membrane. Left and right atrial tissue showed low levels of AT1R mRNA expression in the controls, with statistically significant upregulation of expression in tissue from pathological hearts; CHF atria 1.28+/-0.86 optical density (OD) units, control atria 0.56+/-0.31 OD units, P=0.05 (mean+/-s.d.). There were undetectable levels in ventricles from either control (2/2) or dilated hearts (7/7). The results were independent of the etiology of the heart failure and suggest that increased levels of atrial AT1R mRNA may occur in response to elevated atrial pressures in heart failure.