Significance of plasma endothelin-1 levels in patients with systemic sclerosis.

Endothelin-1 (ET-1) is a novel potent vasoconstrictor peptide discovered in the supernatant fraction of cultured endothelial cells. We measured plasma levels of ET-1 using a sensitive sandwich enzyme immunoassay. Plasma concentrations of ET-1 in 31 patients with systemic sclerosis (SSc) (1.90 +/- 0.47 pg/ml) were higher than those (1.31 +/- 0.10 pg/ml) in 25 age and sex matched healthy subjects. Patients with SSc with diffuse scleroderma had higher levels of ET-1 compared with those with limited scleroderma. Plasma ET-1 levels correlated inversely with carbon monoxide diffusing capacity (DLco). Measurement of plasma ET-1 levels may be useful as a predictor of prognosis of SSc.     

Improvement of plasma endothelin-1 and nitric oxide in patients with systemic sclerosis by bosentan therapy

The aim of this study was to evaluate the effects of bosentan on plasma endothelin-1 (ET-1) and nitric oxide (NO) as pulmonary hypertension (PH)-associated biochemical markers in patients with systemic sclerosis (SSc). Twenty-four SSc patients receiving bosentan for 24 weeks were registered in this prospective observational study. Ten patients were complicated with clinically suspected PH. Plasma levels of ET-1 and NO were assessed at baseline and after 24 weeks of treatment in SSc patients and in 15 healthy controls. Plasma levels of ET-1 and NO at baseline were significantly higher in SSc patients than in healthy controls (p < 0.000), and they were also significantly higher in SSc patients with PH than in those without PH (p < 0.01). Plasma ET-1 levels were significantly decreased after 24 weeks of bosentan therapy (p < 0.0001), and ET-1 levels of SSc patients with PH decreased to a level comparable to that in patients without PH. In the 10 SSc patients with PH, changes in plasma ET-1 levels during the 24 weeks of the study were significantly larger in the 5 patients whose functional class (FC) improved than in the 5 patients whose FC was unchanged (p < 0.05). Plasma NO levels were also slightly decreased in SSc patients after 24 weeks of bosentan therapy. Plasma ET-1 levels could reflect the presence and severity of PH in SSc patients. Additionally, changes in plasma ET-1 levels may indicate the response to bosentan therapy in SSc patients with PH.     

Plasma endothelin-1 levels in patients with systemic sclerosis: influence of pulmonary or systemic arterial hypertension.

OBJECTIVES--To investigate the behaviour of circulating endothelin-1 (ET-1) in patients affected by systemic sclerosis and to elucidate the relationship between systemic and pulmonary plasma peptide and arterial pressure levels. METHODS--Plasma ET-1 concentrations were determined in 48 patients affected by systemic sclerosis (41 women, seven men; mean age 47.2 (SD 5.5) years) with or without systemic or pulmonary hypertension (or both). A group of 18 normal volunteers served as controls (15 women, three men; mean age 45.0 (10.1) years). RESULTS--Plasma ET-1 levels were significantly greater in patients affected by systemic sclerosis (1.65 (0.29) pg/ml) than in controls (0.63 (0.19) pg/ml) (p < 0.0001). Pulmonary artery systolic hypertension alone was present in 14 patients with systemic sclerosis (50.5 (8.49) mm Hg, range 37-67 mm Hg), and systemic hypertension alone (160.7 (5.9)/100.6 (3.2) mm Hg) was present in 11 patients. Both conditions were present in 12 patients, while 11 patients had systemic hypertension. There were no significant differences in plasma ET-1 levels between patients with pulmonary hypertension alone (1.62 (0.21) pg/ml) and those with systemic hypertension alone (1.65 (0.43) pg/ml). In particular, patients with normal pulmonary artery and systemic pressures (n = 11) had plasma ET-1 concentrations identical to those found in patients (n = 12) with both pulmonary and systemic hypertension (1.70 (0.15) v 1.64 (0.35) pg/ml, respectively). No correlations were observed between plasma ET-1 and either pulmonary or systemic pressures. CONCLUSION--Systemic sclerosis is characterised by increased plasma ET-1 levels, but neither pulmonary nor systemic hypertension are accompanied by further increase in plasma peptide levels.     

Capillary density in patients with systemic sclerosis, as determined by microscopy counts and compared with computer-based analysis.

OBJECTIVE: To develop a method enabling capillary density to be determined rapidly and accurately in patients with systemic sclerosis. METHOD: Capillary density was determined in 11 controls and 22 patients: 5 with diffuse cutaneous systemic sclerosis (dSSc), 12 with limited cutaneous systemic sclerosis (lSSc), two with suspected systemic sclerosis (suspSSc), 2 with sclerodermatomyositis, and one with undifferentiated connective tissue disease. Using a microscope equipped with a graticule, nailfold capillaries were counted within a 3 mm length of the nailfold; these counts were made by 4 different observers. The results were compared with the corresponding values obtained by the computerbased analysis of photographs. RESULTS: The median capillary density according to the direct counts was 8.0 loops/mm (6.7-10.0) in the controls, 6.0 loops/mm (range 4.8-8.8) in the dSSc subgroup, 5.6 loops/mm (4.2-6.5) in the lSSc subgroup, and 7.2 loops/mm (6.2-8.2) in the suspSSc subgroup. In the series as a whole, there was no significant difference between the median values for the left hands and those for the right hands, nor between the median value for all digit IVs and the median value for all four digits analysed (II, III, IV, and V). Interobserver variation was small between the 4 different observers. Direct microscopy counts were slightly higher than the corresponding values obtained by computer-based analysis. CONCLUSION: Direct microscopy counting is a rapid, simple, and reliable means of determining capillary density for screening purposes.     

Big endothelin-1 and endothelin-1 plasma levels are correlated with the severity of primary pulmonary hypertension.

STUDY OBJECTIVES: Primary pulmonary hypertension (PPH) is a rare disease of unknown etiology that is characterized by a poor prognosis. This study was undertaken to investigate possible correlations between endothelin (ET)-1 and big ET-1 plasma levels and the severity of PPH. PATIENTS: Sixteen consecutive patients with PPH were included. INTERVENTIONS: Hemodynamics of patients with PPH were measured by right-heart catheterization, and a 6-min walk test was performed. MEASUREMENTS: Plasma levels of the biologically active peptide ET-1 and its precursor big ET-1 were determined in blood samples from the pulmonary artery, peripheral artery, and peripheral vein by radioimmunoassay. RESULTS: A strong correlation was shown between pulmonary vascular resistance, mean pulmonary artery pressure, cardiac output, cardiac index, 6-min walk data, and elevated plasma levels of big ET-1 as well as mature ET-1 plasma levels at all sites of blood sampling (p < 0.01 and p < 0.05, respectively). CONCLUSIONS: Levels of circulating ET-1 might become a prognostic marker for patients with PPH and serve as a tool for the selection of patients who may benefit from treatment with ET-receptor antagonists.     

Evaluation of plasma endothelin-1 levels in patients with cerebral infarction

Endothelin-1 (ET-1) is a vasoconstrictor peptide derived from endothelium. Many authors have shown that ischemic stroke is associated with elevated plasma ET-1 levels. Also, the present findings related to plasma ET-1 levels with clinical status, size of the infarction, location of the infarction, and prognosis of the cerebral infarction were contradictory. In this study, plasma ET-1 levels in 30 patients with cerebral infarction within 72 hours after the onset of focal neurologic deficit and at their seventh day postinfarction were measured by a microplate enzyme immunoassay. Thirty sex- and age-matched healthy subjects were accepted as a control group. The mean plasma ET-1 concentrations in patients on admission, in patients at day 7, and in control subjects were 1.93 +/- 1.79, 1.03 +/- 1.02, and 0.65 +/- 0.32 fmol/mL, respectively. The mean plasma ET-1 level of patients on admission was found to be significantly higher than in patients at day 7 and in control subjects (p < 0.05). No significant difference in ET-1 levels was observed between the patients at day 7 and control subjects. Furthermore, there was no correlation between plasma ET-1 concentration and size of infarction, location of infarction, degree of clinical neurologic deficit, or prognosis of cerebral infarction. It was concluded that plasma ET-1 levels shortly after ischemic stroke were increased, which may be associated with the acute-phase reaction of cerebral infarction and may have deleterious effects on development of neuronal injury.     

Endothelin-1 serum levels correlate with MCP-1 but not with homocysteine plasma concentration in patients with systemic sclerosis

OBJECTIVES: To determine whether homocysteine (Hcy) plasma levels are correlated with molecules indicative of endothelial cell and fibroblast activation, including endothelin-1 (ET-1) and monocyte chemoattractant protein-1 and -3 (MCP-1, MCP-3), in patients with systemic sclerosis (SSc). METHODS: Eighty-two patients were enrolled in this study; the control group included 75 age- and sex-matched subjects. Plasma Hcy was determined by high-performance liquid chromatography; folic acid, and vitamin B(12) plasma levels were determined by a chemiluminescence method. ET-1, MCP-1, and MCP-3 were determined by enzyme-linked immunosorbent assay (ELISA). Analysis of the 677C-->T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene was performed by polymerase chain reaction (PCR) and digestion with the enzyme HinfI. RESULTS: Hcy levels were lower in patients whereas ET-1 was significantly higher in patients and correlated with MCP-1. Stratification of the patients on the basis of Hcy levels was not associated with any statistical difference in the concentration of ET-1, MCP-1, and MCP-3. Patients with diffuse disease presented the highest levels of ET-1 and MCP-1. The distribution of the MTHFR genotypes was not different in patients and controls. CONCLUSIONS: In SSc, Hcy plasma concentration does not influence ET-1, MCP-1, or MCP-3 levels. On the contrary, ET-1, a marker of vascular activation, correlates with MCP-1, a chemokine involved in the fibrotic process of SSc.     

Serum netrin-1 levels in systemic sclerosis patients with capillary abnormalities

BackgroundSystemic sclerosis (SSc) is a rare, potentially destructive systemic autoimmune disease characterized by organ fibrosis and vasculopathy. Netrin-1 is associated with angiogenesis, inflammation, and apoptosis.Aim of the workTo assess the level of serum netrin-1 in SSc patients with capillary abnormalities and to evaluate its relation to disease manifestations.Patients and methodsThis study investigated the relationship between netrin-1 and fibrosis in 56 SSc patients and 58 matched control. The modified Rodnan skin score (mRss) was used to assess skin thickness. Serum netrin-1 level was quantitatively measured using an enzyme-linked immunosorbent assay.ResultsThe study included 56 patients; 53 females and 3 males (F:M 17.7:1) with a mean age of 48·1 ± 13·6 years and disease duration of 13.01 ± 8·7 years. They were 43 (76.7 %) diffuse and 13 (23.3 %) limited subtypes. The median mRss was 6.58 ± 2.2. Raynaud’s disease was present in 50 % and interstitial lung disease in 57.1 %. The median netrin-1 level was significantly higher in SSc patients (268·8 pg/mL; 82·8-1006·6 pg/mL) than in the controls (108·6 pg/mL;21·02-351·5 pg/mL, p < 0·0001). There was no significant difference in the serum netrin-1 levels in SSc patients with and without Raynaud’s disease (p = 0.55), interstitial lung disease (p = 0.18), anti-Scl70 positive antibodies (p = 0·78), and anti-centromere antibody (p = 0·493). Netrin-1 was significantly related to SSc (OR = 1·02, 95 %CI: 1·01 ? 1·03, p < 0·0001). At a cut-off value 126·3 pg/mL, netrin-1 would diagnose SSc (sensitivity 60·3%, specificity 94·6%, 95 %CI: 0·83 ? 0·95, p < 0·0001).ConclusionSSc patients had significantly high levels of serum netrin-1 with a potential role in the pathophysiology of the disease.     

Antiangiogenic plasma activity in patients with systemic sclerosis

OBJECTIVE: Systemic sclerosis (SSc; scleroderma) is a systemic connective tissue disease with an extensive vascular component that includes aberrant microvasculature and impaired wound healing. The aim of this study was to investigate the presence of antiangiogenic factors in patients with SSc. METHODS: Plasma samples were obtained from 30 patients with SSc and from 10 control patients without SSc. The samples were analyzed for the ability of plasma to affect endothelial cell migration and vascular structure formation and for the presence of antiangiogenic activity. RESULTS: Exposure of normal human microvascular dermal endothelial cells to plasma from patients with SSc resulted in decreased cell migration (mean +/- SEM 52 +/- 5%) and tube formation (34 +/- 6%) compared with that in plasma from control patients (P < 0.001 for both). SSc plasma contained 2.9-fold more plasminogen kringle 1-3 fragments (angiostatin) than that in control plasma. The addition of angiostatin to control plasma resulted in inhibition of endothelial cell migration and proliferation similar to that observed in SSc plasma. In vitro studies demonstrated that granzyme B and other proteases contained in T cell granule content cleave plasminogen and plasmin into angiostatin fragments. CONCLUSION: Plasminogen conformation in patients with SSc enables granzyme B and granule content protease to limit the proangiogenic effects of plasmin and increase the levels of antiangiogenic angiostatin. This increase in angiostatin production may account for some of the vascular defects observed in patients with SSc.     

Erectile dysfunction in systemic sclerosis: effects of longterm inhibition of phosphodiesterase type-5 on erectile function and plasma endothelin-1 levels

OBJECTIVE: To investigate the effects of prolonged inhibition of phosphodiesterase type-5, using once-daily long-acting phosphodiesterase type-5 inhibitor (tadalafil) on erectile function and biomarkers of endothelial function in male patients with systemic sclerosis (SSc) and erectile dysfunction (ED). METHODS: In an open-label study, 14 nonconsecutive male patients with SSc with different degrees of ED were enrolled into the study irrespective of their clinical response to tadalafil, and received once-daily tadalafil 10 mg for 12 weeks. Primary endpoints were variations from baseline of penile arterial inflow [peak systolic velocity (PSV, cm/s); measured with dynamic color duplex ultrasound] and the erectile function domain score (measured with the International Index of Erectile Function questionnaire). Secondary endpoints were variations from baseline of morning erections (determined by modified question 13 of the Structured Interview on Erectile Dysfunction questionnaire) and plasma concentrations of endothelin-1 (ET1). RESULTS: The PSV and the erectile function domain score were significantly improved by once-daily tadalafil (from 21.3 +/- 6.4 to 30.0 +/- 7.0 cm/s and from 13.0 +/- 6.8 to 17.0 +/- 9.0 vs baseline, respectively; p <0.05). Question 13 scores decreased dramatically after treatment compared with baseline (from 2.2 +/- 0.2 to 0.8 +/- 0.5 arbitrary units; p < 0.001), and plasma ET1 levels decreased (from 24 +/- 15 to 9.8 +/- 7.4 pg/ml; p < 0.05). CONCLUSION: In men with SSc-related ED, once-daily tadalafil improved both erectile function and vascular measures of cavernous arteries. Increases in morning erections and decreases in plasma ET1 levels were found, which may play a potential role in preventing progression of penile fibrosis and erectile dysfunction.     

Increased plasma levels of endothelin-1 and urotensin-II in patients with coronary heart disease

Research has identified the vasoconstrictors endothelin-1 (ET-1) and urotensin-II (U-II) as having a role in the development of atherosclerotic cardiovascular disease. We aimed to observe alterations in plasma levels of both ET-1 and U-II in patients with coronary heart disease (CHD) undergoing percutaneous transluminal coronary angioplasty (PTCA) and stent therapy from November 2006 through May 2007. We examined plasma levels of ET-1 and U-II in 40 patients with CHD and 40 age-matched healthy subjects by radioimmunoassay (RIA). Chi-square test, Student’s t-test, and one-way analysis of variance were used for statistical analyses. Correlations between variables were tested by simple linear regression analysis. Coronary heart disease patients had significantly higher ET-1 and UII levels than healthy controls (20.05 ± 4.65 vs 8.16 ± 3.38 and 71.90 ± 11.61 vs 20.89 ± 7.00 pg/ml, respectively, all P < 0.01). Importantly, plasma levels of U-II and ET-1 were correlated in patients with CHD (r = 0.64, P = 0.01). On day 1 after PTCA and stent therapy, plasma levels of ET-1 and U-II were significantly higher, by 99% and 25%, respectively, than those before therapy (all P < 0.01). On day 3 after therapy, ET-1 levels were higher by 25% (P < 0.01) than before therapy, and U-II levels decreased rapidly and were close to baseline levels (P > 0.05). On day 7 after therapy, CHD patients had significantly lower ET-1 and U-II levels than before therapy (all P < 0.01). Since ET-1 and U-II levels may be increased in plasma of patients with CHD, their activation might have clinical significance in terms of early intervention in patients with CHD, especially after PTCA and stent therapy.     

Elevated plasma endothelin-1 levels in diabetes mellitus

BACKGROUND: This study compares plasma endothelin-1 (ET-1) levels in patients with diabetes mellitus or hypertension with healthy controls, and investigates whether ET-1 levels are correlated with glycemic control, metabolic parameters, and vascular complications. METHODS: The study population consisted of 103 patients with type 1 diabetes, 124 patients with type 2 diabetes, 35 hypertensive patients without diabetes mellitus, and 99 controls. RESULTS: Plasma ET-1 concentrations were significantly higher in patients with type 1 diabetes (0.28 +/- 0.34 fmol/mL, P =.001), type 2 diabetes (0.31 +/- 0.32 fmol/mL, P <.0001), and hypertension (0.35 +/- 0.26 fmol/mL, P <.0001) compared to controls (0.08 +/- 0.13 fmol/mL). Diabetic patients taking angiotensin converting enzyme (ACE) inhibitors had significantly lower plasma ET-1 levels than patients without (0.22 +/- 0.20 fmol/mL v 0.38 +/- 0.39 fmol/mL, P =.029). There were significant associations between ET-1 levels and age (r = 0.38, P <.05) and systolic blood pressure (BP) (r = 0.27, P <.05) in healthy controls. In diabetes we found only nonsignificant associations between ET-1 levels and age or vascular complications and a weak association between plasma ET-1 levels and glycemic control. CONCLUSIONS: Patients with diabetes or hypertension have elevated ET-1 levels, but do not exhibit positive correlations between ET-1 levels and BP, which was observed in healthy controls. Increased ET-1 levels do not induce hypertension in diabetes, but were lower in diabetic patients taking ACE inhibitors compared to those without ACE inhibitors. There is no significant association between ET-1 levels and vascular complications. These findings suggest that the plasma ET-1 level is not a marker of endothelial dysfunction but changes in plasma ET-1 levels may precede vascular complications associated with hypertension and diabetes.     

Increased plasma endothelin-1 levels in fibromyalgia syndrome

SIR, The fibromyalgia syndrome (FMS) is defined by symptomsof widespread, chronic musculoskeletal pain, stiffness and pressurehyperalgesia at characteristic soft tissue sites, called softtissue tender points. FMS shows clinical overlap with otherstress-associated disorders, including chronic fatigue syndrome(CFS) and depression. The disease is more common in women thanin men, and occurs mostly in middle age. Despite intensive researchin this field, the aetiology of the disorder is     

Association between plasma endothelin-1 levels and Cheyne-Stokes respiration in patients with congestive heart failure

STUDY OBJECTIVES: Elevated plasma endothelin-1 (ET-1) levels have been reported in association with hypoxia and congestive heart failure (CHF). Furthermore, Cheyne-Stokes respiration-central sleep apnea (CSR-CSA) has been found to correlate with the degree of pulmonary hypertension and the severity of CHF; however, the association between ET-1 levels and CSR-CSA has not been investigated previously. SETTING: Veterans Affairs Medical Center. INTERVENTIONS: We studied 46 consecutive patients with CHF (left ventricular function < or = 40%) who underwent right-heart catheterization and overnight polysomnography. Thirty-nine patients completed the study. Sixteen patients (41%) had CSR-CSA, 5 patients (13%) had obstructive apnea, and 18 patients (46%) had no sleep-disordered breathing. Circulating plasma ET-1 levels were assayed in patients with CSR-CSA and in patients with no sleep-disordered breathing using commercially available enzyme-linked immunosorbent assay kits. RESULTS: ET-1 levels were significantly elevated in patients with CSR-CSA (mean +/- SD, 5.4 +/- 1.3 pg/mL) compared to those without central apnea (3.9 +/- 1.1 pg/mL; p < 0.01), and correlated with mean pulmonary artery pressure (r = 0.66, p < 0.01), pulmonary capillary wedge pressure (r = 0.56, p < 0.03), and central apnea frequency (r = 0.66, p < 0.01). In multivariate analysis, the severity of CSR-CSA was the only variable independently associated with plasma ET-1. CONCLUSIONS: We conclude that elevated plasma ET-1 levels are linked to the severity of CSR-CSA. Whether ET-1 represents an important pathogenic factor in CSR-CSA or marker of its occurrence requires further evaluation.     

急性心肌梗死患者血浆内皮素-1水平的观察

测定21例急性心肌梗死患者入院后第1、2、3、4和8天血浆内皮素-1水平。第1、2和3天明显升高；其中12例KillipⅠ级患者各天均无明显改变，而9例KillipⅡ级及以上患者各天均明显升高；7例合并高血压和14例无合并高血压的患者，第1、2和3天都显著升高。     

Cell-free DNA in the plasma of patients with systemic sclerosis

The aim of the present study was to evaluate the concentration of cell-free DNA (cf-DNA) in the plasma of patients with systemic sclerosis (SSc) and to examine the correlation of cf-DNA with clinical variables of the disease. The study population consisted of 122 SSc patients and 16 healthy controls. Epidemiological and clinical data were collected by direct assessment. The β-globin gene was used to determine the total amount of DNA in the plasma by real-time quantitative PCR analysis. cf-DNA was found in all patients (mean concentration 1,420.7 copies/ml) and controls (mean concentration 1,462.5), with no significant difference. In SSc patients, no correlation was found between cf-DNA and the type of organ involvement, but patients with active disease presented significantly higher cf-DNA concentrations than those with inactive disease (p?<?0.05). Our data suggest that cf-DNA could provide a useful biomarker for the assessment of disease activity in SSc patients.