Reduction in hepatic endothelin-1 clearance in cirrhosis

Circulating endothelin-1 (ET-1) levels are increased in cirrhosis. The liver is an important site for circulating ET-1 clearance through the ET(B) receptor. We evaluated ET-1 kinetics in cirrhosis to determine if a reduced liver clearance contributes to this process. Cirrhosis was induced by carbon tetrachloride in rats. Hepatic ET-1 clearance was measured in isolated perfused livers using the single bolus multiple indicator-dilution technique. Plasma ET-1 levels doubled in cirrhosis from 0.49+/-0.04 fmol/ml (mean+/-S.E.M.) to 1.0+/-0.18 fmol/ml ( P <0.01). Liver ET-1 extraction was reduced from 81+/-1% (mean+/-S.E.M.) in controls to 50+/-6% in cirrhosis ( P <0.01). Kinetic modelling revealed a major irreversible binding site for ET-1 that is blocked by the selective ET(B) receptor antagonist BQ788 and a minor non-specific reversible binding site that cannot be blocked with BQ788 or the selective ET(A) antagonist BQ123. Reduced hepatic clearance correlated with the biochemical markers of cirrhosis, portal vein perfusion pressure ( r =-0.457; P <0.001) and the increase in ET-1 levels ( r =-0.462; P =0.002). Immunohistofluorescence with specific anti-(ET(B) receptor) antibodies revealed a preponderant distribution of ET(B) receptors on hepatic stellate cells, which was increased in cirrhosis. We conclude that cirrhosis reduces ET-1 clearance probably by capillarization of hepatic sinusoids and reduced access to ET(B) receptors. This relates to the severity of cirrhosis and may contribute to the increase in circulating ET-1 levels.     

Decreased endogenous secretory advanced glycation end product receptor in type 1 diabetic patients: its possible association with diabetic vascular complications

OBJECTIVE: The binding of advanced glycation end products (AGEs) to their receptor (RAGE) plays an important role in the development of diabetic vascular complications. In the present study, we examined circulating endogenous secretory RAGE (esRAGE) levels in subjects with type 1 diabetes and explored the possible association between esRAGE levels and the severity of diabetic vascular complications. RESEARCH DESIGN AND METHODS: Circulating esRAGE levels in serum were examined in 67 Japanese type 1 diabetic patients (22 men and 45 women, age 24.0 +/- 4.4 years [means +/- SD]) and 23 age-matched healthy nondiabetic subjects (10 men and 13 women aged 24.9 +/- 1.4 years). Daily urinary albumin excretion, the presence of retinopathy, and intima-media thickness (IMT) of the carotid artery were also evaluated. We further explored the association between esRAGE levels and severity of diabetic vascular complications. RESULTS: Circulating esRAGE levels were significantly lower in subjects with type 1 diabetes than in nondiabetic subjects (0.266 +/- 0.089 vs. 0.436 +/- 0.121 ng/ml, respectively, P < 0.0001) and was inversely correlated with HbA(1c) (A1C) levels (r = -0.614, P < 0.0001). In addition, multivariate regression analysis demonstrated that A1C was an independent risk factor for a low esRAGE value. Furthermore, circulating esRAGE levels were inversely correlated with carotid IMT (r = -0.325, P = 0.0017) and was one of the independent risk factors for IMT thickening. Furthermore, there was a significant difference (P = 0.0124) in esRAGE levels between patients without retinopathy (0.286 +/- 0.092 ng/ml) and those with retinopathy (0.230 +/- 0.074 ng/ml). CONCLUSIONS: Circulating esRAGE levels were significantly lower in type 1 diabetic patients than in nondiabetic subjects and were inversely associated with the severity of some diabetic vascular complications.     

Q-T interval (QT(C)) in patients with cirrhosis: relation to vasoactive peptides and heart rate

OBJECTIVE: Prolonged Q-T interval (QT) has been reported in patients with cirrhosis who also exhibit profound abnormalities in vasoactive peptides and often present with elevated heart rate (HR). The aim of this study was to relate QT to the circulating level of endothelins (ET-1 and ET-3) and calcitonin gene-related peptide (CGRP) in patients with cirrhosis. In addition, we studied problems with HR correction of QT. MATERIAL AND METHODS: Forty-eight patients with cirrhosis and portal hypertension were studied during a haemodynamic investigation. Circulating levels of ETs and CGRP were determined by radioimmunoassays. Correction of QT for HR above 60 beats per min was performed using the methods described by Bazett (QT(C)) and Fridericia (QT(F)). RESULTS: Prolonged QT(C) (above 440 ms), found in 56% of the patients, was related to the presence of significant portal hypertension and liver dysfunction (p < 0.05 to 0.001), but not to elevated ET-1, ET-3 or CGRP. When corrected according to Bazett, QT(C) showed no significant relation to differences in HR between patients (r = 0.07, ns). QTF showed some undercorrection of HR (r = -0.36; p < 0.02). During HR variation in the individual patient, QT(C) revealed a small but significant overcorrection (2.6 ms per heartbeat per min; p < 0.001). This value was significantly (p < 0.02) smaller with QTF (1.2 ms per heartbeat per min). CONCLUSIONS: The prolonged QT(C) in cirrhosis is related to liver dysfunction and the presence of portal hypertension, but not to the elevated powerful vasoconstrictor (ET-1) or vasodilator (CGRP, ET-3) peptides. The problems with correction of the QT for elevated HR in cirrhosis are complex, and the lowest HR should be applied for determination of the QT.     

Effects of magnesium sulfate on lipid peroxidation and blood pressure regulators in preeclampsia

OBJECTIVES: To investigate the status of lipid peroxidation and serum levels of several vasoactive substances in preeclamptic (PE) pregnant women before and during treatment with magnesium sulfate (MgSO(4)). DESIGN AND METHODS: The study population included 16 PE women. Circulating levels of malondialdehyde (MDA), endothelin 1 (ET-1), nitric oxide (NO) metabolites, and calcitonin gene-related peptide (CGRP) were measured before (at admission) and during MgSO(4) treatment (at delivery and 24 h postpartum). RESULTS: At admission systolic and diastolic blood pressures were 157 +/- 3 mm Hg and 106 +/- 2 mm Hg, respectively, and decreased significantly during treatment at delivery and 24 h postpartum (P < 0.0001). Before treatment, serum MDA concentrations were 0.383 +/- 0.037 micromol/L, and decreased significantly during MgSO(4) administration at delivery and 24 h postpartum (P < 0.0001). In contrast, serum ET-1 levels at 24 h postpartum were significantly higher as compared with those observed before treatment (79 +/- 3 versus 65 +/- 2 pg/mL, P = 0.002). Serum NO metabolite concentrations were 26 +/- 3 micromol/L, and no significant changes were observed during treatment. Serum levels of CGRP were 50 +/- 3 pg/mL at admission, and increased significantly at partum (P < 0.001). Serum ET-1 correlated negatively with NO metabolites before treatment (r = -0.69, P = 0.002), but not during treatment. In contrast, ET-1 correlated positively with serum CGRP levels during treatment (r = 0.73, P = 0.002 and r = 0.71, P = 0.002, at delivery and 24 h postpartum, respectively), but not before treatment. CONCLUSIONS: This study demonstrates that MgSO(4) administration to PE pregnant women induced significant changes in lipid peroxidation, production of ET-1 and CGRP.     

Increased plasma levels of endothelin 1 and von Willebrand factor in patients with type 2 diabetes and dyslipidemia

OBJECTIVE: Endothelial markers endothelin 1 (ET-1) and von Willebrand factor (vWF) were assessed in patients with type 2 diabetes and dyslipidemia and in patients with hypercholesterolemia. RESEARCH DESIGN AND METHODS: In this case-control study, plasma ET-and vWF levels were measured by enzyme-linked immunosorbent assay in 35 normoalbuminuric type 2 diabetic patients with dyslipidemia (56+/-5 years), in 21 nondiabetic patients with hypercholesterolemia (52+/-7 years), and in 19 healthy control subjects (45+/-4 years). All of the individuals were normotensive and nonsmokers. Urinary albumin was measured by immunoturbidimetry. RESULTS: ET-1 levels were higher (P<0.0001) in type 2 diabetic dyslipidemic patients (1.62+/-0.73 pg/ml) than in both nondiabetic hypercholesterolemic patients (0.91+/-0.73 pg/ml) and control subjects (0.69+/-0.25 pg/ml). vWF levels were significantly increased (P = 0.02) in type 2 diabetic (185.49+/-72.1%) and hypercholesterolemic (163.29+/-50.7%) patients compared with control subjects (129.70+/-35.2%). In the multiple linear regression analysis. ET-1 was significantly associated (adjusted r2 = 0.42) with serum triglyceride levels (P<0.001), age (P<0.01), insulin sensitivity index (P<0.02), and albuminuria levels (P<0.04). vWF levels were associated (adjusted r2 = 0.22) with albuminuria (P<0.001), fibrinogen levels (P<0.02), and BMI (P<0.03). CONCLUSIONS: Compared with hypercholesterolemic patients, type 2 diabetic patients with dyslipidemia have increased levels of ET-1 and vWF which may indicate more pronounced endothelial injury. These findings appear to be related to components of the insulin resistance syndrome.     

Evaluation of nutritional status and factors related to malnutrition in children on CAPD.

OBJECTIVE: The aim of this study was to investigate the nutritional status of children on continuous ambulatory peritoneal dialysis (CAPD) and to relate it to the dose of dialysis and serum levels of inflammatory cytokines and insulin-like growth factor-1 (IGF-1). PATIENTS: 17 CAPD patients (8 girls, 9 boys; mean age 13.1 +/- 3.5 years, median 15 years) were included in the study. Anthropometric measurements and serum albumin levels were used in the evaluation of nutritional status. Serum interleukin (IL)-1beta, IL-6, tumor necrosis factor alpha, and IGF-1 levels were determined in all CAPD patients and in a healthy control group. Weekly Kt/V and creatinine clearance (CCr) were measured to determine adequacy of dialysis. RESULTS: The mean dialysis period was 23.7 +/- 15.2 months (median 23 months). Anthropometric measurements and serum albumin level were as follows: height 130.2 +/- 15.6 cm, height standard deviation score (HtSDS) -4.2 +/- 2.4, body mass index (BMI) 16.3 +/- 1.6 kg/m2, body mass index standard deviation score (BMISDS) -0.8 +/- 0.9, triceps skinfold thickness (TST) 4.2 +/- 1.4 mm, midarm circumference (MAC) 16.21 +/- 2.3 cm, upper arm muscle area (AMA) 1799.1 +/- 535.7 mm2, upper arm fat area (AFA) 334.5 +/- 143 mm2, and serum albumin 3.1 +/- 0.7 g/dL. The BMI was above the fifth percentile in all patients; TST and MAC were below the fifth percentile in 14 patients (82.4%) and 10 patients (58.8%) respectively. The AMA was below the fifth percentile in 8 patients; however, the AFA was below the fifth percentile in all patients. Mean serum albumin level was under 3.5 g/dL in 70.5% of the children. We found significant positive correlations between BMI and Kt/V (r = 0.69, p < 0.01), CCr (r = 0.64, p < 0.05), and IL-6 (r = 0.61, p < 0.01). There was an inverse correlation between BMISDS and dialysis period (r = -0.58, p < 0.05); and between IL-6 and serum albumin (r = -0.49, p < 0.05). A significant positive correlation between BMISDS and serum IGF-1 level (r = 0.62, p < 0.01) was noted. We also found a significant positive correlation between serum IGF-1 level and both HtSDS (r = 0.57, p < 0.05) and TST (r = 0.52, p < 0.05). Significant positive correlations between AFA and CCr and IGF-1 were also noted (both r = 0.56, p < 0.05). CONCLUSION: Although many factors may be responsible for malnutrition and growth retardation, we found that prolonged period of dialysis, inadequate dialysis, and low IGF-1 levels are the most important risk factors in CAPD patients.     

Neuropeptide variability in man

BACKGROUND: Previous studies have established short-term variability in the circulating plasma levels of cardiac peptides such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Our aim was to investigate whether such variable patterns could be observed in other vasoactive peptides. METHODS: We measured the immunoreactivity of vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY), endothelin-1 (ET-1) and calcitonin gene-related peptide (CGRP) in peripheral venous plasma collected at 2-min intervals over a 20-min period from patients with chronic cardiac failure (CCF) and from control subjects. In a second study, blood samples were obtained at 2-min intervals from the pulmonary artery, femoral artery and antecubital vein from patients with normal cardiac function while right atrial pressure and heart rate were constant. RESULTS: Peripheral blood VIP, NPY and ET-1 had peaks and troughs (levels > 2SD from the mean) in both patients and controls, with approximate intervals of 10 min. Levels of CGRP showed little variation. The overall levels [median (range); pmol L-1] of VIP [patients 27 (2.1-85.5); controls 9.8 (0-34)] and NPY [patients 20 (0-110); controls 12 (5-19)] were higher in patients (P < 0.05). Circulating plasma levels of ET-1 and CGRP were about the same in both groups [ET-1: patients 18 (2-84); controls 18 (0-48); CGRP: patients 4 (1-18.5), controls 5.5 (1-15); P = NS]. Levels of CGRP, VIP and ET-1 were similar in the pulmonary and femoral arteries, whereas systemic arterial levels of NPY were higher than in the pulmonary artery. CONCLUSIONS: The data demonstrate marked variability in circulating levels of the neuropeptides studied. In addition, peaks and troughs were observed every 10-15 min from all three vascular beds. If these peptides are secreted in a pulsatile pattern, then interpretations of single measurements should be guarded. Furthermore, this study raises interesting questions about the physiology of hormone secretion in man.     

A retrospective assessment of the effectiveness of fenofibrate 267 mg on high-density lipoprotein cholesterol levels in patients attending a lipid clinic

BACKGROUND: A high-density lipoprotein cholesterol level (HDL-C) <1 mmol/L is associated with increased cardiovascular morbidity and mortality. In clinical trials, fibrates have been shown to increase levels of HDL-C, with subsequent reduction in cardiovascular risk. OBJECTIVE: This study evaluated the use of fenofibrate 267 mg/d in a routine lipid clinic setting to determine how much HDL-C could be increased in everyday clinical practice. METHODS: Blood samples from patients who had taken fenofibrate 267 mg/d between 1998 and 2001 at the Lipid Clinic, Charing Cross Hospital, London, United Kingdom, were analyzed for changes in total cholesterol (TC), HDL-C, and triglycerides during follow-up. Results: Sixty-five consecutive patients (49 men, 16 women; mean age, 54 +/- 1.2 years) were included in the study. The follow-up period ranged from 1 to 36 months (mean, 9.6 months +/- 26.7 days). Patients achieved a 6% overall increase in HDL-C, from 0.91 +/- 0.03 mmol/L to 0.97 +/- 0.03 mmol/L (P = 0.016). The TC/HDL-C ratio decreased by 21% from 7.0 +/- 0.3 mmol/L to 5.5 +/- 0.2 mmol/L (P < 0.001). Patients with lower levels of HDL-C at baseline (<0.9 mmol/L) showed the most improvement, with an 8% increase (P < 0.05). Twenty-eight patients (43%) reached a target HDL-C posttherapy value >1.0 mmol/L. Thirty-nine patients (responders) had increases in their HDL-C levels; 26 patients (nonresponders) had decreases or no change in their HDL-C levels. For the 26 (40%) patients in whom HDL-C did not increase, the TC/HDL-C ratio decreased by 12% from 6.5 +/- 0.3 mmol/L to 5.7 +/- 0.3 mmol/L (P = 0.003). CONCLUSIONS: Fenofibrate 267 mg/d is well tolerated and can achieve significant increases in HDL-C levels in clinical practice. However, these results should be confirmed in a larger routine clinical setting because of the discrepancies between the results of some clinical trials.     

Aging and renal clearance of procainamide and acetylprocainamide

Thirty-two patients had blood and urine collected simultaneously for measurement of procainamide, acetylprocainamide, and creatinine. The ratios of drug clearance to creatinine clearance were calculated for each. The procainamide:creatinine clearance ratio averaged 2.9 +/- 1.6 (SD) and fell as age of the patients rose (r = 0.5, p < 0.01). The acetylprocainamide:creatinine clearance ratio averaged 1.7 +/- 0.8 and also fell with age. The combination of decline in overall renal function with age with this decrease in the rate of renal tubular secretion of these drugs led to a progressive age-related rise in the steady-state serum level of procainamide (r = 0.56, p < 0.01) and acetylprocainamide (r = 0.36, p < 0.1) achieved by any dose of procainamide. Thus, the dosage of procainamide must be individualized for both overall renal function (GFR) and the age-related variations in renal tubular secretion that are of most note in children and the elderly.     

Urinary transforming growth factor-beta1 and alpha1-microglobulin in children and adolescents with type 1 diabetes

OBJECTIVE: Transforming growth factor (TGF)-beta1 is an important mediator in the pathogenesis of diabetic nephropathy. Urinary TGF-beta1 reflects TGF-beta1 production in the kidney, and alpha1-microglobulin tubular dysfunction. These 2 markers were studied in the early phases of type 1 diabetes. RESEARCH DESIGN AND METHODS: There were 113 type 1 diabetic children and adolescents (mean +/- SD: age 14.1 +/- 2.9 years, and diabetes duration 7.4 +/- 2.9 years, HbA1c 9.3 +/- 1.5%) and 39 healthy subjects (age 13.8 +/- 2.8 years) who participated in the study. Of the diabetic patients, 105 were normoalbuminuric (2-3 consecutive overnight urinary albumin excretion rates [AERs] <20 microg/min) and 8 had microalbuminuria (at least 2 AERs 20-200 microg/min). Overnight urinary TGF-beta1 and alpha1-microglobulin levels were measured and the results expressed as the ratio to urinary creatinine concentration. RESULTS: Data are medians (range). Diabetic patients had higher urinary TGF-beta1 levels than those of control subjects: 0.9 ng/mg (0.05-122.3) vs. 0.3 ng/mg (0.05-2.2) creatinine, respectively (P = 0.003). Urinary TGF-beta1 levels correlated with urinary glucose (r = 0.2, P = 0.03) and alpha1-microglobulin (r = 0.2, P = 0.02) levels, but not with HbA1c, AER, age, or duration of diabetes. In 43 patients with urinary TGF-beta1 above the control levels, urinary TGF-beta1 levels correlated with urinary glucose (r = 0.6, P < 0.001) and alpha1-microglobulin (r = 0.6, P < 0.001) levels. Diabetic patients had higher urinary alpha1-microglobulin levels than those of control subjects: 4.8 microg/mg (0.6-48.8) vs. 2.7 microg/mg (0.8-11.6) creatinine, respectively (P < 0.001). Alpha1-microglobulin levels correlated with AER (r = 0.2, P = 0.02), HbA1c (r = 0.3, P = 0.001), urinary glucose (r = 0.5, P < 0.001), and urinary TGF-beta1 levels. CONCLUSIONS: An early rise in urinary TGF-beta1 levels was observed in young type 1 diabetic patients. Urinary TGF-beta1 is associated with 2 interrelated tubular markers, alpha1-microglobulin and urinary glucose.     

Tissue inhibitor of metalloproteinse-1 is a marker of diastolic dysfunction using tissue doppler in patients with type 2 diabetes and hypertension

BACKGROUND: Tissue inhibitor of metalloproteinase-1 (TIMP-1) is associated with increased fibrosis of the extracellular matrix (ECM). Myocardial stiffness is a feature of diastolic dysfunction. We assessed circulating TIMP-1 as a marker of diastolic dysfunction in patients with type 2 diabetes mellitus (DM) and hypertension, who were compared with healthy controls. METHODS: We recruited 54 patients (43 males; mean age 68 +/- 5 years) with treated type 2 DM (i.e. controlled glycaemia, hypertension, hyperlipidaemia), 35 (30 males; 69 +/- 8 years) treated nondiabetic hypertensives, and 31 healthy controls (18 males; 66 +/- 5 years). Circulating TIMP-1 was measured by ELISA. Using transthoracic echocardiography, the early (E) diastolic mitral inflow velocity was measured with pulse wave Doppler, and the early mitral annular velocity (e'), a recognized index of diastolic relaxation, was measured with tissue Doppler. The E/A ratio was also calculated and isovolumic relaxation time measured. RESULTS: Mean e' levels differed significantly between controls, diabetics and hypertensives (P < 0.0001). Circulating TIMP-1 was significantly different between patients and controls (P = 0.006), but there was no statistically significant difference between the DM and hypertension group. In both groups, only e' was negatively correlated with TIMP-1 levels, with a stronger correlation among the hypertensive patients (Spearman r = -0.544, P = 0.001) when compared with the diabetic group (r = -0.341, P = 0.011). CONCLUSION: Diastolic relaxation is impaired in diabetes and hypertensive patients. The relationship between TIMP-1 and e' may reflect increased myocardial fibrosis and consequent diastolic dysfunction, which may be more prominent in hypertension.     

A population-specific formula predicting creatinine excretion in continuous peritoneal dialysis.

OBJECTIVE: The Cockroft-Gault formula was shown to systematically overestimate the decline in creatinine excretion with age in continuous peritoneal dialysis (CPD) patients and is, therefore, not suitable for studying creatinine excretion.The purpose of the present study was to develop and test a population-specific formula predicting average creatinine excretion in CPD. METHODS: Creatinine excretion in urine plus dialysate was measured in 925 CPD patients. Forty patients were excluded because of evidence of noncompliance. The remaining 885 subjects were randomly grouped into a derivation group (n = 432) and a validation group (n = 453). Stepwise multiple linear regression models were used to predict creatinine excretion in the derivation group. The candidate variables, chosen because they were previously shown to be predictors of creatinine excretion in CPD, included weight (W), age (A), gender (G), diabetes (D), and interaction terms between these four variables. Estimates of creatinine excretion from the best-fit regression formula (CrExcr1) and from the Cockroft-Gault formula (CrExcr2) were compared to creatinine excretion (CrExcr) in the validation group. RESULTS: The best-fit regression model in the derivation group included all four candidate variables (W, A, G, D), but no interaction terms. This model was as follows: CrExcr1 = 302.150 - 4.380A + 171.234G - 39.041D + 11.730W (r2 = 0.477, p < 0.001). In the validation set, CrExcr = -15.795 + 0.988CrExcr1 (r2 = 0.447, p < 0.001), and CrExcr = -303.823 + 0.732CrExcr2 (r2 = 0.340, p < 0.001). When the differences between measured and predicted creatinine excretion did not take into account the sign of each individual difference, CrExcr - CrExcr1 = 201 +/- 156 mg/24 hours, and CrExcr - CrExcr2 = 235 +/- 174 mg/24 hr (p < 0.001) in the validation group. When the sign of the difference was taken into account, CrExcr - CrExcr1 = -28 +/- 149 mg/24 hr, and CrExcr - CrExcr2 = 63 +/- 295 mg/24 hr (p < 0.001). CONCLUSIONS: A population-specific formula predicting creatinine excretion in CPD was derived.This formula has greater accuracy than the Cockroft-Gault formula and can be used in studies of creatinine excretion in CPD.     

Angiotensin-converting enzyme genotype, albuminuria and plasma fibrinogen in type 2 diabetes mellitus

AIMS: Increased fibrinogen level is considered an important atherosclerosis risk factor. Patients with type 2 diabetes frequently have increased fibrinogen levels. The aim of the present study was to examine the effect of angiotensin-converting enzyme (ACE) gene polymorphism and the effects of the diabetic environment on plasma fibrinogen in type 2 diabetes. PATIENTS AND METHODS: The study group included 125 patients with type 2 diabetes (40 men, 85 women). The average age of patients was 62 +/- 10 years. Fibrinogen concentration was determined with the thrombin coagulation test. ACE insertion/deletion (I/D) polymorphism was detected using polymerase chain reaction (PCR) assay. RESULTS: II homozygotes (n = 17) had the highest mean fibrinogen levels, ID heterozygotes (n = 75) had medium levels and DD homozygotes (n = 33) had the lowest (p = 0.054, ANOVA). II homozygotes also had significantly higher mean fibrinogen level than ID/DD carriers (4.3 +/- 1.7 vs. 3.5 +/- 1.3 g/l; p = 0.015). The indices of renal functions, i.e. albuminuria (r = 0.37; p < 0.0001) and serum creatinine (r = 0.22; p = 0.015), significantly correlated with fibrinogen levels. The correlation between albuminuria and fibrinogen was significant in the subgroups with genotypes II (r = 0.76; p = 0.001) and ID (r = 0.37, p = 0.002), whereas in the subgroup of DD homozygotes this relationship did not reach statistical significance. In the multivariate regression analysis with age, sex, BMI, creatinine, albuminuria and ACE genotype as independent variables, albuminuria was the only significant predictor of fibrinogen level (p < 0.0001). After interaction between the ACE genotype and albuminuria was included into multivariate analysis, the interaction became the only independent predictor of plasma fibrinogen level (p < 0.0001) in the model, and the model explained 25% of the plasma fibrinogen variance. CONCLUSION: ACE gene polymorphism is associated with plasma fibrinogen level in type 2 diabetes. This association is mediated by an interaction between ACE genotype and albuminuria. Diabetes patients with genotypes II or ID have increased plasma fibrinogen in the presence of albuminuria.     

Protein-losing enteropathy is associated with peritoneal functional abnormalities in peritoneal dialysis patients.

OBJECTIVE: To evaluate the relationship between acquired peritoneal transport disorders and the presence of protein-losing enteropathy (PLE), and their contribution to the protein malnutrition in peritoneal dialysis (PD) patients. PATIENTS AND METHODS: We studied 31 clinically stable PD patients that received a fat overload diet for 3 days. We measured intestinal absorption of fecal fat (normal < 6 g/24-hour stool) and nitrogen (normal < 2 g/24-hr stool), intestinal protein permeability [fecal clearance of alpha1-antitrypsin (Calpha1AT) (normal < 12 mL/24-hr stool)], and nutritional markers [normalized protein nitrogen appearance (nPNA), half-life medium-term proteins, and body mass index]. Peritoneal solute transport was measured by mass transfer coefficient (MTC), and water transport by peritoneal ultrafiltration (UF) capacity. To define protein maldigestion it was necessary to find high fecal nitrogen values with normal Calpha1AT; PLE was defined when both values were elevated. RESULTS: High fecal nitrogen (mean 2.1+/-1 g/24-hr stool) and fat (mean 5.8+/-3.6 g/24-hr stool) were found in 15 patients; 6 patients had high Calpha1AT levels (PLE).These 6 patients showed a worse nutritional status: lower albumin (3.57+/-0.57 g/dL vs 3.98+/-0.38 g/dL, p < 0.05) and transferrin (243+/-70 mg/dL vs 272+/-44.3 mg/dL, p < 0.05), as well as lower triglycerides (131.3+/-31.7 mg/dL vs 187+/-116 mg/dL, p< 0.05). Higher urea MTCs were found in 10 patients, normal in 7, and lower in 14. Higher creatinine MTCs were found in 8 patients, normal in 15, and lower in 8. Normal peritoneal UF capacity was found in 25 and lower in 6 patients. These 6 patients showed higher urea and creatinine MTCs and Calpha1AT. A positive linear correlation between Calpha1AT, urea MTC (r = 0.56, p < 0.01), and creatinine MTC (r = 0.46, p < 0.01) was found. A similar situation occurred between Calpha1AT, fecal fat (r = 0.45, p < 0.05), and fecal nitrogen (r = 0.43, p < 0.05). Thirteen patients with previous history of peritonitis showed higher Calpha1AT than those without peritonitis (10.2+/-8 mL/24-hr stool vs 5.2+/-4.4 mL/24-hr stool, p < 0.05). CONCLUSIONS: We confirm that protein and fat malabsorption, maldigestion, and PLE are present in some PD patients. Higher fecal Calpha1AT is associated with malnutrition and poorer showings of the viability markers of peritoneal membrane function.     

Independent association of matrix metalloproteinase-10, cardiovascular risk factors and subclinical atherosclerosis

OBJECTIVES: Circulating levels of matrix metalloproteinase (MMP)-10 are related to inflammation in asymptomatic subjects with cardiovascular risk factors. Whether MMP-10 is associated with the severity of atherosclerosis remains to be determined. This study examines the relationship of systemic MMP-10 levels with atherosclerotic risk factors and subclinical atherosclerosis. METHODS AND RESULTS: Circulating levels of MMP-1, -9 and -10, and markers of inflammation [fibrinogen, interleukin-6, von Willebrand factor, and high-sensitivity C-reactive protein (hs-CRP)] were measured in 400 subjects (mean age 54.3 years, 77.7% men) with cardiovascular risk factors but free from clinical cardiovascular disease. Subclinical atherosclerosis was evaluated by both the mean carotid intima-media thickness (IMT) and the presence of atherosclerotic plaques with the use of B-mode ultrasound in all subjects. MMP-10 levels were positively correlated with fibrinogen (r = 0.24, P < 0.001), hs-CRP (r = 0.14, P < 0.01) and carotid IMT (r = 0.17, P < 0.01). The association between MMP-10 and IMT remained significant in multiple regression analysis (P < 0.02) when controlling for traditional atherosclerotic risk factors and inflammatory markers. Such an association was not observed for MMP-1 and -9. Subjects in the highest MMP-10 tertile had significantly higher carotid IMT (adjusted odds ratio 6.3, 95% confidence interval 1.3-31.4, P = 0.024). In addition, MMP-10 levels were significantly higher in patients with carotid plaques (n = 78) than in those with no plaques after adjusting for age and sex (P < 0.01). CONCLUSION: Higher serum MMP-10 levels were associated with inflammatory markers, increased carotid IMT and atherosclerotic plaques in asymptomatic subjects. Circulating MMP-10 may be useful to identify subclinical atherosclerosis in subjects free from cardiovascular disease.     

Prognostic value of homocysteinemia in patients with congestive heart failure.

BACKGROUND: Elevated plasma homocysteine levels are associated with increased risk of vascular disease and of congestive heart failure (CHF), with a relationship between homocysteine values and disease severity. Hyperhomocysteinemia is a risk factor for cardiac dysfunction. In this study, the predictive value of elevated homocysteine levels was investigated in the prognosis of ischemic and non-ischemic CHF. METHODS: A total of 159 patients with CHF, 89 with non-ischemic and 70 with ischemic CHF (83% males, mean age 62 years, mean ejection fraction 27%), and 119 controls (79% males, mean age 59.8 years) had fasting blood samples taken to measure plasma homocysteine, vitamin B(12) and folate levels. Coronary angiography was performed for all patients. The mean duration of follow-up was 49.6+/-36.7 months. RESULTS: As in other studies, the mean level of homocysteinemia was significantly higher in the CHF group (15.80 micromol/L) than in the control group (10.90 micromol/L) (p=0.001) whatever the etiology (non-ischemic, 16.11+/-6.84 micromol/L; ischemic, 15.41+/-6.45 micromol/L). This result was observed without vitamin deficiency, but in patients, the mean creatinine value was moderately higher than in controls. We found a positive correlation between plasma homocysteine levels and New York Heart Association (NYHA) classification, creatinine and age. Moreover, hyperhomocysteinemia appears to be a powerful predictive factor of mortality in CHF patients (relative risk of death, 4.23; p=0.0003). In the follow-up of this study, 41.5% of patients with homocysteinemia >17 micromol/L died vs. 21.3% of patients with levels <17 micromol/L. In multivariate analysis, when homocysteine levels were adjusted for a second parameter (age, NYHA, creatinine, diabetes), the risk of death remained significant after each adjustment. CONCLUSIONS: Elevated homocysteine levels observed in CHF patients, whatever the etiology of their heart disease (ischemic or non-ischemic), were correlated with the severity of the disease. Hyperhomocysteinemia appears to be a predictive factor of mortality in CHF patients.     

Elevated plasma asymmetric dimethylarginine as a marker of cardiovascular morbidity in early diabetic nephropathy in type 1 diabetes

OBJECTIVE: Increased plasma concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, has been associated with endothelial dysfunction, insulin resistance, and atherosclerosis in nondiabetic populations. In end-stage renal failure, circulating ADMA is elevated and a strong predictor of cardiovascular outcome. This study investigated the relation between ADMA and diabetic micro- and macrovascular complications in a large cohort of type 1 diabetic patients with and without early diabetic nephropathy. RESEARCH DESIGN AND METHODS: ADMA concentrations in plasma were determined by a high-performance liquid chromatography method in 408 type 1 diabetic patients with overt diabetic nephropathy (252 men; mean age 42.7 years [SD 11.0], mean duration of diabetes 28 years [SD 9], median serum creatinine level 102 micromol/l [range 52-684]). A group of 192 patients with longstanding type 1 diabetes and persistent normoalbuminuria served as control subjects (118 men; mean age 42.6 years [SD 10.2], mean duration of diabetes 27 years [SD 9]). RESULTS: In patients with diabetic nephropathy, mean +/- SD plasma ADMA concentration was elevated 0.46 +/- 0.08 vs. 0.40 +/- 0.08 micromol/l in normoalbuminuric patients (P<0.001). An increase in plasma ADMA of 0.1 micromol/l increased the odds ratio of nephropathy to 2.77 (95% CI 1.89-4.05) (P<0.001). Circulating ADMA increased in nephropathy patients with declining kidney function, as indicated by elevated values in the lower quartiles of glomerular filtration rate (<76 ml.min(-1).1.73 m(-2)) (P<0.001 ANOVA). Mean ADMA levels were similar in patients with or without diabetic retinopathy (P>0.2). However, in 44 patients with nephropathy and history of myocardial infarction and/or stroke, ADMA was significantly elevated at 0.48 +/- 0.08 micromol/l compared with 0.46 +/- 0.08 micromol/l in patients without major cardiovascular events (P=0.05). CONCLUSIONS: Elevated circulating ADMA may contribute to the excess cardiovascular morbidity and mortality in early diabetic nephropathy.     

Association between early detection of soluble TNF-receptors and mortality in burn patients

OBJECTIVES: To describe early sequential profiling of circulating levels of tumor necrosis factor alpha (TNF-alpha), TNF-1 and TNF-2 soluble receptors (sTNFR1 and sTNFR2), and of endothelin (ET-1) in patients with severe burn injury, and its association with mortality. DESIGN: Prospective study. SETTING: Intensive Care Burn Unit at a community hospital. PATIENTS: Twenty patients with total burn surface area (TBSA)> or = 30%. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Patients were enrolled within 6 h from the injury. Blood samples were drawn at zero, 6, 12, and 24 h for sequential ELISA measurement of plasma marker levels. Data are expressed as mean+/-SD. Age, TBSA, and inhalation injury were not significantly different between survivors ( n=9; 30+/-13 years, TBSA 40+/-12%) and nonsurvivors ( n=11, 38+/-15 years, TBSA 56+/-20%). sTNFR1 levels were increased in nonsurvivors (2937+/-1676 pg/ml; 4548+/-1436 pg/ml) as compared to survivors (1313+/-561 pg/ml; 2561+/-804 pg/ml) at 6 h and 24 h, respectively ( P=0.01 and 0.002). sTNFR2 levels were significantly increased in nonsurvivors (4617+/-1,876 pg/ml vs 2611+/-1,326 pg/ml) only at 6 h ( P=0.015). TNF-alpha and ET-1 levels were not different between nonsurvivors and survivors. After adjustment for TBSA, sTNFR1 and sTNFR2 remained significantly higher in nonsurvivors. CONCLUSION: Early and progressive increase in sTNFR1 and sTNFR2 levels is associated with higher risk for poor outcome in severely burned patients.     

Role of endothelin in modulation of heart rate variability in patients with decompensated heart failure

Endothelin-1 (ET-1) can modulate central and peripheral sympathetic outflow. However, if increased ET-1 levels contribute to autonomic perturbations in the setting of congestive heart failure (CHF) is not known. The purpose of this study was to determine if increased ET-1 levels contribute to the depressed HRV in patients with CHF. Sixty-four patients were admitted to the hospital for treatment of decompensated CHF (mean age 59+/-12 years, NYHA Classes III [72%] and IV [28%]). Time- and frequency-domain HRV measures were obtained from 24-hour Holter recordings. Neurohormonal activation was assessed by measuring plasma renin activity (PRA), aldosterone, norepinephrine, and ET-1 levels. Among the time-domain HRV indices, ET-1 correlated negatively with the standard deviation of RR intervals (SDNN) (r = - 0.38, P = 0.002) and standard deviation of all 5-minute mean RR intervals (SDANN5) (r = - 0.48, P < 0.0001), but not with time-domain indices indicative of parasympathetic modulation. Among the frequency-domain HRV indices, ET-1 correlated negatively with the total power (r = - 0.32, P = 0.01) and ultralow frequency power (ULF) (r = - 0.43, P = 0.0004), but not with indices of parasympathetic (high frequency) or sympathovagal (low frequency) modulation. Using multiple linear regression, adjusting for clinical parameters, drug therapies, and other neurohormones, the strong negative relationship between ET-1 and SDNN (P = 0.027), SDANN5 (P = 0.002), and ULF power (P = 0.017) persisted. In conclusion, ET-1 may play an important role in the autonomic dysfunction characteristic of CHF. The correlation between ET-1 levels and prognostically important indices of overall HRV suggests that these HRV measures are better markers of neurohormonal activation in CHF, which may partially account for their greater discriminatory power for risk stratification.     

Inhaled nitric oxide increases endothelin-1 levels: a potential cause of rebound pulmonary hypertension

OBJECTIVE: Inhaled nitric oxide (iNO) is front-line therapy for pulmonary hypertension after repair of congenital heart disease. However, little clinical data exists regarding the effects of iNO on regulators of pulmonary vascular resistance. An imbalance between primary vasodilators, such as NO, and vasoconstrictors, such as endothelin-1 (ET-1), has been implicated in rebound pulmonary hypertension upon iNO withdrawal. The objective of this study was to determine whether iNO therapy alters plasma ET-1 levels. DESIGN: This is a prospective study involving pediatric and adult patients at risk for pulmonary hypertension. SETTING: Pediatric patients were in the cardiac intensive care unit and adult patients were in a tertiary-care hospital. PATIENTS: Group 1 included children with congenital heart disease requiring iNO for treatment of pulmonary hypertension after cardiopulmonary bypass (n = 15), group 2 was adults receiving iNO (n = 10), and group 3 included children at risk for pulmonary hypertension after bypass that did not require iNO (n = 8). INTERVENTIONS: Dosages of iNO were 2-60 ppm. The duration of therapy ranged from 23 to 188 hrs in group 1 and 29 to 108 hrs in group 2. MEASUREMENTS AND MAIN RESULTS: Arterial blood was obtained for the measurement of ET-1 levels before and during iNO therapy and 24 hrs after iNO withdrawal. Group 1 mean ET-1 levels increased to 127% of baseline by 12 hrs of iNO, remained elevated at 48 hrs (p < .05), then decreased to 71% of iNO levels 24 hrs after withdrawal (p < .01). Group 2 ET-1 levels increased to 147%, and 137% of baseline at 12 and 24 hrs of iNO therapy, then fell to 68% of baseline within 24 hrs of discontinuing iNO. ET-1 levels in group 3 decreased after surgery (p < .05). CONCLUSIONS: These data suggest that iNO increased plasma ET-1 levels, which subsequently decreased when iNO was discontinued. Increased circulating ET-1 levels might contribute to rebound pulmonary hypertension upon iNO withdrawal.