Role of TNF-alpha and its 55 and 75 kDa receptors in bronchial hyperreactivity

The pathophysiological role of the tumour necrosis factor (TNF) system was studied in adults (n=37) and children (n=43) non asthmatic offspring of asthmatic parents with and without bronchial hyperreactivity proved by methacholine airway challenge test. SerumTNFalpha and its soluble receptors (sTNF-R1 and R2) were determined by enzyme-linked immunosorbent assay (ELISA). Significantly elevated TNFalpha (adults: mean +/- SD=5.18 +/- 0.87 pg ml(-1), children: 5.08 +/- 1.78) vs. non-hyperreactives (adults: 4.12 +/- 0.43, P < 0.0001, children: 3.75 +/- 0.68, P=0.0084), sTNF-R1 (adults: 144 +/- 0.31 ng ml(-1), children: 1.30 +/- 0 25 vs. adults: 1.21 +/- 0.14, P=0.0305, children: 1.13+/-0.11 ng ml(-1), P=0.0042) and sTNF-R2 (adults: 0.85 +/- 0.40ng ml(-1), children: 0.70 +/- 0.46 vs. adults: 0.56 +/- 0.56 P=0.0084, children: 0.33 +/- 0.17, P=0.0048) and decreased sTNF-R1/R2 ratio (adults: mean +/- SD=0.96 +/- 0.73, children: 2.85 +/- 2.06 vs. adults: 4.82+/-3.40, P=0.0272, children: 4 42 +/- 2 30, P=0.0167) were measured in patients with bronchial hyperreactivityThe provocation doses of methacholine causing a 20% reduction (PD20) in forced expiratory volume in 1 sec (FEV1) were found to be in a significant negative linear correlation with TNFalpha sTNF-R1 and R2 levels in hyperreactive adults and with TNFalpha, sTNF-R2 in hyperreactive children. TNFalpha correlated significantly with its receptors both in hyperreactive adults and children and with the body mass index (BMI) values of adults.The TNF system may contribute to the pathophysiology of bronchial hyperreactivity Altered shedding of sTNF-R1 seems to occur in hyperreactive patients.     

The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men

Testosterone has immune-modulating properties, and current in vitro evidence suggests that testosterone may suppress the expression of the proinflammatory cytokines TNFalpha, IL-1beta, and IL-6 and potentiate the expression of the antiinflammatory cytokine IL-10. We report a randomized, single-blind, placebo-controlled, crossover study of testosterone replacement (Sustanon 100) vs. placebo in 27 men (age, 62 +/- 9 yr) with symptomatic androgen deficiency (total testosterone, 4.4 +/- 1.2 nmol/liter; bioavailable testosterone, 2.4 +/- 1.1 nmol/liter). Compared with placebo, testosterone induced reductions in TNFalpha (-3.1 +/- 8.3 vs. 1.3 +/- 5.2 pg/ml; P = 0.01) and IL-1beta (-0.14 +/- 0.32 vs. 0.18 +/- 0.55 pg/ml; P = 0.08) and an increase in IL-10 (0.33 +/- 1.8 vs. -1.1 +/- 3.0 pg/ml; P = 0.01); the reductions of TNFalpha and IL-1beta were positively correlated (r(S) = 0.588; P = 0.003). In addition, a significant reduction in total cholesterol was recorded with testosterone therapy (-0.25 +/- 0.4 vs. -0.004 +/- 0.4 mmol/liter; P = 0.04). In conclusion, testosterone replacement shifts the cytokine balance to a state of reduced inflammation and lowers total cholesterol. Twenty of these men had established coronary disease, and because total cholesterol is a cardiovascular risk factor, and proinflammatory cytokines mediate the development and complications associated with atheromatous plaque, these properties may have particular relevance in men with overt vascular disease.     

Effect of losartan on circulating TNFalpha levels and left ventricular systolic performance in patients with heart failure.

BACKGROUND: Tumor necrosis factor alpha (TNFalpha) plays an important role in the pathophysiology of heart failure. Recent studies have shown a beneficial effect of losartan in these patients. However, the effect of losartan on TNFalpha levels in heart failure has not yet been studied. We evaluated the effect of losartan on circulating TNFalpha levels and ejection fraction (EF) in patients with congestive heart failure. METHODS: Forty patients with heart failure and EF < or = 40% were enrolled into the study. All of the patients have been given diuretic and digitalis therapy. Twenty patients were given losartan (50 mg/d) (Group I, 10 women, 10 men, 12 dilated cardiomyopathy, 8 ischemic heart disease, mean age 64.9 + 8.9), and another 20 patients were not given losartan because of hypotension or renal dysfunction (Group II, 13 men, 7 women, 10 dilated cardiomyopathy, 10 ischemic heart disease, mean age 61.2 +/- 10.5). EF was measured at the initial evaluation and on the fifteenth day of the therapy by echocardiographic examination using an acoustic quantification method. Circulating TNFalpha levels were also measured at the initial evaluation and on the fifteenth day of therapy by the ELISA method. RESULTS: Losartan significantly increased EF and decreased TNFalpha (EF increased from 29.4 +/- 7.3% to 36.0 +/- 8.5%, P < 0.001, and TNFalpha decreased from 39.2 +/- 37.4 pg/ml to 27.0 +/- 30.0 pg/ml, P < 0.05). Changes in TNFalpha levels and EF were not found to be correlated (r=-0.28, P=0.24). However, in the control group, EF and TNFalpha levels were similar at baseline and at the fifteenth day (EF 31.4 + 8.1% vs 31.7 +/- 7.8%, P=0.1, and TNFalpha 91.5 + 86.0 pg/ml vs 110.0 +/- 80.7 pg/ml, P=0.1, respectively). CONCLUSIONS: Losartan improves left ventricular systolic function and decreases TNFalpha level. The decreased TNFalpha level seems to be independent of EF.     

Invasive assessment of bacterial endotoxin and inflammatory cytokines in patients with acute heart failure

AIMS: To test the hypothesis that during acute heart failure endotoxin might be increased in hepatic veins as a sign of bacterial or endotoxin translocation from the bowel into the blood stream. METHODS AND RESULTS: In patients with acute heart failure (NYHA IV; n=17) levels of endotoxin, soluble (s) CD14, tumor necrosis factor alpha (TNFalpha and interleukin 6 (IL6)) were measured in blood drawn from an antecubital vein on admission and compared with age-matched patients with stable chronic heart failure (n=21) and healthy volunteers (n=9). All levels were systemically elevated during acute heart failure (all P<0.05); once patients were stable enough to undergo cardiac catheterization, endotoxin was found to be significantly higher in hepatic veins (0.62+/-0.05 EU/ml) than left ventricles (0.46+/-0.04 EU/ml; P<0.05), whereas sCD14, TNFalpha and IL6 were not different between these sites. At follow-up (29+/-6 days) endotoxin but not sCD14, TNFalpha or IL-6 was significantly lower as compared to baseline (P<0.05). CONCLUSIONS: Higher levels of endotoxin in hepatic veins as compared to the left ventricle during acute heart failure are suggestive of bacterial or endotoxin translocation from the bowel into the blood stream. This may lead to new treatment strategies. The lack of difference in TNFalpha levels between the pulmonary artery and the left ventricle sheds doubt on the heart as a source of systemically elevated TNFalpha levels.     

Cancer cachexia

OBJECTIVES: Chronic heart failure (CHF) has emerged as an insulin-resistant state, independently of ischaemic aetiology. The underlying mechanisms of this finding are not known. Catecholamines, tumor necrosis factor alpha (TNFalpha) and leptin, the adipocyte specific hormone, have all been implicated as mediators of impaired insulin sensitivity. The purpose of this study was to examine in patients with CHF and in comparison to healthy controls subjects whether norepinephrine, TNFalpha or leptin relate to insulin sensitivity. DESIGN: 41 patients with CHF (age 60+/-2 years, NYHA I/II/III/IV 4/12/22/3, peak oxygen consumption 17.6+/-1.0 ml/kg per min) and 21 healthy controls of similar age and total and regional fat distribution were studied in a cross-sectional study. Insulin sensitivity was assessed by intravenous glucose tolerance testing using the minimal model approach; catecholamines, TNFalpha and soluble TNF receptors 1 and 2 were also measured. Total and regional body fat mass was assessed by dual energy X-ray absorptiometry. RESULTS: Insulin sensitivity was reduced in CHF patients compared to controls by 31% (P<0.01) and fasting insulin was higher in patients than in controls (79.1+/-9.7 vs. 41.4+/-6.0 pmol/l, P<0.01). Patients had, compared to healthy controls, elevated serum leptin levels (8.28+/-0.84 vs. 4.83+/-0.68 ng/ml), norepinephrine (3.45+/-0.34 vs. 1.87+/-0.16 nmol/l, both P<0.01) and soluble TNF-receptors 1 (1280+/-141 vs. 639+/-52 pg/ml) and 2 (2605+/-184 vs. 1758+/-221 pg/ml, both P<0.01). Leptin levels corrected for total body fat mass were higher in CHF patients than in controls (41.3+/-3 vs. 24.3+/-2 pg/ml per 100 g, P<0.001). TNFalpha was not significantly different between the groups. In both groups there was an inverse correlation between insulin sensitivity and serum leptin (r=-0.65, P<0.0001 for pooled subjects); in contrast, no significant relation was found between insulin sensitivity and norepinephrine or TNFalpha. In multivariate regression analysis, leptin emerged as the only significant predictor of insulin sensitivity (standardised coefficient=-0.59, P<0.001), independent of body fat mass, age and peak VO2. CONCLUSION: In moderate CHF, elevated leptin levels directly and independently predict insulin resistance. Elevated serum leptin levels could play a role in the impaired regulation of energy metabolism in CHF. In contrast to observations in other conditions, TNFalpha and norepinephrine are not related to insulin resistance in moderate CHF.     

Lipid peroxidation and antioxidant enzyme levels in type 2 diabetics with microvascular complications

Serum levels of total cholesterol, triglycerides, lipoproteins, lipid peroxides (TBARS) and erythrocyte antioxidant enzyme activities were measured in 105 non insulin dependent diabetic patients, among whom 38 had microvascular complications (MVC) of diabetes. All the diabetic patients had higher concentrations of glycated hemoglobin (HbA1) compared to controls (10.51 +/- 2.42% vs 6.31 +/- 0.85% P <0.001). Significant increase of serum triglycerides (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and very low density lipoprotein cholesterol (VLDL-C) and a significant decrease of high density lipoprotein cholesterol (HDL-C) were observed in the diabetic patients compared to controls (TG: 2.31 +/- 0.9 mmol/l vs 1.53 +/- 0.48 mmol/l P <0. 001; TC: 5.94 +/- 1.4 mmol/l vs 4.3 +/- 0.85 mmol/l P <0.001; LDL-C: 3.96 +/- 1.33 mmol/l vs 2.39 +/- 0.8 mmol/l P <0.001; VLDL-C: 0.46 +/- 0.2 mmol/l vs 0.3 +/- 0.09 mmol/l P <0.001; HDL-C: 0.81 +/- 0.24 mmol/l vs 1.04 +/- 0.18 mmol/l P <0.001). Significantly increased levels of serum TBARS were observed in diabetic patients compared to those in controls (TBARS: 6.7 +/- 1.5 mmol/l vs 5.14 +/- 0.61 mmol/l P <0.001). Erythrocyte catalase (CAT) activity was increased and Glutathione peroxidase (GPx) activity was decreased in diabetic patients compared to controls, but no significant change in Superoxide dismutase (SOD) activity was observed in diabetic patients (CAT: 104.94 +/- 37.1 KU/g Hb vs 85.8 +/- 23.6 KU/g Hb, P <0.01; GPx: 30 +/- 9.7 U/g Hb/min vs 40.84 +/- 12.3 U/g Hb/min, P <0. 001; SOD: 2.4 +/- 1.2 U/mg Hb/min vs 2.55 +/- 0.84 U/mg Hb/min, P=NS). In comparison with the diabetic group without MVC, the diabetic group with MVC had decreased GPx and SOD activities, while no difference was observed between these two groups regarding CAT activity (GPx: 25.32 +/- 8.4 U/g Hb/min vs 34.5 +/- 8.8 U/g Hb/min, P <0.001; SOD: 1.83 +/- 0.53 U/mg Hb/min vs 2.84 +/- 1.4 U/mg Hb/min, P<0.001; CAT: 106.3 +/- 39.9 KU/g Hb vs 103 +/- 34.9 KU/g Hb, P =NS). TBARS concentrations were significantly increased in the group with MVC compared to the group without these complications, indicating a positive relationship between TBARS and MVC of diabetes (7.05 +/- 1.23 mmol/l vs 6.3 +/- 1.02 mmol/l, P <0.001). Serum triglycerides, LDL and VLDL cholesterol concentration were significantly higher in diabetics with MVC than in diabetics without the complications (TG: 2.7 +/- 0.98 mmol/l vs 2.13 +/- 0.82 mmol/l, P<0.01; LDL - C: 4.45 +/- 1.3 mmol/l vs 3.67 +/- 1.3 mmol/l, P <0. 02; VLDL-C: 0.53 +/- 0.19 mmol/l vs 0.43 +/- 0.16 mmol/l, P <0.01), and the serum levels of TC in the group with MVC showed a positive correlation with their lipid peroxide levels (r =0.368, P <0.001). The increase in TBARS and the decreased GPx and SOD activities in diabetics with MVC in this study indicate that these factors may contribute to the occurrence of micro vascular complications in NIDDM patients.     

Functional improvement in heart failure patients treated with beta-blockers is associated with a decline of cytokine levels

BACKGROUND: In patients with severe heart failure (CHF), chronically elevated cytokine levels document a systemic inflammation. Experimental data suggest that activation of the beta-adrenergic system may participate in this inflammatory response. Herein, we studied as to whether beta-adrenergic blockade on top of standard CHF therapy affects plasma cytokine levels (interleukin-6 [IL-6] and tumor necrosis factor alpha [TNFalpha]). Moreover, we studied if beta-blocker related changes of these cytokines correspond to changes in left ventricular (LV) function and exercise capacity. METHODS: In a prospective study, 21 patients with stable CHF (NYHA functional class II-III, ejection fraction <40%, mean age 57.6+/-12.4 years) were treated with captopril (100-150 mg/day), furosemide (40-120 mg/day), and/or digoxin (0.1-0.2 mg/day) for at least 1 month before they entered a 4 week run-in period in which dosages were kept unchanged. Metoprololsuccinate was administered in increasing dosages (up to 190 mg/day) for the following 3 months. Clinical, echocardiographic, spiroergometric, and biochemical changes were assessed at the start and the end of the run-in period as well as after 3 month of beta-blockade. RESULTS: As compared to 210 healthy volunteers, CHF patients, prior to beta-blockade, presented with markedly elevated IL-6 (8.9+/-9.9 vs. 2.1+/-0.5 pg/ml; p<0.05) and TNFalpha levels (1.51+/-0.49 vs. 0.64+/-0.15 pg/ml; p<0.05) levels. In CHF patients, 3 month of beta-blockade lowered heart rate (84+/-14 vs. 68+/-12 bpm; p<0.01), systolic (131+/-7 vs. 118+/-6 mm Hg; p<0.01), and diastolic blood pressure (78+/-5 vs. 71+/-6 mm Hg; p<0.01). Spiroergometric determined VO2 max (17.8+/-4.5 vs. 19.8+/-4.3 ml/min kg; p=0.013) increased significantly during 3 month of beta-blockade. Moreover, LV functional parameters tended to improve but the interindividual response varied and changes were non-significant. Interestingly, IL-6 levels decreased markedly during beta-blockade (8.9+/-9.9 vs. 4.5+/-3.1 pg/ml; p=0.036), whereas TNFalpha levels remained unchanged. Moreover, significant positive correlations were found between decrease of IL-6 levels and left ventricular end diastolic diameters (r2=0.59; p=0.012), whereas an inverse correlation was found between the decrease of IL-6 and the increase of VO2 max (r2=0.54; p=0.037), respectively. CONCLUSION: In heart failure patients, beta-blockade may lower IL-6 but not TNFalpha levels. Changes of IL-6 during beta-blockade may be related to changes of LV function and geometry.     

Glucose and insulin abnormalities relate to functional capacity in patients with congestive heart failure.

AIMS: In addition to diabetes mellitus, less severe abnormalities of glucose and insulin metabolism may be related to functional status in patients with heart failure. We examined the relationship of hyperglycaemia (> or =6.1 mmol. l(-1)) and hyperinsulinaemia (> or =11.2 mU. l(-1)) to functional status and cardiac function in patients with heart failure. METHODS AND RESULTS: Fasting plasma glucose and insulin levels were obtained in 663 heart failure patients. The average left ventricular ejection fraction was 0.28+/-0.07, 63% were in New York Heart Association Functional Class (NYHA-FC) I/II and 37% were in NYHA-FC III/IV. Twenty seven percent had diabetes mellitus, but an additional 8% had undiagnosed diabetes mellitus (glucose > or =7 mmol. l(-1)) and 9% had glucose levels between 6.1 and 7 mmol. l(-1), so that a total of 43% (287) of patients had elevated glucose levels (> or =6.1 mmol. l(-1)). In general, more diabetic patients had NYHA-FC III/IV symptoms, shorter 6 min walk distances, but similar left ventricular ejection fractions compared to non-diabetic patients. The non-diabetic patients in NYHA-FC III/IV had higher glucose and insulin levels than patients in NYHA-FC I/II (6.3+/-0.2 vs 5.6+/-0.1 mmol. l(-1), P<0.001 and 19.6+/-2.3 vs 10. 2+/-0.6 mU. l(-1), P<0.001). Non-diabetic patients with elevated glucose levels had shorter 6 min walk distances compared to those with normal glucose levels (368.2+/-8 m vs 389.+/-4 m, P=0.02), however, left ventricular ejection fraction was similar. CONCLUSION: Glucose abnormalities are extremely common in heart failure patients (43% of patients). Diabetes mellitus and hyperglycaemia or hyperlinsulinaemia in non-diabetic patients were related to worse symptomatic status but not worsening left ventricular ejection fraction compared to patients with normal glucose and insulin levels.     

Influence of serum amyloid A on the decrease of high density lipoprotein-cholesterol in active sarcoidosis

OBJECTIVE: We have previously observed low levels of high density lipoprotein (HDL) cholesterol in active sarcoidosis. The aim of this study was to analyze the role of serum amyloid A (SAA) on this lipid disorder. METHODS: Eighty five untreated sarcoid patients, 40 with active disease and 45 with inactive disease, were recruited. Sarcoidosis activity was evaluated by means of clinical, chest X-ray, gallium-67 scan, serum angiotensin converting enzyme (peptidyl-dipeptidase A) values, and pulmonary function tests. Analysis of lipoprotein metabolism included: serum cholesterol, low density lipoprotein (LDL)-cholesterol, HDL-cholesterol, HDL(2)-cholesterol, HDL(3)-cholesterol, apolipoprotein A-I (apo A-I), apolipoprotein B (apo B), and triglyceride concentrations. Serum amyloid A protein and lecithin-cholesterol acyltransferase (LCAT) activity were measured. RESULTS: In active sarcoidosis we found significantly reduced levels of HDL-cholesterol (1.17+/-0.36 vs. 1. 44+/-0.39 mmol/l, P=0.002), HDL(3)-cholesterol (0.78+/-0.23 vs. 1. 02+/-0.21 mmol/l, P<0.0001), and apo A-I (1.36+/-0.29 vs. 1.61+/-0. 27 g/l, P<0.0001) and significantly increased levels of triglyceride (1.51+/-0.64 vs. 1.03+/-0.46 mmol/l, P<0.0001), and apo B (1.14+/-0. 25 vs. 0.99+/-0.27 g/l, P=0.012) versus inactive sarcoidosis. Serum amyloid A concentrations were significantly increased in the patients with active disease (155.45+/-154.01 mg/ml) compared to the inactive sarcoid patients (89.70+/-65.36 mg/ml) (P=0.011). There were no significant differences in cholesterol, LDL-cholesterol, HDL(2)-cholesterol or LCAT values between groups. Multivariate logistic regression analysis showed that HDL-cholesterol (regression coefficient b=-1.96; S.E.=0.87; P=0.02) and SAA (regression coefficient b=0.01; S.E.=0.004; P=0.01) were the two variables independently associated with disease activity. Moreover, a significant negative correlation was observed between SAA levels and both HDL-cholesterol (r=-0.39; P=0.01) and apo A-I (r=-0.35; P=0.03) levels, in the active sarcoid group. Conversely, no correlation was found in the inactive sarcoid group. CONCLUSION: The low HDL-cholesterol and apo A-I concentrations seen in active sarcoid patients are associated with a significant increase of SAA levels. We suggest that the displacement of apo A-I by SAA on HDL accounts for the lower level of HDL-cholesterol seen in active sarcoidosis.     

The effects of dyslipidemia on left ventricular systolic function in patients with stable angina pectoris.

Large-scale clinical trials have shown that long-term treatment with lipid-lowering therapy results in a significant reduction in the occurrence of heart failure among patients with coronary artery disease without previous evidence of congestive heart failure, suggesting dyslipidemia may have an adverse effect on left ventricular performance. To examine whether dyslipidemia has a detrimental effect on left ventricular systolic function and whether this effect is dependent on the corresponding severity of coronary atherosclerosis, 114 consecutive patients with stable angina and a positive exercise thallium-201 myocardial perfusion single-photon emission computed tomography were studied. All patients underwent measurement of serum lipid profiles, right-sided heart catheterization, left ventriculography, and selective coronary arteriography. Mean serum levels of total cholesterol and triglycerides were 4.5 and 1.4 mmol/l, respectively. In univariate analysis, a significant positive correlation between serum high-density lipoprotein (HDL) cholesterol and left ventricular ejection fraction (LVEF) (r = 0.49, P<0.0001) was found. Patients in the lower tertile of serum HDL cholesterol had a significantly lower mean LVEF than those in the upper tertile (55.9+/-15.2 vs. 72.8+/-6.8%, P<0.0001). Stepwise multiple linear regression analysis revealed that LVEF significantly correlated with HDL cholesterol (P<0.0001), the Gensini score (P = 0.008), and diabetes mellitus (P = 0.08) (r = 0.55, P<0.0001). In subgroup analysis of patients with angiographically normal coronary arteries, serum HDL cholesterol was still significantly associated with LVEF. The present study demonstrated an independent association between low HDL cholesterol and subclinical left ventricular systolic dysfunction in Chinese patients with stable angina whose serum levels of total cholesterol and triglycerides were relatively low. Moreover, this correlation remained significant even in patients with normal coronary angiograms, suggesting HDL cholesterol might influence left ventricular systolic performance through extra-atherosclerotic mechanisms.     

Analysis of the relationship between triglyceridemia and HDL-phospholipid concentrations: consequences on the efflux capacity of serum in the Fu5AH system

The high triglyceride/low HDL-cholesterol trait is a common finding in the general population. The aim of the present study was to analyze and interpret the relationships between triglycerides (TG), HDL-related parameters and serum cholesterol efflux potential in an asymptomatic population including both normo- and hyperlipidemic individuals. In a large sample (n = 1143) of this population, there was a negative correlation between TG and HDL-cholesterol (HDL-C) (r = -0.49, P<0.0001) whereas the negative correlation between TG and HDL-phospholipid (HDL-PL) (r = -0.29, P<0.0001) was weaker, leading to a strong positive correlation between TG and HDL-PL/C ratio (r = 0.58, P<0.0001). Thus, increased TG concentrations were associated with an enrichment of HDL with PL. Since we have demonstrated previously that HDL-PL is the major determinant for cholesterol efflux potential from Fu5AH rat hepatoma cells, we determined the effect of the variations in HDL lipid composition on the cholesterol efflux capacity in a subsample of 198 subjects. Compared with normolipidemic subjects (NLP) (TG< or = 1.7 mmol/l; LDL-C< or = 4.1 mmol/l, n=58), hypertriglyceridemic subjects (HTG) (TG>1.7 mmol/l, n=63) exhibited lower HDL-C levels (1.08+/-0.21 vs. 1.25+/-0.32, P=0.0003) whereas they showed similar HDL-PL concentrations (1.25+/-0.21 vs. 1.25+/-2.7) and, thus, higher HDL-PL/C ratio (1.17+/-0.15 vs. 1.02+/-0.14, P=0.0001). The relative efflux capacity of serum measured in the Fu5AH system (5% serum, 4 h incubation at 37 degrees C) was on average identical in the HTG and NLP groups. Thus, this study provides evidence that despite decreased HDL concentrations, as determined routinely by the HDL-C assay, some HTG subjects maintained serum cholesterol efflux capacity thanks to the enrichment of HDL with PL.     

Tumor necrosis factor alpha and insulin resistance in obese type 2 diabetic patients

The relationship between basal serum tumor necrosis factor alpha (TNFalpha) levels and peripheral tissue (muscle) sensitivity to insulin was examined in 63 subjects with normal glucose tolerance (NGT), 18 subjects with impaired glucose tolerance (IGT), and 123 patients with type 2 diabetes mellitus (T2DM). The BMI was similar in NGT (28.8+/-0.7 kg/m(2)), IGT (31.1+/-1.0), and T2DM (30.0+/-0.4) groups. The fasting serum TNFalpha concentration in T2DM (4.4+/-0.2 pg/ml) was significantly higher than in NGT (3.1+/-0.2) and IGT (3.4+/-0.2; both P<0.05). In T2DM the fasting plasma glucose (FPG=183+/-5 mg/dl) and insulin (FPI=17+/-1 micro U/ml) concentrations were significantly higher than in NGT (FPG=95+/-1; FPI=10+/-1) and IGT (FPG=100+/-2; FPI=13+/-1; all P<0.01). The rate of total body insulin-mediated glucose disposal (Rd; 40 mU/m(2) min euglycemic insulin clamp in combination with (3)H-glucose) was reduced in T2DM (102+/-3 mg/m(2) min) compared with NGT (177+/-10) and IGT (151+/-14; both P<0.01). The serum TNFalpha concentration was inversely correlated with Rd (r=-0.47, P<0.0001) and positively correlated with both FPG (r=0.32, P=0.004) and FPI (r=0.32, P=0.004) in NGT plus IGT. No correlation was observed between serum TNFalpha and Rd (r=-0.02), FPG (r=0.15), or FPI (r=0.15) in T2DM. In stepwise multiple regression analysis using age, sex, BMI, FPG, FPI and serum TNFalpha concentration as independent variables, only BMI and serum TNFalpha concentration were significant and independent predictors of Rd (r(2)=0.29, P<0.0001) in the NGT plus IGT group, while FPG and FPI were significant and independent predictors of Rd (r(2)=0.13, P<0.0001) in T2DM. These results suggest that: (i) an increase in circulating TNFalpha concentration is associated with peripheral insulin resistance and increased plasma glucose and insulin levels prior to the onset of type 2 diabetes; and (ii) the further deterioration in peripheral insulin resistance in T2DM (compared with NGT and IGT) is unrelated to the increase in serum TNFalpha concentration.     

Does pravastatin increase chylomicron remnant catabolism in postmenopausal women with type 2 diabetes mellitus?

OBJECTIVE: We investigated the effects of pravastatin on chylomicron remnant catabolism measured with a 13C stable isotope breath test and plasma apolipoprotein (apo) B-48 and remnant-like particle (RLP)-cholesterol in postmenopausal women with type 2 diabetes mellitus. PATIENTS AND MEASUREMENTS: Nineteen postmenopausal women with type 2 diabetes were randomized to receive 40 mg/day pravastatin or no treatment for 6 weeks followed by a 2-week washout period, and crossed over for a further 6 weeks. Fractional catabolic rate (FCR) of a chylomicron remnant-like emulsion was determined from 13CO2 enrichment in the breath and plasma using isotope-ratio mass spectrometry and multicompartmental modelling. Plasma apo B-48 and RLP-cholesterol concentrations were also measured as static markers of chylomicron remnant metabolism. RESULTS: Pravastatin significantly reduced plasma concentrations of cholesterol (5.9 +/- 0.3 vs. 4.8 +/- 0.2 mmol/l; P < 0.001), low density lipoprotein (LDL)-cholesterol (3.5 +/- 0.2 vs. 2.6 +/- 0.2 mmol/l; P < 0.001), triglyceride (2.1 +/- 0.3 vs. 1.7 +/- 0.2 mmol/l; P = 0.017), non-high density lipoprotein (HDL)-cholesterol (4.4 +/- 0.3 vs. 3.3 +/- 0.2 mmol/l; P < 0.001), lathosterol/total cholesterol ratio (2.6 +/- 0.2 vs. 2.0 +/- 0.3, P = 0.035), apo B-100 (1.1 +/- 0.1 vs. 0.8 +/- 0.1 g/l; P = 0.001), apo B-48 (4.8 +/- 0.9 vs. 3.3 +/- 0.6 mg/l; P = 0.016), and RLP-cholesterol (31.4 +/- 8.2 vs. 18.6 +/- 4.6 mg/dl; P = 0.024). Pravastatin was also associated with an increase in sitosterol/total cholesterol ratio (2.8 +/- 0.3 vs. 3.1 +/- 0.3, P = 0.029). Chylomicron remnant-like emulsion catabolism was not, however, significantly altered by pravastatin estimated by either breath or plasma clearance measurements. CONCLUSIONS: In postmenopausal women, pravastatin decreases plasma concentrations of remnant lipoproteins by a mechanism that may relate chiefly to inhibition of remnant production, but this requires further evaluation.     

Propranolol treatment of congestive heart failure in infants with congenital heart disease: The CHF-PRO-INFANT Trial. Congestive heart failure in infants treated with propanol.

AIM: Infants with congenital heart disease and left-to-right shunts may develop significant clinical symptoms of congestive heart failure in spite of therapy with digoxin and diuretics. We investigated the effects of beta-blockade in infants with severe heart failure. METHODS AND RESULTS: We performed a prospective, randomized, open monocenter trial in infants treated with digoxin and diuretics (n=10) in comparison to 10 infants receiving additional beta-blocker therapy. After 17 days on average beta-blocker treated infants (propranolol:1,6 mg/kg/day) improved significantly with respect to Ross heart failure score (3.3+/-2.3 vs. 8.3+/-1.9, P=0.002), lower renin levels (338+/-236 vs. 704+/-490 microU/l, P=0.008) and lower mean heart rates in Holter ECG (118+/-10 vs. 142+/-11 beats/min, P<0.001). While digoxin and diuretic treated infants had unchanged mean heart rate (149+/-8 vs. 148+/-10 beats/min), less decrease of symptoms (Ross Score: 8.5+/-1.7 vs. 6.8+/-2.3, P=0.02) but a significant increase of renin levels (139+/-102 vs. 938+/-607 microU/l, P=0.001). CONCLUSION: Additional propranolol treatment but not digoxin and diuretics alone can effectively reduce clinical symptoms of heart failure in infants with congenital heart disease, who suffer from increased neurohormonal activation.     

Superiority of endothelin-1 over norepinephrine in exercise-induced alterations of the conduit artery tone of the non-exercised arm in patients with chronic heart failure

This study is aimed at examining the relative importance of norepinephrine and endothelin-1 in treadmill exercise-induced changes in brachial arterial tone of the non-exercised arm in patients with chronic heart failure (CHF). Brachial artery diameter and blood flow were measured before and after exercise in eight healthy volunteers and 18 patients with stable chronic heart failure by high-resolution ultrasound. Maximal exercise resulted in brachial artery dilatation in controls (4.42+/-0.39 vs. 4.77+/-0.39 mm; P<0. 0001) in contrast to constriction seen in the patients (5.27+/-0.67 vs. 5.12+/-0.66 mm; P=0.07). Both groups demonstrated a significant increase in blood flow after exercise. The pre-exercise (2.83+/-0.76 vs. 1.69+/-0.15 pmol/l; P=0.0004), post-exercise (4.15+/-1.5 vs. 2. 02+/-0.34 pmol/l; P=0.0004) and the percent increase (47.15+/-32.5 vs. 19.0+/-10.5%; P=0.02) in endothelin-1 levels were significantly greater in patients than in controls. In contrast to endothelin-1, the exercise-induced percent increase in norepinephrine was greater in controls than patients (100.7+/-51.8 vs. 49.8+/-43.4%; P=0.01). The percent change in the diameter of the brachial artery in response to maximal exercise was significantly correlated to pre- (r=0.634; P=0.003) and post-exercise (r=0.467; P=0.05) endothelin-1 levels in patients but not in controls [pre-exercise (r=0.07; P=0. 86), post-exercise (r=0.310; P=0.47)]. The change in the diameter of the brachial artery did not correlate with pre- or post-exercise plasma norepinephrine levels in either group. These findings suggest that endothelin-1 is potentially more important than norepinephrine in contributing exercise-induced brachial artery constriction in patients with chronic heart failure.     

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

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

The effect of atorvastatin on serum lipoproteins in acromegaly

OBJECTIVE: Acromegaly is associated with long-term adverse effects on cardiovascular mortality and morbidity. Reducing growth hormone secretion improves well-being and symptoms, but may not significantly improve the lipoprotein profile. An additional approach to cardiovascular risk reduction in acromegaly may therefore be to target lipoprotein metabolism directly. In this study we investigated the effect of statin treatment. DESIGN: Double blind, placebo-controlled, crossover study of the effects on circulating lipoproteins of atorvastatin 10 mg daily vs. placebo. Each treatment was given for 3 months in random order. SUBJECTS: Eleven patients with acromegaly. MEASUREMENTS: Lipids, lipoproteins, apolipoproteins, enzyme activity and calculated cardiovascular risk. RESULTS: Atorvastatin treatment compared to placebo resulted in a significant decrease in serum cholesterol (5.85 +/- 1.04 mmol/l vs. 4.22 +/- 0.69 mmol/l; mean +/- SD; P < 0.001), low-density lipoprotein (LDL) cholesterol (2.95 +/- 1.07 mmol/l vs. 1.82 +/- 0.92 mmol/l; P < 0.001), very low-density lipoprotein (VLDL) cholesterol (0.31 (0.21-0.47) mmol vs. 0.23 (0.13-0.30) mmol/l median (interquartile range); P < 0.05), apolipoprotein B (111 +/- 28 mg/dl vs. 80 +/- 18 mg/dl; P < 0.001), and calculated coronary heart disease risk (6.8 (3.3-17.9) vs. 2.8 (1.5-5.7)% over next 10 years; P < 0.01). Serum triglyceride was 1.34 (1.06-1.71) mmol/l on placebo and 1.14 (0.88-1.48) mmol/l on atorvastatin (ns). HDL cholesterol, apolipoprotein A1 and Lp(a) concentrations and cholesteryl ester transfer protein and lecithin: cholesterol acyl transferase activities were also not significantly altered. CONCLUSION: Atorvastatin treatment was safe, well tolerated and effective in improving the atherogenic lipoprotein profile in acromegaly.     

Alterations in serum sodium in relation to atrial natriuretic factor and other neuroendocrine variables in experimental pacing-induced heart failure

The pathophysiologic role of atrial natriuretic factor and other neuroendocrine variables in relation to serum sodium and renal function was evaluated in 15 conscious dogs with severe chronic ventricular pacing-induced heart failure (250 beats/min for 5.1 +/- 0.4 weeks). Six sham-operated dogs observed over an 8 week period served as controls. Development of heart failure was characterized by a progressive increase in plasma norepinephrine, renin activity and aldosterone from control values of 293 +/- 15 pg/ml, 1.4 +/- 0.4 ng/ml per h and 124 +/- 42 pg/ml, respectively, to 1,066 +/- 96 pg/ml, 10.2 +/- 2.4 ng/ml per h and 577 +/- 151 pg/ml (all p less than 0.01), respectively, at severe heart failure. In contrast to other neuroendocrine variables, plasma atrial natriuretic factor increased from a control level of 243 +/- 74 pg/ml to a peak concentration of 724 +/- 149 pg/ml (p less than 0.01) at 2 weeks, then declined and plateaued at twice the level of the control value as severe heart failure developed. At severe heart failure, serum sodium decreased from 147 +/- 0.6 to 141.8 +/- 2.1 mmol/liter (p less than 0.05), whereas urea increased from 6.0 +/- 0.5 to 7.8 +/- 0.6 mmol/liter (p less than 0.05). The change in serum sodium concentration correlated with plasma renin activity and aldosterone (r = -0.77, -0.88, respectively, both p less than 0.01), but not with norepinephrine or atrial natriuretic factor. When sinus rhythm was restored, 14 dogs were observed for 48 to 72 h and 8 dogs were followed up for another 4 weeks after cessation of pacing.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sustained reduction in circulating cholesterol in adult hypopituitary patients given low dose titrated growth hormone replacement therapy: a two year study

OBJECTIVE: To study the effects of short (6 months) and longer-term (up to 24 months) growth hormone (GH) replacement therapy using a dose titration regimen, on lipid and glucose metabolism in GH-deficient, hypopituitary adults. DESIGN: On-going open study of GH treatment up to 24 months. Measurements were performed at baseline and at 6, 12, 18 months and 2 years during therapy (data shown at 6 months and 2 years only). Using a dose titration regimen the median GH dose used to achieve and maintain IGF-I levels above the median, but below the upper limit of the age-related reference range (median IGF-I 202.5 microg/l, range 76-397 microg/l), was 1.2 IU daily (range 0.4-3 IU) [0.8 IU/day, males; 1.6 IU/day, females]. PATIENTS: Ninety GH-deficient hypopituitary adults (54 female, median age 48 years, range 19-79 years) entered the study and 24 (14 female, median age 45 years, range 32-79 years) have concluded the 2 year period of assessment. MEASUREMENTS: Body mass index (BMI), waist and hip circumference ratio (WHR), fasting lipids, glucose and glycated haemoglobin (HbA1c) levels were measured at 6 month intervals during GH therapy. RESULTS: Using the dose titration regimen, compared to pretreatment values, total and low density lipoprotein (LDL)-cholesterol levels were significantly lower at 6 months (mean +/- SEM, 5.61+/-0.1 vs. 5.25+/-0.1, and 3.85+/-0.19 vs. 3.43+/-0.26, respectively, P<0.05), and were maintained throughout the study. Male patients had significantly lower pretreatment total and LDL cholesterol levels than females (mean +/- SEM, 5.33+/-0.16 mmol/l vs. 5.7+/-0.12 mmol/l and 3.8+/-0.23 mmol/l vs. 3.92+/-0.29 mmol/l, respectively, P< 0.05). A decrease in total cholesterol was confined to patients with pretreatment total cholesterol levels above 5.8 mmol/l; patients with the highest pretreatment cholesterol levels (> 6.4 mmol/l) obtained the greatest cholesterol reduction (mean +/- SEM, 7.13 +/- 0.14 mmol/l vs. 5.76+/-0.31 mmol/l, P<0.05). A cholesterol-lowering effect of GH therapy was evident in patients who had elevated pre-GH total cholesterol levels even if they were already receiving and continuing lipid lowering medication (mean +/- SEM, 5.62+/-0.22 vs. 5.03+/-0.285, P<0.05). A modest increment in high density lipoprotein (HDL)-cholesterol was evident at 18 months but there was no significant change in triglycerides at any time point. Fasting plasma glucose increased significantly at 6 months but remained within the reference range. Glycated haemoglobin increased significantly at 6 months and was maintained throughout the study; one patient developed frank diabetes mellitus while receiving treatment. There was a weak but significant correlation between the increment in glycated haemoglobin and pretreatment BMI (r = + 0.215, P<0.05). CONCLUSION: The effect of GH on lowering total and low density lipoprotein-cholesterol is more prominent in patients with higher pretreatment cholesterol levels and is evident even in patients receiving other lipid-lowering medication. A modest increment in mean fasting glucose (within the reference range) and mean glycated haemoglobin persisted throughout the study. One patient developed diabetes mellitus. A GH replacement regimen using low dose and careful titration to avoid elevated IGF-I levels and adverse effects is associated with sustained beneficial effects on circulating lipids.     

Circulating tumor necrosis factor alpha concentrations are higher in abdominal versus peripheral obesity.

Fat tissue is a significant source of endogenous tumor necrosis factor alpha (TNFalpha), the pluripotent cytokine that plays an important role as a mediator of the peripheral insulin resistance found in obesity. The majority of evidence for this role of TNFalpha is from studies in animal models of obesity. To explore further the role of TNFalpha in the pathogenesis of obesity-related insulin resistance in humans, we compared plasma levels of TNFalpha and the other main endocrine cytokine, interleukin-6 ([IL-6] both measured by enzyme-linked immunosorbent assay), in 26 obese women (body mass index [BMI] > 30 kg/m2) and 13 female controls (BMI < 26 kg/m2) without a history of recent or active infection. Glucose and insulin levels were measured at 0, 1, and 2 hours after a 75-g oral glucose load. There was no significant difference in plasma TNFalpha or IL-6 levels between obese and non-obese subjects overall (2.10 +/- 0.19 v 1.65 +/- 0.18 pg/mL and 2.06 +/- 0.29 v 1.50 +/- 0.17 pg/mL, respectively). However, TNFalpha levels were significantly elevated in obese subjects with a 2-hour glucose level more than 140 mg/dL (n = 8) compared with the other obese subjects (n = 18) and the non-obese controls (2.88 +/- 0.46 v 1.75 +/- 0.10 and 1.65 +/- 0.18 pg/mL, respectively, P < .01). Furthermore, the TNFalpha level correlated significantly with the waist to hip ratio ([WHR] r = .53, P < .01) and fasting and post-oral glucose tolerance test (OGTT) insulin levels (r = .47, P < .02), but not with the BMI, and was higher in obese women with a WHR more than 0.90 (n = 14) in comparison to those with a WHR less than 0.90 (n = 12, 2.47 +/- 0.29 v 1.66 +/- 0.18 pg/mL, respectively, P < .03). The corresponding plasma leptin level was significantly higher in obese women versus the control group (41.6 +/- 2.5 v22.3 +/- 2.9 ng/mL, P < .001) and was related to the BMI (r = .60, P < .01) but not to TNFalpha or the WHR. There were no significant differences in the corresponding IL-6 concentration between groups, and IL-6 did not correlate with TNFalpha, leptin, BMI, WHR, or insulin levels. In conclusion, circulating TNFalpha levels are higher in abdominal obesity compared with peripheral obesity, and may contribute to the insulin resistance that more commonly complicates the former pattern of fat distribution.