Tomas Haas

Both fenofibrate and atorvastatin improve vascular reactivity in combined hyperlipidaemia (fenofibrate versus atorvastatin trial — FAT)

OBJECTIVE It has been repeatedly proven that statins improve endothelial function in isolated hypercholesterolaemia but there is far less evidence in the case of combined hyperlipidaemia. Studies assessing the effects of fibrates on endothelium have been neglected. Therefore, we conducted a trial in which the effects of fenofibrate and atorvastatin monotherapy on both endothelium-dependent vascular reactivity and biochemical parameters were compared in patients with combined hyperlipidaemia. METHODS 29 otherwise healthy males (aged 47.4+/-7.8 years) with combined hyperlipidaemia (total cholesterol 7.55+/-1.20 mmol/l, triglycerides 5.41+/-4.54 mmol/l) were included into the randomised, single-blind, cross-over study to receive either 200 mg of micronised fenofibrate or 10 mg of atorvastatin daily--each of the drugs for a period of 10 weeks. Analysed biochemical parameters were as follows: serum total-, LDL- and HDL-cholesterol, apolipoproteins A-I and B, triglycerides, fibrinogen, uric acid, C-reactive protein (CRP), insulin, and homocysteine. Endothelial function was investigated by duplex Doppler ultrasonography at the brachial artery. Two indices of endothelial-dependent postischaemic changes were used - the recently introduced index of peak blood flow (PBF) representing the level of reactive hyperaemia and traditional flow-mediated dilatation (FMD). RESULTS We observed a small improvement in FMD after both fenofibrate and atorvastatin (from 2.26% to 2.98% and 2.87%, respectively; NS). PBF increased from 448 ml/min to 536 ml/min after fenofibrate (P=0.04) and to 570 ml/min after atorvastatin (P=0.03). The effects of both fenofibrate and atorvastatin on endothelial function did not differ significantly (P-values of 0.82 and 0.47 for FMD and PBF, respectively). Significant correlations (P<0.01) between the changes of vascular reactivity and biochemical indices were found between FMD and CRP (r=-0.60) and between both FMD and PBF, and insulinaemia (r=-0.48 and -0.56, respectively) only during treatment with fenofibrate. CONCLUSIONS Both fenofibrate and atorvastatin significantly improved endothelium-dependent vascular reactivity without mutual difference. The PBF was superior to FMD for the detection of this improvement. The beneficial effect of both drugs did not correlate with the change of lipid profile during therapy. The improvement of vascular reactivity during treatment with fenofibrate (opposed to atorvastatin) was related to the reduction of indirect marker of chronic vessel wall inflammation and of insulin resistance. The PBF was more reproducible than FMD because of considerably lower intra-subject variability.

Comparison of laser-Doppler flowmetry with biochemical indicators of endothelial dysfunction related to early microangiopathy in Type 1 diabetic patients

The aim of this study was to compare biochemical markers of endothelial activation with microcirculation measured by laser-Doppler flowmetry in Type 1 diabetic patients with or without microangiopathy. A total of 44 Type 1 diabetic patients were subdivided into those with (n=24) and without (n=20) microangiopathy according to ophthalmological findings and the presence or absence of microalbuminuria. The control group consisted of 25 healthy people of comparable age, sex, and body mass index. Postocclusive reactive hyperemia (PORH) and thermal hyperemia (TH, at 44 degrees C) were measured at the forearm. Serum N-acetyl-beta-glucosaminidase (NAG) activity, serum E-selectin, and ICAM-1 concentrations were used as biochemical markers of endothelial dysfunction. A significantly lower velocity of perfusion increase during postocclusive hyperemia (PORH(max) x t(1)(-1)) and during thermal hyperemia (TH(max) x t(2)(-1)) (P<.01) were accompanied by higher serum NAG activity (20.9+/-4.6 vs. 16.3+/-2.5 U l(-1), P<.01) in diabetic patients with microangiopathy as compared to healthy persons. An inverse relationship was found between PORH(max) x t(1)(-1) and NAG (r=-.33) results in diabetic patients. In addition, higher mean values of serum NAG activity, E-selectin, and ICAM-1 concentrations were associated with significantly lower values of microcirculation parameters (PORH(max) x t(2)(-1) and TH(max) x t(2)(-1)) in six patients without microangiopathy who had at least one of the above biochemical markers higher than mean+2 S.D. range. We suggest that serum NAG activity, E-selectin, and ICAM-1 concentrations may be used together with laser-Doppler flowmetry in Type 1 diabetic patients as early indicators of vascular changes in very early stage of diabetic microangiopathy.

Effect of Atorvastatin and Fenofibrate on autonomic tone in subjects with combined hyperlipidemia

This randomized open-label trial investigated whether autonomic cardiovascular control is altered in middle-aged men with combined hyperlipidemia and whether such alterations are affected by short-term, lipid-lowering therapy with atorvastatin and/or fenofibrate. Compared with normolipidemic subjects, untreated subjects with combined hyperlipidemia had several abnormalities of autonomic tone, indicating increased sympathetic tone and decreased baroreflex sensitivity. The alterations in autonomic cardiovascular control were partially reversible by each of the lipid-lowering drugs.

Soluble leptin receptor levels in patients with anorexia nervosa

Objective: To examine whether changes of serum soluble leptin receptor levels (S-LEPR) can modify leptin half-life and its tissue effects. The aim of our study was to measure S-LEPR levels in patients with anorexia nervosa (AN) before and 6 weeks after partial refeeding. Methods: Anthropometric variables, serum leptin, S-LEPR, insulin, cortisol and TNF-alpha were measured in 15 AN patients before and after partial refeeding and 15 healthy control women. Results: S-LEPR levels in AN patients were significantly higher than in healthy subjects (26.8±8.1 vs. 16.36±2.6 U/mL, p<0.01) and were not affected by partial refeeding (26.8±8.1 vs. 24.2±6.1 U/mL). In contrast, body mass index (BMI), body fat content, and serum leptin levels in AN patients increased significantly after partial refeeding. Except for the inverse relationship of S-LEPR levels to BMI and body fat content no clear relationship of this parameter to serum leptin, cortisol, insulin or TNF-alpha was found. Conclusion: S-LEPR levels are significantly increased in AN patients and this increase is unaffected by partial refeeding. The possibility of etiological role of increased S-LEPR levels in AN patients by affecting leptin central and/or peripherial effects should be further elucidated.

The influence of short-term fasting on serum leptin levels, and selected hormonal and metabolic parameters in morbidly obese and lean females.

The aim of our study was to compare the changes of serum leptin levels after 24-h fasting in morbidly obese and lean females and to search for hormonal and metabolic factors responsible for the changes in serum leptin levels. Fourteen morbidly obese and twelve lean females were included in the study. The blood for leptin, insulin, cortisol, blood glucose (BG), β-OH-butyrate (β-OH), dehydroepiandrosterone (DHEA) and DHEA-sulphate (DHEA-S) measurements was withdrawn before and after a 24-h fast. Basal body mass index (BMI), serum leptin, insulin and β-OH levels were significantly higher in the obese compared to the lean group. The 24-h fasting decreased significantly BMI, serum leptin (by 20% in obese vs. 62% in lean subjects), insulin (by 23.3% in obese vs. 23.1% in lean subjects) and increased β-OH (by 36% in obese vs. 1300% in lean subjects). Basal serum leptin levels correlated positively with BMI in both groups and with insulin levels in the obese group. The multiple regression analysis using Δ leptin as dependent and the basal values of the rest of studied parameters as independent variables revealed that in lean subjects serum cortisol together with DHEA-S and BMI accounted for 71% of variations of the change of serum leptin levels (Δ leptin = 0.31 − 0.0101 cortisol + 0.0012 DHEA-S + 0.37 BMI). In obese subjects the 43.9% of variations of the change of serum leptin levels was explained by BMI together with age and DHEA-S levels (Δ leptin} = 36.09 + 0.35 BMI − 0.717 age − 0.008 DHEA-S). The drop of serum leptin levels after 24-h starvation is significantly blunted in obese compared to lean subjects. The reason for the difference is probably the insulin resistance possibly further modified by different DHEA-S levels.

Effect of folic acid on fenofibrate-induced elevation of homocysteine and cysteine

BACKGROUND An elevated total plasma homocysteine (tHcy) level is considered to be an independent risk factor for atherosclerosis. It has been reported that lipid-lowering therapy with fibric acid derivatives (fibrates) increases tHcy and total plasma cysteine (tCys) levels. The aim of this study was to determine whether therapy with folic acid, a potent tHcy-lowering agent, could modify the fenofibrate-induced elevation of plasma aminothiols. METHODS Patients with combined hyperlipidemia (n = 37) were randomized to receive 9 weeks of treatment with micronized fenofibrate 200 mg/day (F group) or fenofibrate 200 mg/day plus folic acid 10 mg/every other day (F+F group). tCys and tHcy levels were determined before and after the therapy with high performance liquid chromatography. RESULTS The tHcy level increased significantly in the F group by 51.3% and in the F+F group by 14.6% (between-group difference P =.001). Total plasma cysteine (tCys) increased similarly after both treatments (P =.72). The serum creatinine level increased in the F group by 20.7% and in F+F group only by 9.8% (P =.04). The increase of tHcy level in F group correlated with an increase of tCys and creatinine levels (r = 0.74 and 0.64, respectively). The effects on the lipid profile did not differ by treatment group. CONCLUSIONS Folic acid effectively reduces the fenofibrate-induced elevation of tHcy and creatinine, but it does not affect the elevation of the tCys. Folic acid has neutral effect on the lipid-lowering action of fenofibrate. Clinical efficacy of fenofibrate might be improved by folic acid coadministration.

Erythroblastic and/or megakaryocytic dysplasia in de novo acute myeloid leukemias M0-M5 show relation to myelodysplastic syndromes and delimit two main categories.

Erythroblastic and/or megakaryocytic dysplasia (EMD) was evaluated in diagnostic bone marrow smears of 43 consecutively treated patients under 65 years with de novo acute myeloid leukemia (AML) M0-M5 according to FAB criteria. The evaluation was possible in 39 (91%) patients, i.e. in 32 of 34 patients with non-M3 AML treated in the study UHKT-911 and seven of nine cases with AML M3 treated in other studies. Among non-M3 AML 15 patients were categorized without EMD and 17 cases with EMD. Cytogenetic abnormalities of chromosome 5, 7, 3 or a complex karyotype were found in eight of 17 patients with EMD and in one of 15 cases without EMD (P = 0.018). Seven patients in each category exhibited a normal karyotype. Classical induction therapy with three to four doses of daunorubicin 45 mg/m2 and standard doses of cytosine arabinoside (AraC) for 7 days lead to complete remission in 11 of 14 (78.6%) cases without EMD but only in four of 14 (28.6%) cases with EMD (P = 0.021). High doses (2000 mg/m2 per 12-h x 10) of AraC plus daunorubicin induced complete remission in seven of 10 patients with EMD. Patients with EMD showed significantly worse overall survival (P = 0.03) with a median 13.5 months, while the median survival was estimated to 68.7 months in cases without EMD. The dysplastic features of EMD, karyotypes typical for myelodysplastic syndromes (MDS), poor response to classical therapy and survival show a relation of AML with EMD to MDS. AML without EMD may represent a different biological favorable category.

Serum leptin levels in diabetic patients on hemodialysis: the relationship to parameters of diabetes metabolic control.

Leptin is a protein hormone produced predominantly by adipocytes that affects food intake and energy expenditure. Its serum levels are significantly higher in patients with chronic renal failure compared to healthy subjects. The aim of this study was to compare serum leptin levels in hemodialyzed patients with type II diabetes mellitus (n=26) with body content-matched hemodialyzed patients without diabetes (n=26) and to explore the relationship between parameters of the long term diabetes metabolic control and serum leptin levels. Serum leptin levels in diabetic patients did not significantly differ from those of non-diabetic patients (25.3±8.8 vs 25.7±8.7 ng/ml). Serum leptin levels in diabetic patients positively correlated with body fat content, body mass index and predialysis serum insulin levels. No significant relationship were observed between serum leptin levels and blood glucose, glycated hemoglobin, glycated protein, serum urea, creatinine, leukocyte count and total hemoglobin respectively. The multiple stepwise regression analysis revealed that body fat content together with body mass index accounted for 77.8% of variations in predialysis serum leptin levels, while insulin levels and the parameters of diabetes metabolic control had only slight prediction value for leptin concentrations. We conclude that serum leptin levels in hemodialysed patients with type III diabetes mellitus do not significantly differ from those of hemodialysed non-diabetic patients. The body fat content and body mass index are the strongest predictors of serum leptin levels, while parameters of long term diabetes metabolic control play probably only minor direct role in its regulation.

THE CHANGES OF SERUM LEPTIN AND SOLUBLE LEPTIN RECEPTOR LEVELS IN PATIENTS UNDERGOING MOBILIZATION OF PERIPHERAL BLOOD STEM CELLS BEFORE AUTOLOGOUS STEM CELLS TRANSPLANTATION

Background and objectives: Leptin was demonstrated to stimulate the proliferation of hematopoietic stem cells in vitro, but there is scarce information concerning serum leptin levels in patients with hematological diseases. The aim of our study was to measure serum leptin levels in patients undergoing mobilization of peripheral blood stem cells (PBSC) before autologous stem cell transplantation (ASCT). Design and methods: Eighteen patients indicated for ASCT were included in the study. The blood samples were obtained before the initiation of mobilization chemotherapy, at the phase of maximal leukopenia and on the second day of stem cell harvest. Serum leptin levels, soluble leptin receptor, cortisol, insulin, tumor necrosis factor α (TNFα), and interleukin-1 receptor antagonist (IL-1ra) levels were measured in the withdrawn samples. Results: The basal values of parameters measured except for higher levels of IL-1ra in mobilized group did not differ significantly from those of a control group of healthy subjects. Serum leptin levels decreased significantly at the leukopenia phase and remained suppressed in the stem cell harvest phase (means±standard error means (SEM): 12.2±2.4 vs. 7.7±1.5 vs. 9.3±1.9 ng mL−1). No significant changes were found in soluble leptin receptor, insulin, cortisol, and TNFα levels throughout three measurements, while IL-1ra levels increased significantly in the SC harvest phase compared to the previous two measurements. Interpretation and conclusions: As no metabolic variations explaining suppressed leptin levels were found, this suppression could be the result either of G-CSF administration or increased leptin consumption by activated stem cells.

The independent correlation of the impact of lipoprotein(a) levels and apolipoprotein E polymorphism on carotid artery intima thickness

BACKGROUND Apolipoprotein E (apoE) plays a key role in lipoprotein metabolism. It occurs in three isoforms E2, E3 and E4. These isoforms have different impacts on plasma lipoprotein levels. The allele, or gene, coding apoE4 is considered a candidate for premature atherosclerosis development while the apoE2 gene is assumed to be protective. Lipoprotein(a) is also atherogenic and its increased plasma concentration is presumed to be an independent risk factor for premature atherosclerosis. Lipoprotein(a) is a protein depositing directly into the atheromatous plaques, enhancing cholesterol oxidation, competitively inhibiting plasminogen formation and thus having a prothrombogenic effect. The aim of our study was to establish a relationship between common carotid artery intima thickness and two independent risk factors, apoE polymorphism and elevation of plasma lipoprotein(a) levels. METHODS A cross-sectional study was performed on 114 patients who were referred to the lipid clinic for primary hyperlipoproteinaemia. The patients received no treatment prior to examination. Plasma levels of total cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol, apoA, apoB, lipoprotein(a) and the apoE genotype were determined and the carotid artery intima thickness was measured using ultrasonography. RESULTS The relative frequencies of apoE2, E3 and E4 were 0.049, 0.830 and 0.121. The equality of carotid intima thickness was tested using the Kruskal-Wallis test. Medians of intima thickness in a subgroup with the allele E2 were 0.72 mm, in a subgroup with the E3/E3 genotype 0.70 mm and in a subgroup with the E4 allele 0.80 mm. The relationship between carotid intima thickness and lipoprotein(a) levels was tested using Spearmans correlation coefficient. CONCLUSIONS No statistically significant differences of carotid intima thickness among subgroups divided according to their apoE genotype were found. No relationship between carotid intima thickness and lipoprotein(a) levels was found. On the contrary a close relationship between carotid intima thickness and age and also some of the plasma lipid variables was recorded using the method of multivariate linear regression.