Carsten Otto

Effects of Atorvastatin Versus Fenofibrate on Lipoprotein Profiles, Low-Density Lipoprotein Subfraction Distribution, and Hemorheologic Parameters in Type 2 Diabetes Mellitus With Mixed Hyperlipoproteinemia

Diabetic dyslipoproteinemia characterized by hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol, and often elevated low-density lipoprotein (LDL) cholesterol with predominance of small, dense LDL is a strong risk factor for atherosclerosis. It is unclear whether fibrate or statin therapy is more effective in these patients. We compared atorvastatin (10 mg/day) with fenofibrate (200 mg/day), each for 6 weeks separated by a 6-week washout period in 13 patients (5 men and 8 women; mean age 60.0+/-6.8 years; body mass index 30.0+/-3.0 kg/m2) with type 2 diabetes mellitus (hemoglobin A1c 7.3+/-1.1%) and mixed hyperlipoproteinemia (LDL cholesterol 164.0+/-37.8 mg/dl, triglycerides 259.7+/-107 mg/dl, HDL cholesterol 48.7+/-11.0 mg/dl) using a randomized, crossover design. Lipid profiles, LDL subfraction distribution, fasting plasma viscosity, red cell aggregation, and fibrinogen concentrations were determined before and after each drug. Atorvastatin decreased all LDL subfractions (LDL cholesterol, -29%; p <0.01) including small, dense LDL. Fenofibrate predominantly decreased triglyceride concentrations (triglycerides, -39%; p <0.005) and induced a shift in LDL subtype distribution from small, dense LDL (-31%) to intermediate-dense LDL (+36%). The concentration of small, dense LDL was comparable during therapy to both drugs (atorvastatin 62.8+/-19.5 mg/dl, fenofibrate 63.0+/-18.1 mg/dl). Both drugs induced an increase in HDL cholesterol (atorvastatin +10%, p <0.05; fenofibrate +11%, p = 0.06). In addition, fenofibrate decreased fibrinogen concentration (-15%, p <0.01) associated with a decrease in plasma viscosity by 3% (p <0.01) and improved red cell aggregation by 15% (p <0.05), whereas atorvastatin did not affect any hemorheologic parameter. We conclude that atorvastatin and fenofibrate can improve lipoprotein metabolism in type 2 diabetes. However, the medications affect different aspects of lipoprotein metabolism.

The Prevention Education Program (PEP). A Prospective Study of the Efficacy of Family-Oriented Life Style Modification in the Reduction of Cardiovascular Risk and Disease: Design and Baseline Data

We describe design and baseline data of the Prevention Education Program (PEP), a home-based and family-oriented intervention program, aimed to assess and improve cardiovascular risk factors in school children and their families during an intervention period of 10 years. Started in 1994 in the German town of Nuremberg, currently 37 elementary schools (22 control and 15 intervention schools) are enrolled including 1740 families (1740 first graders, 3046 parents, and 1521 siblings). Major cardiovascular risk factors as well as dietary behavior are evaluated yearly using structured interview, physical examination, laboratory analysis, and seven-day-dietary protocols. The intervention package is applied to all families from intervention schools using regular home visits, health curricula and group sessions. Primary outcome is any reduction in cardiovascular risk factors by dietary intervention and health education compared to the control group getting only written information on the individual risk profile. The presented baseline data showing a high prevalence of cardiovascular risk factors in adults and in their children underline the need for such an intervention program in Germany.

Short-term therapy with atorvastatin or fenofibrate does not affect plasma ghrelin, resistin or adiponectin levels in type 2 diabetic patients with mixed hyperlipoproteinaemia

Lipid-lowering therapy is associated with reduced cardiovascular risk. The aim of the present study was to investigate whether lipid-lowering therapy might be associated with changes in the concentrations of metabolically important hormone concentrations. We performed a randomised cross-over open-label trial with atorvastatin (10 mg/day) and fenofibrate (200 mg/day), each for 6 weeks separated by a 6-week washout period in 13 patients (5 men, 8 women, age 60.0±6.8 years, body mass index 30.0±3.0 kg/m2) with type 2 diabetes mellitus and mixed hyperlipoproteinaemia. Plasma ghrelin (RIA, Phoenix Pharmaceuticals, Mountain View, CA, USA), adiponectin (ELISA, Biovendor, Heidelberg, Germany) as well as resistin (ELISA, Linco Research, St. Charles, MO, USA) concentrations were measured before and after atorvastatin as well as before and after fenofibrate. Ghrelin (462±84 pg/ml before vs. 464±102 pg/ml after atorvastatin, n.s.; 454±85 pg/ml before vs. 529±266 pg/ml after fenofibrate, n.s.), resistin (24.4±7.4 pg/ml before vs. 23.7±9.1 pg/ml after atorvastatin, n.s.; 23.4±8.2 pg/ml before vs. 19.9±5.5 pg/ml after fenofibrate, n.s.), adiponectin (10.89±5.33 pg/ml before vs. 12.41±5.75 pg/ml after atorvastatin, n.s.; 12.58±9.87 pg/ml before vs. 10.27±5.23 pg/ml after fenofibrate, n.s.) and insulin levels did not change significantly during lipid-lowering therapy. In patients with type 2 diabetes and mixed hyperlipoproteinaemia, short-term atorvastatin as well as fenofibrate therapy had no significant effects on adiponectin, ghrelin or resistin levels.

Intra-hepatic splenosis as an unexpected cause of a focal liver lesion in a patient with hepatitis C and liver cirrhosis: a case report

IntroductionSplenosis is the heterotopic autotransplantation of splenic tissue, mostly found after splenic trauma or surgery in the abdominal, pelvic or thoracic cavity. Here we report a patient with a history of splenectomy after polytrauma with chronic hepatitis C and liver cirrhosis presenting with an hepatic mass of unknown origin.Case presentationThe lesion could not be exactly classified by ultrasound, computed tomography, angiography and biopsy, classical features of malignancy were not fulfilled, and on the other hand a neoplastic process could neither be excluded. After revision of a MRI performed in our centre it appeared that the liver mass contrasted in the same way as the remaining accessory spleens in the left upper quadrant. A selective Tc-99m-labelled heat-denatured autologous red blood cells scintigraphy of the spleen was performed and showed both the accessory spleens in the left upper quadrant and spleen-typical tissue in projection to the left liver lobe and confirmed the diagnosis of splenosis.ConclusionAlthough intrahepatic splenosis represents an extremely rare condition, this diagnosis should always be taken into consideration in patients with history of abdominal trauma with splenic involvement presenting with an indeterminate focal liver lesion. The diagnosis of splenosis may then be reliably confirmed by Tc-99m-DRBC scintigraphy.

Differential effects of fenofibrate versus atorvastatin on the concentrations of E-selectin and vascular cellular adhesion molecule-1 in patients with type 2 diabetes mellitus and mixed hyperlipoproteinemia: a randomized cross-over trial

BackgroundDiabetic dyslipoproteinemia is characterized by hypertriglyceridemia, low HDL-cholesterol and often elevated LDL-cholesterol and is a strong risk factor for atherosclerosis. Adhesion molecule levels are elevated both in hyperlipoproteinemia and diabetes mellitus. It is unclear whether fibrate or statin therapy has more beneficial effects on adhesion molecule concentrations.MethodsAtorvastatin (10 mg/d) was compared to fenofibrate (200 mg/d) each for 6 weeks separated by a 6 week washout period in 11 patients (6 male, 5 female; 61.8 ± 8.2 years; body mass index 29.8 ± 3.1 kg/m2) with type 2 diabetes mellitus (HbA1c 7.3 ± 1.1 %) and mixed hyperlipoproteinemia using a randomized, cross-over design. Fasting blood glucose, HbA1c, lipid parameters, E-selectin, ICAM-1, VCAM-1, and fibrinogen concentrations were determined before and after each drug.ResultsGlucose and HbA1c concentrations remained unchanged during the whole study period. LDL cholesterol was reduced during atorvastatin therapy, triglycerides were lowered more effectively with fenofibrate. Comparison of pre- and postreatment concentrations of E-selectin showed a reduction during atorvastatin (-7 %, p = 0.11) and fenofibrate (-10 %, p < 0.05) therapy. Atorvastatin treatment reduced VCAM-1 levels by 4% (p < 0.05), while VCAM-1 concentrations remained unchanged (+1%, ns) during fenofibate therapy. However, direct comparisons of post-treatment levels during both forms of therapy were not of statistical significance. ICAM-1 levels were not influenced by either form of therapy.ConclusionsIn addition to the different beneficial effects on lipid metabolism, both drugs appear to lower adhesion molecule plasma concentrations in a different manner in patients with type 2 diabetes and mixed hyperlipoproteinemia. Our observations should be confirmed in a larger cohort of such patients.

Effect of atorvastatin on lipid parameters, LDL subtype distribution, hemorrheological parameters and adhesion molecule concentrations in patients with hypertriglyceridemia.

BACKGROUND AND AIM Hypertriglyceridemia is a risk factor for atherosclerosis that is typically associated with high concentrations of adhesion molecules, impaired hemorrheology and an unfavourable low-density lipoprotein (LDL) subtype distribution. We hypothesised that some of these risk markers might be beneficially influenced by lipid-lowering therapy with atorvastatin in hypertriglyceridemic patients. METHODS AND RESULTS Nineteen patents with primary hypertriglyceridemia were given 10 mg of atorvastatin per day for four weeks. Their cholesterol, triglyceride, LDL and high-density lipoprotein cholesterol (HDL-C) levels, LDL subtype profile, hemorrheological parameters and E-selectin, vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 concentrations were measured before and at the end of atorvastatin therapy. The levels of total and LDL cholesterol respectively decreased by 25% and 24% (both p < 0.001). Furthermore, cholesterol was reduced by 8-29% in all seven LDL subfractions (density range: 1.020-1.066 g/mL) (p < 0.05). The reduction in triglyceride concentrations was of marginal significance (9%, p = 0.1), but its degree positively correlated with the reduction of small-dense LDL (r = 0.5, p < 0.025). Plasma viscosity and blood viscosity at low shear rates were respectively reduced by 2% and 16% (both p < 0.05). The effect of the treatment on the concentrations of HDL-C, fibrinogen and adhesion molecules was not significant. CONCLUSIONS Atorvastatin (10 mg/day) not only reduced the plasma concentrations of atherogenic lipoproteins but also improved the LDL-subtype profile and reduced plasma and blood viscosity in patients with hypertriglyceridemia; however, it failed to significantly lower triglyceride concentrations.

Effects of n-3 fatty acids and fenofibrate on lipid and hemorrheological parameters in familial dysbetalipoproteinemia and familial hypertriglyceridemia

There is increasing evidence that hemorrheological abnormalities are associated with an enhanced risk of atherosclerosis. The n-3 fatty acids (n-3-FA) have been shown to have beneficial effects on atherosclerosis in patients with dyslipoproteinemias. We studied 23 patients with elevated plasma triglycerides to evaluate the influence of fish oil and fenofibrate therapy on hemorrheological parameters (15 patients with familial hypertriglyceridemia [FHTG] and eight with familial dysbetalipoproteinemia [FDL]). The patients (one woman and 22 men aged 45.7 +/- 2.0 years) were treated with increasing doses of n-3-FA (1.8 to 3.6 g/d: 0.9 to 1.8 g eicosapentaenoic acid and 0.6 to 1.2 g docosahexaenoic acid) for 8 weeks. Lipid parameters, whole-blood viscosity at different shear rates, plasma viscosity, fibrinogen concentration, and red blood cell aggregation (RCA) were measured at baseline and at weeks 2, 4, 8 (end of n-3-FA therapy), and 12. Compliance was ensured by measuring plasma concentrations of eicosapentaenoic acid and docosahexaenoic acid. After 12 weeks, patients began treatment with fenofibrate (250 mg daily); investigations were performed again at week 20. Total triglycerides (from 6.90 +/- 1.70 to 3.61 +/- 0.78 mmol/L in FDL and 7.44 +/- 1.50 to 4.15 +/- 0.55 in FHTG), very-low-density lipoprotein (VLDL) triglycerides, and VLDL cholesterol were significantly decreased with n-3-FA therapy in both groups (P < .05). In FHTG, low-density lipoprotein (LDL) cholesterol increased significantly (from 2.75 +/- 0.28 to 3.97 +/- 0.35 mmol/L, P < .01); in FDL, total cholesterol decreased (from 9.76 +/- 1.32 to 7.34 +/- 1.07 mmol/L, P < .05). No significant changes were observed in hemorrheological parameters, except for reduced RCA with 3.6 g n-3-FA in FHTG. However, with fenofibrate therapy, in addition to comparable lipoprotein changes seen with fish oil, fibrinogen levels and plasma and blood viscosity decreased in patients with FDL. We conclude that n-3-FA and fenofibrate have comparable effects on lipid parameters in patients with FDL and FHTG. Because of additional beneficial effects on hemorrheological parameters, fenofibrate may be preferred for the treatment of FDL.

Postprandial hemorrheology and apolipoprotein B metabolism in patients with familial hypertriglyceridemia.

Impaired postprandial lipoprotein metabolism has been found to be related to the extent of coronary artery disease. Moreover, since dyslipoproteinemias are associated with impaired hemorrheology, we investigated the effect of postprandial hypertriglyceridemia on hemorrheological parameters before and after triglyceride-lowering therapy. Triglyceride-rich lipoproteins (TRLs) separated by ultracentrifugation (d < 1.006 g/dL) and chylomicrons and chylomicron remnants (quantified by apolipoprotein [apo] B-48 determination) were determined after a fat load in 10 patients with familial hypertriglyceridemia before and after therapy with gemfibrozil (900 mg daily). Lipid and hemorrheological parameters (plasma and whole-blood viscosity [PV and BV], red cell aggregation [RCA], hematocrit, and fibrinogen) were determined at baseline and every hour up to 6 hours postprandially. Fasting total triglycerides and TRL triglycerides significantly decreased with gemfibrozil therapy (P < .01). Total triglycerides postprandially increased from 9.53 +/- 1.72 to 14.47 +/- 2.07 mmol/L (TRL triglycerides by 61%) before therapy (P < .05) and from 4.61 +/- 1.28 to 7.17 +/- 0.99 mmol/L (TRL triglycerides by 57%) after therapy (P < .05). The postprandial TRL apo B increase was reduced with gemfibrozil (from 11.6 +/- 2.8 to 20.7 +/- 5.0 mg/dL with therapy v 19.0 +/- 7.6 to 33.0 +/- 12.5 mg/dL before therapy, P < .05, respectively) with a proportionally greater increase in apo B-48 (119% and 169%, respectively) compared with apo B-100 (64% and 64%, respectively). Fasting RCA was improved with lipid-lowering therapy (P < .05), but PV, BV, RCA, and fibrinogen did not show any statistically significant postprandial changes either before or after lipid-lowering therapy. In summary, we did not find any statistically significant changes in hemorrheological parameters, despite a strong postprandial increase of triglycerides. In particular, these findings were independent of fasting triglyceride levels. We conclude that triglyceride-lowering therapy by gemfibrozil had no substantial beneficial effects with respect to hemorrheology in patients with familial hypertriglyceridemia.

Influence of fiber, xylitol and fructose in enteral formulas on glucose and lipid metabolism in normal subjects

SummaryTo verify the benofit of nonglucose carbohydrates and fiber in enteral formula diets we studied the postprandial metabolism of eight healthy subjects after the intake of two helpings (25 g carbohydrates each) of five commonly used enteral formulas over 4 h. There were no significant differences in postprandial concentrations of blood glucose among the formulas. The area under the curve of postprandial insulin values, however, was significantly smaller after consumption of the fructose-containing formula (1948±285 μU min ml−1, P<0.05) than after fiber-free (3222 ±678 μU min ml−1) or two fiber-containing products (2664±326 μU min ml−1, P<0.05; and 3040±708 μU min ml−1, P<0.05). The insulin area of the xylitol-containing formula (2307±364 μU min ml−1) was significantly smaller compared to the fiber-free product (P<0.05). In addition, we found the postprandial increase in triglycerides to be significantly higher after the xylitol-containing formula (from 0.93±0.14 to 1.25±0.22 mmol/1) than after the fiber-free product (from 0.82±0.13 to 0.97±0.16 mmol/1, P<0.05) or the two fiber-containing products (from 0.88±0.16 to 0.96±0.18 mmol/1, P<0.05; and from 0.80±0.08 to 0.95±0.10 mmol/l, P<0.05). We conclude that a patient with type 11 diabetes may benefit from replacing glucose and glucose-equivalent carbohydrates with fructose or xylitol.

Standardized ultrasound as a new method to induce platelet aggregation. Evaluation, influence of lipoproteins and of glycoprotein IIb/IIIa antagonist tirofiban

Most of the published studies concerning platelet aggregation were performed with chemical stimulation procedures, however, mechanical stimulation might be a better simulation of physiological activation of platelets. In order to evaluate the influence of ultrasound on platelet aggregation in vitro, we developed an ultrasound device in a standardized set-up, and we evaluated the influence of lipoproteins and the glycoprotein IIb/IIIa inhibitor tirofiban on ultrasound induced platelet aggregation. A cylindrical shaped plastic test tube with 1 ml of platelet-rich plasma was placed in an ultrasound bath (35 kHz) for 5 s. The ultrasound energy transfer into the sample (Delta W=3.77 J) was calculated using the average temperature increase (averaged by 0.935 degrees C) of the sample. Platelet aggregation was quantified immediately after stimulation with ultrasound or adenosine diphosphate (ADP 2.1 and 4.2 microM) by the Myrenne Aggregometer PA2 at low (40 s(-1)) and afterwards at high (2500 s(-1)) shear. To evaluate the influence of lipoproteins, seven healthy male volunteers were investigated before and after a fat load (50 g fat per m(2) body surface), and 11 patients suffering from hypercholesterolemia and atherosclerotic disease before and after a single low-density lipoprotein (LDL) apheresis. Platelet aggregation after ultrasound stimulation was well correlated with platelet aggregation after ADP (r between 0.50 and 0.95). However, when exposed to high shear, the low shear-induced platelet aggregates were more stable after ultrasound stimulation compared with ADP stimulation either with or without tirofiban. After the fat load triglyceride concentration increased from 0.86+/-0.39 to 2.10+/-1.10 mmol l(-1) (P<0.05) resulting in a reduced formation of platelet aggregates after weak (ADP 2.1 microM) but not after strong (ADP 4.2 microM or ultrasound) stimuli. After a single LDL apheresis LDL cholesterol dropped from 3.99+/-0.90 to 1.06+/-0.55 mmol l(-1) (P<0.005). No changes in platelet aggregation were observed with the exception of a lower aggregation when exposed to high shear after stimulation with 2.1 microM ADP. In conclusion, we found the ultrasound stimulation of platelet-rich plasma easy to perform. The platelet aggregation after ultrasound stimulation correlated well with stimulation after ADP. While a reduction in LDL cholesterol concentration had only slight effects on platelet aggregation, an increase in triglyceride concentration resulted in a reduced formation of platelet aggregates after weak stimulation.