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We characterized lipid and lipoprotein changes associated with a lopinavir/ritonavir-containing regimen. We enrolled previously antiretroviral-naive patients participating in the Swiss HIV Cohort Study. Fasting blood samples (baseline) were retrieved retrospectively from stored frozen plasma and posttreatment (follow-up) samples were collected prospectively at two separate visits. Lipids and lipoproteins were analyzed at a single reference laboratory. Sixty-five patients had two posttreatment lipid profile measurements and nine had only one. Most of the measured lipids and lipoprotein plasma concentrations increased on lopinavir/ritonavir-based treatment. The percentage of patients with hypertriglyceridemia (TG >150 mg/dl) increased from 28/74 (38%) at baseline to 37/65 (57%) at the second follow-up. We did not find any correlation between lopinavir plasma levels and the concentration of triglycerides. There was weak evidence of an increase in small dense LDL-apoB during the first year of treatment but not beyond 1 year (odds ratio 4.5, 90% CI 0.7 to 29 and 0.9, 90% CI 0.5 to 1.5, respectively). However, 69% of our patients still had undetectable small dense LDL-apoB levels while on treatment. LDL-cholesterol increased by a mean of 17 mg/dl (90% CI -3 to 37) during the first year of treatment, but mean values remained below the cut-off for therapeutic intervention. Despite an increase in the majority of measured lipids and lipoproteins particularly in the first year after initiation, we could not detect an obvious increase of cardiovascular risk resulting from the observed lipid changes.

Objectives: The interaction between lipoprotein(a), an emerging cardiovascular risk factor, and antiretrovirals (ARVs) has been less well studied than the interaction between either cholesterol or triglycerides and these drugs. In this study we assessed the effect of initiating antiretroviral therapy (ART) on lipoprotein(a) levels., Methods: Fasting samples from 95 patients initiating ART with nucleoside/nucleotide reverse transcriptase inhibitors plus nonnucleoside reverse transcriptase inhibitors or protease inhibitors were obtained. Lipids and lipoproteins were determined until week 48., Results: As in the general population, the study population showed a highly skewed lipoprotein(a) distribution (median 9.9 mg/dL, range 0.1-110 mg/dL). The study population was divided into individuals with lipoprotein(a) >or=30 mg/dL at baseline (n=28) and those with <30 mg/dL (n=67). Almost exclusively, patients with high lipoprotein(a) at baseline (median 51.6 mg/dL) showed a profound increase of median 26.7 mg/dL (week 24). This effect was not associated with specific ARVs and was independent of changes in other lipids. The low-lipoprotein(a) group (baseline median 7 mg/dL) showed a small increase of median 2.6 mg/dL (week 24)., Conclusions: Marked increases in lipoprotein(a) after initiation of ART were mainly restricted to patients with high baseline levels. This may have clinical implications as patients with high lipoprotein(a) are at higher risk for myocardial infarction and stroke.

In 1997 the current database for the relation of polyunsaturated fatty acids in the diet to breast cancer was extensively reviewed by expert committees of the American Institute for Cancer Research and the World Cancer Research Fund. They concluded: "Diets high in polyunsaturated or vegetable fats possibly have no relationship with the risk of breast cancer, independent of any contribution to total fat intake". On the other hand they stated that "Diets high in saturated fat possibly increase the risk of breast cancer" and "Diets high in monounsaturated fat per se possibly have no relationship with the risk of breast cancer, independent of that of total fat." The data in literature clearly confirm these interpretations. No new data exist which have changed the knowledge on the association between intake of fatty acids and breast cancer.

An increase in the uptake of long-chain Omega-3 fatty acids from fish with the diet or as ethyl esters resulted in a decreased risk for cardiac death. As mechanism for this rapidly occurring benefit (within 90 days of treatment significantly different to placebo) antiarrhythmic effects at cardiac myocytes and plaques stabilization can be discussed. The results of the GISSI Prevenzione Trial show that 175 patients have to be treated for one year to avoid one death. Regarding other available data for secondary prevention this efficacy is superior to pravastatin and at the same level as simvastatin or aspirin. Only beta-blocking agents are superior, but it is of interest that long-chain Omega-3 fatty acids from fish display their beneficial effects even in patients already treated with beta-blockers. As the intake of 0.85 g of long-chain Omega-3 fatty acids from fish per day can be regarded as save and the positive effect on total mortality occurs already after 90 days their regular use is a promising additional measure for secondary prevention.

Background: Hyperlipidaemia associated with antiretroviral treatment has led to concerns for an increased cardiovascular risk in HIV-infected patients., Objective: To assess this cardiovascular risk by comparing the lipoprotein pattern of antiretroviral-treated and untreated HIV-positive patients with patients with familial combined hyperlipidaemia (high cardiovascular risk) or familial hypertriglyceridaemia (low cardiovascular risk)., Methods: Fasting serum samples were drawn from consecutive patients with HIV infection or lipoprotein disorders. Total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, triglycerides, apolipoprotein A1 and B were determined in serum. Very low density lipoprotein (VLDL) was prepared by ultracentrifugation and analysed for cholesterol, triglycerides and apolipoprotein B., Results: Lipoprotein disorders were found in 114/187 HIV-positive patients (61%). Of these, according to the Fredrickson classification, 10% were type IIa (elevated LDL-cholesterol), 14% type IIb (elevated LDL- and VLDL-cholesterol) and 76% were type IV (elevated VLDL-cholesterol). VLDL composition was analysed in 34 HIV-positive patients with type IV hyperlipidaemia. The ratio of VLDL-triglycerides to VLDL-apolipoprotein B in these patients was 16.2 +/- 6.0. This ratio was not different from 14 patients with famlial hypertriglyceridaemia (16.9 +/- 6.0; = 0.61), but differed substantially from 10 patients with familial combined hyperlipidaemia (6.8 +/- 1.0; < 0.0001)., Conclusions: In HIV-infected patients with high VLDL, large VLDL particles were found with no increase in number. This pattern resembles familial hypertriglyceridaemia. It is different from familial combined hyperlipidaemia, where an increase in number of small-sized VLDL particles occurs. Further research is needed to assess the contribution of VLDL-associated hypercholesterolaemia in those taking antiretroviral drugs to the cardiovascular risk profile of HIV-positive patients.

The elimination of fibrinogen from plasma improves plasma viscosity and whole blood viscosity. For extracorporeal adsorption of fibrinogen the pentapeptide gly-pro-arg-pro-lys was coupled to sepharose CL-4B. Columns containing 100 ml of coupled sepharose CL-4B were used to eliminate fibrinogen from the plasma of 8 healthy male subjects (mean age 27.4 +/- 4.3 years, height 180.9 +/- 8.3 cm, weight 85.1 +/- 13.6 kg). Four treatments were performed in each proband (days 1, 2, 4 and 7). Plasma fibrinogen concentration was lowered from 221.1 +/- 39.0 to 123.5 +/- 21.7 mg/dl (2275 +/- 477 ml plasma treated) by the first treatment, from 172.8 +/- 42.3 to 105.6 +/- 16.5 mg/dl (1609 +/- 761 ml) by the second, from 140.5 +/- 13.8 to 98.8 +/- 8.6 mg/dl (1224 +/- 118 ml) by the third and from 160.2 +/- 23.6 to 106.4 +/- 9.7 mg/dl (1513 +/- 521) by the fourth. Plasma viscosity was improved from 1.40 +/- 0.18 mPa s before the first treatment to 1.23 +/- 0.06 mPa s after fourth treatment, whole blood viscosity from 4.49 +/- 0.36 mPa s to 3.83 +/- 0.27 mPa s (P < 0.01). No clinical side effects and no clinically relevant change of laboratory parameters including in vitro tests on thrombocyte function were observed. Seven men and three women (48-75 years old, 9 patients suffered from diabetes mellitus, one patient from peripheral arterial occlusive disease, 5 patients were on regular hemodialysis) were treated by fibrinogen adsorption. Each column contained 135 ml of coupled sepharose CL-4B. Treatments were scheduled on day 1, 2, 4, 6, 8, 10, 13, 16, 19, 22, 25 and 28. 144 treatments with fibrinogen adsorption were performed. No clinical side effects due to the fibrinogen-adsorption procedure were observed. In these 10 patients the fibrinogen concentration before the first treatment was 473.7 +/- 183.7 mg/dl. In the first treatment session it was lowered to 241.4 +/- 125.8 mg/dl by treating 4270 +/- 1180 ml of plasma. In the following 134 treatments the pre-treatment concentration of fibrinogen was 262.6 +/- 83.4 mg/dl, the post-treatment concentration was 120.6 +/- 37.2 mg/dl. The mean volume of plasma treated was 3737 +/- 1643 ml, the mean duration of a treatment session (except the first treatment) was 143.7 +/- 63.1 min. In 7 patients a mean post-treatment fibrinogen concentration of < or = 123 mg/dl was obtained, in the other patients 133, 177 and 184 mg/dl. Yet, the decrease of fibrinogen concentration was also pronounced in these 3 patients: -82%, -67%, and -73%, respectively. Accelerated wound healing was observed in 9 of the 10 patients. In conclusion, affinity chromatography using the pentapeptide gly-pro-arg-pro-lys is an effective, selective and safe procedure to lower fibrinogen concentration in plasma thereby improving blood viscosity. It could be a therapeutic option in severe blood vessel disease where drug therapy is not sufficient and invasive procedures like bypass or angioplasty cannot be applied.

A functional microcirculation is crucial for the normal function of an organism. In many physiopathological situations, impaired microcirculation may contribute to the development or progress of diseases. Microcirculation is closely interrelated with blood and especially plasma rheology. Thus, improvement of plasma viscosity has beneficial effects on rheology, microcirculation, and the related tissue microenvironment. However, at best tools that only have a minor influence on plasma viscosity exist so far. Fibrinogen is known to be the major contributor to plasma viscosity, making it an interesting target for therapeutic intervention. An adsorber specific for fibrinogen was developed on the basis of the TheraSorb technology. The TheraSorb technology (PlasmaSelect AG, Teterow, Germany) allows the selective removal of components from human blood plasma by means of an affinity chromatography column. A ligand specific for a defined plasma component is coupled to a solid matrix (sepharose) thus binding and eliminating the target molecule from plasma. Using a fibrinogen specific pentapeptide as ligand, selective removal of fibrinogen, fibrin, and degradation products, containing the target sequence of these molecules, can be obtained. The LIFE-18, a state-of-the-art integrated plasma therapy instrument, is used to perform the treatment. The procedure improves plasma and whole blood viscosity in a dose dependent manner as shown in Phase 1 and 2 clinical trials. This article describes the first clinical experience in patients with diabetic foot syndrome and provides an outlook for further clinical and scientific investigations related to this promising new procedure.

The elimination of fibrinogen from plasma improves plasma viscosity and whole-blood viscosity. For extracorporeal adsorption of fibrinogen, the pentapeptide gly-pro-arg-pro-lys was coupled to sepharose CL-4B3. Adsorbers containing 135 ml of coupled sepharose CL-4B were used to eliminate fibrinogen from the plasma of 7 men and 3 women (48-75 years old). Nine patients suffered from diabetes mellitus, 1 patient from peripheral arterial occlusive disease, and 5 patients were on regular hemodialysis. Treatments were scheduled on Days 1, 2, 4, 6, 8, 10, 13, 16, 19, 22, 25, and 28. One hundred forty-four treatments with fibrinogen adsorption were performed. No clinical side effects due to the fibrinogen adsorption procedure were observed. In these 10 patients, fibrinogen concentration before the first treatment was 473.7 +/- 183.7 mg/dl. In the first treatment session, fibrinogen concentration was lowered to 241.4 +/- 125.8 mg/dl by treating 4,270 +/- 1,180 ml of plasma. In the following 134 treatments, the pretreatment concentration of fibrinogen was 262.6 +/- 83.4 mg/dl, and the posttreatment concentration was 120.6 +/- 37.2 mg/dl. The mean amount of plasma treated was 3,737 +/- 1,643 ml, and the mean duration of a treatment session (except first treatment) was 143.7 +/- 63.1 min. In 7 patients, a mean posttreatment fibrinogen concentration of < or = 123 mg/dl was obtained; in the other patients, concentrations of 133, 177, and 184 mg/dl were obtained. Yet, the decrease of fibrinogen concentration was also pronounced in these 3 patients: -82%, -67%, and -73%, respectively. During the treatment period of 28 days, wound healing was observed in 9 of the 10 patients. In conclusion, affinity chromatography using the pentapeptide gly-pro-arg-pro-lys is an effective, selective, and safe procedure to lower fibrinogen concentration in plasma. It could be a therapeutic option in severe blood vessel disease in which drug therapy is not sufficient and invasive procedures such as bypass or angioplasty cannot be applied. Yet, more information is needed, for example, about the fibrinogen concentration that has to be reached to get the maximal improvement of micro- and/or macrocirculation.

Dyslipoproteinemias are associated with hemorrheologic abnormalities (elevated fibrinogen concentration, higher viscosity of plasma and blood). Epidemiologic data suggest that not only elevated lipoprotein concentrations (eg, low-density lipoprotein [LDL] cholesterol), but also hemorrheologic abnormalities could causally be involved in the atherosclerotic process. To elucidate potential effects of hemorrheological disturbances, we investigated patients suffering from primary hyperlipoproteinemias with both low (familial hypertriglyceridemia, n = 25) and high (type III hyperlipoproteinemia, n = 21; familial hypercholesterolemia, n = 19; mixed hyperlipoproteinemia, n = 19) atherosclerotic risk, as well as healthy controls (n = 49) in a cross-sectional design. Dyslipoproteinemias were classified by lipoprotein measurements (using ultracentrifugation), family history, and apolipoprotein E phenotype. Hemorrheology was characterized by the measurement of fibrinogen concentration, viscosity of plasma and blood at different shear rates, and red cell aggregation (RCA) at stasis and low shear. Fibrinogen concentration was lower in controls (2.38 +/- 0.09 g/L) compared with familial hypercholesterolemia (3.19 +/- 0.19 g/L), to type III hyperlipoproteinemia (3.02 +/- 0.12 g/L), to familial hypertriglyceridemia (2.95 +/- 0.21 g/L) and to mixed hyperlipoproteinemia (3.01 +/- 0.12 g/L) (P < .05, respectively) without differences between dyslipoproteinemia groups. Plasma viscosity was higher in patients with type III hyperlipoproteinemia (1.42 +/- 0.03 mPas), with familial hypertriglyceridemia (1.47 +/- 0.04 mPas), and with mixed hyperlipoproteinemia (1.43 +/- 0.02 mPas) compared with controls (1.29 +/- 0.01 mPas) (P < .05, respectively). After including 6 lipoprotein parameters in a general linear model, plasma viscosity, blood viscosity, and RCA were higher in familial hypertriglyceridemia compared with healthy controls and familial hypercholesterolemia (P < .05, respectively). As most of the hemorrheologic abnormalities were still significant after adjusting for lipoprotein concentrations, they seem to be at least partly independent from direct lipoprotein effects. Hemorrheologic abnormalities in familial hypertriglyceridemia (low atherosclerotic risk) were at least as marked as in dyslipoproteinemias with high atherosclerotic risk, suggesting that it might be most important to determine lipoprotein concentrations and to define exactly the type of dyslipoproteinemia for estimating the individual cardiovascular risk in these patients.

Epidemiological studies suggest that the plasma fibrinogen concentration is the main determinant of plasma viscosity (PV), but the concentration of other macromolecules (eg, immunoglobulins) and low-density lipoprotein (LDL) cholesterol and triglycerides are also correlated with PV. However, only a few data exist concerning the in vitro effects of these plasma constituents on PV. Therefore, we investigated PV before and after the specific elimination of fibrinogen and LDL in hypercholesterolemic and hypertriglyceridemic plasma. First, hypercholesterolemic samples (n = 7) were pumped simultaneously through 2 columns: a fibrinogen-depleting column containing the pentapeptide Gly-Pro-Arg-Pro-Lys (GPRPK) and a LDL-depleting column containing specific antibodies against apolipoprotein B-100. In the plasma and in each fraction from the column, the cholesterol level was measured enzymatically, fibrinogen was determined by immunonephelometry, and PV was analyzed using a low-shear rotation viscosimeter. After the fibrinogen-depleting column, the fibrinogen concentration decreased from 3.21 +/- 0.20 to 0.94 +/- 0.16 g/L (P < .005), inducing a decrease in PV from 1.27 +/- 0.02 to 1.17 +/- 0.01 mPas (milliPascal seconds) (P < .005). Despite a marked reduction of the LDL cholesterol after the LDL-depleting column (from 6.40 +/- 0.23 to 4.08 +/- 0.32 mmol/L, P < .005), PV remained unchanged. Second, hypertriglyceridemic samples (n = 7) were pumped through the fibrinogen-depleting column, which reduced the fibrinogen concentration from 4.29 +/- 0.79 to 1.62 +/- 0.69 g/L (P < .001) and PV from 1.42 +/- 0.06 to 1.03 +/- 0.05 mPas (P < .01) while the triglyceride concentration remained unchanged. Our results confirm the epidemiological correlation between the fibrinogen concentration and PV in patients with hypercholesterolemia and hypertriglyceridemia. The influence of fibrinogen on PV seems much more pronounced than the direct effect of lipoprotein concentrations. Therefore, the elevated PV in patients with hypercholesterolemia and especially with hypertriglyceridemia seems mainly due to elevated fibrinogen levels.

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.

Low density lipoprotein (LDL) apheresis is a treatment option for patients with severe hypercholesterolemia not adequately responding to drug treatment who have developed coronary heart disease. We regularly treated 18 patients with immunoadsorption, 8 with heparin induced extracorporeal LDL precipitation (HELP) and 8 with dextran sulfate adsorption for a mean of 4.6 +/- 2.6 years. The effects on LDL cholesterol, high density lipoprotein (HDL) cholesterol, and lipoprotein (a) were comparable among all 3 techniques. Twelve patients were treated for longer than 5 years and 18 patients for longer than 3 years. The evaluation of coronary angiograms (23 patients) revealed a definite regression of coronary lesions in 3 patients; in all other patients, there was a halt in progression. Three patients suffered a sudden cardiac death and 1 patient a nonfatal myocardial infarction due to the occlusion of a coronary bypass. In 9 of 11 patients, no atherosclerotic lesions developed in the coronary bypasses. No severe side effect of either procedure was observed. In conclusion, aggressive lipid lowering by LDL apheresis can stabilize coronary atherosclerosis in most patients.

Oxidation of low-density lipoprotein (LDL) plays a major role in the development of atherosclerosis. Hypercholesterolemia has been associated with enhanced in vitro oxidation of LDL, and lipid-lowering therapy reduces LDL oxidizability. In the present study, we investigated whether LDL apheresis performed with different techniques affects in vitro diene formation (lag phase) and modification of apolipoprotein B-100 (apoB). Baseline and posttreatment diene formation was correlated with the baseline pattern of plasma total fatty acids. We then performed a computer-simulation study to test the hypothesis that LDL apheresis-induced changes in LDL oxidizability are related to changes in the mass ratio between freshly produced and older LDL. In 19 patients aged 49+/-7 years with heterozygous familial hypercholesterolemia (FH) regularly treated with either immunoadsorption, heparin-induced LDL precipitation (HELP), or dextran sulfate (DS) adsorption, we determined lipoprotein levels, the lag phase, apoB modification, and the fatty acid pattern in plasma samples drawn at the onset and termination of one LDL apheresis. LDL apheresis significantly decreased total cholesterol, high-density lipoprotein (HDL) cholesterol, LDL cholesterol, and triglycerides by 50.4%, 14.9%, 62.6%, and 33.6%, respectively. The lag phase increased by a significant mean of 9.8%; the charge of apoB was not altered. The lag phase before treatment positively correlated with the baseline concentration of plasma total palmitic, myristic, and oleic acid. The increase in the lag phase during treatment correlated with a high pretreatment concentration of lauric, linoleic, and docosahexanoic acid. The simulation study indicates that a temporary imbalance between two LDL compartments, one representing freshly secreted LDL and the other representing older LDL, could explain the observed increase in the lag phase after LDL apheresis. In conclusion, in patients with heterozygous FH, LDL apheresis performed with different techniques decreases the susceptibility of LDL to oxidation. This decrease may be related to a temporary mass imbalance between freshly produced and older LDL particles. Furthermore, the baseline fatty acid pattern influences pretreatment and posttreatment susceptibility to oxidation.

Aims: Epidemiological data have shown that haemorheological disorders are associated with an increased risk of atherosclerosis. We evaluated the effect of the nicotinic acid derivative acipimox on haemorheological and lipid parameters in 18 patients with mixed hyperlipoproteinaemia using a randomized, double-blind, placebo-controlled, cross-over study protocol., Methods: Patients (7 women, 11 men, aged 49.3+/-3.0 years) were investigated with acipimox (dose adjusted to weight, 500 or 750 mg daily) compared with placebo treatment each for 12 weeks. Lipid parameters, whole blood viscosity, plasma viscosity, fibrinogen, and red cell aggregation at native and standardized (0.45) haematocrit as well as red cell filterability were measured at baseline, at week 12 (change of therapy), and at week 24., Results: Total cholesterol concentration (8.30+/-0.32 vs 8.72+/-0.36 mmol/l(-1)) and apolipoprotein B (198.5+/-9.9 vs 217+/-9.9 mg dl(-1)) were significantly lower (P<0.05) during acipimox therapy compared with placebo, no significant changes were observed for triglycerides and low-density lipoprotein [LDL] cholesterol. However, total high-density lipoprotein [HDL] cholesterol (1.24+/-0.05 vs 1.10+/-0.05 mmol l(-1), P<0.001) as well as HDL2 and HDL3 cholesterol (P<0.05) were significantly higher during acipimox therapy. The LDL cholesterol to HDL cholesterol ratio significantly improved during acipimox therapy (4.63+/-0.25 vs 5.49+/-0.26, P<0.001). Red cell aggregation at native and standardized haematocrit were the only haemorheological parameters which improved during acipimox therapy in comparison with placebo (shear rate 3 s(-1):10.69+/-0.40 vs 11.50+/-0.44 U, P<0.05, for native red cell aggregation; 10.40+/-0.36 vs 11.28+/-0.39 U, P<0.05, for standardized red cell aggregation)., Conclusions: We conclude, that the cardiovascular risk profile improves during acipimox therapy due to an elevation in HDL cholesterol and its subfractions as well as a decrease in red cell aggregation.

Low-density lipoprotein (LDL) apheresis is a potent treatment for patients with coronary heart disease and severe hereditary forms of LDL hypercholesterolemia not adequately responsive to drug treatment. Until now, the beneficial effect of aggressive reduction of LDL cholesterol by LDL apheresis on the course of coronary heart disease has been demonstrated in one 3-year study and several studies lasting 2 years. We now report on the clinical course, lipoprotein concentrations, coronary angiograms, and side effects in patients undergoing LDL apheresis for as long as 8.6 years. Thirty-four patients (21 men and 13 women) with coronary heart disease and heterozygous familial hypercholesterolemia (FH) not adequately responsive to lipid-lowering drugs received weekly (four patients biweekly) LDL apheresis for 4.6 +/- 2.6 years under diet and lipid-lowering drug therapy; after 0.5 to 3 years, simvastatin in the maximal tolerable dose was added. The baseline LDL cholesterol concentration was 6.9 +/- 1.6 mmol/L. Combined treatment in the steady state yielded a pretreatment and posttreatment LDL cholesterol concentration of 4.8 +/- 0.9 and 1.8 +/- 0.4 mmol/L, respectively. The calculated interval mean LDL cholesterol was 3.3 +/- 0.6 mmol/L. Evaluation of the coronary angiographies revealed a definite regression of coronary lesions in four patients (11.8%); in 19 patients, there was a cessation of progression. Two patients developed atheromatous lesions in bypass grafts (L.H., 60% stenosis; S.M., occlusion). Of 23 patients eligible for the scoring of anginal symptoms, five (21.7%) reported a reduction of the frequency and severity of angina pectoris. The mean coronary symptom score in 23 patients changed from 1.65 +/- 0.83 at baseline to 1.39 +/- 0.66 at the end of the study. During the whole observation period, we observed three sudden deaths, one nonfatal myocardial infarction, and five patients requiring hospital admission because of unstable angina pectoris, one of which was followed by a transluminal coronary angioplasty. Aggressive reduction of LDL cholesterol with combined LDL apheresis and drugs induced regression of coronary lesions in four of 34 patients and prevented progression in 29 patients for as long as 8.6 years. The effect on LDL and high-density lipoprotein (HDL) cholesterol and lipoprotein(a) [Lp(a)] was comparable with all three apheresis techniques. Therefore, no obvious difference between the three techniques was found regarding changes in coronary lesions.

Mild hyperhomocysteinemia has been associated with an increased risk to develop premature coronary heart disease. Recently, the homocysteine concentration has been positively correlated with several main cardiovascular risk factors. We addressed the issue as to whether patients with coronary heart disease and a low cardiovascular risk profile also have a higher prevalence of hyperhomocysteinemia than matched controls. Ninety-five patients (aged 50.5 +/- 6.6 years) and 34 controls (50.0 +/- 6.7 years) less than 60 years of age were selected from a sample of patients after coronary angiography. Subjects with hypertension, diabetes, and moderate or severe hyperlipidemia were excluded. We determined plasma aminothiols (total homocysteine, cysteine, and glutathione), lipoprotein fractions, fibrinogen, and uric acid, the body mass index (weight in kilograms divided by height in meters squared), and the waist to hip ratio. Furthermore, 37 healthy subjects aged 30.8 +/- 7.5 years underwent aminothiol determinations. Patients and controls were similar with regard to age and primary cardiovascular risk factors. Total homocysteine concentrations in the patient group (9.2 +/- 2.4 micromol/L) were significantly higher than in the healthy subjects (8.0 +/- 2.0 micromol/L). However, they did not differ from the levels in the age-matched controls (9.3 +/- 3.0 micromol/L). Neither total cysteine nor glutathione concentrations were significantly different between patients and controls. Male patients (n = 85) had higher mean very-low-density lipoprotein (VLDL) triglycerides (1.36 +/- 0.90 mmol/L) and lower high-density lipoprotein 3 (HDL3) cholesterol (0.75 +/- 0.21 mmol/L) than male controls (n = 28; 1.01 +/- 0.62 and 0.88 +/- 0.26 mmol/L, respectively). Female patients did not have any significant differences in lipoprotein concentrations versus the controls. Among further cardiovascular risk factors, we found a higher prevalence of central obesity in male patients. In conclusion, there was not a higher incidence of hyperhomocysteinemia among patients with premature coronary heart disease and a low cardiovascular risk profile. The higher prevalence of hyperhomocysteinemia found in other studies may be related to the primary risk factors seen in these populations, and may therefore be an indicator of the global cardiovascular risk.

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.

LDL-apheresis is a treatment option for patients with coronary heart disease and severe hypercholesterolemia not adequately responding to drug treatment. 34 patients (21 men, 13 women), aged 47 +/- 9 years, with coronary heart disease and heterozygous familial hypercholesterolemia not adequately responsive to lipid lowering drugs received weekly (4 patients biweekly) LDL apheresis for 3.5 +/- 2.5 years, after 0.5 - 3.0 years simvastatin in the maximally tolerable dose was added. Baseline LDL cholesterol concentration under diet and lipid lowering drugs in the patients receiving immunoadsorption, dextran sulfate adsorption and HELP apheresis was 265.4 +/- 54.9, 230.8 +/- 75.8 and 253.7 +/- 55.7 mg/dl, respectively. The calculated mean LDL cholesterol concentration of the last 5 treatments of the observation period was 123.7 +/- 22.8, 126.8 +/- 26.7 and 138.8 +/- 19.7 mg/dl, respectively. The evaluation of coronary angiographies revealed a definite regression of coronary lesions in 3 patients (8.8%), in all other patients there was a stop in progression. 3 patients died of cardiac complications during the observation period. We conclude that aggressive lipid lowering with combined LDL-apheresis and drugs can stabilize coronary atherosclerosis in most patients with refractory hypercholesterolemia.

Lowering of plasma cholesterol and particularly of LDL cholesterol has been shown to be an effective way of primary and secondary prophylaxis of coronary heart disease. A broad range of drugs is available (bile acid binding resins, HMG CoA reductase inhibitors, fibrates, nicotinic acid, probucol, beta-sitosterol) for therapy. The choice of the drug is based on the efficacy, possible side effects and proven effects on coronary heart disease.

Previous studies show conflicting results concerning an influence of apolipoprotein E (apo E) phenotype on lipoprotein(a) (Lp(a)) plasma levels. We speculated that it is not the apo E phenotype itself but rather its effect on plasma lipid concentrations that might influence Lp(a) levels. In 1562 subjects concentrations of triglycerides, LDL-cholesterol and Lp(a) were measured by standard laboratory methods. Apo(a) and apo E isoforms were determined by sodium dodecyl sulfate gel electrophoresis and isoelectric focusing, respectively, followed by immunoblotting. An univariate analysis revealed a significant influence of apo(a) isoforms, apo E phenotype, triglycerides and LDL-cholesterol on Lp(a) plasma levels (ANOVA: P < 0.001, P < 0.02, P < 0.001 and P < 0.001, respectively). In a multivariate analysis, however, the influence of the apo E phenotype was no longer significant (P>0.10), whereas apo(a) isoforms, LDL-cholesterol quintiles and triglyceride quintiles explained 29.2, 2.8 and 1.0% of the variation of the Lp(a) levels (for all three variables: P < 0.001). We conclude that apo E polymorphism does not exert an independent effect on Lp(a) concentrations. Any influence is mediated through the effect of apo E polymorphism on plasma lipids.

Metabolic side-effects of antihypertensive drugs may increase the risk of coronary heart disease despite an adequate blood pressure reduction. Since combinations of different antihypertensive drugs are often necessary and frequently used, we performed a randomized study comparing the effects of a fixed combination of hydrochlorothiazide and sotalol (group A), or hydrochlorothiazide and captopril (group B) on blood pressure and on lipid and glucose metabolism in 40 men with essential hypertension over 1 year. Significant blood pressure reductions (p < 0.001) were achieved in both treatment groups: from 160/105 to 128/88 mmHg in group A (mean doses: hydrochlorothiazide 33 and sotalol 197 mg) and from 162/106 to 135/89 mmHg in group B (hydrochlorothiazide 33 and captopril 64 mg) after 12 months, respectively. No significant changes in body weight were observed in either treatment group. Triglycerides increased (p < 0.05) in both treatment groups (from 183 to 262 mg/dl in A, and from 160 to 196 mg/dl in B) and HDL cholesterol decreased (p < 0.001 and < 0.05) in both groups (from 45.1 to 35.7 mg/dl in A, and from 49.3 to 46.3 mg/dl in B), whereas LDL cholesterol increased significantly (p < 0.05) only in group A from 153 to 164 mg/dl. No significant changes were observed in total cholesterol nor in lipoprotein(a) concentrations in either treatment group. Fasting plasma glucose and hemoglobin A1 increased significantly (p < 0.05) only in group A after 1 year of treatment (from 91.6 to 98.0 mg/dl, and from 6.3 to 6.9%, respectively). Serum levels of creatinine and potassium decreased, and uric acid increased significantly under either combination. Our data show that the diuretic/beta-blocker combination has adverse effects on lipid and glucose metabolism after long-term therapy. The effects of the diuretic/ACE inhibitor combination on lipid metabolism are less pronounced and there are no adverse effects on glucose metabolism. However, the ACE inhibitor component could not completely counteract the metabolic effects of the diuretic. Both combinations have no effects on Lp(a). We conclude that the combination of hydrochlorothiazide with an ACE inhibitor has a better metabolic profile for the treatment of essential hypertension than the combination with a beta-blocker.

Platelet phospholipid composition was analyzed before and after extracorporeal removal of low density lipoproteins (LDL) by LDL apheresis in six patients with familial hypercholesterolemia. Elevated levels of total plasma cholesterol and the portion of plasma cholesterol carried by LDL were reduced by 56 and 66% after LDL apheresis. Platelet cholesterol contents remained unaffected. While the phosphatidylcholine (PC):sphingomyelin (SM) ratio in plasma lipoproteins was increased by 22% following apheresis, the same parameter was lowered by 14% in platelets. LDL apheresis induced decreases in the percentages of distinct molecular species containing arachidonic acid in platelet diacyl subgroups of PC, phosphatidylinositol (PI) and phosphatidylserine (PS) as well as in alkenylacyl (plasmalogen) phosphatidylethanolamine (PE). Directly after apheresis, the percentages of molecular species with arachidonic acid of diacyl PC, diacyl PI and alkenylacyl PE were reduced by 20, 23 and 8%, respectively. Two days after the procedure, total arachidonic acid of diacyl PC, diacyl PS and alkenylacyl PE was lowered by 11, 20 and 8%. Overall, the amount of phospholipid bound arachidonic acid was reduced by 16% after apheresis (from 79.1 to 66.4 nmol/10(8) platelets). The results are thus in agreement with previous data indicating decreased phospholipid bound arachidonic acid in red blood cells after apheresis (Engelman B. Bräutigam C, Kulschar R et al. Biochim Biophys Acta 1994:1196:154). Urinary 2,3-dinor thromboxane B2, an estimate of platelet thromboxane A2 (TXA2) production, tended to be decreased following the procedure. The percentage change in the TXA2 metabolite was positively related to the magnitude of change induced by apheresis in phospholipid bound arachidonic acid. In summary, the results suggest that in patients with hypercholesterolemia, the level of plasma LDL is an important determinant of the arachidonic acid content of several platelet phospholipids.

Islet cell antibodies and glutamic acid decarboxylase II (GAD II) antibodies have been discussed in the autoimmune pathogenesis of insulin-dependent diabetes mellitus (IDDM). Hence, immunosuppressants, intravenous immunoglobulins, and plasmapheresis have been used in an effort to modulate autoimmune activity and thereby prevent the destruction of pancreatic beta-cells. We describe the autoantibody (islet cell antibody and GAD II) kinetics and clinical course in a patient with newly diagnosed IDDM treated with a specific immunoglobulin apheresis technique. Five days after the initial diagnosis a 37-year-old patient with IDDM underwent a series of seven immunoglobulin aphereses. Immunoglobulin (IgG, IgA, IgM), islet cell antibody, GAD II, and C-peptide concentrations were monitored for a time course of 74 days. Daily insulin requirements were recorded. One single immunoglobulin apheresis decreased IgG by 66.2 +/- 9.1%, IgA by 66.8 +/- 8.7%, and IgM by 57.7 +/- 12.9%. GAD II antibodies were reduced by 61.9 +/- 12.4%. The islet cell antibody titer declined from 1:32 to 1:4 after the treatment series. There were no relevant changes in the safety parameters determined nor were there any clinical side effects. The efficient decrease in islet cell antibodies and glutamic acid decarboxylase II antibodies in a patient with IDDM encourages further investigations into the impact of this treatment on the clinical course of this autoimmune disorder.

Extracorporeal procedures such as plasmapheresis or protein a apheresis have been applied successfully to remove autoantibodies in the treatment of severe forms of various autoimmune diseases. A newly developed immunoapheresis technique that uses columns containing polyclonal anti human immunoglobulin (Ig) antibodies was investigated in four patients with idiopathic thrombocytopenic purpura (ITP). A series of two to four treatments were performed, and the period between the two series was dependent on the actual thrombocyte count. A total of 38 treatments was carried out. During the first apheresis, IgG declined to a mean of 52.7% of the initial concentration. The IgG subclasses one through four were decreased to the same extent. The IgA was lowered to 64.4%, and IgM was lowered to 66.7%. A series of four aphereses yielded a 75-80% decline of the different Ig species. A further decrease in Ig would have been possible, but was not aimed at in this study. All Ig fractions reincreased between the two series. In two patients, a rise in thrombocytes as a response to treatment was observed. Apart from three hypotensive reactions and one episode of hypocalcemia, no further side effects occurred in 38 treatments. The authors conclude that Ig apheresis with anti human Ig antibodies is an effective and safe form of treatment. Its effect on the clinical course of autoimmune diseases merits further investigation.

High serum concentrations of lipoprotein (a) [Lp(a)] are considered a risk factor for premature atherosclerosis. Besides apolipoprotein B-100, Lp(a) consists of apolipoprotein (a) [apo(a)], which shows a remarkable size polymorphism. The serum concentration of Lp(a) is considerably influenced by this apo(a) phenotype. Because Lp(a) is synthesized in the liver, we wondered whether and to what extent Lp(a) levels might be affected by acute liver disease. We compared Lp(a) serum concentrations in 74 patients (54% male, 46% female; mean age, 46 years) with acute viral hepatitis (32, 28, and 14 with hepatitis A, B, and C, respectively) with those in 404 healthy controls (57% men, 43% women; mean age, 47 years). In addition, the intraindividual course of Lp(a) concentration during and after acute hepatitis was followed in a subgroup of 23 patients (15, 6, and 2 with hepatitis A, B, and C, respectively). During acute hepatitis, median Lp(a) concentrations in the patient group were significantly diminished compared with controls (7 vs. 17 mg/dL;P < .0001, Mann-Whitney test). Any bias by an unequal isoform distribution was excluded because there was no significant difference in the isoform distribution between patients and controls (P > .10, chi2 test). Furthermore, the decrease in Lp(a) concentration during acute hepatitis was independent of the molecular weight of the apo(a) isoform. Longitudinally observed patients showed a marked increase in Lp(a) concentration during convalescence (7 to 32 mg/dL;P < .0001, Wilcoxon test). Our results show that acute hepatitis is associated with decreased Lp(a) serum levels. Further studies are needed to evaluate whether Lp(a) serum concentration might be clinically useful as a parameter of liver function.

Apheresis is a treatment option for patients with severe hypercholesterolemia and coronary artery disease. It is, however, unknown whether such therapy changes kinetic parameters of lipoprotein metabolism, such as apolipoprotein B (apoB) secretion rates, conversion rates, and fractional catabolic rates (FCR). We studied the long-term effect of regular apheresis therapy on metabolic parameters of apoB in five patients with heterozygous familial hypercholesterolemia (FH) using endogenous labeling with D3-leucine, mass spectrometry, and multicompartmental modeling. Patients were studied prior to (study 1) and after 3-6 months of weekly apheresis therapy (study 2). LDL-apoB concentration was 183 +/- 16 mg d-1 prior to apheresis therapy (study 1), 135 %/- 7 mg. dl-1 at the beginning of study 2, and 163 +/- 10 mg . dl-1 at the end of study 2. VLDL-apoB and IDL-apoB were not different between the two studies and did not change during study 2. Separate modeling of the two studies revealed very similar parameters in each patient. In a second step simultaneous modeling of both studies was performed taking the changing pool size as a non-steady-state condition into account. ApoB tracer data of both kinetic studies and the change in pool size could be described with one set of kinetic parameters (VLDL-apoB FCR 4.32 +/- 1.06 d-1, LDL-apoB FCR 0.17 +/- 0.05 d-1, apoB secretion rate 11.9 +/- 3.7 mg . kg-1 . d-1). These parameters are well within the range of those previously published for FH heterozygotes in steady state. We conclude that regular apheresis therapy did not alter kinetic parameters of apoB metabolism in these patients with heterozygous FH in the long term and that the decreased rate of delivery of neutral lipids or apoB to the liver does not regulate plasma apoB metabolism.

Objective: To investigate whether obesity influences cardiac autonomic nerve function., Design: Comparing two groups of subjects with different degrees of obesity to normal weight controls., Subjects: 19 healthy controls (mean age 33 y, BMI 21.7 +/- 0.2 kg/m2) and 17 obese non-diabetic subjects (mean age 39 y, BMI 33.7 +/- 1.8 kg/m2)., Measurements: Insulin sensitivity was calculated by an oral glucose tolerance test. Autonomic nerve function was evaluated by analysing the variation of the heart frequency at rest (coefficient variation of R-R intervals, REST 1), during deep respiration, at a Valsalva maneuver (longest/shortest R-R interval during inspiration hold) and by the Ewing test (ratio between the 30th and 15th R-R interval after reaching up-right position)., Results: The obese showed a lower insulin sensitivity than healthy controls (3.09 vs 4.60 mg x l2/mmol x mU x min, P < 0.001). Their variation in heart frequency was reduced (REST 1: 1.95 vs 2.9, P < 0.01, Valsalva: 1.30 vs 1.52 and Ewing test: 1.03 vs 1.14, P < 0.05). However, patients with moderate (BMI 31.7 kg/m2) or severe obesity (39.0 kg/m2) with identical insulin sensitivity had no significant difference in autonomic nerve function. Except for the Ewing test all measured parameters for the evaluation of cardiac autonomic nerve function correlated with the degree of diminished insulin sensitivity (REST 1: r = 0.475, P < 0.001)., Conclusion: Moderate obesity with significantly decreased insulin sensitivity is associated with impaired cardiac autonomic nerve function.

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.

Low-density lipoprotein (LDL) apheresis is applied in patients with coronary heart disease because of severe inherited forms of hypercholesterolemia, for which dietary and combined drug treatment cannot lower LDL cholesterol concentrations less than 130 mg/dl. The following article describes the changes in lipoprotein levels in a total of 19 patients undergoing weekly LDL apheresis. Immunoadsorption, operating with polyclonal antibodies against apolipoprotein B-100, was used in 6 patients. Five patients were put on heparin-induced extracorporeal LDL precipitation (HELP) therapy; 6 received dextran sulfate adsorption treatments. Under steady-state conditions a single treatment reduced LDL cholesterol by 149 + or - 3 mg/dl with immunoadsorption, 122 + or - 2 mg/dl with HELP, and 124 + or - 18 mg/dl with dextran sulfate adsorption. Lipoprotein (a) (Lp[a]) declined by 52 to 65%. Very low density lipoprotein (VLDL) cholesterol and VLDL triglycerides declined by 45 to 55% because of the activation of lipoprotein lipase and precipitation during the HELP procedure. In all procedures, there was a small reduction in the different high-density lipoprotein fractions, which had returned to normal after 24 h. The long-term HDL3 cholesterol levels increased significantly. During all procedures there was a decrease in the molar esterification rate of lecithin cholesterol acyltransferase activity. All changes in lipid fractions were paralleled by changes in the corresponding apolipoprotein levels. It is concluded that all three techniques described are powerful tools capable of lowering LDL cholesterol in severe hereditary forms of hypercholesterolemia. In HELP and dextran sulfate adsorption, the amount of plasma is limited by the elimination of other plasma constituents. Immunoadsorption may thus be preferred in very severe forms of hypercholesterolemia.

The beneficial effect of cholesterol-lowering therapy for secondary prevention in patients with coronary artery disease (CAD) is well established. The therapeutic goal in this situation is a low-density lipoprotein (LDL) cholesterol level of 100 mg/dl. Cholesterol-lowering therapy will not only lead to a reduction in the progression of lesions but also and probably more importantly will reduce lesion activation and rupture and improve endothelial vasomotor function. Depending on the underlying hyperlipoproteinemia, the first choice for single drug therapy is a bile acid-binding resin or a hepatic hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor in isolated LDL hypercholesterolemia, and nicotinic acid, a fibric acid, or a HMG-CoA reductase inhibitor in combined hyperlipidemia. Combination therapy usually consists of a bile acid-binding resin with either an HMG-CoA reductase inhibitor, a fibric acid, or nicotinic acid in LDL hypercholesterolemia and nicotinic acid with a fibric acid in combined hyperlipidemia.

Recent evidence indicates that plasmalogen phospholipids are particularly sensitive to oxidation and may possess antioxidative properties. Approximately 4.4%-5.5% of phosphatidylcholine (PC), and 53%-60% of phosphatidylethanolamine (PE) consisted of the plasmalogen phospholipids, plasmenylcholine and plasmenylethanolamine, respectively, in whole plasma, low density lipoprotein (LDL) and high density lipoprotein (HDL) of 11 normolipidemic donors. Of total plasmalogen phospholipids in plasma, slightly more was associated with LDL particles (about 42%) than with HDL (36%). Plasmalogen phospholipid levels were analyzed in 12 patients with familial hypercholesterolemia (FH) regularly treated by LDL apheresis, of whom 6 were supplemented with vitamin E (alpha tocopherol, 400 IU/day), the remaining 6 not receiving the antioxidant. Before apheresis (pre), total plasmalogen phospholipid levels in plasma and LDL (expressed as mumol/mmol cholesterol of compartment) decreased as follows: patients receiving vitamin E > normolipidemia > patients not receiving vitamin E. In both hypercholesterolemic groups, the contents of plasmalogen phospholipids in whole plasma and LDL were 3-5-fold higher than those of vitamin E. Directly after apheresis (post), plasmalogen phospholipid levels in plasma were raised by about 50% in the two hypercholesterolemic groups, mostly due to increases in plasmenylethanolamine levels. Two days after apheresis (48 h post), plasmalogen contents were still elevated in plasma and red blood cell membranes of patients receiving vitamin E, while they had already reached pre-apheresis values in those not supplemented with alpha tocopherol. Molecular species of plasma diacyl phospholipids containing polyunsaturated fatty acids were elevated at pre in patients receiving vitamin E as compared to patients without supplementation. At 48 h post, LDL apheresis induced an increase in these molecular species only in patients receiving vitamin E. In conclusion, the contents of plasmalogen phospholipids in plasma lipoproteins are at least three times higher than those of vitamin E. LDL apheresis raises the level of plasmalogen phospholipids in plasma, the increase persisting longer in patients supplemented with vitamin E. Supplementation with vitamin E appears to protect plasmalogen phospholipids in plasma lipoproteins against oxidative degradation.

Hypercholesterolemia is a risk factor for the development of coronary disease. It does not present with symptoms and can be diagnosed by laboratory examination only. Screening is the only means to detect subjects at risk at a time when preventive measures can effectively be applied. We therefore initiated the Bavarian Cholesterol Screening Project (BCSP). Occasional screening was performed in 150,089 subjects (81,286 women, 68,803 men) in 214 campaigns. The mean cholesterol value was 243 +/- 52 mg/dl for women and 231 +/- 53 mg/dl for men; 37.3% of women and 38.1% of men had values of 201-250 mg/dl, 42.2% of women and 33.7% of men values > 250 mg/dl. Also, the following risk factors were recorded: smoking in 11.3% of women and in 20.2% of men, hypertension in 19.8% of women and 17.4% of men, diabetes mellitus in 4.2% of women and 4.1% of men, obesity in 16.8% of women and 20.9% of men, and a family history of myocardial infarction in 34.8% of women and 26.0% of men. Of the 27,084 men who had their cholesterol checked for the first time, 35.6% had levels between 201 and 250 mg/dl, and 22.9% had levels above 250 mg/dl. Of the 27,870 women whose cholesterol level had not been checked before, 38.8% had levels between 201 and 250 mg/dl, and 27.1% had levels above 250 mg/dl. More than 70% of the subjects with levels between 200 and 250 mg/dl had at least one additional risk factor. We conclude, on the basis of this study, that the risk factor hypercholesterolemia is unknown in as much as 20% of the population of Bavaria. These newly detected subjects were offered the opportunity to recognize this risk and take subsequent measures of prevention. Screening projects for hypercholesterolemia therefore can be an effective means of improving public health.

Objective: To investigate the effect of dexfenfluramine (d-F) on basal and isoproterenol stimulated lipolysis in human fat cells in vitro., Design: Adipocytes were incubated in Krebs-Ringer-Hepes buffer either with 10(-6) M or 10(-7) M isoproterenol alone, with 0.02-200 micrograms/ml (74.7 nmol/l-747 mumol/l) of d-F or both., Measurements: Glycerol release at 2 h incubation time was measured as an estimate for lipolysis., Results: The addition of d-F did not significantly influence basal lipolysis of 58.6 nmol/2 h. Stimulation by 10(-6) M and 10(-7) M isoproterenol increased glycerol release to 92.5 nmol/2 h and 83.4 nmol/2 h, respectively. Adding increasing doses of d-F and 10(-6) M isoproterenol caused a dose-dependent inhibition of isoproterenol stimulated lipolysis. Glycerol release was significantly decreased to 84.1 nmol/2 h at 20 micrograms/ml, to 77.8 nmol/2 h at 60 micrograms/ml and to 61.9 nmol/2 h at 200 micrograms/dl d-F. Glycerol release induced by 10(-7) M isoproterenol was significantly inhibited to 69.7 nmol/2 h at 20 micrograms/ml, to 61.5 nmol/2 h at 60 micrograms/ml and to 51.9 nmol/2 h at 200 micrograms/ml d-F. 50% inhibition occurred at 80 micrograms/ml d-F with 10(-6) M isoproterenol and at 28 micrograms/ml with 10(-7) M isoproterenol., Conclusion: d-F may decrease the release of free fatty acids from adipose tissue. This would lead to a reduced flux to the liver and may partly account for the triglyceride lowering effect of d-F in obese subjects.

Because it disturbs microcirculation, chylomicronemia can cause severe clinical complications such as acute pancreatitis. Dietary measures are very important in the prevention and treatment of this condition. Dietary supplementation with (n-3) fatty acids has been shown to be of benefit in short-term treatment of chylomicronemia. To evaluate the long-term efficacy of (n-3) fatty acids we added 2.16 or 4.32 g/d (for 3 mo) and 3.24 g/d (for a further 8 mo after 1 mo of no treatment) (n-3) fatty acids to the diet of eight patients with primary chylomicronemia. Serum triglycerides decreased significantly from 15.0 +/- 2.5 to 9.9 +/- 2.8 mmol/L (P < 0.01) after 11 mo of treatment, and VLDL triglycerides decreased from 12.3 +/- 2.8 to 9.0 +/- 2.4 mmol/L (P < 0.01), resulting in a significant decrease of plasma viscosity from 1.56 +/- 0.17 mPa-s to 1.47 +/- 0.12 mPa.s (P < 0.01). Total cholesterol, HDL and LDL cholesterol as well as lipoprotein (a) and fibrinogen concentrations were not affected by fish oil treatment. The presence of chylomicrons and chylomicron remnants (apolipoprotein B 48 concentration in the lipoprotein fraction with a density lower than 1.006 kg/L) was significantly reduced from 4.82 +/- 1.08 to 1.06 +/- 0.38 mg/L (P < 0.01). Body weight increased significantly from 71.0 +/- 4.6 kg to 75.2 +/- 5.3 kg after 11 mo of treatment with (n-3) fatty acids.(ABSTRACT TRUNCATED AT 250 WORDS)

In order to evaluate whether changes in plasma phospholipid composition are rapidly transmitted to the red blood cell membrane (RBCM) under in vivo conditions, the levels of major phospholipids in plasma, low density and high density lipoproteins (LDL and HDL) as well as in RBCM were determined before (pre), directly after (post) and 2 days after (48 h post) LDL apheresis in six patients with severe hypercholesterolaemia. LDL apheresis induced a 30-70% decrease in plasma and LDL cholesterol and total phospholipid levels within 2-3 h. Concomitantly, the percentages of plasma phosphatidylcholine (PC) and the PC/sphingomyelin (SM) ratio were increased compared to initial values. The percentage of plasma lyso PC (LPC) determined before apheresis in the patients was 30% lower with respect to the mean level of LPC in a normolipidaemic control. For LPC of LDL no differences were observed between normolipidaemia and hypercholesterolaemia. LDL apheresis induced a rise by about one third in the percentage of plasma LPC. At 48 h post, plasma LPC levels reapproached pre-apheresis levels, while the percentages of PC and the PC/SM ratio remained elevated. The pattern of changes induced by apheresis in plasma PC, SM and LPC levels was mimicked by changes in RBCM phospholipids. Strong positive relationships were noted for PC, SM and PC/SM as determined at pre, post and 48 h post between plasma and RBCM. In summary, changes in plasma PC, LPC, and PC/SM ratios as induced by LDL apheresis are rapidly transmitted to the RBCM under in vivo conditions, most probably as a result of phospholipid transfer between both compartments.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of alpha-melanocyte-stimulating hormone (alpha-MSH), beta-melanocyte-stimulating hormone (beta-MSH), beta-lipotropin (beta-LPH), and beta-endorphin (beta-EPH) at concentrations from 10(-9) M up to 10(-6) M on human adipose tissue lipoprotein lipase (LPL) were studied in a cell-free system. alpha-MSH and beta-MSH did not exert any effect on LPL; no degradation of these peptides in the incubation medium could be detected by HPLC analysis. beta-LPH and beta-EPH failed to alter enzyme activity. However, HPLC analysis revealed an unspecific rapid degradation of the peptides due to the activity of tissue proteases. Therefore, the protease inhibitors amastatin, antipain, APMSF, and TPCK were tested at concentrations of 10(-5), 10(-4), and 10(-3) M for their efficacy to inhibit degradation. None of the inhibitors was able to substantially reduce proteolysis of beta-LPH, as was the case with amastatin, APMSF, and TPCK for beta-EPH. However, antipain at 10(-4) M preserved at least 20% of the initial peptide concentration from proteolysis up to 150 min. Antipain caused a decrease in lipoprotein lipase activity (LPLA), which was dependent on concentration. The adverse effect of antipain at concentrations of 10(-4) M on LPL was completely abolished by beta-EPH at a concentration of 10(-6) M.

In order to evaluate whether acute changes in fatty acids bound to phospholipids in plasma are transmitted into red blood cell membrane (RBCM) phospholipids, molecular species of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were analyzed after reduction of apo B containing lipoproteins through low density lipoprotein (LDL) apheresis in patients with severe hypercholesterolemia. As compared to the control, increases and decreases in molecular species with arachidonic acid (20:4) and with linoleic acid (18:2), respectively, at sn-2 of plasma diacyl-PC were seen in the patients before the apheresis. Directly after the procedure, the sum of species of plasma and RBCM PC plus PE with 20:4 were reduced. Two days after apheresis major species of plasma diacyl-PC reapproached preapheresis values while, in contrast, the composition of plasma alkenylacyl(plasmalogen)-PE was distinctly altered. In plasmalogen-PE of RBCM similar modifications were induced by the apheresis as in the same subgroup in plasma. In vitro experiments using vesicles with plasmalogen-PE labeled at sn-2 with either [14C]20:4 or a fluorescent pyrenedecanoyl residue indicated fast incorporation of the subgroup into the RBCM. In contrast, diacyl-PE was not taken up by the RBCM. In conclusion, apo B containing lipoproteins are partially responsible for the supply of phospholipids with arachidonic acid to RBCM, in particular by means of the fast incorporation of plasmalogen-PE. The transmission of changes induced by apheresis in plasma into those of the RBCM suggest that erythrocytes play an important role in the homeostasis of fatty acids bound to plasma phospholipids in vivo.

Lipoprotein(a) [Lp(a)] concentrations are known to be stable under various dietary and drug regimens. Little is known about the influence of hyperlipoproteinemia on Lp(a) levels. Therefore, we investigated Lp(a) concentrations and apolipoprotein(a) [apo(a)] polymorphism in 147 patients with hypertriglyceridemia and in 93 patients with hypercholesterolemia and compared them with 404 subjects without hyperlipoproteinemia (controls). Despite a similar apo(a) isoform and phenotype distribution, Lp(a) concentrations differed significantly (P < .0001) between the three groups. The median Lp(a) level in control subjects was 17 mg/dL (mean, 38 mg/dL), compared with 38 mg/dL (mean, 56 mg/dL) in patients with hypercholesterolemia and 9 mg/dL (mean, 21 mg/dL) in those with hypertriglyceridemia. These differences persisted after exclusion of 61 subjects with coronary heart disease. The inverse correlation between the molecular weight of the apo(a) isoforms and the Lp(a) concentration was preserved within each group (P < .001), but for every molecular weight range studied the level of Lp(a) was always higher in patients with hypercholesterolemia and always lower in those with hypertriglyceridemia than in controls. We conclude that hypertriglyceridemia or hypercholesterolemia have profound--but divergent--influences on the concentration of Lp(a).

Beyond cholesterol, inflammatory ether phospholipids such as platelet-activating factor (paf) may play a role in atherogenesis. (1) We detected a paf-like compound ('LA-paf') associated with human serum lipoproteins, mainly in LDL but not with the lipoprotein-poor fraction. (2) LA-paf was also found in washed human platelets, from where it was partially released during platelet aggregation in response to paf (50 nM) or thrombin (1 U). In addition, resident monocyte/macrophage-like U937 cells carried huge amounts of LA-paf (41 ng per 10(7) cells) and metabolized added [3H]paf to a labelled compound co-eluting with the retention time of LA-paf in standard HPLC. (3) Functionally, LA-paf had a comparable potency to synthetic paf, because LA-paf aggregated washed aspirin-treated platelets in a concentration-dependent manner. The specific paf receptor antagonist WEB2086 inhibited the platelet aggregation induced by three distinct LA-paf preparations as compared with synthetic paf with similar inhibitory concentrations (IC50: 35.6 +/- 12.8, 24.0 +/- 4.0, 38.0 +/- 15.8 nM for LA-paf, and 43.6 +/- 6.5 nM for synthetic paf), indicating that LA-paf interacted with paf receptors. (4) However, LA-paf had a distinct retention time using high-pressure liquid chromatography (HPLC) as compared with synthetic paf. LA-paf eluted at 9-15 min and synthetic paf at 21-24 min. In addition, total and non-specific [3H]paf binding to intact washed human platelets was affected differently by the two unlabelled agonists: while LA-paf increased total and non-specific (but not specific) binding in a significant manner (P < 0.002 and P < 0.007) as LDL did (P < 0.006 and P < 0.03), synthetic paf decreased total binding (P < 0.03). Similarly, low-density lipoproteins (LDL) increased significantly the total [3H]paf binding. In contrast, paf did not affect specific [125I]LDL binding to human fibroblasts. Our results show the presence of LA-paf in lipoproteins, washed human platelets and monocyte/macrophage-like cells. As LDL and LA-paf purified from the same LDL particles increased significantly the total [3H]paf binding to intact human platelets, it might modulate platelet adherence to vascular endothelial cells.