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Biomedical subjects

A F Stalenhoef

Publications and source records attributed to A F Stalenhoef.

At least 37 records · Page 2Linked to original sources
PubMed2000

The rebound of lipoproteins after LDL-apheresis. Kinetics and estimation of mean lipoprotein levels.

We studied the rebound of lipoproteins in 20 hypercholesterolemic men [mean total cholesterol (TC) levels 9.6+/-1.8 mmol/l] after LDL-apheresis (LA) to determine the rate of recovery and the change in cholesterol synthesis, and to find a uniform estimation for time-averaged levels. After 10-20 months on biweekly LA using dextran sulfate cellulose columns and concomitant simvastatin administration, time-averaged levels (+/-SD) measured by integration of the area under the curve were as follows: TC 4.4+/-1.0 mmol/l, LDL cholesterol (LDL-C) 2.5+/-1.0 mmol/l, apolipoprotein B (apo B) 1. 3+/-0.3 g/l, triglycerides (TG) 1.7+/-0.7 mmol/l, HDL-C 1.1+/-0.2 mmol/l, and lipoprotein(a) [Lp(a)] 53.7+/-49.4 mg/dl. Mean acute reductions in TC, LDL-C, apo B, Lp(a), and TG were 61, 77, 75, 76, and 62%, respectively. HDL-C levels were not influenced. Median recovery half times for TC, LDL-C, apo B, and Lp(a) were 3.0, 4.0, 2. 3, and 3.5 days, respectively. The rebound of Lp(a) was identical to LDL-C, in 12 and 13 days post-treatment, respectively, whereas apo B and TC returned to pre-treatment levels in 7.5 and 10 days, respectively, due to the fast rebound of VLDL particles. Notwithstanding these differences, time-averaged levels (C(AVG)) could be estimated uniformly for the four latter parameters with the formula: C(AVG)=C(MIN)+0.73(C(MAX)-C(MIN)), where C(MAX) and C(MIN) are the immediate pre- and post-treatment levels. During long-term treatment the whole-body cholesterol synthesis was increased as measured by the ratio lathosterol to cholesterol of 3.24+/-1.49 mmol/mmol, whereas no further transient increase in the recovery period after LA was found. In conclusion, long-term LA and simvastatin therapy induced acute and chronic changes in lipids and lipoproteins showing the feasibility of biweekly treatment. It was shown that time-averaged levels, as a measure for the effective plasma levels, can be accurately estimated from pre- and post-treatment levels only.

Adult↗
PubMed2000

The effect of concentrated n-3 fatty acids versus gemfibrozil on plasma lipoproteins, low density lipoprotein heterogeneity and oxidizability in patients with hypertriglyceridemia.

We evaluated in a double-blind randomized trial with a double-dummy design in 28 patients with primary hypertriglyceridemia, the effect of gemfibrozil (1200 mg/day) versus Omacor (4 g/day), a drug containing the n-3 fatty acids eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), on lipid and lipoprotein levels, low density lipoprotein (LDL) subfraction profile and LDL oxidizability. Both Omacor and gemfibrozil therapy resulted in a similar significant decrease in serum triglyceride (TG), very low density lipoprotein (VLDL) triglyceride and VLDL cholesterol concentrations and an increase in high density lipoprotein (HDL) and LDL cholesterol concentrations. The increase in LDL cholesterol was due to a significant increase in cholesterol content of the relatively buoyant LDL subfractions LDL1, LDL2 and LDL3, whereas the relative contribution of the dense LDL subfractions LDL4 and LDL5 to total LDL tended to decrease. So, both therapies resulted in a more buoyant LDL subfraction profile, reflected by a significant increase of the value of parameter K (+10.3% on Omacor vs. +26.5% on gemfibrozil therapy, gemfibrozil vs Omacor P>0.05). Cu(2+)-induced oxidation of LDL was measured by continuous monitoring of conjugated dienes. After 12 weeks of Omacor treatment LDL appeared more prone to oxidative modification in vitro than LDL after gemfibrozil treatment, as measured by the significantly decreased lag time, preceding the onset of the lipid peroxidation. In both groups the rate of oxidation did not change with therapy. The amount of dienes formed during oxidation increased significantly on Omacor treatment, but not on gemfibrozil treatment. Plasma thiobarbituric acid reactive substances were higher after Omacor and lower after gemfibrozil treatment, although not significantly. We conclude that both Omacor and gemfibrozil have favorable effects on lipid and lipoprotein concentrations and the LDL subfraction profile. However, Omacor increased the susceptibility of LDL to oxidation, whereas gemfibrozil did not affect the resistance of LDL to oxidative modification in vitro. The clinical relevance of these changes remains to be established in the light of other postulated favorable effects of n-3 fatty acids on the course of cardiovascular disease.

Adult↗
PubMed2000

Comparison of the measurement of lipids and lipoproteins versus assay of apolipoprotein B for estimation of coronary heart disease risk: a study in familial combined hyperlipidemia.

We compared in 506 members of families with familial combined hyperlipidaemia (FCH), two approaches to selecting subjects with an apparent increased risk for coronary heart disease: assay of apolipoprotein (apo) B only versus measurement of plasma lipids and lipoproteins. When comparing both criteria, there was an overlap of 81.2% at apo B levels < or = 1250 mg/l and of 86.9% at apo B levels > 1250 mg/l. At apo B < or = 1250 mg/l all subjects were normolipidemic. However, 18.8% of these subjects had sub-normal HDL-cholesterol concentrations (< 0.9 mmol/l) but were not considered to have an increased risk because of very low LDL-cholesterol levels (< 2.5 mmol/l). At apo B concentrations > 1250 mg/l we observed a group with normal plasma lipid levels (13.1%). In this group, defined as normolipidemic hyperapobetalipoproteinemia, and considered to have an increased risk for coronary heart disease, apo B determination was thus most informative. The selection of the subgroup with 'normolipidemic hyperapobetalipoproteinemia' on the basis of the conventional approach could be refined using a cut off limit for plasma triglycerides < 1.5 mmol/l. This limit distinguished optimally between an atherogenic very dense LDL pattern versus a dense and buoyant pattern. Thus, based on the results of our study, the determination of apo B appeared to be, if not superior, at least as effective as the conventional lipid and lipoprotein parameters in classifying subjects at increased risk for coronary heart disease.

Adult↗
PubMed2000

Chylomicron processing in familial dysbetalipoproteinemia and familial combined hyperlipidemia studied with vitamin A and E as markers: a new physiological concept.

In previous work we identified a transfer/diffusion process occurring in the postprandial state that more or less contributes to the accumulation of beta-VLDL in familial dysbetalipoproteinemia (FD). Here we present a new theoretical concept underlying chylomicron processing developed on the basis of extended quantitative analyses of fat loading experiments, with both vitamins A and E, performed in patients with familial combined hyperlipidemia (FCH) in comparison to patients with FD and control subjects. Recovery of triglycerides from the fat load in the plasma triglyceride pool was <4%, indicating a very effective lipolysis process with an active remnant generation. Vitamin A from the fat load was, over 48 h, quantitatively recovered in the plasma lipoprotein pool; vitamin E was recovered to 2241%. Nevertheless, transfer/diffusion of both vitamins showed similar patterns. At equilibrium, their contents correlated strongly with the lipoprotein concentrations, the slopes being similar for control subjects and both groups of patients. Only in those FD patients with the highest lipid values, did the vitamin A/lipoprotein mass ratio in the Sf>100 fraction deviate from the total group mean. In the Sf 15-100 fraction, most specific for 'remnants', vitamin A/cholesterol ratios for all subjects were uniform proving that beta-VLDL formation is a thermodynamic process regulated by concentration gradients and the lipophilicity of lipoprotein constituents, not a typical feature for patients with FD. In patients with FD, vitamin A in the plasma pool was recovered excessively (276%) in line with recognition in various pools as a result of the transfer/diffusion process in plasma.

Adult↗
PubMed2000

The V73M mutation in the hepatic lipase gene is associated with elevated cholesterol levels in four Dutch pedigrees with familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCHL) is a heritable lipid disorder characterized by multiple lipoprotein phenotypes within a single family. Previously, we have shown an increased incidence of mutations in the LPL gene which was associated with elevated levels of very low density lipoprotein (VLDL) and decreased levels of high density lipoprotein among the families studied. Now, we report the results of our study on the hepatic lipase gene. We found the HL V73M variant to be present in four FCHL families. By means of a pedigree-based maximum log-likelihood method we analyzed the effect of this variant on the lipid levels in these families. Carriers of the HL V73M variant revealed significantly higher levels of total cholesterol (P < 0.01) and apoB (P <0.01). These findings show that the HL V73M mutant explains another part of the variability in the phenotype observed among FCHL family members, compared with mutations in the LPL gene. Family analysis shows that in these FCHL families, carriers of mutations in the LPL or HL genes have an increased risk for FCHL compared with their non-carrier relatives.

Adult↗
PubMed2000

Smoking characteristics, antioxidant vitamins, and carotid artery wall thickness among life-long smokers.

We studied the associations between the common carotid-intima-media thickness (IMT), as a marker of atherosclerosis, and smoking characteristics and antioxidant vitamins among 158 male life-long cardiovascular disease (CVD)-free smokers. An "increased" carotid IMT was defined as the upper 25%. The prevalence of increased IMT was 2.5 times (odds ratio (OR) = 2.5; 95% CI: 1.1, 5.6) higher among smokers inhaling smoke deeply into the lungs than among moderate and non-inhalers. This association decreased when adjusted for other CVD risk factors. Smokers with an increased carotid IMT did not differ significantly in mean antioxidant vitamin intake and status with the remaining group. However, classical CVD risk factors contributed importantly to increased carotid IMT. In our study, depth of inhalation was the only smoking characteristic associated with carotid IMT although attenuated after adjustment for traditional risk factors for CVD. Furthermore, in these life-long smokers not using any vitamin supplements, no associations were found for antioxidant vitamins.

Aged↗
PubMed2000

The effect of cholesterol lowering on carotid and femoral artery wall stiffness and thickness in patients with familial hypercholesterolaemia.

BACKGROUND: Early in the process of atherosclerosis, changes in vessel wall stiffness and thickness may occur. The present study evaluates the effect of cholesterol reduction on artery wall stiffness and intima media thickness in patients with familial hypercholesterolaemia (FH). MATERIALS AND METHODS: Forty-five patients with familial hypercholesterolaemia (mean age 46+/-10 years) with untreated LDL cholesterol concentration > 9 mmol L(-1), were studied before and after one year of cholesterol lowering therapy with statins (simvastatin, atorvastatin 40-80 mg day(-1). The distensibility (DC in 10-3 kPa(-1) and compliance (CC in mm2. kPa(-1) of the common carotid artery (CCA) (right and left side) and common femoral artery (CFA) (right side) were determined by a wall track system (Pie Medical). The intima media thickness (IMT) (both right and left) of the CCA, bulb (BUL), internal carotid artery (ICA) and CFA were measured in mm by high-resolution ultrasound (Biosound). RESULTS: The mean concentration of total cholesterol (TC), LDL-cholesterol (LDL-C) and triglycerides (TG) were reduced significantly by 43%, 51% and 25%, respectively, whereas HDL-cholesterol (HDL-C) increased by 13% (P<0.001). In the CFA, the DC and CC increased significantly (DC from 7.9+/-3.0 to 9.1+/-3.7 in 10(-3) kPa(-1); CC 0.5+/-0.2-0.6+/-0.3 in mm2. kPa(-1), whereas the DC and CC did not change in the CCA. In contrast, the IMT of the CCA decreased significantly in both men and women whereas an IMT decrease was also seen in the BUL and ICA in premenopausal women. A LDL-cholesterol reduction of 44.8% and 45.4% was necessary to induce significant decreases in IMT and increases in DC and CC. CONCLUSIONS: One year of cholesterol lowering therapy in FH decreases the wall stiffness in the CFA and the arterial wall thickness in the CCA.

Adult↗
PubMed2000

Apolipoprotein E-deficient mice have an impaired immune response to Klebsiella pneumoniae.

BACKGROUND: All lipoproteins are able to bind to bacterial lipopolysaccharide (LPS), thereby neutralizing its deleterious effects. However, we demonstrated, recently, that in the absence of apolipoprotein E (apoE), eight-fold increased very-low-density lipoprotein levels were not sufficient to protect apoE-deficient (apoE-/-) mice against LPS. During a live Gram-negative infection, mechanisms other than LPS-neutralization may play a role in the pathogenesis of the disease. In the present study we further examined the role of apoE in Gram-negative sepsis. METHODS: Survival, bacterial outgrowth in liver, spleen, kidneys and blood, and tumour necrosis factor-alpha (TNF-alpha) production were measured in apoE-/- mice and control C57BL/6J mice, after an intravenous infection with Klebsiella pneumoniae. RESULTS: Mice that lack apoE showed higher mortality in response to K. pneumoniae than control mice (90% vs. 23% respectively after 2 weeks). ApoE-/- mice had 10-100 times more outgrowth of the bacteria in their organs than controls. Furthermore, circulating TNF-alpha concentrations 90 min after a challenge, were almost twice as high in the apoE-/- mice compared to controls (13.0 +/- 2.9 ng mL-1 vs. 7.6 +/- 3.8 ng mL-1). When apoE-/- and control mice were rendered neutropenic, the discrepancy in survival and outgrowth of K. pneumoniae disappeared. CONCLUSIONS: The apoE-/- mice were more susceptible than control C57BL/6 mice to a K. pneumoniae infection. The absence of apoE may render these mice more susceptible, since this protein is of importance in the detoxification of lipopolysaccharide of Gram-negative bacteria. On the other hand, the phagocytic capacity of granulocytes seems to be decreased in apoE-/- mice, resulting in increased outgrowth and mortality.

Animals↗
PubMed2000

Smoking or its cessation does not alter the susceptibility to in vitro LDL oxidation.

BACKGROUND: Enhanced induction of low density lipoprotein (LDL) oxidation may play a role in the increased cardiovascular risk in smokers. We determined LDL oxidisability in vitro in non-smokers, smokers and in subjects after smoking cessation. PATIENTS AND METHODS: Plasma lipids and copper induced LDL oxidation in vitro were measured in 31 persistent smokers, 47 smokers who tried to stop smoking and 25 non-smokers. In the smoking cessation group, blood was collected before then 1, 3, 6 and 12 months after smoking cessation, and in the persistent smoking and non-smoking groups at baseline and after 12 months. Plasma thiobarbituric acid reactive substances (TBARS) were measured 3 times (at baseline then after 1 and 3 months) in all subjects who refrained from smoking (controlled by urinary cotinine concentrations) for at least 3 months. RESULTS: At baseline, no differences in mean age, body mass index and lipid profiles between groups were present. Seventeen subjects of the smoking cessation group (36%) managed to quit during 12 months. Smoking cessation was associated with an increase in mean weight (P </= 0.001) and waist-hip ratio (P </= 0.001). No major differences in LDL oxidisability were found between groups. A significant transient increase in high density lipoprotein (HDL) cholesterol was seen (from 1.20 +/- 0.39 to 1.34 +/- 0.42 mmol L-1) after 1 month of smoking cessation that disappeared after 3 months. However, after 1 month of smoking cessation, plasma TBARS decreased significantly (P < 0.05). CONCLUSIONS: Neither the previously observed increased cardiovascular risk in smokers nor the decreased risk in those who stopped smoking seem to be mediated by permanent changes in lipid profiles or by alterations in the susceptibility to in vitro oxidation of LDL.

Adult↗
PubMed2000

alpha-tocopherol supplementation decreases production of superoxide and cytokines by leukocytes ex vivo in both normolipidemic and hypertriglyceridemic individuals.

BACKGROUND: alpha-Tocopherol plays an important role in protecting LDL against oxidation. However, additional effects of alpha-tocopherol at the intracellular level may contribute to the clinical outcome of intervention studies. OBJECTIVE: We investigated whether alpha-tocopherol influences the inflammatory responses of immune cells in normolipidemic and hypertriglyceridemic subjects. DESIGN: RRR-alpha-Tocopherol was administered for 6 wk at a dose of 600 IU (402 mg)/d to 12 primary hypertriglyceridemic and 8 normolipidemic (fasting triacylglycerol >3.0 and <2.0 mmol/L, respectively) subjects. Cytokine production [tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1beta, and IL-8] by mononuclear cells and superoxide production by polymorphonuclear cells and in diluted whole blood were determined before and after the intervention. RESULTS: Cytokine and superoxide production did not differ significantly between hypertriglyceridemic and normolipidemic subjects. alpha-Tocopherol supplementation resulted in a 2- to 3-fold increase in the concentration of alpha-tocopherol in plasma and LDL. Whereas superoxide production in response to phorbol 12-myristate 13-acetate decreased in all subjects, response to oxidized LDL increased in 19 of 20 subjects. Response to opsonized zymosan before alpha-tocopherol supplementation was not significantly different from that after supplementation. Lipopolysaccharide-induced cytokine production by mononuclear cells decreased after supplementation with alpha-tocopherol. CONCLUSIONS: alpha-Tocopherol differentially influences inflammatory responses of immune cells. These effects of alpha-tocopherol may be relevant in chronic inflammatory processes such as atherogenesis.

Cells, Cultured↗
PubMed1999

The rebound of lipoproteins after LDL-apheresis. Effects on chemical composition and LDL-oxidizability.

The changes in low density lipoprotein (LDL) composition and oxidizability after LDL-apheresis (LA) using dextran sulfate cellulose columns were evaluated in 12 hypercholesterolemic men (mean+/-S.D. total cholesterol (TC) 9.7+/-1.8 mmol/l). After 10-20 months on biweekly LA combined with simvastatin 40 mg per day immediate pre-apheresis levels of TC, LDL-cholesterol, and apolipoprotein B were decreased to 5.3+/-1.3 mmol/l, 3.3+/-1.2 mmol/l, and 1.6+/-0.4 g/l, respectively, whereas apheresis induced mean acute reductions of 61, 78, and 76%, respectively. Measurements of copper-induced LDL-oxidizability in vitro showed an increased resistance against oxidation after LA until day 3 post-treatment: lag time (min) (day 0 (before LA) versus day 1 (post-LA)) 112+/-27 versus 130+/-26 (P=0.001), maximal rate of diene production (nmol/min per mg LDL) 11.1+/-2.7 versus 9.1+/-2.1 (P=0.001), and time to maximal diene production (min) 186+/-39 versus 209+/-35 (P=0. 001). Analysis of the chemical composition of LDL revealed a 25% (P<0.001) reduced content of cholesteryl esters and a decrease of the cholesterol to protein ratio of 1.20+/-0.25 to 0.70+/-0.22 (P<0. 001) through the 3rd day post-LA. Linoleic acid and arachidonic acid content of LDL decreased 11 and 18%, respectively, at the expense of palmitic acid. Vitamin E levels (mg/l) were significantly lowered due to reduction of the lipoprotein pool by apheresis; however, vitamin E content of LDL did not change in the days after apheresis when expressed per g protein or per micromol linoleic acid. The changes in fatty acid pattern were strongly associated with changes in LDL-oxidizability indices (P</=0.01). Thus, LA effectively decreased LDL pool size, inducing the presence of less buoyant lipoproteins, which were less susceptible to in vitro oxidation. This was not explained by changes in vitamin E levels, but by short-term changes in the fatty acids composition.

Apolipoproteins B↗
PubMed1999

[Serum triglycerides as a risk factor for atherosclerosis].

The importance of plasma triglycerides as a risk factor for the development of coronary artery disease (CAD) has been controversial for many years. In univariate analysis plasma triglycerides predict CAD in several studies, but this effect is attenuated when high-density lipoprotein (HDL) cholesterol is included in the analysis. The controversy can be explained by the complexity of lipoprotein metabolism. Plasma triglycerides serve as markers for metabolic and clinical conditions associated with increased CAD risk. Several recent studies shed new light on the significance of triglycerides for the development of CAD, depending on their level in plasma: there appears to be an optimal concentration < 1.1 mmol/l, an intermediate range with increased risk at values 1.1-4 mmol/l, above which level the risk decreases. Very high levels of triglycerides confer increased risk of pancreatitis.

Biomarkers↗
PubMed1999

Lipoprotein (a) concentrations in patients with familial combined hyperlipidemia and hypertension.

BACKGROUND: Lipoprotein (a) (Lp(a)) is an independent risk factor for coronary heart disease (CHD), and its association with hyperlipidemia and/or hypertension greatly increases the risk of premature CHD. METHODS: The present study assessed plasma concentrations of Lp(a) in hyperlipidemic subjects from families with well-defined familial combined hyperlipidemia (FCH) (n = 262) and from patients with hypertension (n = 168), and to compare it with Lp(a) plasma levels in healthy volunteers (n = 371). Lp(a) concentrations were measured using a specific radioimmunoassay. RESULTS: The Lp(a) plasma concentrations were similar in FCH patients (median 204 mg/l, range 16-2163 mg/l) and in the control group (155, 16-1846 mg/l; P > 0.05). The Lp(a) levels in patients with hypertension (157, 10-1985 mg/l) did not differ from those of controls (P > 0.05). The Lp(a) concentrations were similar in patients with essential hypertension (EH) and normal lipid levels, and in hyperlipidemic EH patients. A tendency towards higher levels of Lp(a) was observed in patients with secondary hypertension due to renal artery stenosis (RAS) (n = 26, Lp(a) 232, 16-1110 mg/l), but this was not statistically significant. CONCLUSIONS: Plasma concentrations of Lp(a) are similar in patients with FCH, with EH, either normo- or hyperlipidemic, and with RAS, when compared with healthy controls. However, measuring the Lp(a) levels in patients with either hyperlipidemia or hypertension remains important for assessing the risk potential for severe atherosclerosis in these patients.

Aged↗
PubMed1999

Integrin mediated adhesion of mononuclear cells from patients with familial hypercholesterolemia.

BACKGROUND: Low-density lipoproteins (LDL) can induce the adhesion of monocytes to endothelial cells. Monocytes of patients with familial hypercholesterolemia (FH) are exposed to high concentrations of LDL, and it has been reported that adhesiveness of these cells in hypercholesterolemic patients is enhanced. We investigated whether LFA-1 or VLA-4 mediated adhesion is altered in FH patients and whether HMG-CoA reductase inhibitors influence this adhesion. PATIENTS AND METHODS: LFA-1 and VLA-4 mediated adhesion to ICAM-1 and VCAM-1 coated beads was investigated using freshly isolated monocytes and T-lymphocytes from patients with homozygous FH, heterozygous FH (before and after cholesterol lowering treatment), and from controls. In addition, the expression of beta1- and beta2-integrins on these cells was determined. RESULTS: Both LFA-1 and VLA-4 mediated adhesion and integrin expression of monocytes and CD3+ cells from patients with homozygous FH and heterozygous FH was similar to that of monocytes from a control population. Treatment with HMG-CoA reductase inhibitors did not affect the adherence to ICAM-1 or VCAM-1, and did not influence the expression of integrins. CONCLUSIONS: In contrast to studies by others, we demonstrated in the present study that the actual LFA-1 and VLA-4 mediated adhesion of T-lymphocytes and monocytes is not altered in patients with FH.

Adolescent↗
PubMed1999

Apolipoprotein E knock-out mice are highly susceptible to endotoxemia and Klebsiella pneumoniae infection.

Lipoproteins are able to neutralize bacterial lipopolysaccharide (LPS) and thereby inhibit the proinflammatory cytokine response. In a previous study, we demonstrated that hypercholesterolemic low density lipoprotein receptor knock-out (LDLr-/-) mice are protected against lethal endotoxemia and gram-negative infection. In the present study we investigated the susceptibility of apolipoprotein E knock-out mice (apoE-/-) to LPS and to Klebsiella pneumoniae. These mice have increased plasma lipoprotein concentrations in the very low density lipoprotein (VLDL)-sized fraction. Despite 8 -fold higher plasma cholesterol levels compared to controls, and in contrast to LDLr-/- mice, apoE-/- mice were significantly more susceptible to endotoxemia and to K. pneumoniae infection. Circulating TNFalpha concentrations after intravenously injected LPS were 4 - to 5-fold higher in apoE-/- mice, whereas IL-1alpha, IL-1beta, and IL-6 did not differ. This TNF response was not due to an increased cytokine production capacity of cells from apoE-/- mice, as ex vivo cytokine production in response to LPS did not differ between apoE-/- and control mice. The LPS-neutralizing capacity of apoE-/- plasma was significantly less than that of controls. Most likely, the absence of apoE itself in the knock-out mice explains the failure to neutralize LPS, despite the very high cholesterol concentrations.

Animals↗