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Item does not contain fulltext In 50 consecutive children admitted to the intensive care unit with the clinical diagnosis of dengue hemorrhagic fever (DHF)/dengue shock syndrome (grade III or IV), 20 patients with mild DHF (grade I or II), and 20 healthy control patients, the plasma lipid profile was measured. Levels of total plasma cholesterol, high-density lipoprotein, and low-density lipoprotein were significantly decreased in patients with the severest cases, compared with patients with mild DHF and healthy controls. Changes in the plasma lipid profile differentiate between patients with different stages of DHF disease severity and could be used as a potential predictor for clinical outcome.

Item does not contain fulltext In a randomized, double-blind, placebo-controlled trial we evaluated the effect of dietary chocolates enriched with a wood-based phytosterol-phytostanol mixture, containing 18 % (w/w) sitostanol, compared with placebo dietary chocolates in seventy subjects with primary hypercholesterolaemia (total cholesterol levels below 8 mmol/l). For 4 weeks, participants consumed three servings of the phytosterol-enriched chocolate/d that provided 1.8 g unesterified phytosterols/d or a placebo chocolate in conjunction with a low-fat, low-cholesterol diet. Plasma total and LDL-cholesterol levels were statistically significantly reduced by 6.4 % (-0.44 mmol/l) and 10.3 % (-0.49 mmol/l), respectively, after 4 weeks of phytosterol-enriched-chocolate treatment. Plasma HDL-cholesterol and triacylglycerol levels were not affected. Consumption of phytosterol-enriched chocolates significantly increased plasma lathosterol concentration (+20.7 %), reflecting an increased endogenous cholesterol synthesis in response to phytosterol-induced decreased intestinal cholesterol absorption. Furthermore, the chocolates enriched with phytosterols significantly increased both plasma sitosterol (+95.8 %) and campesterol (+64.1 %) levels, compared with the placebo chocolate group. However, the absolute values of plasma sitosterol and campesterol remained within the normal range, that is, below 10 mg/l. The chocolates with phytosterols were palatable and induced no clinical or biochemical side effects. These findings indicate that dietary chocolate enriched with tall oil-derived phytosterols (1.8 g/d) is effective in lowering blood total and LDL-cholesterol levels in subjects with mild hypercholesterolaemia and thus may be helpful in reducing the risk of CHD in these individuals.

Item does not contain fulltext In 3 patients, 2 women aged 21 and 34 years and a man aged 56 years, with complaints related to wide-ranging and extensive vascular conditions, an organ-specific diagnostic approach and treatment did not lead to the correct diagnosis of the underlying clinical condition. Hereafter a structured, partly protocol-based approach was started which considered the entire vascular system and risk factors for vascular disease. The youngest women died a few years later due to ventricular fibrillation, while the two other patients were assisted in reducing those risk factors that could be influenced. As a result, the planned bypass operation was no longer necessary for the male patient. A structured evaluation by a multidisciplinary team can optimise the care of these patients. The basis of such a team consists of a vascular specialist and vascular nurse-practitioner, both of whom should have specific knowledge of risk factors, aetiology, life style intervention and treatment of these disorders.

Background — Cholesteryl ester transfer protein (CETP) mediates the transfer of neutral lipids between lipoproteins. High plasma levels of CETP are correlated with low HDL cholesterol levels, a strong risk factor for coronary artery disease. In earlier studies, JTT-705, a novel CETP inhibitor, was shown to increase plasma HDL cholesterol and to inhibit the progression of atherosclerosis in cholesterol-fed rabbits. This study describes the first results using this CETP inhibitor in humans. Methods and Results — In a randomized, double-blind, and placebo-controlled trial, we evaluated the efficacy and safety of daily treatment with 300, 600, and 900 mg JTT-705 in 198 healthy subjects with mild hyperlipidemia. Treatment with 900 mg JTT-705 for 4 weeks led to a 37% decrease in CETP activity ( P P P =0.017), whereas levels of triglycerides, phospholipid transfer protein, and lecithin-cholesterol acyltransferase were unaffected. In line with the increase of total HDL, a rise of HDL 2, HDL 3 , and apolipoprotein A-I was also noted. JTT-705 showed no toxicity with regard to physical examination and routine laboratory tests. Conclusions — We show that the use of the CETP inhibitor JTT-705 in humans is an effective means to raise HDL cholesterol levels with minor gastrointestinal side effects ( P =0.06). Although these results hold promise, further studies are needed to investigate whether the observed increase in HDL cholesterol translates into a concomitant reduction in coronary artery disease risk.

Background: High sensitivity C-reactive protein (hs-CRP) has emerged as the best studied and most promising marker of inflammation in atherosclerotic vascular disease. Materials and methods: The ASAP (effects of Atorvastatin vs. Simvastatin on Atherosclerosis Progression) study was a 2-year randomised, double-blind trial with 325 familial hypercholesterolemia patients, treated with torvastatin 80 mg or imvastatin 40 mg. Intima media thickness (IMT) of carotid artery segments and hs-CRP levels were determined at baseline, 1 and 2 years. Results: Baseline median hs-CRP values were 2.1 mg/l (interquartile range (IQR) 0.9-5.2) and 2.0 mg/l (IQR 0.8-3.0) and after 2 years these levels decreased to 1.1 mg/l (IQR 0.6-2.4) and 1.5 mg/l (IQR 0.6-3.0) in the atorvastatin 80 mg and sinivastatin 40 mg group, respectively. These changes were significant within as well as between the two groups. No correlations were observed between change in hs-CRP after 2 years and change in lipids. A significant correlation was found in univariate analysis between the decrease of hs-CRP and the reduction of IMT. Conclusions: Our results show that atorvastatin 80 mg reduces hs-CRP levels to a greater extent than sinivastatin 40 mg. Furthermore, we show that the extent of hs-CRP reduction is associated with the progression rate of the atherosclerotic process as measured by IMT. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved

Contains fulltext : 185418.pdf (Publisher’s version ) (Open Access) Native LDL (nLDL) increases expression of adhesion molecules on endothelial cells through induction of Ca(2+) mobilization. Ca(2+) mobilization is also involved in the induction of proinflammatory cytokines, important mediators involved in atherogenesis. The aim of the study was to evaluate the capacity of nLDL to affect spontaneous and lipopolysaccharide (LPS)-stimulated cytokine production. Preincubation of human peripheral blood mononuclear cells (PBMC) with nLDL for 24 h did not influence spontaneous production of tumor necrosis factor alpha (TNF alpha) or interleukin-8 (IL-8), but significantly potentiated LPS-induced production of these cytokines. nLDL preincubation of PBMC did not increase the expression of the LPS receptors Toll-like receptor-4, CD14, or CD11c/CD18. Potentiation of cytokine production by nLDL was mediated through induction of Ca(2+) mobilization, because: a) nLDL induced a sustained pattern of repetitive Ca(2+) transients in human PBMC; b) the Ca(2+) chelator fura 2-acetoxymethyl ester, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, an intracellular Ca(2+) chelator, inhibited the potentiating effect of nLDL on LPS-induced cytokine synthesis; c) induction of Ca(2+) mobilization by thapsigargin potentiated LPS-induced cytokine production. nLDL are able to potentiate LPS-induced production of cytokines by human PBMC, and this effect is probably mediated through induction of Ca(2+) mobilization. This may represent an important pathogenetic mechanism in atherogenesis induced by hyperlipoproteinemia.

Item does not contain fulltext Antioxidants have been postulated to exert beneficial effects in atherosclerosis. Atherosclerosis is associated with raised plasma levels of soluble intercellular adhesion molecule-1 (sICAM-1) and autoantibodies against oxidized low-density lipoprotein (oxLDL). It is not known whether antioxidants affect these plasma factors in chronic smokers. In a randomized double-blind placebo-controlled study involving 128 male normolipidemic chronic smokers the effect of a 2-year alpha-tocopherol treatment (400 IU dL-alpha-tocopherol daily) on plasma levels of sICAM-1 and autoantibodies against oxLDL was evaluated. In addition, we monitored production of superoxide by leukocytes ex vivo. It was found that compared to nonsmokers (n = 33) plasma levels of IgG but not IgM autoantibodies against oxLDL and concentrations of sICAM-1 in smokers were significantly elevated (30 and 42%, respectively). After supplementation with alpha-tocopherol concentration of TBARS in plasma and in vitro oxidizability of LDL had decreased, but autoantibodies and sICAM-1 had not changed. Production of superoxide was not different between alpha-tocopherol- and placebo-treated smokers. It is concluded that in chronic smokers, long-term treatment with alpha-tocopherol does not normalize the raised levels of sICAM-1 and autoantibodies against oxLDL, both risk factors for initiation or progression of cardiovascular disease, despite a decrease in in vitro oxidizability of LDL.

To compare the effects of concentrated n-3 fatty acids (Omacor™) and gemfibrozil in patients with severe hypertriglyceridaemia. The primary objective was to measure the change in serum triglyceride (TG), and the secondary objectives were to study the changes in total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), very low density lipoprotein cholesterol (VLDL-C), apolipoproteins and free fatty acids. 89 patients with severe hypertriglyceridaemia (defined as plasma TG >4.5 mmol/L) were randomised to receive in a double-blind fashion either Omacor™, a capsule containing the n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) at a dosage of 4 g/day, or gemfibrozil 1200 mg/day for 12 weeks. The baseline characteristics of the two randomised groups were similar. Compared with baseline, n-3 fatty acids and gemfibrozil reduced mean TG levels by 28.9 and 51.2%, respectively (p = 0.007). TC was decreased 10.2% with n-3 fatty acids, and 13.0% with gemfibrozil (p = 0.51), and VLDL-C was reduced 11.8 and 19.4% (p = 0.49) with n-3 fatty acids and gemfibrozil, respectively. HDL-C was increased by both compounds; n-3 fatty acids elevated HDL-C by only 1.2%, whereas it was elevated 27.9% by gemfibrozil (p = 0.012). Our study indicated that both n-3 fatty acids and gemfibrozil markedly decreased TG levels in patients with severe hypertriglyceridaemia. Gemfibrozil, however, decreased TG levels and increased HDL-C significantly more than n-3 fatty acids.

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Item does not contain fulltext BACKGROUND: High LDL-cholesterol is a risk factor for atherosclerosis. We aimed to determine whether aggressive cholesterol lowering with statins was more effective than conventional statin treatment in this disease. We investigated the effect of high-dose atorvastatin on carotid atherosclerosis progression. METHOD: We did a randomised, double-blind clinical trial in 325 patients with familial hypercholesterolaemia. Patients were given either atorvastatin 80 mg (n=160) or simvastatin 40 mg (n=165) daily, on an intent-to-treat basis. The primary endpoint was the change of carotid intima media thickness (IMT), as measured by quantitative B-mode ultrasound, over 2 years. FINDINGS: The overall baseline IMT, combining the measurements of the common and internal carotid artery and the carotid bifurcation on both sides, was 0.93 mm (SD 0.22) and 0.92 mm (0.21) in the atorvastatin and simvastatin groups, respectively. After treatment with atorvastatin for 2 years, IMT decreased (-0.031 mm [95% CI -0.007 to -0.055]; p=0.0017), whereas in the simvastatin group it increased (0.036 [0.014-0.058]; p=0.0005). The change in thickness differed significantly between the two groups (p=0.0001). Atorvastatin showed greater reductions in cholesterol concentrations than did simvastatin. HDL-cholesterol concentrations increased in both groups. Both drugs were equally well tolerated. INTERPRETATION: Our results show that aggressive LDL-cholesterol reduction by atorvastatin was accompanied by regression of carotid intima media thickness in patients with familial hypercholesterolaemia, whereas conventional LDL lowering was not.

Item does not contain fulltext Human cystathionine beta-synthase is a heme protein that catalyzes the condensation of serine and homocysteine to form cystathionine in a pyridoxal phosphate-dependent reaction. Mutations in this enzyme are the leading cause of hereditary hyperhomocysteinemia with attendant cardiovascular and other complications. The enzyme is activated approximately 2-fold by the allosteric regulator S-adenosylmethionine (AdoMet), which is presumed to bind to the C-terminal regulatory domain. The regulatory domain exerts an inhibitory effect on the enzyme, and its deletion is correlated with a 2-fold increase in catalytic activity and loss of responsiveness to AdoMet. A mutation in the C-terminal regulatory domain, D444N, displays high levels of enzyme activity, yet is pathogenic. In this study, we have characterized the biochemical penalties associated with this mutation and demonstrate that it is associated with a 4-fold lower steady-state level of cystathionine beta-synthase in a fibroblast cell line that is homozygous for the D444N mutation. The activity of the recombinant D444N enzyme mimics the activity of the wild-type enzyme seen in the presence of AdoMet and can be further activated approximately 2-fold in the presence of supraphysiolgical concentrations of the allosteric regulator. The mutation increases the K(act) for AdoMet from 7.4 +/- 0.2 to 460 +/- 130 microM, thus rendering the enzyme functionally unresponsive to AdoMet under physiological concentrations. These results indicate that the D444N mutation partially abrogates the intrasteric inhibition imposed by the C-terminal domain. We propose a model that takes into account the three kinetically distinguishable states that are observed with human cystathionine beta-synthase: "basal" (i.e., wild-type enzyme as isolated), "activated" (wild-type enzyme + AdoMet or the D444N mutant as isolated), and superactivated (D444N mutant + AdoMet or wild-type enzyme lacking the C-terminal regulatory domain).

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Familial combined hyperlipidemia (FCH) is characterized by a variable expression of hypercholesterolemia and/or hypertriglyceridemia. We evaluated the variability in lipid phenotype expression over a 5-year period and studied factors affecting the lipid phenotype expression. A total of 32 families (299 subjects) were studied in 1994 and in 1999. Subjects were classified as having FCH when total cholesterol and/or triglyceride levels exceeded the 90th percentile adjusted for age and sex. In 1994, 93 (31%) of the 299 subjects were affected, whereas 206 (69%) of the subjects were unaffected relatives. In 1999, a diagnosis of FCH was consistent in 69 (74%) of the 93 subjects. So, 26% of the FCH subjects in 1994 showed a sporadic normolipidemic pattern (ie, total cholesterol and/or triglycerides P =0.03) and body mass index (odds ratio 1.14, 95% CI 1.05 to 1.24; P K (apoB 1461±305 versus 997±249 mg/L, respectively [ P K value −0.22±0.19 versus −0.02±0.19, respectively [ P K value show less variability in time and are more consistently associated with FCH, inasmuch as affected FCH subjects, compared with the unaffected relatives, persistently show a higher apoB level and a lower value of parameter K , reflecting small dense LDL, even when they present a sporadic normolipidemic pattern. In conclusion, our results emphasize the need for reevaluation of the diagnostic criteria for FCH. We demonstrate that apoB and small dense LDL are attractive new candidates for defining FCH. Further studies are indicated to evaluate the role of apoB and small dense LDL as diagnostic criteria for FCH.

Contains fulltext : 185468.pdf (Publisher’s version ) (Open Access) Stearoyl-CoA desaturase (SCD) is expressed at high levels in several human tissues and is required for the biosynthesis of oleate (18:1) and palmitoleate (16:1). These monounsaturated fatty acids are the major components of phospholipids, triglycerides, wax esters, and cholesterol esters. Mice with a targeted disruption of the SCD1 gene have very low levels of VLDL and impaired triglyceride and cholesterol ester biosynthesis. In the HYPLIP mouse, a model of hyperlipidemia, there was a 4-fold increase in hepatic SCD activity, a 1.8-fold increase in the desaturation index, and a 2-fold increase in plasma triglycerides. We used the plasma ratio of 18:1/18:0 (the "desaturation index") as an in vivo measure of SCD activity in human subjects. In human subjects with triglycerides ranging from 0.3 to 20 mM, the desaturation ratio accounted for one-third of the variance in plasma triglyceride levels. A 2-fold increase in the desaturation index was associated with a 4-fold increase in plasma triglycerides. In human subjects exposed to a high carbohydrate diet, the desaturation index explained 44% of the variance in triglycerides. We propose that many of the factors that influence plasma triglyceride levels do so by converging upon the regulation of SCD activity.

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Item does not contain fulltext Elevated levels of total homocysteine and low folate in blood are independent and graded risk factors for arterial occlusive disease. An impairment of folate distribution can be an important cause of hyperhomocysteinemia. Glutamate carboxypeptidase II (GCPII) regulates the absorption of dietary folates. In the present study, we examined the relationship of a 1561C-->T variant in the GCPII gene with fasting, post-methionine load plasma homocysteine, folate and vitamin B(12) levels and the risk of cardiovascular disease (CVD) in 190 vascular disease patients and in 601 apparently healthy controls. Fasting as well as post-load homocysteine concentrations associated with the 1561TT genotype tended to be lower, whereas the homocysteine concentrations of the 1561CT individuals were not different from their 1561CC peers. The 1561C-->T polymorphism significantly increased both red blood cell folate and plasma folate concentrations (ANOVA P=0.013; test for linear trend P=0.03, respectively), but had no effect on vitamin B(12) levels (ANOVA P=0.35). Since not only homocysteine itself is considered to be positively associated with the risk of CVD, but also a decreased folate status, the results of this study indicate that the 1561C-->T polymorphism may affect the predisposition to CVD.

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Item does not contain fulltext OBJECTIVE: To evaluate literature data on the use of acetylsalicylic acid (ASA) as a primary prevention measure for cardiovascular events. DESIGN: Literature search. METHOD: Using Medline, all randomised placebo-controlled trials of ASA published between 1985 and 1 May 2001, and which used cardiovascular morbidity and death as outcome measures were identified (search query: 'aspirin' and 'primary prevention'). Using the raw data presented in the source publication on death, fatal and non-fatal myocardial infarctions and cerebrovascular accidents (CVAs), all relative and absolute risk reductions were recalculated with confidence intervals. RESULTS: In healthy middle-aged men, men with an increased cardiovascular risk profile and persons with diabetes mellitus or hypertension, the use of ASA reduces the incidence of myocardial infarction and has a neutral effect on cerebrovascular events. The protective effect of ASA seemed most marked in those persons with an increased risk of manifest atherosclerotic vascular disease. CONCLUSION: Notwithstanding these findings, for each patient it remains essential to weigh up the cardiovascular risk profile against the small increased risk of complications when prescribing ASA.

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Contains fulltext : 142827.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To study (i) the influence of methotrexate (MTX) therapy on homocysteine and folate metabolism in patients with rheumatoid arthritis (RA), (ii) the influence of the C677T mutation in the methylenetetrahydrofolate reductase gene (MTHFR) on the change in plasma homocysteine levels during MTX treatment, and (iii) the interference of folate and homocysteine metabolism with the efficacy and toxicity of treatment with MTX. METHODS: The 113 patients enrolled in this study were participating in a 48-week, multicentre, double-blind, placebo-controlled study comparing the efficacy and toxicity of MTX treatment with and without folic or folinic acid supplementation. The MTX dose was 7.5 mg/week initially and increased to a maximum of 25 mg/week if necessary. Concentrations of total folate, 5-methyl tetrahydrofolate (in serum and in erythrocytes) and of homocysteine, cysteine and cysteine-glycine and the MTHFR genotype were determined before the start of the study, after 6 weeks, and after 48 weeks or on withdrawal from the study. Blood was drawn from fasting patients at a standardized time in the morning, 16 h after intake of MTX. The laboratory results were related to parameters of efficacy and toxicity of MTX treatment. RESULTS: Baseline values were distributed equally in the three treatment groups. The mean plasma homocysteine level (normal range 6-15 micromol/l) before the start of MTX was relatively high in all groups: 15.4 micromol/l [95% confidence interval (CI) 13.5 to 17.2] in the MTX plus placebo group (n=39), 14.3 micromol/l (95% CI 12.2 to 16.4) in the MTX plus folic acid group (n=35) and 15.9 micromol/l (95% CI 13.7 to 18.1) in the MTX plus folinic acid group (n=39). After 48 weeks of MTX therapy, the mean homocysteine level showed an increase in the placebo group (+3.6 micromol/l, 95% CI 1.7 to 5.6). In contrast, a decrease was observed in the groups supplemented with folic or folinic acid (folic acid, -2.7 micromol/l, 95% CI -1.4 to -4.0; folinic acid, -1.6 micromol/l, 95% CI -0.1 to -3.0). The differences in the change in plasma homocysteine level between the placebo group and each of the two folate-supplemented groups were statistically significant (P

Item does not contain fulltext The introduction of statins has been a breakthrough in the treatment of hypercholesterolaemia. Statins are safe and effective in reducing the risk of coronary heart disease in the general population. The 'Heart protection study' has provided evidence for the benefit of statin treatment in much broader populations than is presently indicated in the Dutch national guidelines, i.e. also in high-risk persons with diabetes mellitus, and irrespective of age or cholesterol level. The use and cost of statins, which have been referred to as 'lifestyle-drugs' in the lay press, have risen enormously. Recently, the Dutch College of Healthcare Insurers issued a report in which recommendations concerning the reimbursement of the costs for cholesterol-lowering drugs are based on 'generally accepted insights into the appropriate use of these drugs'. Lifestyle and/or age are not exclusion criteria for treatment with statins. The expiration of patents of some statins and modifications to the reimbursement system in 2003 could lead to cost reductions.

A 25-year-old woman was found unconscious at home in December, 1999. In the previous 3 days she had had a flu-like illness and strangury. As a child she had failed to thrive and had mild mental retardation. At the age of 24 years anorexia nervosa was diagnosed. On admission she had a blood pressure of 90/60 mm Hg, temperature 38·5°C, and decreased consciousness. The Glasgow Coma Score (GCS) was E-3, M-5, V-3: eyes opening to speech, localising to painful stimuli, and speaking in inappropriate words. Pupillary reactions were normal, tendon reflexes were symmetrical and brisk, and plantar responses were normal. Laboratory results were: erythrocyte sedimentation rate 16 mm/h, leucocytes 18·9 10/L, urea 1·3 mmol/L, creatinine 42 μmol/L, aspartate aminotransferase (AST) 78 IU/L (normal range

Item does not contain fulltext Sitosterolemia is a rare autosomal recessive disorder characterized by (a) intestinal hyperabsorption of all sterols, including cholesterol and plant and shellfish sterols, and (b) impaired ability to excrete sterols into bile. Patients with this disease have expanded body pools of cholesterol and very elevated plasma plant-sterol species and frequently develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. In previous studies, we have mapped the STSL locus to human chromosome 2p21. Recently, we reported that a novel member of the ABC-transporter family, named "sterolin-1" and encoded by ABCG5, is mutated in 9 unrelated families with sitosterolemia; in the remaining 25 families, no mutations in sterolin-1 could be identified. We identified another ABC transporter, located

Item does not contain fulltext OBJECTIVE: At higher doses, simvastatin has been shown to produce significantly greater increases in high-density lipoprotein (HDL) cholesterol and apolipoprotein (apo) A-I than atorvastatin. To extend and confirm these findings, a 36-week, randomized, double-blind, dose-titration study was performed in 826 hypercholesterolemic patients to compare the effects of simvastatin and atorvastatin on HDL cholesterol, apo A-I, and clinical and laboratory safety. PRIMARY HYPOTHESIS: Simvastatin, across a range of doses, will be more effective than atorvastatin at raising HDL cholesterol and apo A-I levels. METHODS: A total of 826 hypercholesterolemic patients were enrolled in this double-blind, randomized, parallel, 36-week, dose-escalation study. Patients randomized to simvastatin received 40 mg/day for the first 6 weeks, 80 mg/day for the next 6 weeks, and remained on 80 mg/day for the final 24 weeks. Patients randomized to atorvastatin received 20 mg/day for the first 6 weeks, 40 mg/day for the next 6 weeks, and 80 mg/day for the remaining 24 weeks. RESULTS: During the first 12 weeks of the study, simvastatin increased HDL cholesterol and apo A-I more than the comparative doses of atorvastatin, while producing slightly lower reductions in low-density lipoprotein (LDL) cholesterol and triglycerides. At the maximal dose comparison, simvastatin 80 mg and atorvastatin 80 mg, the HDL cholesterol and apo A-I differences favoring simvastatin were larger than at the lower doses. In addition, at the maximal dose comparison, the incidence of drug-related clinical adverse experiences was approximately two-fold higher with atorvastatin 80 mg than with simvastatin 80 mg (23 versus 12%, p < 0.001), due predominantly to a greater incidence of gastrointestinal symptoms with atorvastatin (10 versus 3%, p < 0.001). The incidence of clinically significant alanine aminotransferase elevations was also higher with atorvastatin 80 mg than with simvastatin 80 mg (3.8 versus 0.5%, p < 0.010), especially in women (6.0 versus 0.6%). CONCLUSIONS: At the doses compared in this study, simvastatin led to greater increases in HDL cholesterol and apo A-I levels than atorvastatin. At the maximum dose comparison, there were fewer drug-related gastrointestinal symptoms and clinically significant aminotransferase elevations with simvastatin.

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Item does not contain fulltext KUN, 07 februari 2001 Promotor : Stalenhoef, A.F.H.

Item does not contain fulltext Sitosterolaemia (also known as phytosterolaemia, MIM 210250) is a rare recessive autosomal inherited disorder, characterised by the presence of tendon and tuberous xanthomas, accelerated atherosclerosis and premature coronary artery disease. The defective gene is hypothesised to play an important role in regulating dietary sterol absorption and biliary secretion, thus defining a molecular mechanism whereby this physiological process is carried out. The disease locus was localised previously to chromosome 2p21, in a 15 cM interval between microsatellite markers D2S1788 and D2S1352 (based upon 10 families, maximum lodscore 4.49). In this study, we have extended these studies to include 30 families assembled from around the world. A maximum multipoint lodscore of 11.49 was obtained for marker D2S2998. Homozygosity and haplotype sharing was identified in probands from non-consanguineous marriages from a number of families, strongly supporting the existence of a founder effect among various populations. Additionally, based upon both genealogies, as well as genotyping, two Amish/Mennonite families, that were previously thought not to be related, appear to indicate a founder effect in this population as well. Using both homozygosity mapping, as well as informative recombination events, the sitosterolaemia gene is located at a region defined by markers D2S2294 and Afm210xe9, a distance of less than 2 cM.

Item does not contain fulltext Homocysteine is a sulfhydryl containing amino acid which is produced as an intermediate product in the metabolism of the essential amino acid methionine. Apart from environmental factors such as the intake of folate and other B vitamins, the level of homocysteine in the blood is determined by the genetically based activities of several enzymes involved in the methionine or folate cycle. The well-known congenital defect homocystinuria is due to homozygosity for mutated cystathionine beta synthase. It is characterized by severe hyperhomocysteinemia, which leads to arterial and venous disease at a very young age. Mild to moderate hyperhomocysteinemia, due to either heterozygosity for severe mutations in the genes of enzymes involved or based upon homozygosity for more mild mutations, has also been recognized as a risk factor for vascular disease in the last decade. However, ongoing clinical intervention studies still need to demonstrate a casual role of mildly increased homocysteine levels in vascular disease.

Item does not contain fulltext Molecular defects in genes encoding enzymes involved in homocysteine metabolism may account for mild hyperhomocysteinemia, an independent and graded risk factor for cardiovascular disease (CVD). We examined the relationship of two polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, the 677C-->T and 1298A-->C variants, to MTHFR activity, homocysteine concentrations, and risk of CVD in a population of 190 vascular disease patients and 601 apparently healthy controls. The mean specific and residual MTHFR activities were significantly lower in 677CT and 677TT individuals (both PC mutation alone showed no effect on MTHFR activities. However, when the 677C-->T genotype was taken into account, the 1298A-->C mutation also caused a significant decrease in MTHFR activities, which was observed in both the homozygous 1298CC (PC mutation had no effect on fasting or postload homocysteine levels. Since homocysteine itself is considered to be positively associated with the risk of CVD, these findings indicate that the 1298A-->C mutation cannot be considered a major risk factor for CVD.

Item does not contain fulltext Familial hypercholesterolemia is a hereditary metabolic disorder characterised by high low-density lipoprotein cholesterol levels and an extreme risk of premature cardiovascular disease. In patients with heterozygous familial hypercholesterolemia a substantial variation is seen in both the severity of the hypercholesterolemia and onset of atherosclerotic disease symptoms. We discuss the contribution of additional atherogenic risk factors of metabolic, environmental and genetic origin. Subclinical disease measurements, such as the intima media thickness (IMT), assessed by ultrasonography, may contribute to a better risk prediction of future cardiovascular disease in these patients.

Item does not contain fulltext Administration of bacterial lipopolysaccharide (LPS) in rodents induces the release of pro-inflammatory cytokines [tumor necrosis factor (TNF), interleukin (IL)-1, IL-6] and of ACTH and corticosterone. IL-6 is probably an important cytokine in the interaction between the immune system and the hypothalamus-pituitary-adrenal (HPA) axis, but so far the role of IL-6 in lipopolysaccharide (LPS)-induced HPA activation has not been established unequivocally. We examined the effects of intraperitoneal administration of LPS (range 0.25-2000 pg/mouse) on plasma corticosterone, TNFalpha and IL-1alpha levels in IL-6-deficient (IL-6 -/-) and wildtype control (IL-6 +/+) mice. Plasma corticosterone levels increased within one hour in both mouse strains. The corticosterone response was significantly reduced in IL-6 -/- mice, but no differences in TNFalpha or in IL-1alpha plasma levels were found between the two strains. Next, we studied the involvement of IL-1alpha or TNFalpha in the responses to LPS in IL-6 -/- and IL-6 +/+ mice by infusion of recombinant human IL-1 receptor antagonist (IL-1ra), or by injection of anti-TNFalpha antibodies. Pretreatment with IL-1ra or with anti-TNFalpha did not affect the corticosterone response to LPS, neither in IL-6 -/-, nor in IL-6 +/+ mice. Our data suggest that in the stimulation of the HPA axis by LPS in mice blockade of either IL-1alpha or TNFalpha may be compensated for by other mediators. The reduced adrenal response after LPS administration found in IL-6 -/- mice indicates a distinct role for IL-6 in the activation of the HPA axis by LPS.

Item does not contain fulltext Molecular defects in genes encoding enzymes involved in homocysteine metabolism may account for mild hyperhomocysteinaemia, an independent and graded risk factor for cardiovascular disease (CVD). Although heterozygosity for cystathionine beta-synthase (CBS) deficiency has been excluded as a major genetic cause of mild hyperhomocysteinaemia in vascular disease, mutations in (non-)coding DNA sequences may lead to a mildly decreased CBS expression and, consequently, to elevated plasma homocysteine levels. We assessed the association between a 31 bp VNTR, that spans the exon 13-intron 13 boundary of the CBS gene, and fasting, post-methionine load and increase upon methionine load plasma homocysteine levels in 190 patients with arterial occlusive disease, and in 381 controls. The 31 bp VNTR consists of 16, 17, 18, 19 or 21 repeat units and shows a significant increase in plasma homocysteine concentrations with an increasing number of repeat elements, in particular after methionine loading. In 26 vascular disease patients the relationship between this 31 bp VNTR and CBS enzyme activity in cultured fibroblasts was studied. The CBS enzyme activity decreased with increasing number of repeat units of the 31 bp VNTR. RT-PCR experiments showed evidence of alternative splicing at the exon 13-intron 13 splice junction site. The 31 bp VNTR in the CBS gene is associated with post-methionine load hyperhomocysteinaemia that may predispose individuals to an increased risk of cardiovascular diseases.

We hypothesize that smokers with the null genotype for GSTM1 (GSTM1-0), who thus lack the detoxification enzyme glutathione S-transferase mu1, develop atherosclerosis at an increased rate compared to smokers with the positive genotype (GSTM1-1). We used data from a 2-year randomized placebo-controlled trial on the effect of vitamin E on atherosclerosis among 189 male smokers. Progression of atherosclerosis was measured by 2-year change of the common carotid intima media thickness (CCA-IMT) as measured by B-mode ultrasonography. The frequency of GSTM1-0 genotype was 0.5 in both the placebo and the vitamin E group. Smokers with GSTM1-0 genotype had a tendency to higher baseline CCA-IMT values than those with GSTM1-1 (0.97 versus 0.92 mm, P = 0.09). Within the placebo group, more CCA-IMT progression was found for smokers with the GSTM1-0 than for smokers with the GSTM1-1 genotype after adjustment for baseline IMT and major CVD risk factors (0.050 versus -0.002 mm, P = 0.046). In the vitamin E group no effect of GSTM1 genotype on atherosclerosis progression was found. Overall, smokers with GSTM1-0 genotype had a higher mean 2-year progression compared to those with GSTM1-1 as shown by a difference in increase of 0.042 mm (95% CI 0.006; 0.078, P = 0.02). In conclusion, our data suggest that smokers lacking the detoxifying enzyme GST mu1 develop progression of atherosclerosis at an increased rate. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.

Objective To examine whether a reduced daily glucose load by overnight application of the less-absorbed glucose polymer icodextrin would have favorable effects on lipid profiles of continuous ambulatory peritoneal dialysis (CAPD) patients. Study Design Randomized crossover study with two subsequent periods of 6 weeks. Setting Home PD unit of a secondary-care hospital. Patients Twenty-one nondiabetic CAPD patients (15 male, 6 female; mean age 50.3 ± 11.8 years). Intervention Participants were randomly assigned to receive an overnight dwell with either standard glucose solution or with a 7.5% icodextrin-containing solution. Main Outcome Measures Relation between reduction in the total amount of intraperitoneal infused glucose and parameters of glucose (plasma glucose, insulin, and HbA1C) and lipid metabolism [free fatty acids, plasma lip-ids, lipoproteins, and low density lipoprotein (LDL) sub-fraction profile]. Results After the icodextrin dwells, a reduction of plasma total cholesterol (from 5.43 ± 0.85 to 4.86 ± 0.70 mmol/L, p < 0.001) and LDL cholesterol (from 3.38 ± 0.87 to 2.93 ± 0.73 mmol/L, p = 0.001) was observed. Also, high density lipoprotein (HDL) cholesterol (from 0.95 ± 0.27 to 0.90 ± 0.24 mmol/L, p = 0.029) was reduced, but the plasma total cholesterol-to-HDL ratio remained similar. Plasma free fatty acids and triglyceride levels tended to decrease (from 0.16 ± 0.10 to 0.13 ± 0.08 mmol/L, p = 0.06, and from 2.14 ± 1.96 to 1.92 ± 1.03 mmol/L, respectively). Evaluation of LDL subfraction profiles after ultra-centrifugation showed a more buoyant LDL subfraction profile with fewer dense LDL particles in 6 patients and no changes in 14 patients after icodextrin. The effects on lipids were not accompanied by a decrease in fasting plasma glucose (from 5.76 ± 1.29 to 5.86 ± 0.80 mmol/L) or insulin levels (from 19.5 ± 14.4 to 20.3 ± 13.0 mU/L). Conclusion These results suggest a beneficial effect on lipid profiles of CAPD patients with the use of an overnight dwell with icodextrin.

Item does not contain fulltext BACKGROUND: Although beta-carotene has shown inverse associations with chronic diseases involving free radical damage in observational epidemiological studies less attention has been paid to five other major carotenoids also showing antioxidant activity in vitro. METHODS: We studied the associations between 7.2-year mortality and serum levels of six carotenoids, and alpha-tocopherol, measured in stored serum, sampled in 1991/1992 during a health survey among 638 independently living elderly subjects aged 65-85 years. Proportional hazards regression was used to estimate hazard ratios of all-cause mortality for the lowest tertiles of serum vitamins with the highest tertiles, adjusting for possible confounding effects. RESULTS: During a follow-up period of 7.2 years 171 elderly died. The adjusted hazard ratios for all-cause mortality for the lowest tertiles of vitamins compared with the highest tertiles were between 1.02 and 1.73. The strongest increase in mortality risk was seen for beta-cryptoxanthin (1.52, 95% CI : 1.00, 2.32), lutein (1.56, 95% CI : 1.05, 2.31) and zeaxanthin (1.32, 95% CI : 0.89, 1.97) and their sum (oxygenated carotenoids: 1.73, 95% CI : 1.12, 2.67). Tests for trend were significant (P < 0.05) for all-cause mortality risk and serum levels of total carotenoids, oxygenated carotenoids and beta-cryptoxanthin. CONCLUSIONS: Our findings suggest that serum levels of individual carotenoids, particularly the oxygenated species are inversely associated with all-cause mortality and should be considered as candidates for further investigations.

Item does not contain fulltext BACKGROUND: Cafestol is a diterpene in unfiltered coffee that raises plasma triacylglycerol in humans. OBJECTIVE: We studied whether cafestol increases plasma triacylglycerol by increasing the production rate or by decreasing the fractional catabolic rate of VLDL(1) [Svedberg flotation unit (S(f)) 60-400] apolipoprotein (apo) B. In addition, we studied the effect of cafestol on the composition of VLDL(1) and VLDL(2) (S(f) 20-60). DESIGN: Eight healthy normolipidemic men were administered a daily dose of 75 mg cafestol for 2 wk. A bolus injection of 7 mg L-[5,5,5-(2)H(3)]leucine/kg body wt was given after a baseline period with no cafestol and again after treatment with cafestol. We derived kinetic constants to describe the metabolism of VLDL(1) apo B by using a multicompartmental model. RESULTS: Cafestol significantly increased plasma triacylglycerol by 31% or 0.32 mmol/L (95% CI: 0.03, 0.61); the increase was due mainly to a nonsignificant rise in VLDL(1) triacylglycerol of 57% or 0.23 mmol/L (95% CI: -0.02, 0.48). Cafestol significantly increased the mean rate of VLDL(1) apo B production by 80% or 755 mg/d (95% CI: 0.2, 5353), whereas it did not significantly change the mean fractional catabolic rate of VLDL(1) apo B (mean increase of 3 pools/d; 95% CI: -4, 10]). Cafestol did not change the composition of VLDL(1). A significant increase in the ratio of VLDL(2) cholesteryl ester to triacylglycerol indicates that VLDL(2) became enriched with cholesteryl esters at the cost of triacylglycerol. CONCLUSION: Cafestol increases plasma triacylglycerol by increasing the production rate of VLDL(1) apo B, probably via increased assembly of VLDL(1) in the liver.

Stalenhoef AFH, Hectors M, Demacker PNM (University Medical Centre Nijmegen, Nijmegen, The Netherlands). Effect of plant sterol-enriched margarine on plasma lipids and sterols in subjects heterozygous for phytosterolaemia. J Intern Med 2001; 249: 163–166. Objective. Margarine with added plant sterols lowers plasma cholesterol levels. It is of importance to know whether these margarines can be used safely in carriers of a hereditary disorder with increased absorption of plant sterols. Design. In an open feeding study of 8 weeks with a 2-week run-in period and 2 final weeks as a washout period on control margarine (0.3% plant sterols), two obligate heterozygous parents of a patient with classical sitosterolaemia were subjected for 4 weeks to a diet containing margarine enriched with plant sterols (8%). Fasting blood samples were taken weekly. Primary outcomes were plasma lipid and lipoprotein levels and plant sterol levels. Results. Both parents were hyperlipidaemic. Total plasma cholesterol levels were decreased by 11 and 12%, respectively, after 4 weeks of the consumption of 40 g day−1 of plant sterol-enriched margarine. This was mainly due to changes in LDL-cholesterol, whereas the other lipoproteins, including lipoprotein(a), were unaffected. Total plant sterol levels increased maximally 139% from 0.31 to 0.82% of total sterols in the father, and maximally 83% from 0.32 to 0.66% of total sterols in the mother. Conclusion. An intake of around 3 g day−1 of plant sterols by subjects heterozygous for phytosterolaemia increased campesterol or sitosterol levels in blood to similar levels as found in normal subjects. In addition, plasma cholesterol levels were reduced to the same extent as in normal or hypercholesterolaemic individuals.

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Item does not contain fulltext OBJECTIVE: Tibolone is a synthetic steroid with tissue-specific estrogenic, progestogenic, and androgenic properties. The drug relieves climacteric symptoms and prevents osteoporosis but does not stimulate the endometrium. We have previously shown that in laboratory animals tibolone inhibits the atherogenesis induced by a high-cholesterol diet. Therefore, we compared the antiatherosclerotic effect of oral tibolone at different dose levels with that of oral 17beta-estradiol (E2) and ethinyl estradiol (EE). DESIGN: Atherosclerotic lesion formation (increase in vessel wall cholesterol deposition and fatty streak formation) was measured in ovariectomized rabbits after 20 weeks on an atherogenic diet (fed daily 80 g of a rabbit chow containing 0.4% cholesterol, 3.75% peanut oil, and 3.75% coconut oil) in eight groups: group 1, placebo (n = 35); group 2, control (n = 34) received normal rabbit chow; group 3, E2 group (E2 4 mg, n = 12); group 4, EE group (EE 60 microg, n = 10); and groups 5-8, tibolone (6 mg, n = 12; 2 mg, n = 13; 0.6 mg, n = 25; and 0.15 mg, n = 11, respectively). During the study, blood samples were obtained for the evaluation of plasma triglycerides, cholesterol, lipoproteins, and glutamate pyruvate transaminase. After 20 weeks, the animals were killed, and cholesterol concentration and the formation of fatty streaks in the wall of the aortic arch were evaluated. RESULTS: In the placebo group, the atherogenic diet induced a mean increase in total plasma cholesterol concentration from 1.1+/-0.1 mmol/L (control group) to 34.1+/-1.8 mmol/L (mean +/- SE). This resulted in an accumulation of cholesterol in the aortic arch from 48+/-4 (control group) to 608+/-44 nmol/mg protein and in the formation of fatty streaks (41.8+/-3.2% of the surface of the aortic arch was covered with fatty streaks). Tibolone had strong dose-dependent antiatherosclerotic effects. It reduced the accumulation of cholesterol in the aortic arch at doses of 6 to 0.15 mg by 99, 97, 87, and 57% and the formation of fatty streaks by 98, 97, 81, and 38%, respectively. E2 had only a marginal antiatherosclerotic effect, whereas EE showed an effect comparable to that of tibolone at doses of 2 to 0.6 mg. With EE, the accumulation of cholesterol in the vessel wall was reduced by 93% and the formation of fatty streaks by 73%. Mean plasma cholesterol concentrations were also reduced by tibolone (64, 70, 61, and 47%) and EE (57%). This reduction was mainly mediated via a reduction in beta-very-low-density lipoprotein cholesterol. Analysis, however, indicated that the observed antiatherosclerotic effects of tibolone and EE, at least partly, are due to a direct effect on the vessel wall and independent of the changes in plasma cholesterol. At equipotent antiatherosclerotic doses, EE showed a stronger uterotropic effect (measured as the increase in uterine weight) than tibolone. EE increased uterine weight from 0.57 g/kg body weight (BW) (control group) to 3.5 g/kg BW; tibolone at doses of 6, 2, 0.6, and 0.15 mg increased uterine weight to 2.5, 2.8, 2.2, and 1.3 g/kg BW, respectively. CONCLUSION: Tibolone can protect the arterial vessel wall against atherosclerotic lesions induced by a hypercholesterolemic diet. However, it has much less estrogenic effects on the uterus compared with EE at equipotent doses, indicating tissue selectivity for tibolone. The clinical implications of these findings require investigation.

Contains fulltext : 146756.pdf (Publisher’s version ) (Open Access) 168 p.

Item does not contain fulltext OBJECTIVES: We evaluated the effect of therapy with folic acid and cobalamin on coronary endothelial function, expressed as a change in volumetric coronary blood flow (CBF), in hyperhomocysteinemic patients with coronary artery disease (CAD). BACKGROUND: Hyperhomocysteinemia is an independent risk factor for CAD. The mechanism responsible for this increased risk is unclear, but it is generally assumed that hyperhomocysteinemia causes endothelial dysfunction. It is unknown whether lowering plasma homocysteine levels with folic acid and cobalamin improves coronary endothelial function in patients with hyperhomocysteinemia and symptomatic CAD. METHODS: Fifteen patients scheduled for elective percutaneous transluminal coronary angioplasty (PTCA) with plasma homocysteine levels of >or=16 micromol/l were randomized for six months of treatment with folic acid 5 mg and cobalamin 400 microg daily or placebo. Coronary endothelial function was evaluated in a non-PTCA vessel using acetylcholine infusion in dosages of 10(-8) M, 10(-7) M, and 10(-6) M. Endothelium- dependent CBF is determined using intracoronary Doppler velocity and quantitative coronary angiography at baseline and after six months. RESULTS: In the folic acid/cobalamin treated group, CBF increased after acetylcholine infusion with 96% (standard deviation 54; 95% confidence interval [CI]: 44% to 154%) compared with a decrease of 16% (standard deviation 35; 95% CI: -20% to +30%) of the CBF in the placebo-treated group (p < 0.005). CONCLUSIONS: This is the first prospective randomized placebo-controlled intervention study evaluating coronary endothelial function in hyperhomocysteinemic patients with CAD. Our results suggest that coronary endothelial function improves after treatment with folic acid and cobalamin.