Enhanced platelet activation in hyperhomocysteinemic individuals.
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Aged↗
Biomedical subjects
L Ose
Publications and source records attributed to L Ose.
Increased levels of C-reactive protein and interleukin-6 in hyperhomocysteinemic subjects.
OBJECTIVE: Elevated plasma homocysteine concentration is considered to be an independent risk factor for cardiovascular disease. However, the mechanisms by which hyperhomocysteinemia are related to vascular disease are unclear. High-sensitivity C-reactive protein (CRP), a marker of inflammation, has been reported to be an independent predictor of future myocardial infarction among clinically healthy individuals. Interleukin (IL)-6 is a regulator of CRP and has a key role in initiation of inflammation. The aim of this study was to investigate whether individuals with increased plasma homocysteine concentrations have altered levels of serum CRP and IL-6. MATERIAL AND METHODS: Serum concentrations of CRP and IL-6 were measured in 39 individuals with hyperhomocysteinemia and in 39 control subjects matched for gender, age and body mass index (BMI). In addition, the inflammatory effect of IL-6 on peripheral blood mononuclear cells was measured. RESULTS: Compared to controls, hyperhomocysteinemic subjects have elevated serum levels of CRP and IL-6 (p < or =0.001 and p < 0.005, respectively). Importantly, this raised level of IL-6 was also seen in hyperhomocysteinemic individuals without accompanying hypercholesterolemia or cardiovascular disease. IL-6 increased the release of monocyte chemoattractant protein-1 from peripheral blood mononuclear cells, with particularly enhancing effects in cells from patients with hyperhomocysteinemia. CONCLUSIONS: These data suggest that enhanced inflammation may be associated with homocysteine-related cardiovascular disease, possibly involving IL-6-related mechanisms.
Adult↗
Increased inflammatory markers in children with familial hypercholesterolaemia.
BACKGROUND: While data are abundant on increased levels of inflammatory markers in adult patients with hypercholesterolaemia, such data in children are limited. Therefore, we sought to investigate the degree and character of inflammation in children with heterozygous familial hypercholesterolaemia (FH) by measuring levels of neopterin, high-sensitivity C-reactive protein (hsCRP), and soluble CD40 ligand (sCD40L). MATERIALS AND METHODS: In the present study, we compared the concentration of inflammatory markers in children suffering from heterozygous FH (n = 207) with those in unaffected siblings (n = 84). Furthermore, we investigated the effect of 2-year treatment with pravastatin (20-40 mg qd) or placebo on plasma levels of those markers. RESULTS: Our main finding was that serum levels of neopterin and hsCRP were significantly higher in FH children compared with healthy siblings, whereas sCD40L was not. Body mass index and high-density lipoprotein cholesterol levels were significant independent predictors of hsCRP and neopterin. Furthermore, pravastatin therapy decreased neopterin, but not hsCRP and sCD40L, in the FH children, but these changes were not different from the placebo group. CONCLUSION: These findings indicate low-grade monocyte/macrophage hyperactivity in the early stages of atherogenesis, but our findings also suggest that inflammation as well as anti-inflammatory effects of statins are less prominent features of atherosclerosis in FH children than in FH adults.
Adolescent↗
Altered composition of HDL3 in FH subjects causing a HDL subfraction with less atheroprotective function.
BACKGROUND: Subjects with familial hypercholesterolemia (FH) are associated with increased risk of premature atherosclerosis and coronary artery disease (CAD). However, onset of clinically manifested CAD varies widely among subjects with heterozygous FH. The purpose of this study was to investigate whether FH subjects with an identical mutation in the low-density lipoprotein (LDL) receptor gene have a high-density lipoprotein (HDL)3 that is characterized by a less atheroprotective functions than that of healthy controls and within subgroups of FH. DESIGN: Twenty-two adults <75 years of age with FH and 17 healthy sex- and age-matched controls were included. HDL3 was isolated and the composition was characterized from each subject, and its ability to suppress tumor necrosis factor(TNF)-alpha stimulated expression of ICAM-1 on HUVEC was investigated. In addition, plasma level of soluble sICAM-1 and VCAM-1 was measured. RESULTS: Compared to controls, FH subjects had lower content of phospholipids in their HDL3 subfraction and a higher serum ICAM-1 level. No differences in sVCAM-1 were observed. HDL3 isolated from FH with body mass index(BMI)>25 and from FH subjects with premature CAD contained higher content of triglycerides compared to the HDL3 from FH subjects with BMI<25 and without CAD, respectively. Most important, when testing the function of HDL3 in the two FH subgroups characterized by elevated BMI and premature CAD, lower inhibition of ICAM-1 expression on HUVEC was observed. CONCLUSIONS: The altered composition of HDL3 from FH subjects with BMI>25 and FH subjects with premature CAD may be responsible for a HDL3 subfraction with less protective properties assessed as inhibition of ICAM-1 expression on HUVEC consequently leading to more proatherogenic endothelial surface.
Adult↗
Long-term compliance and changes in plasma lipids, plant sterols and carotenoids in children and parents with FH consuming plant sterol ester-enriched spread.
OBJECTIVE: To study the compliance and changes in plasma lipids, plant sterols, fat-soluble vitamins and carotenoids in children and parents with familial hypercholesterolemia (FH) consuming a plant sterol ester-enriched (PSE) spread. DESIGN: A 26-week open-label follow-up of children who had previously been studied in a controlled cross-over design. The parents were also included in the open-label arm of the study. SETTING: Outpatient clinic for treatment of hyperlipidemia. SUBJECTS: A total of 37 children (7-13 y) and 20 parents (32-51 y) diagnosed with 'definite' or 'possible' heterozygous FH. In all, 19 of the parents, but no children, used statins. All were patients at the Lipid Clinic, National Hospital in Oslo. INTERVENTIONS: Subjects were recommended to eat 20 g/day of PSE spread as part of their lipid-lowering diet. RESULTS: The mean intake of PSE spread was 13.7 and 16.5 g/days in the children and parents, respectively, corresponding to 1.2 and 1.5 g of plant sterols. Plasma total cholesterol decreased by 9.1% in both children (P<0.001) and parents (P=0.002). The corresponding decreases in LDL cholesterol were 11.4% (P<0.001) and 11.0% (P=0.012). Increases in serum lathosterol, campesterol and sitosterol, adjusted for total cholesterol, were observed in the children (31, 96, 48%, respectively, P<0.001) at the end of the controlled cross-over period. In the parents, serum campesterol and sitosterol, adjusted for total cholesterol, increased by 92 and 39%, respectively (P< 0.001). Lipid-adjusted serum alpha- and beta-carotene decreased by 17.4% (P=0.008) and 10.9% (P=0.018), respectively, in the children at the end of the controlled PSE period, but increased again during the follow-up. In the parents, serum alpha- and beta-carotene concentrations were unchanged, while serum lutein and lycopene decreased by 7.3% (P=0.037) and 14.6% (P=0.044), respectively. CONCLUSIONS: Sustained efficacy of cholesterol reduction and long-term compliance of PSE intake were demonstrated in this study.
Adolescent↗
Psychological factors and cardiovascular disease.
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Cardiovascular Diseases↗
Expression of matrix metalloproteinase-9 in mononuclear cells of hyperhomocysteinaemic subjects.
Atherosclerotic plaque instability and rupture requires extracellular matrix modification, a complex process regulated by matrix metalloproteinases (MMPs). We hypothesized that homocysteine's atherogenic effects may involve MMP-mediated mechanisms. Our results showed the following: (i) Compared with healthy control subjects (n = 9), patients with hyperhomocysteinaemia (n = 9) had elevated mRNA levels of MMP-9 and tissue inhibitors of metalloproteinases-1 (TIMP-1) in freshly isolated peripheral blood mononuclear cells (PBMCs), which were positively correlated with homocysteine and negatively correlated with folate and vitamin B12 levels. (ii) Peripheral blood mononuclear cells obtained from these patients released markedly enhanced the amount of MMP-9 upon oxidized LDL (oxLDL) stimulation, whereas no such enhancing effect was seen in cells from healthy controls. (iii) During folic acid 6 weeks' treatment, normalization of homocysteine levels was accompanied by a significant reduction in mRNA levels of MMP-9 and TIMP-1 in PBMCs, as well as a marked reduction in oxLDL-stimulated release of MMP enzyme activity. These novel findings may suggest that homocysteine exerts its atherogenic effect in part by elevating levels and activity of MMPs, which in turn may enhance matrix degradation, potentially promoting atherogenesis and plaque instability. Moreover, our findings suggest that folic acid supplementation may down-regulate these inappropriate responses in these patients.
Female↗
Reproducibility and validity of a short food questionnaire for the assessment of dietary habits.
BACKGROUND AND AIM: Dietary changes such as reducing the consumption of foods high in saturated fat, and increasing the daily intake of unsaturated fat, fibre and vitamins may have beneficial effects on long-term health. Accurate dietary information is essential for dietary counselling. Most of the methods used to examine an individual's diet (food records, diet interview, food frequency questionnaires) are too complicated and time-consuming for routine clinical use. There is a need for a fast and simple tool for food assessment. The aim of this study was to evaluate a short and simple food questionnaire for use in clinical practice that emphasises the intakes of fat, fibre, fruit and vegetables representative of the usual diet of an individual or group. METHODS AND RESULTS: A 15-item questionnaire was completed twice on the same day by 111 participants in order to study reproducibility, and its validity was checked by comparing the results with those of a 7-day food record for 101 subjects. The participants reported a positive attitude to the questionnaire. The reproducibility and validity studies comparing the sum scores of the questionnaire and food record gave correlation coefficients of respectively 0.95 and 0.73, thus indicating good agreement. The reproducibility study showed weighted Kappa coefficients ranging from 0.97 for milk and snacks to 0.75 for vegetables. In the validity assessment, the weighted Kappa coefficients ranged from 0.73 for butter and margarine to 0.14-0.25 for vegetables, fish and snacks, which is a less satisfactory result. The correlation coefficient between the sum score of the questionnaire and the percentage of dietary saturated fat was-0.59. CONCLUSIONS: This simple self-administered questionnaire allows for the rapid assessment of the constituents of the usual diet of an individual. It provides a good estimate of dietary fat and fibre but is less accurate in terms of the intake of vegetables, fish and snacks. It also offers an opportunity to discuss central points in the improvement of dietary habits and may be a useful health educational tool in clinical practice.
Adult↗
Two genes that map to the STSL locus cause sitosterolemia: genomic structure and spectrum of mutations involving sterolin-1 and sterolin-2, encoded by ABCG5 and ABCG8, respectively.
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 <400 bp upstream of sterolin-1, in the opposite orientation. Mutational analyses revealed that this highly homologous protein, termed "sterolin-2" and encoded by ABCG8, is mutated in the remaining pedigrees. Thus, two highly homologous genes, located in a head-to-head configuration on chromosome 2p21, are involved as causes of sitosterolemia. These studies indicate that both sterolin-1 and sterolin-2 are indispensable for the regulation of sterol absorption and excretion. Identification of sterolin-1 and sterolin-2 as critical players in the regulation of dietary-sterol absorption and excretion identifies a new pathway of sterol transport.
ATP Binding Cassette Transporter, Subfamily G, Mem↗
[Familial hypercholesterolemia--prognosis and treatment].
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Anticholesteremic Agents↗
[Genetic screening and treatment in familial hypercholesterolemia].
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Genetic Testing↗
Disposition of homocysteine in subjects heterozygous for homocystinuria due to cystathionine beta-synthase deficiency: relationship between genotype and phenotype.
We have investigated 31 subjects from five unrelated families with one or more members with cystathionine beta-synthase (CBS) deficiency. On the basis of their CBS genotype, the subjects were grouped as normal (n = 11) or heterozygotes (n = 20). Based on pyridoxine effect in the probands, the heterozygotes were further classified as pyridoxine-responsive (n = 9) or non-responsive (n = 11). Heterozygous subjects had normal fasting total plasma homocysteine (tHcy), but median urinary tHcy excretion rate was significantly elevated compared to healthy controls (0.39 micromol/h vs 0.24 micromol/h, P < 0.05). An abnormal tHcy response after methionine loading identified 73% of the pyridoxine non-responsive heterozygotes, but only 33% of the pyridoxine responsive participants. The increase in cystathionine or the change in tHcy relative to cystathionine did not improve diagnostic accuracy of the methionine loading test. After Hcy loading, the maximal increase in tHcy was significantly elevated, whereas t(1/2) was normal in heterozygotes. In conclusion, a single biochemical test cannot discriminate CBS heterozygotes from controls. Abnormal tHcy response after methionine loading was the most sensitive test. Our data suggest that the urinary tHcy excretion rate is a simple, non-invasive approach for studying mild disturbances in Hcy metabolism.
Adolescent↗
[Treatment goals for blood lipids in high risk patients of atherosclerotic disease].
BACKGROUND: The results from clinical studies with statins have directed attention to the benefits of risk factor intervention in atherosclerotic disease, and achievement of treatment goals for blood lipids. MATERIAL AND METHODS: In 1999, a total of 3,935 patients treated with a statin were screened in 412 general practices in Norway for their blood lipids, in order to evaluate the achievement of the new European treatment guidelines (total cholesterol < 5 mmol/l and LDL cholesterol < 3 mmol/l). Inclusion criterion was ongoing medication with a statin, independent of indication. Consecutive patients were interviewed and examined when they attended their regular check-ups. The mean age of the patients was 63 years; 42% of them were women. Two-thirds of the patients were in secondary prevention. RESULTS: Before treatment, the mean level of total cholesterol was in primary prevention 8.8 mmol/l, in secondary prevention and in diabetes 7.5 mmol/l. In the total material, 36% of the patients achieved the treatment goal of total cholesterol and LDL cholesterol. Significantly more patients in secondary prevention than in primary prevention achieved the treatment goal (44% versus 17%), more patients with than without diabetes achieved it (45% versus 34%), and more men than women (42% versus 27%). These differences were mainly due to differences in base levels of total cholesterol and LDL cholesterol. To assess the statin doses, the average dose of each type of statin was converted to a simvastatin dose. The average dose in this manner was found to be 23.8 mg, with small differences between the subgroups. INTERPRETATION: The doctors did not uptitrate the statin doses according to the lipid levels and in line with the evidence from the clinical trials. General practitioners in Norway should intensify their use of lipid lowering therapy.
Adult↗
Effect of folic acid treatment on endothelium-dependent vasodilation and nitric oxide-derived end products in hyperhomocysteinemic subjects.
PURPOSE: An elevated plasma homocysteine concentration is an independent risk factor for cardiovascular diseases. In this study, we tested the hypothesis that hyperhomocysteinemia induces endothelial dysfunction mediated, at least in part, through nitric oxide-dependent mechanisms and that folic acid supplementation improves endothelial function in hyperhomocysteinemic subjects. SUBJECTS AND METHODS: Endothelial function was evaluated in healthy controls and hyperhomocysteinemic subjects by measuring plasma levels of the nitric oxide-derived end products nitrite and nitrate and by assessing vasodilatory responses in the skin microcirculation and forearm vasculature. In the subjects with hyperhomocysteinemia, these measurements were repeated after 6 weeks and 12 months of folic acid supplementation. RESULTS: Compared with healthy controls, hyperhomocysteinemic subjects had significantly lower median plasma levels of nitric oxide-derived end products (12.1 microM [range 4.4 to 41.8] versus 24.6 microM [13.6 to 53.2]; P <0.001), a significantly lower endothelium-dependent vasodilatory response to acetylcholine (P <0.01), hyperemic response in the microcirculation (P <0.01), and total forearm blood flow during reactive hyperemia (P = 0.01). There was no significant difference in the endothelium-independent response. Folic acid treatment for 12 months increased the plasma level of nitric oxide-derived end products by 121% (95% confidence interval [CI], 72% to 170%), the vasodilatory response to acetylcholine by 124% (95% CI, 36% to 212%), and the ischemia-mediated hyperemic responses in the microcirculation by 60% (95% CI, 25% to 96%) and in the forearm vasculature by 47% (95% CI, 21% to 73%). CONCLUSIONS: Homocysteine appears to induce its atherogenic effect, at least in part, by depressing endothelial function, possibly through nitric oxide-dependent mechanisms. This effect can be reversed by folic acid supplementation.
Adult↗
Fine mapping of a gene responsible for regulating dietary cholesterol absorption; founder effects underlie cases of phytosterolaemia in multiple communities.
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.
Arteriosclerosis↗
Serum cholesterol response to replacing butter with a new trans-free margarine in hypercholesterolemic subjects.
UNLABELLED: Margarine leads to lower total and LDL cholesterol (LDL-C) levels than butter but may contain trans fatty acids that increase atherogenic lipids. A food company has used data concerning the cholesterolemic effects of individual fatty acids, including trans fatty acids, to develop a commercially available and virtually trans-free margarine. OBJECTIVE: The effect of this novel margarine on serum lipids and lipoproteins was compared with that of butter in free-living, hypercholesterolemic subjects. DESIGN AND SETTING: A two-period, outpatient cross-over trial at a university hospital lipid clinic. SUBJECTS: The study involved 77 subjects, and was completed by 53 men and 19 women aged 35-65 years with total serum cholesterol levels of between 6.0 and 7.9 mmol/L. INTERVENTION: Two 23-day regimens, separated by a 4-week washout period, included individualised dietary prescriptions supplemented with butter or margarine designed to provide 15% of total dietary energy. RESULTS: In comparison with butter, margarine intake lowered total and LDL-C levels by respectively 11.1% (99% CI: 8.1-14.1) and 11.3% (99% CI: 7.6-15.1). The reduction in LDL-C was < 3% in nearly one-fifth of the subjects despite appropriate changes in serum triglyceride fatty acids. Of the tested clinical and demographic variables, only the percentage of energy obtained from saturated fat during the margarine intake period was associated with dietary responsiveness (explaining 12% of the variation; p < 0.01). CONCLUSION: Our results suggest that a margarine designed to meet nutritional recommendations for hypercholesterolemia is more efficacious than butter in reducing atherogenic lipid levels in hypercholesterolemic subjects.
Adult↗
Lipid treatment goals achieved in patients treated with statin drugs in Norwegian general practice.
Statin drug treatment has still not achieved complete acceptance, and titration to recommended target goals is still not used by physicians in Norway.
Adult↗
[The diet of patients with atherosclerotic disease compared with the standard diet in the population].
BACKGROUND: In the guidelines for follow-up of patients with established atherosclerotic disease, the importance of diet and other life style intervention strategies in reducing cardiovascular risk is emphasised. MATERIAL AND METHODS: In a survey in 363 general practices in 1997-99 we examined the diet of 3,160 patients with established atherosclerosis treated with a lipid lowering agent, and compared it with the diet of 530 persons interviewed in an omnibus survey, representative of the general Norwegian population above 40 years of age. A simple questionnaire was used for diet registration. We compared the quality of the patients' diet with their lipid levels and fulfilled treatment goals. RESULTS: A greater proportion of the patients used skimmed milk, polyunsaturated margarine and vegetable oil, and they ate less fat cheese and less fat meat compared to the other group. There were only small differences in the use of fish, fruit and vegetables. A more healthy diet in the patients reflected a better achievement of the treatment goals for blood lipids. INTERPRETATION: Patients with established cardiovascular disease seemed to have a more healthy diet than the general population. The use of fruit and vegetables has to be encouraged.
Adult↗