Hypercholesterolemia: Poledne R

Vaverková H, Soska V, Rosolová H, Ceska R, Cífková R, Freiberger T, Pit'ha J, Poledne R, Stulc T, Urbanová Z, Vráblík M, Czech Atherosclerosis Society. · III. interní klinika LF UP a FN, Olomouc. · Cas Lek Cesk. · Pubmed #17650596 No free full text.

Abstract: The present guidelines are based on the recommendations published in 2005 entitled "Prevention of Cardiovascular Diseases in Adulthood" summarizing the conclusions of nine Czech medical societies and agree with them in the assessment of individual risk of mortality from cardiovascular disease (CVD) according to SCORE tables. They reflect new research data in pathophysiology of dyslipidemias (DLP) and particularly the results of recent clinical trials of lipid-lowering therapy and their meta-analyses. They establish priorities for the screening and management of DLP, present suitable diagnostic methods, additional investigations of potential use in risk assessment, including some emerging risk factors and detection of sub-clinical atherosclerosis in persons in a moderate-risk category. Major changes include a lower LDL-cholesterol treatment target (< 2.0 mmol/L for all CVD individuals) and a possible use of apolipoprotein B as a secondary target in selected persons (< 0.9 g/L in high risk without CVD, < 0.8 g/L for CVD patients) and nonHDL-cholesterol (< 3.3 mmol/L in high risk without CVD, < 2.8 mmol/L for CVD patients). Therapy of individual DLP phenotypes (monotherapy and combination therapy) as well as basic principles for control examination at lipid-lowering medication are described. Recommended therapeutic lifestyle changes are shown. Enclosed are five annexes: DLP diagnosis; causes of secondary DLP; additional investiga- tions of potential use in risk stratification; familial hypercholesterolemia; list of recommended foods; two variants of SCORE tables for risk assessment for the Czech Republic; the scheme of recommended procedures and treatment algorithm in DLP asymptomatic individuals.

Vaverková H, Soska V, Rosolová H, Ceska R, Cífková R, Freiberger T, Pit'ha J, Poledne R, Stulc T, Urbanová Z, Vráblík M, Anonymous00126. · III. interní klinika Lékarské fakulty UP a FN Olomouc. · Vnitr Lek. · Pubmed #17419181 No free full text.

Abstract: The present guidelines are based on the recommendations published in 2005 entitled "Prevention of Cardiovascular Diseases in Adulthood" summarizing the conclusions of nine Czech medical societies and agree with them in the assessment of individual risks of mortality from cardiovascular disease (CVD) according to SCORE tables. They reflect new research data in pathophysiology of dyslipidemias (DLP) and particularly the results of recent clinical trials of lipid-lowering therapy and their meta-analyses. They establish priorities for the screening and management of DLP, present suitable diagnostic methods, additional investigations of potential use in risk assessment, including some emerging risk factors and detection of sub-clinical atherosclerosis in persons in a moderate-risk category. Major changes include a lower LDL-cholesterol treatment target (< 2.0 mmol/L for all CVD individuals) and a possible use of apolipoprotein B as a secondary target in selected persons (< 0.9 g/L in high risk without CVD, < 0.8 g/L for CVD patients) and nonHDL-cholesterol (< 3.3 mmol/L in high risk without CVD, < 2.8 mmol/L for CVD patients). Therapy of individual DLP phenotypes (monotherapy and combination therapy) as well as basic principles for control examination at lipid-lowering medication are described. Recommended therapeutic lifestyle changes are shown. Enclosed are five annexes: DLP diagnosis; causes of secondary DLP; additional investigations of potential use in risk stratification; familial hypercholesterolemia; list of recommended foods; two variants of SCORE tables for risk assessment for the Czech Republic; the scheme of recommended procedures and treatment algorithm in DLP asymptomatic individuals.

Kovár J, Suchánek P, Hubácek JA, Poledne R. · Institute for Clinical and Experimental Medicine, Laboratory for Atherosclerosis Research, Vídenská 1058/9, 140 21 Prague 4, Czech Republic. · Physiol Res. · Pubmed #15479137 links to  free full text

Abstract: The aim of the study was to ascertain whether the A-204C polymorphism in the cholesterol 7 -hydroxylase (CYP7A1) gene plays any role in determining LDL-cholesterol (LDL-C) concentration responsiveness to a high-fat diet. The concentrations of total cholesterol and LDL-cholesterol were measured in eleven healthy men (age: 30.9+/-3.2 years; BMI: 24.9+/-2.7 kg/m(2);;) who were homozygous for either the -204A or -204C allele, after 3 weeks on a low-fat (LF) diet and 3 weeks on a high-fat (HF) diet. During both dietary regimens, the isocaloric amount of food was provided to volunteers; LF diet contained 22 % of energy as a fat and 2.2 mg of cholesterol/kg of body weight a day, HF diet 40 % of fat and 9.7 mg of cholesterol/kg of body weight a day. In six subjects homozygous for the -204C allele, the concentrations of cholesterol and LDL-cholesterol were significantly higher on HF than on LF diet (cholesterol: 4.62 vs. 4.00 mmol/l, p<0.05; LDL-C: 2.15 vs. 1.63 mmol/l, p<0.01, respectively); no significant change was observed in five subjects homozygous for the -204A allele. There were no other differences in lipid and lipoprotein-lipid concentrations. Therefore, the polymorphism in the cholesterol 7alpha-hydroxylase promotor region seems to be involved in the determination of cholesterol and LDL-C responsiveness to a dietary fat challenge.

Hubácek JA, Bobková D, Bohuslavová R, Poledne R. · Institute for Clinical and Experimental Medicine, Prague, Czech Republic. · Folia Biol (Praha). · Pubmed #18226361 links to  free full text

Abstract: PHHC rats represent a suitable experimental model of polygenic hypercholesterolemia. It has been found that its metabolic defect is not related to alimentary cholesterol absorption and LDL clearance. We have tested possible changes in cholesterol clearance from the liver to bile acids by analysis of the expression of the cholesterol 7alpha-hydroxylase (cyp7A1) gene in PHHC (N = 20) and Wistar (controls) (N = 19) male rats. The animals were fed standard laboratory diet (CD) or control diet containing 5% fat and 2% cholesterol (HCD) for two weeks. SSCP and RT-PCR were used for mutation analysis and study of gene expression, respectively. Although the basal cholesterolemia in PHHC was similar to controls (1.80 +/- 0.48 and 1.52 +/- 0.39 mmol/l, respectively), it rose in rats fed on HCD to 9.81 +/- 1.65 mmol/l in PHHC rats and only to 2.19 +/- 0.41 mmol/l in controls. Similarly to the basal cholesterol concentration, the gene expression of cyp7A1 in the liver of rats on CD was the same in both compared groups on the control diet. In controls on HCD, cyp7A1 gene expression increased almost 4-fold immediately on the first day and achieved up to approximately 20-multiple basal expression in the end of the feeding period. Compared to the controls, after switching to HCD the cyp7A1 gene expression in PHHC rats did not change dramatically. These results suggest that the cyp7A1 gene plays an important role in development of hypercholesterolemia in PHHC rats.

Szitányi P, Pistulková H, Hubácek JA, Stuchlíková H, Poledne R. · Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, General Teaching Hospital, Prague, Czech Republic. · Physiol Res. · Pubmed #18052682 links to  free full text

Abstract: The inconsistency of data regarding intrauterine programming of cardiovascular risk factors may be largely caused by genetic predisposition and later lifestyle. We analyzed whether low birth weight and apolipoprotein E (Apo E) polymorphism participate in the onset of hypercholesterolemia in children. Our approach was based on hypothesis that genetically enhanced susceptibility of different individuals might influence the effects of intrauterine programming. Two groups were selected from 2000 children at the beginning of an ongoing study: high-cholesterol group (HCG, n=67) and low-cholesterol group as a control (LCG, n=72). Both groups were divided into tertilles according to birth weight and we compared birth weight and apo E gene polymorphism between and within groups. The birth weight in HCG was 0.3 kg lower than the controls (p<0.001). The frequency of apoE4 was 31 % in HCG and only 10 % in LCG. The frequency of apoE4+ genotypes was not significantly different between tertilles based on birth weight in HCG. We suppose that intrauterine undernutrition, demonstrated by a lower birth weight, participates in the development of hypercholesterolemia already in childhood. The effects of low birth weight and the candidate gene - apoE, are synergic.

Bobková D, Honsová E, Kovár J, Poledne R. · Laboratory for Atherosclerosis Research, Institute for Clinical and Experimental Medicine, Center for Experimental Cardiovascular Research, Prague, Czech Republic. · Physiol Res. · Pubmed #15588132 links to  free full text

Abstract: Loss of apolipoprotein E synthesis causes increased serum cholesterol concentrations and the sensitivity to high-fat diet in mice. We analyzed the changes in lipoprotein and hepatic structures in apolipoprotein E-deficient mice kept on control diet and cholesterol diets. Basal cholesterolemia of heterozygous (+/-) mice (2.2+/-0.28 mmol/l) was the same compared to wild-type (+/+) mice (2.3+/-0.15 mmol/l), but was lower compared to homozygous (-/-) mice (10.3+/-1.40 mmol/l). In +/- mice, cholesterolemia rose to 3.2 mmol/l on cholesterol diet and to 9 mmol/l on cholate diet, to 3 mmol/l and 3.6 mmol/l in +/+ mice, and to 23.4 mmol/l and 70.5 mmol/l in -/- mice, respectively. While the ratio of cholesterol/triglyceride concentrations in VLDL, IDL and LDL fractions was not increased in +/- mice and +/+ mice, it was increased in -/- mice on control diet. On the cholesterol diet, this ratio rose and was dramatically increased by cholate diet in all groups of mice. Even though cholate supplementation increased cholesterol concentration, it led to substantial toxic changes in hepatic morphology of all animals. In conclusion, one functional apo E allele in +/- mice is effective in keeping serum cholesterol concentrations in normal range on a control diet, but not on the cholesterol and cholate diets.

Hubácek JA, Pistulková H, Skodová Z, Lánská V, Poledne R. · Institut klinické a experimentální medicíny, Praha. · Cas Lek Cesk. · Pubmed #15077570 No free full text.

Abstract: BACKGROUND: High plasma lipids are one of the risk factor of atherosclerosis. Both environmental (diet, physic activity) and genetic factors have been implicated in the development of hyperlipidaemia. Apolipoprotein (apo) CI plays an important role in plasma cholesterol and triglycerides transport by VLDL particles. The aim of the study was to establish the role of the insertion/deletion polymorphism in apoCI gene in the determination of plasma lipids in children. METHODS AND RESULTS: Using PCR and restriction analysis (HpaI) we have measured I/D polymorphism in APOCI gene in two groups of children selected from opposite ends of the cholesterol distribution curve of 2000 children. Eighty-two children in high-(HCG) and eighty-six children in low-(LCG) cholesterolemic groups participated on the study. No significant difference was found in the frequencies of the APOCI genotypes or alleles between HCG vs. LCG. Association between LDL cholesterol and genotypes within the LCG was found--the D/D homozygotes have higher lipid level compared to the others (p < 0.05). In LCG opposite, but insignificant (p = 0.09) trend was observed. CONCLUSIONS: The widespread I/D polymorphism in the gene for APOCI determines the plasma lipid levels in childhood and it could become another important genetic marker that plays a role in the genetic determination of cholesterolemia.

Hubácek JA, Pistulková H, Skodová Z, Lánská V, Poledne R. · Centrum experimentální medicíny IKEM, Centrum experimentálního výzkumu chorob srdce a cév, Praha. · Cas Lek Cesk. · Pubmed #14515446 No free full text.

Abstract: BACKGROUND: High plasma cholesterol is one of the risk factors of atherosclerosis. Both environmental (diet, physic activity) and genetic factors have been concerned in the development of hypercholesterolemia. Cholesterol 7 alpha hydroxylase (CYP-7A1) is a key enzyme in the bile acid synthesis and it plays an important role in cholesterol catabolism. The aim of the study was to establish the role of A-204-->C polymorphism in CYP-7A1 gene in plasma lipid determination in children. METHODS AND RESULTS: Using PCR and restriction analysis (BsaI) we have measured A-204-->C polymorphism in CYP-7A1 gene in two groups of children selected from opposite ends of the cholesterol distribution curve of 2000 children. Eighty-two children in high- (HCG) and eighty-six children in low- (LCG) cholesterolemic groups participated in the study. No significant difference was found in the frequencies of the genotypes or alleles of the A-204-->C polymorphism in the CYP-7A1 gene between HCG and LCG. In HCG, C/C-204 homozygotes have the highest and A/A homozygotes the lowest levels of LDL-cholesterol (4.21 +/- 0.68 mmol/l vers. 3.69 +/- 0.60 mmol/l, p < 0.05). No associations between lipid parameters and genotypes within the LCG group were found. CONCLUSIONS: The A-204-->C polymorphism in the gene for CYP-7A1 is not the major determinant of plasma lipid levels in childhood. Its impact is expressed only on high cholesterol background.

Hubácek JA, Pistulková H, Skodová Z, Lánská V, Poledne R. · Institut klinické a experimentální medicíny, Praha. · Cas Lek Cesk. · Pubmed #11284423 No free full text.

Abstract: BACKGROUND: High plasma lipids are one of the risk factor of atherosclerosis. The contribution of environmental and genetic factors to plasma lipids is roughly equal. Cholesterol ester transfer protein (CETP), lipoprotein lipase (LPL) and apolipoprotein (apo) CIII play an important role in plasma lipid metabolism. The aim of the study was to establish the role of polymorphisms in these genes in plasma lipid determination. METHODS AND RESULTS: Using PCR and restriction analysis we have measured Taq1 polymorphism in CETP, asparagine 291/serine polymorphism in LPL and C3238G polymorphism in apo CIII genes in two groups of children selected from opposite ends of the cholesterol distribution curve of 2000 children. 82 children in high- (HCG) and 86 in low- (LCG) cholesterol group participated in the study. No significant difference was found in the frequencies of the CETP and apo CIII genotypes between LCG and HCG. In the LCG, significantly more carriers (p < 0.05) of the LPL serine291 allele were found. CONCLUSIONS: Common polymorphisms in the CETP and apo CIII genes do not determine the plasma lipid levels in childhood. The carriers of the rare allele in the LPL gene could be genetically predisposed to low plasma lipid levels.

Szitányi P, Hanzlová J, Poledne R. · Institute for Clinical and Experimental Medicine, Cardiac Centre, Laboratory for Atherosclerosis Research, Charles University, Prague, Czech Republic. · Physiol Res. · Pubmed #11252539 links to  free full text

Abstract: A low birth weight is a new risk factor for the development of premature atherosclerosis. The effect of intrauterine undernutrition on hypercholesterolemia in later life was studied in an experimental model using the Prague Hereditary Hypercholesterolemic (PHHC) rat. Compared to animals in the control group (Wistar rats), animals with an increased sensitivity to high-cholesterol diet (PHHC rats) display hypercholesterolemia. Only in PHHC animals, individuals undernourished in their intrauterine life (hypotrophic group, HG) had a significantly higher total cholesterol, compared with individuals without food restriction in pregnancy (eutrophic group, EG). Restricted food intake in pregnancy led to smaller nests and a decreased number of pups in each litter. We found no significant diferences in birth weight between HG and EG. In spite of similar birth weights in PHHC and Wistar rats, intrauterine undernutrition caused an increase in cholesterolemia in the HG group of the PHHC rats. The effect of intrauterine undernutrition on the development of hypercholesterolemia will most likely play a role in individuals with geneticaly determined increased susceptibility to a high-cholesterol diet. The use of this model of intrauterine undernutrition for the study of hypercholesterolemia has proved to be feasible.

Hubácek JA, Pitha J, Stávek P, Schmitz G, Poledne R. · Laboratory of Atherosclerosis Research, Institute for Clinical and Experimental Medicine, Prague, Czech Republic. · Physiol Res. · Pubmed #11043917 links to  free full text

Abstract: In the process of population screening for apo E gene polymorphism with the PCR and subsequent restriction analysis, we identified a female who demonstrated heterozygosity for an unusual restriction fragment caused by the loss of a CfoI restriction site. Sequence analysis of the apo E gene was performed and a carrier of the mutant allele with C --> T substitution at cDNA position 3817 was identified, which caused an Arg136 --> Cys change. The first-line relatives have been screened for this rare mutation with PCR and restriction analysis of PCR products. The complete lipoprotein parameters have been determined in the probands family. In the family, only one child had the same mutant allele as his mother had. The proband (7.49 mmol/l) with her siblings had hypercholesterolemia and a high body mass index (BMI 31.6 kg/m2). By contrast, her son had a normal lipid spectrum with normal BMI. We described the mutation apo E2* (Arg136 --> Cys) in a family with elevated lipid levels, but there was no confirmation of the connection between this mutation and type III hyperlipoproteinemia or hyperlipoproteinemia at all. In the case of this mutation, other factors (mainly genetic) are important for the development of lipid metabolism disorders.

Vrablík M, Horínek A, Ceska R, Poledne R, Hubácek M. · III. interní klinika 1. LF UK a VFN, Praha. · Cas Lek Cesk. · Pubmed #10566225 No free full text.

Abstract: BACKGROUND: Apolipoprotein E is a polymorphic protein playing a crucial role in the metabolism of plasma lipoproteins. Three alleles referred to as epsilon 2, epsilon 3 and epsilon 4 code for three common isoforms of apoE. The most frequent allele in the population at large is epsilon 3 allele. epsilon 2 and epsilon 4 alleles are connected with lipoprotein disorders as well as with other diseases. The aim of our study was to establish frequencies of apoE coding alleles in patients with different types of hyperlipidaemia (HLP) and to reveal differences in their distribution in comparison with the general population. METHODS AND RESULTS: Therefore apoE genotype was assayed in 752 patients with primary HLP and 291 subjects randomly selected from the general Czech population. Allele frequencies were determined separately in a group of patients with familial hypercholesterolaemia (FH), polygenic hypercholesterolaemia (PHC), familial combined hyperlipidaemia (FCH) and in patients with type III. hyperlipidaemia (III). In patients with HLP a significantly higher frequency of epsilon 4 allele than in control subjects was found. In the group of FH patients frequency of the epsilon 2 allele was higher than in control subjects. In patients with PHC a significantly higher frequency of the epsilon 4 allele and lower frequency of the epsilon 2 allele were observed. In the group of FCH patients distribution of epsilon alleles did not differ from the control group. Frequency of the epsilon 2 allele in patients with type III. hyperlipidaemia was significantly higher than in controls. CONCLUSIONS: We conclude that there exist significant differences in frequencies of apoE coding alleles between patients with primary hyperlipidaemia and a randomly selected population sample. The revealed differences in allelic distribution suggest that the impact of apoE polymorphism is not uniform in all types of hyperlipidaemia.

Hubacek JA, Pistulková H, Valenta Z, Poledne R. · Institute of Clinical and Experimental Medicine, Prague, Czech Republic. · Vasa. · Pubmed #10483321 No free full text.

Abstract: BACKGROUND: Hypercholesterolaemia is one of the main risk factors of atherosclerosis. Both environmental and genetic factors have been implicated in the development of hypercholesterolaemia. The enzyme hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase plays an important role in cholesterol synthesis. Thus we supposed that polymorphisms in this gene could influence cholesterolaemia. PATIENTS AND METHODS: Using PCR, we measured the (TTA)n repeat polymorphism near the Alu sequence of the gene for HMG-CoA reductase in two groups of children selected from opposite ends of the cholesterolaemia distribution curve obtained from measuring cholesterolaemia in 2000 children. Eighty-two children in high- and eighty-six children in low-cholesterolaemic groups participated on the study. RESULTS: A significant difference was found in the frequencies of the genotypes of the 10+ add alleles (43.9% in high-cholesterolaemic children vs 24.4% in low-cholesterolaemic children p < 0.025). No differences were demonstrated in the frequencies of other genotypes (allele 10+ even and without allele 10). No associations between lipid parameters and genotypes or genotype subgroups within the group of high- and low-cholesterolaemic children were found. CONCLUSION: The (TTA)n repeat polymorphism in the gene for HMG-CoA reductase could be another genetic marker that plays a role in the genetic determination of cholesterolaemia.