[Familial hyperlipoproteinemias--correlations between phenotypes and genotypes]. / Familiární hyperlipoproteinémie--korelace nálezu ve fenotypu s genotypem.

Within the grant project patients with familial hyperlipoproteinaemias have been examined. The examination was performed in the oldest lipid clinic and research laboratory in the world. The classification of lipid metabolism disorders was based upon a detailed biochemical analysis of plasma lipids including electrophoresis and assessment of apolipoprotein levels. Then optimal treatment regimen could be established. The project was aimed to evaluate the efficacy of different treatment regimens in different types of hyperlipoproteinaemias. Biochemical parameters and mainly the impact of treatment of hyperlipoproteinaemia on morphology and function of the vessel wall was monitored. The non-invasive ultrasound measurement of the intima thickness of carotid arteries was used. For more precise diagnosis of genetically determined disorders of lipid metabolism a large scale of methods of molecular biology was introduced. These methods enable confirmation of familial hypercholesterolaemia, familial defective apolipoprotein B-100 or studying polymorphism of apolipoprotein E. The effort of the authors of the project was to maximally utilise the results of basic and applied research in formulating recommendations for everyday practice of physicians.

[Genetic predisposition for the multiple metabolic syndrome. Part 4. Apolipoprotein E and lipoprotein (a)]. / Genetická predispozice pro mnohocetný metabolický syndrom. 4. cast. Apolipoprotein E a lipoprotein (a).

Apolipoprotein E (apo E) is a genetically polymorphous glykoprotein made up of 299 amino acids. It is an important part of triacylglycerol rich lipoproteins [chylomicrons, lipoproteins with a very low density (VLDL) and their "residues"]. Apo E is a ligand of apo B, E receptors and thus regulates in a marked way the homeostasis of lipids and lipoproteins in plasma. The genetic polymorphism of apo E is controlled by three alleles epsilon 2, epsilon 3, epsilon 4 which influence individual plasma cholesterol levels and thus the process of atherogenesis. Lipoprotein (a) [Lp(a)] is a plasma lipoprotein which is another independent, genetically determined risk factor in the process of atherogenesis. The basis of its structure is a micelle of LDL which is linked by a disulphidic covalent with the glycoprotein of the apolipoprotein (a). Lp (a) was detected in atherosclerotic plaques and it is assumed that it participates in the penetration of lipids into the vascular wall. Its thrombogenic properties were also detected due to its structural relationship with plasminogen to which it is linked and inhibits competitively the transformation of plasminogen to plasmin.

[Negative aspects of the Western life style and possibilities of intervention in patients with familial combined hyperlipidemia]. / Negativní aspekty západního zivotního stylu a moznosti intervence u pacientu s familiární kombinovanou hyperlipidémií.

BACKGROUND: Evaluation of the effect of intervention on changes in the lifestyle of patients with combined familial hyperlipidaemia (CFH). METHODS AND RESULTS: The group comprised 154 patients with CFH where changes in the lipid profile, diet, basic anthropometric data and smoking were recorded 3-6 months following intervention. In addition to little willingness to have a check-up examination the authors recorded significant shortcomings in the lifestyle of these patients with a high cardiovascular risk: a large number of smokers (51%), serious shortcomings in the composition of the diet (excessive intake of animal fats a proteins, inadequate intake of vegetable proteins, dietary fibre and vitamins, in particular E and C), overweight and a high percentage of body fat. CONCLUSIONS: While the attention devote to pharmacotherapy with hypolipidaemic agents is justified we should not forget systematic intervention as regards changes in lifestyle. This appeal is even more urgent in conjunction with the low motivation and willingness of patients to change their lifestyle. Special attention should be focused on smokers (in addition to effect on lipids also greater cumulation of risk factors).

[Genetic predisposition in multiple metabolic syndrome. Part 2. Candidate genes in type II diabetes mellitus]. / Genetická predispozice pro mnohocetný metabolický syndrom. 2. cást. Kandidátní geny pro diabetes mellitus II. typu.

The author presents a review on candidate genes of proteins involved in the metabolism of glucose, lipids and other metabolites (glucose carriers, insulin receptors, proinsulin, glucokinase, amyline, glycogen synthase). One of the main causes of enhanced atherogenesis in patients with type II diabetes (NIDDM) are marked genetically conditioned deviations of the lipid, lipoprotein and apolipoprotein metabolism. In the metabolic dyshomeostasis of multiple metabolic syndrome participate in the process of atherogenesis also: isoforms of apolipoprotein E4, isoforms of apolipoprotein A-IV-1/1, hyperuricaemia, raised levels of the plasminogen activator inhibitor 1 (PAI-1), hyperfibrinogenaemia, hyperhomocysteinaemia and other metabolites (cytokines, endothelin etc.). Patients with a greated genetic sensitivity manifest diabetes sooner and more intensely and die at a younger age in particular from cardiovascular disease, but also on account of a higher incidence of tumours diseases.

[Genetic predisposition in multiple metabolic syndrome. Part 3. Metabolism of lipids, lipoproteins and apolipoproteins]. / Genetická predispozice pro mnohocetný metabolický syndrom. 3. cást. Metabolismus lipidu, lipoproteinu a apolipoproteinu.

The author discusses metabolic processes during exogenous and endogenous lipid transport and deviations in the metabolism of lipids, lipoproteins and apolipoproteins in multiple metabolic syndrome and in so-called diabetic dyslipidaemia. Specific phenotypic manifestations of diabetic dyslipidaemia include hypertriacylglycerolaemia, hypercholesterolaemia, elevated plasma levels of LDL-cholesterol and apolipoprotein B and reduced levels of HDL-cholesterol and apolipoprotein B and reduced levels of HDL-cholesterol and apolipoprotein A-I. Other recent findings relating to this syndrome include evidence of elevated concentrations of small and dense LDL micelles (< 25 nm), so-called LDL phenotype B, which are easily modified (e.g. by oxidation, glycation etc.), and subsequent uptake by "scavenger" receptors into macrophages which after filling become foam cells and penetrate into the vascular wall. Elevated levels of small and dense LDL micelles, the accelerating process of atherogenesis, were proved in all multiple metabolic syndrome carriers. The atherogenic lipoprotein phenotype hastens markedly atherogenesis and subsequent manifestation of cardiovascular diseases.

[Genetic predisposition for multiple metabolic syndrome. Part 1. Diabetes mellitus type 2--incidence and prevalence]. / Genetická predispozice pro mnohocetný metabolický syndrom. 1. cást. Diabetes mellitus II. typu--incidence a prevalence.

Multiple metabolic syndrome (MMS) implies a frequent coincidence of four basic serious metabolic risk factors for subsequent manifestation of cardiovascular disease. The latter include: central type obesity, arterial hypertension, dyslipoproteinaemia and diabetes mellitus type II (non-insulin-dependent diabetes mellitus--NIDDM). MMS is also described as syndrome X, Reaven's syndrome, insulin resistance syndrome, metabolic syndrome or as the "deadly quartet". NIDDM in humans is conceived as a syndrome the pathogenesis of which is multifactorial and it is not an unequivocal nosological unit. It many epidemiological studies reliable evidence was provided that in the aetiology of NIDDM a marked genetic influence is involved. Its genetic predisposition is conditioned by the interaction of candidate genes and a complex of influences of the external environment. Evidence was provided that MMS phenotypes cumulate only in members of some families. The mode of genetic transmission of NIDDM remains obscure.

The effect of four-year hypolipidaemic treatment on the intimal thickness of the common carotid artery in patients with familiar hyperlipidaemia.

BACKGROUND: Cholesterol lowering in patients with above-average cholesterol levels has been shown to reduce the progression of atherosclerosis. We assess the effects of lipid lowering therapy on the progression of early, preintrusive carotid arterial atherosclerosis in high risk patients with familial hyperlipidaemia free of symptomatic cardiovascular disease. METHODS: Fifty-two patients with familial hyperlipidaemia by were treated by diet and various hypolipidaemic drugs. Eighteen individuals were not taking hypolipidaemic drugs. In a prospective study by B-mode ultrasound we assessed the intima-media thickness of the distal common carotid arterial (CCA) far wall at baseline and after 4 years. RESULTS: In a subgroup of 25 patients with familial hypercholesterolaemia there was a significant decrease in total and LDL cholesterol and reduction in the intima-media thickness (IMT) of the common carotid artery from 0.78+/-0.22 mm to 0.69+/-0.17 mm (p=0.004). In a subgroup of 27 patients with familial combined hyperlipidaemia significant decreases in total and LDL cholesterol and triglycerides were associated with a decrease in the IMT of common carotid. artery from 0.72+/-0.22 mm to 0.67+/-0.15 mm (p=0.044). In 18 individuals, who were not taking hypolipidaemic drugs, there were no significant changes in the levels of cholesterol and triglycerides and in the IMT of the common carotid artery (increase from 0.58+/-0.18 mm to 0.62+/-0.13 mm, p>0.05). CONCLUSIONS: Lipid-lowering therapy in patients with familial hyperlipidaemia free of symptomatic cardiovascular disease reverses the progression of early, preintrusive atherosclerosis of the carotid artery. It is a beneficial sign indicating the possibility for atherosclerosis regression.

[Screening and treatment of children and adolescents with hypercholesterolemias and dyslipidemias]. / Vyhledávání a lécení detí a mladistvých s hypercholesterolémií a s dyslipidémií.

Evidence was provided that atherogenesis develops for several decades before pathological changes are manifested. It may thus be stated, that the "incubation period" of atherosclerotic pathological consequences is very long but it is reduced markedly already from childhood and adolescence in subjects with an atherogenic lipoprotein phenotype. Atherogenic lipoprotein phenotype comprises subjects suffering from one or more, frequently from a combination of several of the following metabolic indicators: hypercholesterolaemia, elevated levels of LDL-cholesterol, apolipoprotein B, lipoprotein (a), reduced levels of HDL-cholesterol and apolipoprotein A-1. The atherogenic lipoprotein phenotype is in 95% conditioned by inborn metabolic errors, i.e. familial hyperlipoproteinaemia and dyslipoproteinaemia. In the population the following are encountered most frequently: combined familial hyperlipidaemia, familial hypertriacylglycerolaemia and familial hypercholesterolaemia. Active screening and treatment of children and adolescents from these affected families is of great importance in primary prevention of atherosclerotic complications in adult age.

Decreasing common carotid artery intimal thickness during hypolipidemic therapy.

It has been demonstrated in recent years that ultrasound can be used to measure common carotid artery intimal thickness; an increase in intimal thickness is regarded as an early stage of atherosclerosis. This study was designed to establish whether or not intimal thickness can be modulated by therapy. Twenty-nine patients with familial hyperlipoproteinemias had follow-up ultrasound of the common carotid artery after twenty-nine months of comprehensive therapy. In 21 patients with familial hypercholesterolemia, intimal thickness decreased from 0.83 to 0.68 mm (P < 0.01), in 9 with familial combined hyperlipoproteinemia, the decrease was from 0.77 to 0.74 mm (a decrease was seen in only 50% of patients). With the group taken as a whole, the larger decrease was observed in patients treated with statins while the reduction was less marked in those administered fibrates. The authors found a decrease in common carotid artery intimal thickness following hypolipidemic therapy in patients with hyperlipoproteinemias. Their impression is that this was a manifestation of atherosclerosis regression.

[Favorable effect of treatment with statins on the intima of the common carotid artery in patients with familial hyperlipoproteinemia]. / Príznivý vliv lécby statiny na intimu arteria carotis communis u nemocných s familiárními hyperlipoproteinémiemi.

BACKGROUND: In recent years evidence was provided that by measuring the width of the intima of the carotid artery, evaluated by sonography, it is possible to assess the development of arteriosclerosis. The authors used this method to evaluate hypolipidaemic treatment. METHODS AND RESULTS: The authors followed-up by clinical and laboratory methods and treated for a period of 47 months 63 patients with familial hyperlipoproteinaemia. At the beginning and at the end of the follow-up period they made sonographic examinations of the common carotid artery. In 31 patients treated by statins they observed statistically significant changes: cholesterol declined by 23%, LDL cholesterol by 25.3%. The maximal rate in the common carotid artery (ACC) declined from 93 +/- 22 to 73 +/- 13 cm/s. The diameters of the ACC increased from 6.0 +/- 0.8 to 6.5 +/- 0.8 mm. The intima of the ACC diminished from 0.84 +/- 0.26 to 0.75 +/- 0.20 mm. In 22 patients treated with fibrates the anticipated lipid changes occurred. The diameter of ACC did not change, the decline in the width of the intima of the ACC was not statistically significant. In 10 patients who decided that they wanted only dietary treatment the changes in the investigated parameters were small. CONCLUSIONS: In patients with familial hyperlipidaemia who were treated with statins for almost four years the authors observed a diminution of the width of the intima of the common carotid artery which is considered a sign of regressing atherosclerosis.

[Patients with familial combined hyperlipidemia and smoking]. / Pacienti s familiární kombinovanou hyperlipidémií a kourení.

BACKGROUND: Evaluation of the negative impact of active smoking on lipid and lipoprotein serum levels and the relationship with body mass index (BMI) and waist/hip ratio (WHR). METHODS AND RESULTS: The group was formed by 178 (77 men and 101 women), mean age 54 years (SD 6.2 attending the lipid out-patient department at the Third Medical Clinic, First Medical Faculty, Charles University Prague. Attention was paid to whether the patients were treated with hypolipidaemic agents or not. A statistically significant difference (p < 0.05) was found between smokers and non-smokers as regards total cholesterol (mean values and SD) in the group of 80 treated women (smokers 7.84 mmol/l, SD 1.21). Significantly higher values of LDL cholesterol in smokers as compared with non-smokers (6.00 mmol/l SD 2.08 vs. 4.8 mmol/l, SD 1.26) were recorded in the group of treated women. Other results were also to the disadvantage of smokers (with the exception of non-treated women), though the difference was not statistically significant: non-treated female smokers had a higher LDL cholesterol (4.24 mmol/l, SD 1.42) as compared with non-treated non-smokers (5.3 mmol/1, SD 0.60). In treated men the LDL cholesterol value in smokers (5.20 mmol/l SD 1.20) were also higher than in non-smokers (4.54, SD, 1.15). Triacylglycerols in women (smokers vs. non-smokers): in the group of treated women 3.11 mmol/l, SD 4.86 vs 1.94 mmol/l SD 1.08, in the group of non-treated women 3.74 mmol/l, SD 4.77 vs. 1.94 mmol/l, SD 0.74. Triacyglycerols in men (smokers vs. non-smokers): in the treated men 3.87 mmol/l SD 3.54 vs. 2.62 mmol/l, SD 1.63, in the non-treated men 10.62 mmol/l, SD 9.86 vs. 2.86 mmol/l, SD 1.63. HDL-cholesterol in women (smokers vs. non-smokers): in the treated group 1.24 mmol/l SD 0.46 vs. 1.39 mmol/l, SD 0.35, in the group of non-treated men 1.54 mmol/l, SD 0.37, vs. 2.86 mmol/l, SD 1.64. HDL cholesterol in men (smokers vs. non-smokers): in the treated group 1.15 mmol/l, SD 0.30 vs. 1.27 mmol/l, SD 0.31, in the non-treated group 1.09 mmol/l, SD 0.40 vs. 1.15 mmol, SD 0.28. In female smokers treated and non treated and in non-treated male smokers the WHR values were higher, in treated smokers lower despite the surprisingly higher BMI. CONCLUSION: Active smoking has an adverse impact on serum lipid and lipoprotein levels in patients with familial combined hyperlipidaemia.

[Familial hypobetalipoproteinemia]. / Familiární hypobetalipoproteinémie.

BACKGROUND: Familial hypobetalipoproteinaemia (FHBL) is a relatively rare inborn error of metabolism which must be considered in the differential diagnosis of hypocholesterolaemia which cannot be explained by secondary causes (severe malnutrition, generalization of neoplastic disease etc.). METHODS AND RESULTS: In the submitted paper the authors present the results assembled in a family with four heterozygotes with FHBL. The proband is a 27-year-old woman (total cholesterol (TCh) 1.70, triacylglycerols (TG) 0.20, HDL-cholesterol (HDL-ch.) 1.38, LDL-cholesterol (LDL-ch.) 0.34 all in mmol/l, apolipoprotein B (apo B) 0.25, lipoprotein(a)(Lp(a) 0.09 all in g/l, isoforms of apolipoprotein E/E3 (iso apo E). Mother (age 53 years) of the proband (TCh 3.06, TG 0.37, HDL-ch. 1.99, LDL-ch. 0.90 all in mmol/l, Apo B 0.37, Lp(a) 0.14 all in g/l, iso apo E3/E3)). Two of the proband's sisters (23 and 20 years) (TCh 3.92 and 2.55 resp., TG 0.57 and 0.23 resp. HDL-ch. 1.86 and 1.63 resp., LDL-ch. 1.80 and 0.82 resp. all in mmol/l, Apo B 0.73 and 0.37 resp., Lp(a) 0.47 and 0.63 resp. all in g/l, iso apo E2/E3 and E2/E3 resp.). The diagnosis confirms the autosomal dominant transmission. During the proband's pregnancy (during the 38th week), contrary to normocholesterolaemic women the TCh did not rise (1.43 mmol/l, the TG level (0.62 mmol/l), Apo B (0.43 and Lp(a) 0.18 all in g/l rose. CONCLUSIONS: According to the available literature this is the first description of FHBL in our literature and a priority investigation of plasma lipid concentrations, lipoproteins and apolipoproteins in a women with a heterozygous form of FHBL during pregnancy.

[The effect of 4 years' of hypolipemic treatment on the width of the common carotid artery intima in patients with familial hyperlipidemias]. / Vliv ctyrleté hypolipidemické lécby na sírku intimy arteria carotis communis u nemocných s familiárními hyperlipidémiemi.

Sixty-four patients with familial hyperlipoproteinaemia were treated for almost four years by dietetic treatment and various hypolipidaemic drugs. In 25 patients with familial hypercholesterolaemia who had clinical signs of ischaemic heart disease total and LDL-cholesterol declined and the width of the intima of the common carotid artery diminished from 0.78 mm to 0.69 mm (p = 0.004). In the above artery the maximal flow rate of blood declined. The increase was, however, not statistically significant. In 12 patients with familial hypercholesterolaemia who suffered from ischaemic heart disease the width of the intima of the common carotid artery and maximum flow rate did not change, however, the diameter of the artery increased (from 6.3 to 6.6 mm, p = 0.034). In 27 patients with familial combined hyperlipidaemia during the drop of cholesterol, LDL-cholesterol and triacylglycerols the width of the intima of the common carotid artery diminished (from 0.72 to 0.67 mm, p = 0.044), the diameter of the artery increased (from 6.1 to 6.4 mm, p = 0.014). The authors assume that the reduction of the width of the intima during hypolipidaemic treatment reflected the decline of cholesterol in the arterial wall and is a favourable sign which indicates possible regression of atherosclerosis.

[The effect of micronized fenofibrate on lipid parameters and fibrinogen in heterozygous familial hypercholesterolemia and familial combined hyperlipidemia]. / Vliv mikronizovaného fenofibrátu na lipidové parametry a fibrinogen u heterozygotu familiární hypercholesterolémie a familiární kombinované hyperlipidémie.

BACKGROUND: The aim of the study was to approve the hypolipidemic potency of the new drug from the group of fibrate derivates Lipanthyl 200 M(R) (micronized fenofibrate, cps a 200 mg, Laboratoires Fournier, France) in patients with familial hyperlipoproteinemias. The drug has been administered in constant dose of 200 mg daily with the evening meal for three months. Clinical examinations and monitoring of safety laboratory have been performed in addition to complete analysis of lipids, lipoproteins and apolipoproteins during the study. METHODS AND RESULTS: The group of 30 patients consisted from 14 heterozygotes of familial hypercholesterolemia and 16 patients affected by familial combined hyperlipidemia. Levels of total, HDL- and LDL-cholesterol, triglycerides, apolipoproteins A-I and B and Lp(a) have been measured and concentrations of fibrinogen in plasma as well. Concentration of total cholesterol 8.29 +/- 1.3 mmol/l on the beginning of the study decreased after one and three months of the treatment to 6.94 +/- 1.19 resp. 6.98 +/- 1.21 mmol/l, concentration of triglycerides has been reduced from 2.86 +/- 1.29 mmol/l to 1.70 +/- 0.86 and 1.74 +/- 0.99 mmol/l respectively HDL-cholesterol raised from 1.14 +/- 0.32 mmol/l to 1.27 +/- 0.36 and to 1.34 +/- 0.37 mmol/l in contrast to decrease of LDL-cholesterol 5.88 +/- 1.53 mmol/l on the beginning of the study to 4.87 +/- 1.49 and 4.79 +/- 1.60. Apo B in plasma fall after three month period of the treatment from 1.83 +/- 0.43 g/l to 1.46 +/- 0.47 g/l. On the other hand the concentration of apolipoprotein apo A-I1.20 +/- 0.35 g/l increased to 1.40 +/- 0.32 g/l. Fibrinogen in plasma was reduced from 3.63 +/- 0.69 g/l to 2.77 +/- 0.50 g/l. Also this decrease was statistically significant. CONCLUSIONS: Micronized fenofibrate is a potent hypolipidemic drug with only rare side effects. It is very good tolerated by the patients. Micronized fenofibrate is particularly prescribed for combined hyperlipidemia, however we can use it also in some patients with familial hypercholesterolemia. For to the treatment very resistant hyperlipoproteinemias we should consider combined drug therapy.

[Hyperhomocysteinemia]. / Hyperhomocysteinémie.

Similarly as in other inborn metabolic diseases the cause of hyperhomocysteinaemia are interactions between genetically conditioned changes most frequently due to reduced cystathionine-beta synthase activities and negative factors of the external environment. Negative environmental factors include above all a high dietary animal protein consumption which is the main methionine donor and a low intake of protein of plant origin. Another negative factor is a low intake of foods of plant origin. Fruits and vegetables are among others important sources of folic acid and pyridoxine. Substitution therapy with vitamin preparations is essential in homozygotes and in high risk heterozygotes of cystathionine beta-synthase. This treatment is also necessary during the periconception period in hyperhomocysteinaemic fertile women to reduce the risk of neurotubal defects in their future children. So far investigations are lacking which would provide evidence of a reduced risk of ischaemic heart disease and other cardiovascular diseases in isolated treatment of mildly elevated levels of plasma homocysteine. To elucidate the part played by hyperhomocysteinaemia in hastening of the atherogenetic process further studies are essential, focused on the interaction of elevated homocysteine plasma levels, dyslipoproteinaemias, hyperfibrinogenaemia and other metabolic indicators in this process.

[Analysis of nutritional habits in patients with familial combined hyperlipidemia]. / Analýza nutricních návyku pacientu s familiární kombinovanou hyperlipidémií.

BACKGROUND: Our objective was to analyze dietary habits of patients with the IIb phenotype of familial combined hyperlipidaemia. These patients were instructed on the proper composition of their diet and they thought that they adhered to these recommendations. METHODS AND RESULTS: The authors examined 41 patients with IIb phenotype of familial combined hyperlipidaemia. Based on their seven-day dietary records their daily intake was calculated and compared with recommended daily allowances as regards energy intake, intake of plant and animal proteins, fats, linoleic acid, carbohydrates, calcium, iron, potassium, fibre, vitamin A, thiamin, pyridoxine, vitamin C, E, cholesterol and NaCl (Progana programme). With the above results the total serum cholesterol, serum triglyceride, HDL and LDL serum cholesterol and nutritional status (body mass index, percentage of body fat and waist hip/ratio) were compared. When the energy intake was acceptable (99% of the recommended allowance), the fat intake was excessive (138%) as well as the intake of animal protein (148%), cholesterol (145%) and NaCl (159% of the recommended allowance), while the intake of plant proteins and fibre and some vitamins was inadequate. A statistically significant relationship was revealed only as regards the linoleic acid intake and total serum cholesterol (inverse relationship at the 95% probability level, r = 0.43), the other investigated relationships were insignificant. The body mass index values (in men and women 26) and the percentage of body fat (22% in men and 34% in women) are above the recommended range. CONCLUSIONS: Dietary errors in the investigated group thus did not pertain, to the quantity of the diet but its composition. From the results ensures that doctors should pay great attention to explaining dietary principles to their patients.