[Assessment of Risk Factors for Atherosclerosis in Individuals of Different Categories of Cardiovascular Risk Using the Aterostop Calculator].

Aim        To analyze first results of using the Aterostop calculator for a comprehensive evaluation of the risk for cardiovascular diseases (CVD).Material and methods        A cross-sectional study analyzed major and additional risk factors in 460 subjects without apparent disease and in patients with documented CVD of atherosclerotic origin using the application (calculator) Aterostop developed in the National Medical Research Center of Cardiology in Moscow, Russia.Results   45.4% of evaluated persons belonged to the categories of very high and extreme risk. Age and frequencies of smoking, arterial hypertension, and diabetes mellitus (DM) increased with the increase in risk; the growth of DM was exponential. 129 (28%) individuals used lipid-lowering medications at the time of study. Their plasma levels of low-density lipoprotein cholesterol (LDL-C) were significantly lower than in those who did not received this treatment. However, achieving the target level was inversely proportional to the risk: the greatest proportion of individuals who reached the LDL-C target was in the category of low risk and the smallest proportion was in the category of extreme risk (75 % vs. 3.7 %, respectively).Conclusion            The results obtained with the calculator Aterostop were consistent with earlier reports of insufficient effectiveness of primary and secondary prevention of atherosclerotic CVDs, which requires more tight and fruitful cooperation of the physician and the patient.

[Giant Aneurysms in Coronary Arteries of a Young Woman].

Coronary arteries aneurysms with their thrombotic occlusion are known to be detected in young patients who have suffered Kawasaki disease in childhood. The other vascular beds are usually not involved. In the literature one can find not enough information regarding diagnostics of this pathology, as well as no specific treatment algorithm. We present here a clinical case of re-emergence of giant aneurysms of coronary arteries in the young female patient with subsequent immuno-histological confirmation of previous Kawasaki disease.

[The effect of ABCA1 rs2230806 common gene variant on plasma lipid levels in patients with dyslipidemia.]

The aim of this work was to assess the relationship of rs2230806 SNP of ABCA1 with lipid profile in patients with severe dyslipidemia. The study included 363 patients (42.8% of males), the average age was 48.7 years, 35.5% of patients received hypolipidemic drugs (mainly statins). Quantitative determination of total cholesterol (ТС) and triglycerides (TG) in fasting serum was carried out by a unified enzymatic method, and high density lipoproteins (HDL) - by a direct homogeneous method. Genotype according to the rs2230806 position in the ABCA1 gene was determined by polymerase chain reaction (PCR) «in real time¼ using adjacent samples and melting reaction products after PCR. The frequencies of alleles and genotypes of variant rs2230806 of ABCA1 gene in patients with dyslipidemia did not differ from those in the control group of healthy individuals (athletes). The levels of plasma lipids - TC, TG and HDL cholesterol, on average, in patients with dyslipidemia were 7.8±3,4, 3,4±6,5 and 1.29±0.4 mmol/l, respectively. Compared to different genotypes, the plasma lipid concentrations did not differ significantly, but the analysis of different inheritance models of the allelic variant studied showed a significant association with the level of TG in the additive model, in which each minor allele (a) further enhanced the effect on the level of plasma TG at 1.02 mmol/l (p=0.044). The results of this study demonstrate the effect of a common variant rs2230806 of the ABCA1 gene on the plasma TG level in patients with severe dyslipidemia.

[Mass spectrometry analysis of blood plasma lipidome as method of disease diagnostics, evuation of effectiveness and optimization of drug therapy].

A new method for the analysis of blood lipid based on direct mass spectrometry of lipophilic low molecular weight fraction of blood plasma has been considered. Such technique allows quantification of hundreds of various types of lipids and this changes existing concepts on diagnostics of lipid disorders and related diseases. The versatility and quickness of the method significantly simplify its wide use. This method is applicable for diagnostics of atherosclerosis, diabetes, cancer and other diseases. Detalization of plasma lipid composition at the molecular level by means of mass spectrometry allows to assess the effectiveness of therapy and to optimize the drug treatment of cardiovascular diseases by phospholipid preparations.

[THE EFFECT OF SATINS: ACTIVATION OF LIPOLYSIS AND ABSORPTION BY INSULIN-DEPENDED CELLS LIPOPROTEINS OF VERY LOW DENSITY, INCREASING OF BIO-AVAILABILITY OF POLYENOIC FATTY ACIDS AND DECREASING OF CHOLESTEROL OF LIPOPROTEINS OF LOW DENSITY].

The Russian cardiologic R&D production complex of Minzdrav of Russia, 121552 Moscow, Russia The statins are synthetic xenobiotics alien to animal cells. They are unlikely capable to manifest pleiotropic effect. It is feasible to evaluate effect of statins by stages: a) initially a specific inhibition of synthesis of cholesterol alcohol; b) further indirect activation of hydrolysis of triglycerides in lipoproteins of very low density; c) nonspecific activation of cells' receptor absorption of palmitic and oleic lipoproteins of very low density and then d) linoleic and linolenic lipoproteins of low density with all polyenoic fatty acids. On balance, statins activate absorption ofpolyenoic fatty acids by cells. Just they manifest physiological, specific pleiotropic effect. The statins inhibit synthesis of pool of cholesterol alcohol-lipoproteins of very low density condensed between phosphatidylcholines in polar mono-layer phosphatidylcholines+cholesterol alcohol on surface oftriglycerides. The low permeability of mono-layer separates substrate-triglycerides in lipoproteins of very low density and post-heparin lipoprotein lipase in hydrophilic blood plasma. The higher is ratio cholesterol alcohol/phosphatidylcholines in mono-layer of lipoproteins of very low density the slower is lipolysis, formation of ligand lipoproteins of very low density and their absorption by cells under apoB-100-endocytosis. The statins normalize hyperlipemia by force of a) activation of absorption oflipoproteins of very low density by insulin-depended cells and b) activation of absorption of lipoproteins of low density by all cells, increasing of bio-availability of polyenoic fatty acids, activation of apoB-100-endocytosis. The limitation in food of content of palmitic saturated fatty acid and increasing of content of ω-3 polyenoic fatty acids improve "bio-availability" of polyenoic fatty acids and their absorption by cells and also decreases cholesterol alcohol/phosphatidylcholines and biological pleiotropic effect of essential polyenoic fatty acids. According our opinion, atherosclerosis is intracellular deficiency of polyenoic fatty acids. The value of cholesterol alcohol-lipoproteins of low density is equimolar to content of lipoproteins of low density in blood which under low bio-availability can't to absorb cells byforce of apoB-100-endocytosis.

[The unity of pathogenesis of insulin resistance syndrome and non-alcoholic fatty disease of liver. The metabolic disorder of fatty acids and triglycerides].

The pathogenesis of non-alcoholic fatty disease of liver (steatosis) is still as unclear as a loss of hepatocytes similar to apoptosis, development of biological reaction of inflammation, its transformation into steatohepatitis with subsequent fibrosis and formation of atrophic cirrhosis. The article suggests that steatosis is developed due to higher concentration of palmitic saturated fatty acid (C 16:0) in food, intensification of its endogenic synthesis from food carbohydrates and glucose and development of insulin resistance. It is displayed in in hormone ability to activate both oxidation in cells of glucose and synthesis of oleic monoene fatty acid from palmitic saturated fatty acid (C 18:1). The insulin resistance initiates pathologic process on the level of paracrine associations of cells resulting in permanent increase of concentration of non-etherified fatty acids in intercellular medium and intensification of their passive absorption by cells. The phylogenetically ancient mitochondrions will not to oxidize glucose until non-etherified fatty acids are present in cytosol and hence there is an opportunity to oxidize them. To eliminate undesirable action of polar saturated palmitic fatty acid, the cells etherify it by spirit glyceride into triglycerides to deposit in cytosol or to secrete into blood in a form of lipoproteins of very low density. Under insulin resistance, saturated palmitic fatty acid synthesized by hepatocytes from glucose, does not further transform into oleic monoenic fatty acid. The cells are to etherify endogenic (exogenic) palmnitic saturated fatty acid into composition of aphysiologic palmitic triglycerides (saturated palmitic fatty acid in position sn-2 of spirit glyceride). At that, triglycerides of palmitat-palmitat-oleat and even tripalmitat type are formed. The melting temperature of tripalmitat is 48 degrees C and melting temperature of physiologic trioletat is 13 degrees C. The intracellular lipases factually can't hydrolyze palmitic triglycerides. So, hepatocytes, overloaded by them, are destroyed in a way similar to apoptosis. The formed corpuscles of apoptosis disorder the biologic function of endoecology and trigger biologic reaction of inflammation. At that, steatosis changes into steato-hepatitis. The prevention of steatosis consists in dramatic restriction of concentration of palmitic saturated fatty acid in food. The treatment effect is targeted to: decreasing the formation of palmitine triglycerides by force of concurrent etherification of palmitic saturated fatty acid not into triglycerides but into phosphatidylcholine (symmetric phospholipids of soya); intensification of oxidation of palmitic saturated fatty acid in peroxisomes (glytazones and fibrates); decrease of insulin resistance (binuanide metformine).

[Clinical and laboratory detection of phenotypic characteristics in patients with high hypertriglyceridemia].

The purpose of the study was to define the values of clinical and biochemical (phenotypic) differences in 2 groups of patients: 1) those with moderate (< or =4.5 mmol/l) blood triglyceride (TG) levels and 2) those with high (more than 4.5 mmol/l) blood TG levels and to reveal significant parameters of a diagnostic algorithm for primary and secondary forms of hypertriglyceridemia (HTG). Ninety-six (54%) patients females) with a TG level of more than 2.3 mmol/l were examined. The age was 12 to 71 years (median [quartiles] 50 years [41-61 years]); women accounted for 54%. The patients had the following diseases: coronary heart disease (CHD) (44.89%), myocardial infarction (13.5%), arterial hypertension (87.9%). The diagnosis of HTG included an algorithm for the clinical, biochemical, and clinicogenealogical examination of patients. Biochemical blood analysis involved lipoprotein parameters: cholesterol, triglycerides, low-density lipoprotein cholesterol, lipid electrophoresis, apolipoproteins Al, B-100, E, and C-III. The data were processed using the statistical packages STATISTICA 6.0 and SPSS 17.0. Comparison revealed no age- and gender-related differences in the parameters between Groups 1 and 2 There was a significant correlation between the high levels of TG and the following indicators: total cholesterol, chylomicrones, lipoprotein(a), LP-E , LP B:E, LP C-III4, and LP C-III, smoking (a risk factor) and with the indicators of other metabolic disturbances--total C, chylomicrones, lipoprotein(a), LP-E-total, LP B:E, LP-C3-total, and LP-C3, which determined the impact of nutrition had a hereditary predisposition through the polygenic mechanisms of gene expression under the influence of a number of factors. Pancreatitis was found to be implicated in the development of HTG. Higher TG levels correlated with the parameters, the diagnosis of which reveals additional metabolic disturbances via environmental and polygenic mechanisms

[Effect of polymorphisms of cytochrome P450 and apolipoprotein E genes on therapeutic efficacy of statins].

Statins are widely used in clinical practice for lowering of levels of atherogenic blood plasma lipids and treatment of atherosclerosis. Variability of response of the body to these drugs might be determined by genetic factors (gene polymorphisms) related to metabolism of drugs. Among them central place belongs to enzymes of subfamily 3A of cytochrome P450 (CYP). In this review we present results of studies assessing effect of various allele variants of CYP3A4 and CYP3A5 on efficacy and tolerability of atorvastatin, lovastatin,, and simvastatin in different populations of patients. We also present data on populational frequency of genetic polymorphisms under study. In addition we cover the problem of possible influence of apoE genotype on efficacy of statins. The available data do not allow yet to recommend pharmacogenetic testing for wide clinical practice.

[Diagnostics of moderate and high hypertriglyceridemia in patients in polyclinic practice: primary and secondary lipid metabolic disorders].

AIM: To define clinical and biochemical differences in groups of patients with moderate (< or =4.5 mmol/l and high (more than 4.5 mmol/l) blood triglyceride (TG) levels. To define the markers of biochemical and lipid parameters that could specify an algorithm for the differential diagnosis and treatment of different forms of hypertriglyceridemia. SUBJECTS AND METHODS: Patients (96 (54%) females) aged 12 to 71 years (median 50 years; quartiles, 41-61 years) with a TG level of more than 23 mmol/l and the following diseases: coronary heart disease (CHD) (44.8%), myocardial infarction (13.5%), arterial hypertension (87.9%), xanthomas (36.5%), and a family history of diseases (51%). The diagnosis of hyperlipidemia included a classical algorithm for clinical, biochemical, and clinicogenealogical examinations. Extended biochemical blood analysis, the determination of lipoprotein cholesterol (C), TG, low-density lipoprotein C, lipid electrophoresis, and assay of apolipoproteins A1, B-100, E, and C3 were made. RESULTS: The groups with moderate (< or =4.5 mmol/l and high (more than 4.5 mmol/l) blood triglycerides showed no differences in age and gender, systolic and diastolic blood pressures, the incidence of coronary heart disease, arterial hypertension, peripheral artery atherosclerosis, cardiac arrhythmias, and xanthomas. There was a significant correlation of high TG levels with smoking (a risk factor) and with the indicators of other metabolic disturbances--total C, chylomicrones, lipoprotein(a), LP-E-total, LP B:E, LP-C3-total, and LP-C3, which determined the impact of nutrition (and the development of pancreatitis), but also had a hereditary predisposition through the polygenic mechanisms of gene expression under the influence of a number of factors. CONCLUSION: Higher TG levels correlated with the parameters, the diagnosis of which makes it possible to reveal additional metabolic disturbances via environmental and polygenic mechanisms.

[Familial hypercholesterolemia in Russia: genetic and phenotypic characteristics].

AIM: To make qualitative and quantitative analyses of phenotypical characteristics and to study a spectrum and frequency of mutations in LDLR and APOB genes in patients with familial heterozygous hypercholesterolemia (FHHC). MATERIAL AND METHODS: Clinical symptoms of FHHC were studied in males and females. Mutations were detected with PCR, analysis of SSCP of all the exones of LDLR gene and a fragment of exone 26 of APOB gene with subsequent sequestration of DNA fragments with anomalous electrophoretic motility, analysis of restriction fragments length polymorphism. RESULTS: LDLR gene mutations were detected in 50%, of APOB gene in 2.6% patients with FHHC, 70% of LDLR gene mutations have never been discovered before. Three known mutations were detected in the APOB gene: R3500Q (1.9% cases), H3543Y (0.55%), R3531C (0.15%). Incidence of coronary heart disease in untreated FHHC patients is 61.5%, of myocardial infarction--31%. Life span of both males and females with FHHC was subnormal, especially of men (median: 53 years in 95% CI, 49.2-56.8 years and 62 years in 95% CI 59.2-64.8 years, respectively). Incidence rate of basic clinical symptoms increased with age and significantly correlated with LDLP cholesterol. CONCLUSION: Frequency and severity of clinical symptoms and complications in FHHC and in Russian population agree with those of the European countries. The same occurs with frequency and mutations of the APOB gene, while mutations of the LDLR gene in 70% cases are unique for Russian population and are not described in other countries. This makes impossible to use foreign test kits for FHHC diagnosis in Russia.

[Treatment of patients with hypertriglyceridemia].

AIM: To assess a hypolipidemic effect and tolerance of phenofibrate (lipantil 200M) in different variants of treatment in patients with combined hyperlipidemia having moderate and high levels of triglycerides (TG). MATERIAL AND METHODS: A total of 26 patients (16 males, 10 females; age 32-67, mean age 55.1 years) received lipantil 200M (phenofibrate) in a dose 200 mg for 12 weeks either as monotherapy or in combination with statins (or fibrate) or plasmapheresis. Clinical, biochemical and blood lipid parameters were studied at baseline and after 12-week treatment. Baseline mean value and standard deviation of a blood cholesterol level was 8.3 (15.4) mmol/l, TG--7.2 (70.5) mmol/l). RESULTS: A mean cholesterol level decreased by 26.1%, TG--by 64.4%. Correlation with initial values was found. Systolic and diastolic blood pressure diminished significantly. No significant changes were found in the levels of AST, ALT, GGT, CPK, alkaline phosphotase, total bilirubin, creatinine. Before the treatment blood glucose was elevated in 14 patients, after 12-week therapy it remained elevated in 10 patients. CONCLUSION: Lipantil 200M (phenofibrate) had a good hypolipidemic effect in patients with combined hyperlipidemia in different baseline levels of cholesterol and TG elevation and in different variants of treatment. Significant side effects were not registered.

[Phenotypical features of a heterozygous form of familial hypercholesterolemia].

AIM: To conduct a quantitative and qualitative analysis of phenotypical manifestations in patients with a heterozygous form of familial hypercholesterolemia (FHC) and to reveal factors involved in their development. MATERIAL AND METHODS: A total of 247 patients with a clinical diagnosis of heterozygous FHC participated in the trial. Clinical manifestations of the disease in men and women were analysed and compared. Blood lipids were compared to those in the controls. A correlation analysis was used to reveal correlations between symptoms of the disease and lipid levels in the blood. RESULTS: Tendon xanthomas were most frequent (79%) clinical sign with location primarily in Achilles' tendon. Incidence of basic clinical manifestations increased with age and significantly correlated with LDLP cholesterol. Two clinical signs were seen in 1/3 of the patients, three--in 13% (sex differences were insignificant). Mean levels of total cholesterol and LDLP serum cholesterol in heterozygous patients were 1.9 and 2.5 times higher than in the controls. Total cholesterol was significantly higher in women. A mean level of HDLP cholesterol was significantly lower while triglycerides were higher than in the control group. The disease symptoms manifested in men 5 years earlier than in women, FHC was diagnosed in men 7.5 years earlier. CONCLUSION: Patients with heterozygous FHC are characterized by higher levels of LDLP cholesterol, lower level of HDLP cholesterol and higher triglycerides in the serum than in healthy controls. Sex-related differences by severity and prevalence of basic symptoms in heterozygous FHC patients were not found. The time of clinical symptoms appearance and diagnosis evidences for more rapid progression of the disease in men.

[Genetic factors of risk of ischemic heart disease development in patients with familial hypercholesterolemia].

UNLABELLED: Ischemic heart disease (IHD) develops in patients with familial hypercholesterolemia (FHC) 15-20 years earlier than in general population. However age of onset of the disease, its clinical manifestations are variable and not completely determined by cholesterol level and class of low density lipoprotein receptor mutations. AIM: To elucidate associations of some auxiliary genetic factors -- such as C151565T, C677T, R353Q polymorphisms of glycoprotein IIIa (GPIIIa), methylenetetrahydrofolate reductase (MTHFR) and coagulation factor VII genes, respectively, -- with the presence of IHD in patients with FHC. MATERIAL: Patients with clinical diagnosis of heterozygous FHC (n=198) with (n=106) and without (n=92) IHD. RESULTS: Patients with compared with those without IHD had similar frequency of T-allele of MTHFR gene (p=0.519), more often had T-allele of GPIIIa gene (23 and 12.5%, respectively, p=0.009), and less often -- Q-allele of factor VII gene (13 and 21%, respectively, p=0.048). Multifactorial analysis showed that risk of IHD was higher in patients with TT compared with CC genotype of the GPIIIa gene (OR 1.53, 95%CI 1.12-2.3), and lower in patients with RQ and QQ compared with RR genotype of factor VII gene (OR 0.41, 95%CI 0.19-0.75). CONCLUSION: In patients with FHC polymorphisms in factor VII and GPIIIa genes but not C677T polymorphism of MTHFR gene were associated with the presence of IHD.

[Low density lipoprotein receptor gene mutations in patients with clinical diagnosis of familial hypercholesterolemia.]. / Mutatsii gena retseptora lipoproteinov nizkoi plotnosti u patsientov s klinicheskim diagnozom semeinoi giperkholesterinemii.

UNLABELLED: Low density lipoprotein receptor (LDLR) gene mutations cause familial hypercholesterolemia which is associated with elevated risk of ischemic heart disease. AIM: To define LDLR gene mutations in unrelated patients with heterozygous familial hypercholesterolemia in Russia. METHODS: PCR- single-strand conformation polymorphism analysis, automated DNA sequencing, and test for the presence of the apolipoprotein (apo) B-3500 mutation known to induce hereditary defect in apo-B-100. RESULTS: We found 6 novel mutations of LDLR gene designated E8X, 230insG, 671_679dupGACAAATCT, W422R, D461Y, and V698L. We also identified three missense mutations - C139G, E207K and R395W, which were previously described in FH patients from western populations. None of the studied persons had apo-B-3500 mutation. CONCLUSION: These findings broaden knowledge on mutations responsible for development of familial hypercholesterolemia and confirm molecular heterogeneity of this disease in Russia.

[Multiple molecular-genetic defects in a woman with mixed hyperlipoproteinemia and early ischemic heart disease]. / Mnozhestvennye molekuliarno-geneticheskie defekty u zhenshchiny so smeshannoi formoi giperlipoproteinemii i rannei ishemicheskoi bolezn'iu serdtsa.

AIM: Analysis of genes of apolipoprotein E (apoE), LDLP receptor and methylentetrahydrofolate reductase (MTHFR) in a female patient with mixed hyperlipoproteinemia (HLP) and early ischemic heart disease (IHD). MATERIAL AND METHODS: A patient with a mixed form of HLP and 5 her relatives were examined genetically. The genotype of apoE and MTHFR was determined using a restrictive analysis of PCR fragments. Conformation of one chain DNA was used to analyse gene of LDLP-receptor with following sequencing of anomalous DNA. RESULTS: The proband had changes in all examined genes: nucleotide replacement of A370T gene of LDLP receptor, nucleotide replacement of MTHFR gene C677T and epsilon 2/epsilon 2-genotype of apoE. None of the relatives carried more than one polymorphism by the studied genes. CONCLUSION: Early IHD in females can be caused by combination of polymorphisms of genes associated with development of atherosclerosis.

[Clinical signs of homozygous familial hypercholesterolemia]. / Klinicheskie proiavleniia gomozigotnoi formy semeinoi giperkholesterinemii.

During 15 years 12 patients with clinically verified diagnosis homozygous familial hypercholesterolemia were treated in the A.L. Myasnikov Institute of Clinical Cardiology. The paper presents description of main phenotypic manifestations of the condition (xanthomas, levels of lipids, the state of cardiovascular system) based on results of investigation of these patients.

[Application of DNA analysis for differential diagnosis of familial hypercholesterolemia and familial defect of apolipoprotein b-100]. / Differentsial'naia diagnostika s pomoshch'iu analiza DNK seme'ino'i giperkholesterolemii i seme'inogo defekta APOB-100.

AIM: To determine occurrence of apolipoprotein B-100 mutation in codon 3500 (apoB3500) in patients with primary hypercholesterolemia in Russia. MATERIALS AND METHODS: The study included 71 patients with clinical diagnosis of familial hypercholesterolemia (FH) and 24 relatives. All the subjects were tested for the presence of apoB3500 mutation using polymerase chain reaction and cleavage with restriction enzyme HhaII. Samples demonstrating anomalous pattern were further analysed by automatic DNA sequencing. RESULTS: Apob3500 mutation was detected in two (2.8%) female patients. In both cases cholesterol levels were severely increased although clinical features were different. CONCLUSION: Some cases of primary hypercholesterolemia in Russia may be due to familial defective apoB-100. Further screening of FH patients is required for a precise estimation of the incidence rate of familial defective apoB-100 in this country.