- [Show abstract] [Hide abstract] ABSTRACT: Aim: Genetic variants affecting statin uptake, metabolism or predisposing to muscular diseases may confer susceptibility to statin-induced myopathy. Besides the SLCO1B1 rs4149056 genotype, common genetic variants do not seem to determine statin-associated myopathy. Here we aimed to address the potential role of rare variants. Patients & methods: We performed whole exome sequencing in 88 individuals suffering from statin-associated myopathy and assessed the burden of rare variants using candidate-gene and exome-wide association analysis. Results: In the novel candidate gene CLCN1, we identified a heterozygote truncating mutation p.R894* in four patients. In addition, we detected predictably pathogenic case-specific variants in MYOT, CYP3A5, SH3TC2, FBXO32 and RBM20. Conclusion: These findings support the role of rare variants and nominate loci for follow-up studies.
- [Show abstract] [Hide abstract] ABSTRACT: A meeting of European experts in cardiovascular (CV) disease and lipids was convened in Paris, France, on 10 November 2014 to discuss lipid profile, and in particular atherogenic dyslipidaemia (AD), and associated CV risk. Key points that were raised and discussed during the meeting are summarised in this paper, which also accounts for further discussion and agreement on these points by the group of experts. Elevated levels of low-density lipoprotein cholesterol (LDL-c) are commonly associated with a greater CV risk than low LDL-c levels, and are routinely managed with statins. However, even for patients controlled on statins and achieving low LDL-c levels, abnormal lipid profiles observed in some patients (i.e. elevated triglyceride levels, with/without low levels of high-density lipoprotein cholesterol [HDL-c]) have been linked to the presence of a residual CV risk. Therefore, it is recommended that both triglyceride and HDL-c levels be measured, to allow for the overall CV residual risk to be adequately managed. Favourable safety and clinical data support the combination of statins with other lipid-lowering agents, such as fenofibrate. Patients who have elevated triglyceride levels plus low levels of HDL-c are most likely to achieve clinical benefit from fenofibrate-statin combination therapy. In these patients with AD, achieving target non-HDL-c levels should be a key focus of CV risk management, and the use of non-HDL-c was advocated to provide a better measure of CV risk than LDL-c levels. © 2015 Elsevier Ireland Ltd. All rights reserved.
- [Show abstract] [Hide abstract] ABSTRACT: Background: Gene SLCO1B1, encoding solute organic anionic transport polypeptide OATP1B1, belongs to the group of candidates potentially influencing statin treatment safety. OATP1B1 regulates (not only) the hepatic uptake of statins. Its genetic variation was described as an important predictor of statin-associated myopathy in a cohort of patients treated with a maximum dose of simvastatin. However, the impact of SLCO1B1 gene polymorphism on this risk in patients treated with other statins or lower doses of simvastatin needs to be assessed. Therefore, we performed the present study. Material/methods: SLCO1B1 tagging rs4363657 polymorphism was analyzed in 2 groups of patients with dyslipidemia (treated with simvastatin or atorvastatin, 10 or 20 mg per day), subgroup with statin-induced myalgia (N=286), and subgroup (N=707) without myalgia/myopathy, and in 2301 population controls without lipid-lowering treatment. Results: Frequency of the individual genotypes in patients with myalgia/myopathy (TT=62.3%, CT=34.5%, CC=2.8%) did not significantly differ (both P values over 0.19) from that in patients without muscle symptoms (TT=61.4%, CT=32.9%, CC=5.7%) or from the population controls (TT=63.9%, CT=32.5%, CC=3.6%). Null results were also obtained for the dominant and recessive models of the analysis. Conclusions: In Czech patients treated with low statin doses, there is no association between SLCO1B1 gene polymorphism and risk of myalgia/myopathy.
- [Show abstract] [Hide abstract] ABSTRACT: The study was aimed to determine risk factors of atherosclerosis after one month lifestyle intervention in overweight/obese children and also FTO and MC4R gene variants associated with obesity. 350 non-diabetic Czech children (age 13.7 ± 2.1 years, 163 ± 10.6 cm hight) was examined. Before and after 4 weeks of lifestyle intervention (comprising a reduction of energy intake), biochemical and anthropometrical measurements were performed. The mean weight loss achieved was 6.2 ± 2.1 kg (P < 0.001). Significant associations between BMI decrease and FTO and MC4R variants were found. Carriers of the FTO GG genotype and/or MC4R CC genotype lost significantly more body weight in comparison to the non-carriers (P < 0.0009 for BMI and P < 0.002 for body weight). The differences remain significant after adjustment for sex age and baseline values (P = 0.004 for BMI and P = 0.01 for body weight). It is necessary to look for the risk individuals with wrong response to the regime intervention. This individuals is necessary early treat with drugs to prevention clinically complications.Key words: childhood obesity - components of metabolic syndrome - predisposition - response to intervention.
Article: [News in lipid lowering treatment][Show abstract] [Hide abstract] ABSTRACT: Options for modification of lipoprotein metabolism and, thus, for reduction of atherothrombotic complication have widened over recent years. Apart from the development of novel approaches new pharmacological formulations of common lipid lowering drugs have been prepared- e.g. statin-containing nanoparticles, fibrate nanoparticles with a much higher bioavailability etc. Even the oldest lipid lowering agents - resins - have not been forgotten due to its once again discovered positive impact of these agents on glucose homeostasis while optimally complementing the action of statins. Clinical trials of therapies targeting HDL particle metabolism are being in progress despite we have not gathered any unambiguous evidence of positive effect of the CETP inhibitors or apoA1 mime-tics on the progression of atherosclerosis. Brand new approaches in the treatment of dyslipidemia including MTTP and PCSK9 inhibition or therapies utilizing anti-sense technologies rapidly accumulate evidence from clinical studies. We have already learned about their lipid-modifying efficacy particularly in patients with familial hypercholesterolemia, however, data from other patients´ populations can be expected quite soon.
- [Show abstract] [Hide abstract] ABSTRACT: Cardiovascular (CV) disease belongs to the most important mortality causes worldwide. Early identification of risk factors and increased CV risk may help decrease of morbidity and mortality. An optimal age for CV risk factors screening ages of 40 in males and of 50 in females have been identified. CV risk profile of persons in these age categories has been examined by general practitioners and recorded for the purposes of this cross-sectional survey. 1812 persons, males at average age of 40 years and females at average age of 50 years, were included into the survey. In each of the examined family and personal history including pharmacological were recorded into the study protocol as well as abusus and physical activity patterns. Basic anthropometrical parameters, e.g. heart rate, blood pressure, body mass index and laboratory measures including blood lipids and glycaemia. The participating physicians recorded newly identified risk factors CV disease and determined the global CVD risk according to the SCORE charts. Percentage of those already treated for any of the main CVD risk factors and, among these, also attaining the treatment goals. The percentage of patients with a newly identified CV risk factor was calculated. We also tested the hypothesis of a relationship between positive family history of any of the followed risk factors and its risk in the examined probands using Pearson´s test. 961 males, average age of 42.9 ± 4.7 years, and 851 females , average age of 51.2 ± 3.6 years, were enrolled into the study. 49% of males and 31% of females were overweight and 32% men and 31% of women were obese. There were 36% of smokers among men and 22% among women. The prevalence of type 2 diabetes was 11% in males and also in females. Arterial hypertension was diagnosed in 43% of males and 45% of females while dyslipidemia was present in 39% of males and 41% of females. Pharmacological treatment of any of the above mentioned diseases was used in 48% of the probands, however, only 7% of them attained treatment goals of blood pressure, LDL-cholesterol and glycaemia. Type 2 diabetes was newly identified in 3% of both males and females, arterial hypertension in 8% of males and 5% of females and dyslipidemia was newly detected in 20% of probands of both genders. Non-pharmacological treatment was recommended to 62% of male and to 65% of female participants, respectively. Pharmacological treatment was initiated in 53% of males and 51% of females. In both genders this was mostly antihypertensive treatment with ACE inhibitors (29% of males and 24% of females) and lipid lowering therapy with a statin (29% of males, 27% females). The analysis of relationship between the positive family history of any of the followed diseases and their presence in the probands examined revealed significant increases of the risk for arterial hypertension, type 2 diabetes mellitus and dyslipidemia. The survey following CV risk profile in a cohort of 40 years old men and 50 years old women showed high prevalence of CV risk factors in these age categories in the Czech probands. The high frequency of modifiable risk factors and the need to initiate pharmacological treatment in more than one half of the examined population documents the need of early detection of risk. Genetic determination of individual major risk factors for CVD mirrored in the positive family history represents an important component of the global cardiovascular risk and must be actively detected and taken into account for the risk stratification.
- [Show abstract] [Hide abstract] ABSTRACT: Currently, the familial hypercholesterolemia (FH) rises the interest. The reason is that this genetic disorder is targeted by newly emerged and highly effective hypolipidemic agents, PCSK-9 inhibitors, lomitapid and mipomersen. Present paper discusses 2 patient study groups, before 50 years and nowadays. Although direct statistical analysis is impossible some changes in clinical features of FH might be found over the course of the time. In fact, the basic FH characteristic has not changed dramatically. Severe isolated hypercholesterolemia with total cholesterol 9-10 mmol/l, LDL-cholesterol 7-8 mmol/l and normal values of triglycerides dominates in laboratory analysis. Interestingly, the values of triglycerides increase and almost reach the pathological range in comparison to the values from the period 50 years ago. The values of HDL-cholesterol are normal. Manifestation of CHD in male patients over 40 years of age and in female patients over 50 years of age is not exceptional (rarely occur cases of myocardial infarction in third decade of age). Typical clinical manifestation of FH is xanthomatosis. The early detection and aggressive treatment in FH patients cause that xanthoma tendinosum, xanthelesma and arcus lipoides are less frequent as decades ago. Obesity, diabetes mellitus (DM) and hypertension do not belong to typical clinical sign of FH.
- [Show abstract] [Hide abstract] ABSTRACT: Background Ezetimibe's mechanism of action, complementary to that of statins, makes it a useful therapeutic option in patients intolerant of lipid-lowering drugs or in those not achieving target lipid levels. Objectives To evaluate the efficacy and safety of ezetimibe in a longterm follow-up of lipid clinic patients with emphasis on motivation for use and the impact on achievement of target lipid levels. Methods Two hundred and ninety-five clinic patients who were prescribed and took ezetimibe in the 13-month period following the drug's availability in Canada were identified from our database. Patients’ history and laboratory data were collected before and at first visit after the ezetimibe therapy was started. Paired t-test and chi-square test were used for statistical comparisons of ezetimibe's effect on lipid parameters and the achievement of target lipid-levels respectively. Results Ezetimibe treatment increased significantly the proportion of patients achieving lipid targets (by 25% for LDL-C and by 21.7% for TC/HDL-C) significantly by 18% (p < 0.001) and TC/HDL-C by 15% (p < 0.011). The effect of ezetimibe in combination with other lipid-lowering therapies was similar; LDL-C decreased by 22% (p < 0.001) and TC/HDL-C by 15.4% (p < 0.011). The same lipid-lowering effect was seen in patients with diabetes. In this subgroup, addition of ezetimibe to ongoing therapy led to three- and two-fold increase in LDL-C and TC/HDL-C target levels achievement, respectively. Only 7% of patients discontinued ezetimibe treatment due to side effects. Conclusion In patients referred to the lipid clinic (typically because of side effects or failure to reach targets on other lipid-lowering therapy) treatment with ezetimibe significantly increased proportion of those achieving their target lipid levels. This was not accompanied by significant side effects.
- [Show abstract] [Hide abstract] ABSTRACT: Objective: Obesity is linked with a state of increased oxidative stress, which plays an important role in the etiology of atherosclerosis and type 2 diabetes mellitus. The aim of our study was to evaluate the effect of rapid weight loss on oxidative stress markers in obese individuals with metabolic syndrome (MetS). Design and methods: We measured oxidative stress markers in 40 obese subjects with metabolic syndrome (MetS+), 40 obese subjects without metabolic syndrome (MetS-), and 20 lean controls (LC) at baseline and after three months of very low caloric diet. Results: Oxidized low density lipoprotein (ox-LDL) levels decreased by 12% in MetS+ subjects, associated with a reduction in total cholesterol (TC), even after adjustment for age and sex. Lipoprotein associated phospholipase A₂ (Lp-PLA₂) activity decreased by 4.7% in MetS+ subjects, associated with a drop in LDL-cholesterol (LDL-C), TC, and insulin levels. Multivariate logistic regression analysis showed that a model including ox-LDL, LpPLA₂ activity, and myeloperoxidase (MPO) improved prediction of MetS status among obese individuals compared to each oxidative stress marker alone. Conclusions: Oxidative stress markers were predictive of MetS in obese subjects, suggesting a higher oxidative stress. Rapid weight loss resulted in a decline in oxidative stress markers, especially in MetS+ patients.
- [Show abstract] [Hide abstract] ABSTRACT: BACKGROUND: Diabetes mellitus and low levels of high-density lipoprotein cholesterol (HDL-C) are among several known risk factors for coronary artery disease. Recent research has shown potential mechanistic links between these two diseases. OBJECTIVES: The aim of our study was to characterize, by examining particular coronary artery disease risk factors, patients with extremely high and low levels of HDL-C who were referred to a prevention clinic. METHODS: We compared the phenotypes of 113 patients with HDL-C levels greater than the 90th percentile with 212 patients with levels less than the 10th percentile by using a retrospective chart review. RESULTS: The cohort with high HDL-C had a remarkable difference in the incidence of type 2 diabetes (1.8% vs 21.7%). The high HDL-C cohort also had a greater age (52.1 years vs 46.7 years), more light or moderate alcohol consumption (70.8% vs 49.4%), more healthy diet (30.1% vs 22.4%), more light or moderate exercise (90.8% vs 52.2%), and a lower body mass index (25.2 kg/m(2) vs 28.1 kg/m(2)). CONCLUSIONS: Compared with the low HDL-C group-and also the general population-the high HDL-C cohort had a remarkably low prevalence of diabetes mellitus.
- [Show abstract] [Hide abstract] ABSTRACT: This position statement of the Executive Committee of the Czech Society for Atherosclerosis (CSAT) summarizes the most important aspects and novelties of the latest European guidelines for the management of dyslipidemia. In particular the position statement comments on: cardiovascular risk stratification, indications for plasma lipid and lipoprotein levels assessment as well as target lipid values, evaluation of current options for both lifestyle and pharmacological treatment of lipid metabolism disorders and, also, recommendation for laboratory monitoring of patients treated with lipid lowering agents. The statement deals with actual concepts of management of dyslipiemia in everyday practice, e.g. therapy of dyslipidemia in special patients´ groups. This statement does not replace the latest guidelines but focuses on the changes from the former guidelines for dyslipidemia management, published by CSAT in 2007.Key words: dyslipidemia - risk stratification - LDL-cholesterol - statins - fibrates - niacin - ezetimibe - resins.
- [Show abstract] [Hide abstract] ABSTRACT: Objectives: Statins significantly reduce CV morbidity and mortality. Unfortunately, one of the side effects of statins is myopathy, for which statins cannot be administered in sufficient doses or administered at all. The aim of this study was to demonstrate the effect of coenzyme Q10 in patients with statin myopathy. Design/setting: Twenty eight patients aged 60.6±10.7 years were monitored (18 women and 10 men) and treated with different types and doses of statin. Muscle weakness and pain was monitored using a scale of one to ten, on which patients expressed the degree of their inconvenience. Examination of muscle problems was performed prior to administration of CQ10 and after 3 and 6 months of dosing. Statistical analysis was performed using Friedman test, Annova and Students t-test. Results: Pain decreased on average by 53.8% (p<0.0001), muscle weakness by 44.4% (p<0.0001). The CQ10 levels were increased by more than 194% (from 0,903 μg/ml to 2.66 μg/ml; p<0.0001). Conclusion: After a six-month administration of coenzyme Q10, muscle pain and sensitivity statistically significantly decreased.
- [Show abstract] [Hide abstract] ABSTRACT: Objectives: A significant inter-individual variability in statin treatment efficacy is likely to have a strong genetic background. A candidate gene with the potential to influence statin treatment efficacy is SLCO1B1. This gene codes for the solute carrier organic anion transporter, which has been shown to regulate the hepatic uptake of statins and some other drugs. Materials and methods: The SLCO1B1 rs4149056 (T>C) polymorphism was successfully analysed in a group of 253 patients with dyslipidemia (treated with simvastin or atorvastatin, 10 or 20 mg per day) and 470 healthy normolipidemic controls. The polymorphism was analysed using nested PCR-RFLP. Lipid levels (total, LDL and HDL cholesterol; triglycerides) were analysed before and after 10-13 weeks of treatment. Results: After treatment, as expected, there was a significant decrease both in the total cholesterol (7.60±1.36 → 5.37±1.12 mmol/L, p<0.001) and LDL cholesterol (5.04±1.34 → 3.17±0.99 mmol/L, p<0.001) levels. The distribution of the individual genotypes in the patients (TT=61.7%, CT=31.6%, CC=6.7%) was similar (p=0.35) to that of the normolipidemic controls (TT=64.4%, CT=31.3%, CC=4.3%). Homozygous CC males exhibited the lowest (Δ -21.2±7.2%) decrease of total cholesterol in contrast to the females, in whom the same genotype was associated with the highest (Δ -33.5±7.6 %) decrease (p=0.04 for gene-gender interaction). Conclusions: The results of our pilot study suggest possible gender-dependent effects of the rs4149056 variant within the SLCO1B1 gene on statin treatment efficacy.
- [Show abstract] [Hide abstract] ABSTRACT: The aim of this work is to give summary of changes in recommendation for hormone replacement therapy (HT) and cardiovascular prevention during last decade. Conclusions from observational studies demonstrated a positive effect of HT in both the primary and secondary prevention of coronary heart disease (CHD). But large randomized trials failed to prove this positive effect; on the contrary, the cardiovascular risk was increased in the beginning of therapy. But estrogen arm of Women's Health Initiative (WHI) show neutral influence and the Estrogen in the Prevention of Atherosclerosis Trial (EPAT) indicate possible positive effects of some HT regimens. Also reanalysis of WHI in age-related groups show the window of opportunity. The prevention of CHD was excluded from possible indications of HT. Many questions regarding optimal choice in the individual treatment strategies have been raised. HT in its individualized form remains the first choice therapy for the acute climacteric syndrome, for the prevention and the therapy of urogenital atrophy and prevention of osteoporosis. Early start of HT has neutral or slightly positive effect on cardiovascular prevention.
- [Show abstract] [Hide abstract] ABSTRACT: Objectives: This study aimed to determine whether there is a relationship between common FTO (rs17817449) and MC4R (rs17782313) gene variants and body mass reduction or weight loss after a one-month lifestyle intervention in overweight/obese children. Design and methods: We genotyped 357 unrelated non-diabetic Czech children (age 13.7 ± 4.9 years, average BMI at baseline 30.8 ± 4.6 kg/m(2)). Biochemical and anthropometrical measurements were performed before and after 4 weeks of lifestyle interventions (comprising a reduction in energy intake to the age-matched optimum and a supervised exercise program consisting of 5 exercise units per day, 50 min each). Results: The mean weight loss achieved was 6.2 ± 2.1 kg (P<0.001). Significant associations were found between a BMI decrease and the FTO and MC4R variants. Carriers of the FTO GG genotype and/or MC4R CC genotype lost significantly more body weight compared to noncarriers (P<0.0009 for BMI and P<0.002 for body weight). These differences remained significant following adjustment for sex, age and baseline values (P=0.004 for BMI and P=0.01 for body weight). Conclusions: FTO and MC4R gene variants modify the impact of an intensive lifestyle intervention on BMI decrease in overweight/obese children. Carriers of the FTO GG genotype and MC4R CC genotype benefit significantly more from the lifestyle intervention.
- [Show abstract] [Hide abstract] ABSTRACT: Objective: The aim of the study was to evaluate the importance of screening for thrombophilic mutations after the first early pregnancy loss. Setting: Thrombophilic mutations were examined in a sample of 100 women with at least one miscarriage. DNA was isolated from venous blood sample. We used methods of microarray, fragmentation analysis, High Resolution Melting and PCR-ARMS with following gel electrophoresis and visualisation. Chi-square test and in cases of low expected frequencies Yates correction were used to compare relative frequencies of individual mutations. The comparison of averages was performed by t-test. Results: We detected prevalence of factor V and II mutation of 9% and 3%, respectively. Single MTHFR mutation was found in 59% and double heterozygous MTHFR mutation in 23% of cases. No mutation was present in only 6% of the study group. Heterozygous mutations of factor V occurred 1.8 times more frequently in our study group compared to the general Czech women population. Also, the frequency of factor II mutation was 1.5-3 times higher. No carrier of these mutations had overt coagulation disorder, history of thromboembolic disease or that of habitual abortions. Conclusions: The frequency of thrombophilic mutations in the group of women with early pregnancy loss is 1.5-3 times higher than in the general population.
Article: Dyslipidemia in 2012[Show abstract] [Hide abstract] ABSTRACT: Therapy of dyslipidemia is a corner stone of prevention of cardiovascular complications in high-risk patients. Best documented lipid lowering agents are statins being used as a monotherapy as well as the core of combination treatment regimens. Fibrates, ezetimibe, niacin and (in the Czech Republic practically unavailable) resins represent other treatment options of dyslipidemia. Complex intervention of all lipid abnormalities using combination of different drug classes represents an option to accomplish further reduction of cardiovascular atherothrombotic complications.
Charles University in PraguePraha, Praha, Czech Republic
Military University Hospital PraguePraha, Praha, Czech Republic