Statin-induced changes in mitochondrial respiration in blood platelets in rats and human with dyslipidemia.

3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are widely used drugs for lowering blood lipid levels and preventing cardiovascular diseases. However, statins can have serious adverse effects, which may be related to development of mitochondrial dysfunctions. The aim of study was to demonstrate the in vivo effect of high and therapeutic doses of statins on mitochondrial respiration in blood platelets. Model approach was used in the study. Simvastatin was administered to rats at a high dose for 4 weeks. Humans were treated with therapeutic doses of rosuvastatin or atorvastatin for 6 weeks. Platelet mitochondrial respiration was measured using high-resolution respirometry. In rats, a significantly lower physiological respiratory rate was found in intact platelets of simvastatin-treated rats compared to controls. In humans, no significant changes in mitochondrial respiration were detected in intact platelets; however, decreased complex I-linked respiration was observed after statin treatment in permeabilized platelets. We propose that the small in vivo effect of statins on platelet energy metabolism can be attributed to drug effects on complex I of the electron transport system. Both intact and permeabilized platelets can be used as a readily available biological model to study changes in cellular energy metabolism in patients treated with statins.

Statin-associated myopathy: from genetic predisposition to clinical management.

Statin-associated myopathy (SAM) represents a broad spectrum of disorders from insignificant myalgia to fatal rhabdomyolysis. Its frequency ranges from 1-5 % in clinical trials to 15-20 % in everyday clinical practice. To a large extent, these variations can be explained by the definition used. Thus, we propose a scoring system to classify statin-induced myopathy according to clinical and biochemical criteria as 1) possible, 2) probable or 3) definite. The etiology of this disorder remains poorly understood. Most probably, an underlying genetic cause is necessary for overt SAM to develop. Variants in a few gene groups that encode proteins involved in: i) statin metabolism and distribution (e.g. membrane transporters and enzymes; OATP1B1, ABCA1, MRP, CYP3A4), ii) coenzyme Q10 production (e.g. COQ10A and B), iii) energy metabolism of muscle tissue (e.g. PYGM, GAA, CPT2) and several others have been proposed as candidates which can predispose to SAM. Pharmacological properties of individual statin molecules (e.g. lipophilicity, excretion pathways) and patients´ characteristics influence the likelihood of SAM development. This review summarizes current data as well as our own results.

Biomarkers of cardiometabolic risk in obese/overweight children: effect of lifestyle intervention.

Obesity is a strong cardiometabolic (CM) risk factor in children. We tested potential CM risk in obese/overweight children and the effect of an intensive lifestyle intervention using newer CM markers: atherogenic index of plasma AIP [Log(TG/HDL-C)], apoB/apoAI ratio and a marker of insulin resistance HOMA-IR. The participants (194 girls, 115 boys, average age 13) were enrolled in an intensive, one-month, inpatient weight reduction program. The program consisted of individualised dietary changes and the exercise program comprised aerobic and resistance training. Anthropometrical and biochemical parameters in plasma and CM risk biomarkers - (AIP, apoB/apoAI ratio and HOMA-IR) were examined before and after the intervention. AIP and HOMA-IR significantly correlated with BMI while apoB/apoAI ratio did not. Only AIP and HOMA-IR showed systematic increases according to the level of obesity by BMI quartiles. Lifestyle intervention significantly improved anthropometrical and biochemical values and the biomarkers too. The response of lipid parameters to the intervention was considerably higher in boys than in girls. The children were stratified into three risk categories according to AIP, where 13.8 % of boys and 5.3 % of girls fell into high risk category. The monitored biomarkers may complement each other in the prognosis of CM risk. AIP was strongly related to obesity and to lipid and glycid metabolism, while the relationship of the apoB/apoAI ratio to obesity and glycid metabolism was not significant. The obese children benefited from the intensive lifestyle intervention which improved the anthropometrical and biochemical parameters and CM risk biomarkers.

FTO and MC4R gene variants determine BMI changes in children after intensive lifestyle intervention.

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.

Impact of variants within seven candidate genes on statin treatment efficacy.

Statins are the most commonly used drugs in patients with dyslipidemia. Among the patients, a significant inter-individual variability with supposed strong genetic background in statin treatment efficacy has been observed. Genome wide screenings detected variants within the CELSR2/PSRC1/SORT1, CILP2/PBX4, APOB, APOE/C1/C4, HMGCoA reductase, LDL receptor and PCSK9 genes that are among the candidates potentially modifying response to statins. Ten variants (SNPs) within these genes (rs599838, rs646776, rs16996148, rs693, rs515135, rs4420638, rs12654264, rs6511720, rs6235, rs11206510) were analyzed in 895 (46 % men, average age 60.3+/-13.1 years) patients with dyslipidemia treated with equipotent doses of statins (~90 % on simvastatin or atorvastatin, doses 10 or 20 mg) and selected 672 normolipidemic controls (40 % men, average age 46.5 years). Lipid parameters were available prior to the treatment and after 12 weeks of therapy. Statin treatment resulted in a significant decrease of both total cholesterol (7.00+/-1.53-->5.15+/-1.17 mmol/l, P<0.0001) and triglycerides (2.03+/-1.01-->1.65+/-1.23 mmol/l, P<0.0005). Rs599838 variant was not detected in first analyzed 284 patients. After adjustment for multiple testing, there was no significant association between individual SNPs and statin treatment efficacy. Only the rs4420638 (APOE/C1/C4 gene cluster) G allele carriers seem to show more profitable change of HDL cholesterol (P=0.007 without and P=0.06 after adjustment). Results demonstrated that, although associated with plasma TC and LDL cholesterol per se, variants within the CELSR2/PSRC1/SORT1, CILP2/PBX4, APOB, APOE/C1/C4, HMGCoA reductase, LDL receptor and PCSK9 genes do not modify therapeutic response to statins.

[Comprehensive management of cardiovascular risk. Focusing on telmisartan]. / Komplexní lécba kardiovaskulárního rizika. Zamereno na telmisartan.

Cardiovascular diseases (CVD) represent a significant health problem in all countries world-wide and in the developed world, including the Czech Republic, in particular. The underlying cause in the majority of CVD patients is atherosclerosis and its complications, respectively. The present paper focuses on prevention and timely treatment of atherosclerosis. Management should be comprehensive and should target the risk factors (RF). Hypertension, hyperlipoproteinaemia and dyslipidemia (HLP and DLP), type 2 diabetes mellitus (T2DM), visceral fat obesity and cigarette smoking are the dominating RFs. Even though all RFs have to be managed simultaneously and it is not possible to focus on just one of them, for the sake of clarity, this paper discusses hypertension and the use of telmisartan, a representative of one the most up-to-date group of antihypertensives. There is a growing evidence that it is not always just a reduction of a specific risk that is important but also the mode of treatment. For example, to reduce a CV risk in a patient with hypertension but also, for example, with metabolic syndrome, it is more beneficial to treat the patient with rennin-angiotensin system (RAS) blocking agents, possibly in a combination with calcium channels antagonists, than to use "traditional" (older) treatment approach with a combination of a beta/blocker and diuretic. Among the RAS-modifying agents, ACE inhibitors and sartans are the most widely used. Among sartans, telmisartan is very well-tolerated and has evidence from a large interventional study for its effect on reducing the CV risk.

[Hyperlipoproteinaemia and dyslipoproteinaemia II. Therapy: non-pharmacological and pharmacological approaches]. / Hyperlipoproteinemie a dyslipoproteinemie II. Terapie: Nefarmakologická a farmakologická lécba.

At present, literally no one disputes hyperlipoproteinaemia and dyslipidemia (HLP and DLP) treatment as a rational therapeutic approach in the prevention of cardiovascular diseases (CVD). This approach is in line with the current principles of evidence-based medicine (EBM) and is sufficiently evidenced particularly by the results of large intervention studies. Nevertheless! When the results of the recent studies are critically appraised, these by no means are (mostly, there, obviously, are exceptions) as conclusive as the studies conducted in 1980s and 1990s. Consequently, positive results are being sought in subanalyses, subgroup evaluations and multiple-study metaanalyses. This paper is not intended as a critique of new drugs. These certainly are developed to be safe, effective and well-tolerated. However, the newer studies suffer from a range of issues: the populations studied are already very well managed, it is not possible to compare against placebo and sometimes, let us be honest, the trial design itself is problematic (often it is an uncritical effort to treat as wide as possible range of patients as well as new groups of patients who might not be suitable for the given treatment). Certainly, we should not start disputing the well-evidenced hypotheses and seek alternatives to the long-established arguments and approaches as a consequence to some less convincing studies. We must not overlook the most robust results of statin studies as well as 'positive' studies with other hypolipidemics. There is no doubt that the effect ofstatins on LDL-cholesterol represents a significant move towards cardiovascular disease prevention. Despite this, we currently recognise with increased intensity that this very effective and well-evidenced treatment has its limits and that a high proportion of patients dies or are faced with cardiovascular diseases even though they are treated with a correct dose ofa statin and a target LDL-C level is achieved. This remaining risk (represents more than 50% ofevents) has been termed 'RESIDUAL RISK'. The issue of residual risk is crucial in patients with type 2 diabetes mellitus (DM2T) or in all patients with HDL-C-low DLP. As was repeatedly emphasised, a statin will be a cornerstone of pharmacological treatment of a DLP. However, a question arises what to combine it with. The most convincing data exist for niacin (combination of niacin with laropiprant minimising the incidence of unwanted flushes). We surely should not marginalize other hypolipidemics used mainly in combinations: resin and ezetimibe to treat LDL-C, niacin, fibrates and possibly omega-3-fatty acids to manage the residual risk (HDL and TG). Last but not least we should not forget non-pharmacological treatment as the pivotal treatment approach in all patients.

Omega-3 fatty acids and cardiovascular disease risk: do we understand the relationship?

There is a large body of evidence documenting the effects of long-chain polyunsaturated fatty acids with the first double bond at the third position from methyl-terminal (so called omega-3 fatty acids (FAs)) on different components of cardiovascular disease (CVD) risk. However, it may seem the more answers on the topic we learn, the more questions remain to be elucidated. There are three levels of evidence documenting the impact of fish omega-3 FAs on CVD risk. Epidemiological data have shown unequivocally the increased intake of fish is associated with lower CVD morbidity and mortality. Numerous experimental studies have shown (almost always) positive effects of omega-3 FAs on lipoprotein metabolism, coagulation and platelet function, endothelial function, arterial stiffness etc. Most importantly, there are a few prospective clinical endpoint trials (DART, JELIS, GISSI Prevenzione and GISSI-HF) that have examined the impact of omega-3 FAs supplementation on cardiovascular outcomes in different patient populations. Recent meta-analyses of these and other clinical studies have yielded somewhat conflicting results. In this review we will summarize current evidence of omega-3 FAs effects on cardiovascular risk focusing on new data from recent clinical trials as well as possible practical implications for clinical practice.

[Statin pharmacokinetics]. / Farmakogenetika lécby statiny.

Reducing high levels of plasmatic lipoids (LDL-cholesterol and triglycerides) is one of the most important steps in the prevention and treatment of cardiovascular diseases. In the majority of cases, treatment based on lifestyle changes (changes in dietary habits, more physical activity) is not sufficient and pharmacotherapy becomes necessary. Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are a well tolerated first-choice drug in patients with dyslipidemia. However, great variability of statin effects has been observed in different patients on the same therapy, and the cause clearly resides in different genetic characteristics of each individual, influencing the effect of therapy. The influence of different genetic variants has been described, but the control of response to hypolipidemic therapy is most likely subject to polygenic control. The analysis of multiple gene combinations may help detect the "hyper-" and "hypo-" responders, i.e. individuals with a good response to treatment (allowing for starting with a lower dose of the drug), and those with an insufficient response to treatment (in whom statin shall not be the drug of first choice), or it may help detect the patients who are more likely to develop severe adverse events. Studies with different designs describe that for instance genes (and their variants) for cytochromes, apolipoprotein E and A1 and cholesterol 7alpha-hydroxylase may be important genetic determinants of the effect of pharmacological treatment of dyslipidemia and play a role in the individualisation of treatment.

Lipoprotein(a) and its position among other risk factors of atherosclerosis.

Lipoprotein(a) [Lp(a)] comprises of an LDL particle and apolipoprotein(a) [apo(a)] and its elevated levels are considered a risk factor for atherosclerosis. The aim of our study was to find out whether elevated Lp(a) levels are associated with increased risk of atherosclerosis in patients with multiple other risk factors. We further tested the association of three polymorphisms of the apo(a) gene promoter with Lp(a) levels. No significant correlation was detected between Lp(a) levels and lipid and clinical parameters tested. The study demonstrated a significantly (p=0.0219) elevated Lp(a) level (mean 28+/-35 mg/dl, median 0.14) in patients with coronary heart disease (CHD). In a group with premature CHD the correlation was not significant anymore. There was a significant correlation between polymorphic loci of the promoter region of apo(a) gene and Lp(a) levels (+93C T, p=0.0166, STR, p<0.0001). Our study suggests that elevated Lp(a) level is an independent risk factor of CHD in carriers of other important CHD risk factors. Observed association of sequence variants of the promoter of apo(a) gene with Lp(a) levels is caused in part due to linkage to a restricted range of apo(a) gene length isoforms.

[Genetic aspects of high variability of lipoprotein(a) levels]. / Genetické aspekty velkého rozpetí hladin lipoproteinu(a).

Increased levels of lipoprotein(a) are supposed to be an independent risk factor for atherosclerosis. Apolipoprotein(a) determines structural and functional characteristics of the lipoprotein particle. The lipoprotein(a) concentration is almost entirely genetically determined at the apolipoprotein(a) gene locus, nevertheless it varies widely between individuals in all populations studied so far. Large part of the variance is correlated to the apolipoprotein(a) gene length polymorphism. Some of the variance could be additionally related to polymorphic sites either in the coding sequence or in the transcription regulatory regions. Only a few functional variants were discovered in the coding sequence of apolipoprotein(a) gene so far. Moreover, analyses of relevant regulatory regions (promoter, DHII and DHIII enhancers) have revealed less variability than was expected. Despite the lipoprotein(a) levels are under dominant control of a single locus its genetic determination is quite complex. The basic role belongs to the apolipoprotein(a) gene length polymorphism and to a panel of sequence variants affecting apolipoprotein(a) gene expression and lipoprotein(a) particle production rate. Besides, minor impact of other locuses and modulation by non-genetic factors should be considered.

[Lipoprotein (a)]. / Lipoprotein (a).

The lipids are transported by lipoproteins in the blood system. Lipoprotein (a) [Lp (a)] is a unique lipoprotein of the human plasma discovered by professor Berg in 1963. Lp (a) consists of apolipoprotein (a) and LDL particles (apolipoprotein B100). The level and size of Lp (a) are highly variable and largely determined heredity. Clinical studies on animal models have shown that elevated Lp (a) levels are linked with a higher risk of atherosclerosis, even though not all of the conclusions based on the studies that have been carried are convincing. Concentration over 35 mg/dl is considered to be a risk level. Surprisingly high Lp (a) levels in old age are associated with longevity. This may be explained by the physiological role of Lp (a) in tissue reparation, wound healing and anti-cancer effect.

[Serum lipids in drug addicts]. / Sérové lipidy u drogove závislých osob.

UNLABELLED: The background and aim is to study profile of serum lipids in drug addicts using heroin. METHODS AND RESULTS: The study involved 107 drug addicts using heroin (83 men and 24 women). Mean age was 29.3 years (variation 20-47 years). Mean time of using heroin was 6.5 years. Serum lipids (total cholesterol, HDL-cholesterol, triacylglycerol) were measured using enzyme methods. LDL-cholesterol and Body Mass Index (BMI) were calculated. All parameters were significantly decreased (mean levels of total cholesterol 4.31, triacylglycerol 1.29, HDL-cholesterol 1.08 and LDL-cholesterol 2.70 mmol/l). Levels of HDL-cholesterol under 1.0 mmol/l were found in 32%. Statistical measurments were performed by t-test and results compared with control group. CONCLUSIONS: Levels of HDL-cholesterol lower than 1.0 mmol/l (32%) are of importance and patients must be further controlled.