Cholesterol measurement and current guidelines.

The concentration of total cholesterol has so far been part of the SCORE tables for estimating the risk of cardiovascular events; in the new SCORE2 tables, it has already been replaced by non-HDL-cholesterol. Total cholesterol continues to serve as a guide for the presence of dyslipoproteinemia and is necessary for the calculation of LDL-cholesterol and non-HDL-cholesterol. The importance of HDL-cholesterol as a separate risk factor is already limited, but it is necessary for the calculation of non-HDL-cholesterol and LDL-cholesterol. LDL-cholesterol remains an essential indicator of risk, it is needed for decision making and control of hypolipidemic therapy. Non HDL-cholesterol can be used as a therapy target instead of LDL-cholesterol. Triglycerides remain necessary for residual risk assessment, for the calculation of LDL-cholesterol and for the diagnosis of certain types of dyslipoproteinemias.

Dyslipidemia and PCSK9 inhibitors - practical focused update of indication and reimbursement criteria.

PCSK9 inhibitors are modern and effective hypolipidemic drugs for lowering LDL-cholesterol, which belong to the „biological therapy“. Their prescription is limited to specialized centers and to the fulfillment of other conditions set by SÚKL. This article lists the current valid criteria under which they can be indicated for reimbursement from public health insurance, and comments conditions and limitations in terms of the possibility of their fulfillment in clinical practice.

Early and concurrent therapy of dyslipidemia and hypertension: when to start it and how to maintain patient´s good and long-term adherence?

Treatment of dyslipidemia and hypertension is a key step for reducing the risk of atherosclerotic cardiovascular disease. Dyslipidemia and hypertension often occur in one patient at the same time, so both of these risk factors need to be addressed at the same time. It is better to start therapy before the patient is at high risk of a fatal cardiovascular event. To improve the patients prognosis, it is important not only to achieve the target LDL-cholesterol value and the optimal blood pressure value, but it is also very important (and often more difficult) to maintain the patients good and long-term adherence to established combination pharmacotherapy. For better adherence to long-term therapy also contributes reduction the number of tablets, which can be achieved through the use of a fixed combination of statins and antihypertensive agents.

Don't we forget about biological therapy of hypercholesterolemia with PCSK9-inhibitors?

In many patients it is difficult to achieve the current very low target LDL-cholesterol levels, recommended for the prevention of atherosclerotic cardiovascular events. If statin therapy or statins in combination with ezetimibe are not sufficient, addition of PCSK9 inhibitors should be considered. PCSK9 inhibitors reduce LDL-CH by an average of 50-60 % and reduce the risk of atherosclerotic cardiovascular events. They are currently reserved for patients with atherosclerotic cardiovascular disease and for patients with familial hypercholesterolaemia, in whom despite intensive hypolipidemic therapy statins with ezetimibe the target LDL-cholesterol value is not reached. In these patients, PCSK9 inhibitors may also be indicated in case of statin intolerance.

A summary of the EAS consensus concerning the causal relationship between low-density lipoproteins and atherosclerotic cardiovascular diseases, prepared by the Board of the Czech Society for Atherosclerosis.

This article summarised opinion of the European Society for Atherosclerosis on the causal relationship between low density lipoprotein (LDL) and the development of atherosclerosis. The fact that there is a clear causal relationship between the LDL concentration and the development of atherosclerotic cardiovascular disease (ASKVO) is evidenced by congenital lipid metabolism disorders and results of prospective epidemiological studies, Mendelian randomized trials, and randomized controlled trials. It is documented that the effect of LDL exposure on ASKVO development is cumulative; the additive effect of other risk factors is also discussed. In conclusion the facts, underlying the rational approach to the therapy of patients with dyslipidemia, are summarized. Key words: atherosclerotic cardiovascular disease - LDL - low density lipoprotein - EAS.

Some causes of poor adherence to long-term statin therapy and their solution.

Statins are among the most important drugs in preventive cardiology because they greatly improve the prognosis of risk patients in both primary and secondary prevention of atherosclerotic cardiovascular disease. Adherence to long-term statin therapy is poor and decreases with the duration of statin use. A number of fake news about adverse effects of statins disseminated on the internet, such as damage of the brain, liver or kidney, contribute to worsening adherence. Statins therapy is sometimes unnecessary discontinued before planned surgery. The worse adherence to statin therapy may be also due to the fact that the patient does not know the connection between cholesterol lowering and improving his cardiovascular prognosis. Key words: adherence - brain - cholesterol - liver function - renal function - statins - surgery.

[Is it possible to improve long-term compliance of patients to statin therapy?] / Lze zlepsit komplianci pacientu k dlouhodobé terapii statiny?

Statins are key drugs for patients in secondary prevention of cardiovascular disease, as well as for primary prevention patients at high or very high risk of fatal cardiovascular events. However, long-term compliance of patients to statin therapy is relatively low, decreasing with the time of statin use; moreover a significant proportion of patients stop statins medication over the course of several years. To the early termination of statin treatment often contributes apprehension of the occurence of statin´s side effects (i.g. increased creatine kinase in the blood and muscle problems), although these symptoms are usually not causally related to statin therapy. To the low compliance may also contribute administration of statins in the evening hours, as well as the fear of developing diabetes or drug interactions. The above issues are discussed in the text of this article.Key words: compliance - creatinkinase - diabetes mellitus -LDL-cholesterol - statins.

Histopathology Image Analysis in Two Long-Term Animal Experiments with Helical Flow Total Artificial Heart.

Histopathological analysis can provide important information in long-term experiments with total artificial heart (TAH). Recently, a new type of blood pump, the helical flow total artificial heart (HF-TAH) was developed. This study aimed to investigate the changes in selected vital organs in animal experiments with implanted HF-TAH. Samples from lung, liver, and kidneys from two female goats (No. 1301 and No. 1304) with implanted HF-TAH were analyzed. Tissue samples were fixed in 10% formaldehyde and 4 µm thick transverse sections were stained with hematoxylin-eosin (HE). Additional staining was done for detection of connective tissue (Masson-Goldner stain) and for detection of iron (hemosiderin) deposits (Perls stain). Sections were scanned at 100× and 500× magnification with a light microscope. Experiment no. 1301 survived 100 days (cause of termination was heavy damage of the right pump); experimental goat no.1304 survived 68 days and was sacrificed due to severe right hydrodynamic bearing malfunction. Histopathological analysis of liver samples proved signs of chronic venostasis with limited focal necrotic zones. Dilated tubules, proteinaceous material in tubular lumen, and hemosiderin deposits were detected in kidney samples. Contamination of the organs by embolized micro-particles was suspected at the autopsy after discovery of visible damage (scratches) of the pump impeller surface (made from titanium alloy) in both experiments. Sporadic deposits of foreign micro-particles (presumably titanium) were observed in most of the analyzed parenchymal organs. However, the described deposits were not in direct connection with inflammatory reactions in the analyzed tissues. Histopathological analysis showed the presence of minimal contamination of the lung, kidney, and liver tissue samples by foreign material (titanium very likely). The analysis showed only limited pathological changes, especially in liver and kidneys, which might be attributed to the influence of artificial perfusion often observed in chronic TAH experiments.

[Notes on the HOPE-3 study]. / Komentár ke studii HOPE-3.

The study HOPE-3 aimed to determine whether treatment with statin and with antihypertensive drugs (candesartan and hydrochlorothiazide) in routine clinical practice in people without cardiovascular diseases (men aged over 55, women over 65 years) will reduce cardiovascular events. Another objective was to answer whether the effect of the above-mentioned treatment will be the same in different ethnic (anthropometric) populations. All drugs were administered as an "polypills". The study demonstrated that use of antihypertensive medication in this population does not reduce the incidence of cardiovascular events. In contrast, statin treatment reduced cardiovascular events statistically highly significant (p = 0.002). The effect of treatment was the same for all ethnic groups included to the study (total of 6 continents).Key words: antihypertenzive drugs - cardiovascular prevention - dyslipidemia - hypertension - statins.

[Familial hypercholesterolemia in the Czech Republic in 2016]. / Familiární hypercholesterolemie v Ceské republice v roce 2016.

Familial hypercholesterolemia (FH) is the most frequent autosomal dominant hereditary disease which is characterized by a decreased LDL-cholesterol catabolism and early clinical manifestation of atherosclerosis affecting blood vessels. The MedPed (Make early diagnosis to Prevent early deaths) project aims to diagnose patients with FH as early as possible, so that they can profit the most from a therapy started in a timely manner and avoid premature cardiovascular events. Currently, as of 31 October 2016, the Czech national database keeps records of 6 947 patients with FH from 5 223 families. Considering the prevalence of FH equalling 1 : 250, this represents 17.4 % of the overall expected number of patients with FH in the Czech Republic. Determining the mutation responsible for FH, now using a next generation sequencing technology in the Czech Republic, brings with it higher diagnostic accuracy, better cooperation of patients and in particular facilitation of cascade screening in families. Although we are among the most successful countries in the world with regard to FH detection, the majority of patients are still undiagnosed. Moreover, as it turns out, most FH patients do not reach the target values with the current therapeutic possibilities. In this regard the newly approved hypolipidemic drugs, PCSK9 inhibitors, to be hopefully available also in the Czech Republic in the near future for chosen patients with FH at high risk, hold great promise.Key words: cascade screening - familial hypercholesterolemia - LDL-cholesterol - MedPed.

[The common position of the Czech professional associations on the consensus of the European Atherosclerosis Society and the European Federation of Clinical Chemistry and Laboratory Medicine regarding investigation on blood lipids and interpretation of their levels]. / Spolecné stanovisko ceských odborných spolecností ke konsenzu European Atherosclerosis Society a European Federation of Clinical Chemistry and Laboratory Medicine k vysetrování krevních lipidu a k interpretaci jejich hodnot.

The aim of this opinion is to summarize and to comment the consensus of the European Atherosclerosis Society and European Federation of Clinical Chemistry and Laboratory Medicine, which covers two main areas: 1) whether it is necessary / required to be fasting or non-fasting before blood sampling for lipids measurement, and what are the changes in the concentration of blood lipids during the day; 2) What decision limits (cut off value) of lipids and lipoproteins should be reported from laboratories and what is the recommended procedure for people with extreme / critical blood lipid values. Following parameters are discused: total cholesterol, LDL cholesterol, HDL cholesterol, non-HDL cholesterol, triglycerides, apolipoprotein A1, apolipoprotein B, lipoprotein(a). This opinion should be the object of interest both for professionals in clinical laboratories and for physicians in hospitals and out-patients departments.Key words: apolipoproteins - blood collection - cholesterol - laboratory testing - lipoprotein(a) - cut off limits - triglycerides.

[PCSK9 inhibitors - new possibilities in the treatment of hypercholesterolemia: For which patients will be indicated?Czech atherosclerosis society statement]. / PCSK9 inhibitory - nové moznosti v lécbe hypercholesterolemie: U koho budou indikovány?Stanovisko Ceské spolecnosti pro aterosklerózu.

First line drug for the treatment of hypercholesterolemia are statins, which reduce LDL-cholesterol up to 50 %; such reduction is sufficient for most patients to achieve the target values. The exceptions are patients with familial hypercholesterolemia and patients with statin intolerance. To achieve target LDL-cholesterol in these two groups of patients will be possible with new drugs - PCSK9 inhibitors, which decrease LDL-cholesterol by an additional 50-60 %. The first two PCSK9 inhibitors (alirocumab and evolocumab) already had been approved for clinical use by European regulatory authorities. The primary indication for combination statin with PCSK9 inhibitor should be undoubtedly patients with a confirmed diagnosis of familial hypercholesterolemia, who are treated in the Czech Republic primarily in specialized centers of MedPed project. Furthermore, this treatment should be available for other patients at very high risk of cardiovascular diseases, who cannot achieve target LDL-cholesterol (eg. for statins intolerance).

[The effect of a simvastatin and ezetimib combination on blood lipids and cardiovascular events in diabetic patients (comments on the subanalysis results within the IMPROVE-IT study)]. / Vliv kombinace simvastatinu s ezetimibem na krevní lipidy a na kardiovaskulární príhody u diabetiku (komentár k výsledkum subanalýzy studie IMPROVE-IT).

IMPROVE-IT study demonstrated that the addition 10 mg of ezetimibe to 40 mg of simvastatin in patients after acute coronary syndrome reduces significantly not only their LDL-cholesterol, but also the number of cardiovascular events. Recently published subanalysis of this study was focused on whether these combinations of drugs is more preferable for patients with diabetes mellitus or for patients without diabetes. The addition of ezetimibe to a simvastatin resulted in a greater decline of LDL-cholesterol level in diabetic group than in patients without diabetes. In patients with diabetes mellitus their cardiovascular morbidity and mortality were decreased significantly; reduction of these clinical end-points in the group of patients without diabetes were not statistically significant.

[How to treat dyslipidemia in patients with metabolic syndrome]. / Jak na dyslipidemii u pacientu s metabolickým syndromem.

Typical feature of dyslipidemia in patients with metabolic syndrome is increase triglycerides, decrease HDL-cholesterol and presence of small atherogenic LDL particle; nevertheless majority of patients do not reach target level of LDL-cholesterol for their risk category as well. An essential part of treatment should be non-pharmacological approach - lifestyle changes (weight loss, change in eating habits, increased physical activity). In patients in primary prevention without diabetes decision about pharmacotherapy depend on their risk of fatal cardiovascular events in the perspective of 10 years (table SCORE). In diabetic patients and in patients in secondary prevention is pharmacotherapy indicated, unless their LDL-cholesterol does not reach its target values. The primary goal of treatment is LDL-cholesterol, so pharmacotherapy should be started with statins. If the target of LDL-cholesterol is reached and hypertriglyceridemia and/or low HDL-cholesterol persist, it is recommended to add fenofibrate to statin.

Effect of nateglinide on the incidence of diabetes and cardiovascular events.

BACKGROUND: The ability of short-acting insulin secretagogues to reduce the risk of diabetes or cardiovascular events in people with impaired glucose tolerance is unknown. METHODS: In a double-blind, randomized clinical trial, we assigned 9306 participants with impaired glucose tolerance and either cardiovascular disease or cardiovascular risk factors to receive nateglinide (up to 60 mg three times daily) or placebo, in a 2-by-2 factorial design with valsartan or placebo, in addition to participation in a lifestyle modification program. We followed the participants for a median of 5.0 years for incident diabetes (and a median of 6.5 years for vital status). We evaluated the effect of nateglinide on the occurrence of three coprimary outcomes: the development of diabetes; a core cardiovascular outcome that was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure; and an extended cardiovascular outcome that was a composite of the individual components of the core composite cardiovascular outcome, hospitalization for unstable angina, or arterial revascularization. RESULTS: After adjustment for multiple testing, nateglinide, as compared with placebo, did not significantly reduce the cumulative incidence of diabetes (36% and 34%, respectively; hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15; P=0.05), the core composite cardiovascular outcome (7.9% and 8.3%, respectively; hazard ratio, 0.94, 95% CI, 0.82 to 1.09; P=0.43), or the extended composite cardiovascular outcome (14.2% and 15.2%, respectively; hazard ratio, 0.93, 95% CI, 0.83 to 1.03; P=0.16). Nateglinide did, however, increase the risk of hypoglycemia. CONCLUSIONS: Among persons with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors, assignment to nateglinide for 5 years did not reduce the incidence of diabetes or the coprimary composite cardiovascular outcomes. (ClinicalTrials.gov number, NCT00097786.)

Effect of valsartan on the incidence of diabetes and cardiovascular events.

BACKGROUND: It is not known whether drugs that block the renin-angiotensin system reduce the risk of diabetes and cardiovascular events in patients with impaired glucose tolerance. METHODS: In this double-blind, randomized clinical trial with a 2-by-2 factorial design, we assigned 9306 patients with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors to receive valsartan (up to 160 mg daily) or placebo (and nateglinide or placebo) in addition to lifestyle modification. We then followed the patients for a median of 5.0 years for the development of diabetes (6.5 years for vital status). We studied the effects of valsartan on the occurrence of three coprimary outcomes: the development of diabetes; an extended composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, arterial revascularization, or hospitalization for unstable angina; and a core composite outcome that excluded unstable angina and revascularization. RESULTS: The cumulative incidence of diabetes was 33.1% in the valsartan group, as compared with 36.8% in the placebo group (hazard ratio in the valsartan group, 0.86; 95% confidence interval [CI], 0.80 to 0.92; P<0.001). Valsartan, as compared with placebo, did not significantly reduce the incidence of either the extended cardiovascular outcome (14.5% vs. 14.8%; hazard ratio, 0.96; 95% CI, 0.86 to 1.07; P=0.43) or the core cardiovascular outcome (8.1% vs. 8.1%; hazard ratio, 0.99; 95% CI, 0.86 to 1.14; P=0.85). CONCLUSIONS: Among patients with impaired glucose tolerance and cardiovascular disease or risk factors, the use of valsartan for 5 years, along with lifestyle modification, led to a relative reduction of 14% in the incidence of diabetes but did not reduce the rate of cardiovascular events. (ClinicalTrials.gov number, NCT00097786.)

Noninvasive prediction of the exercise-induced elevation in left ventricular filling pressure in post-heart transplant patients with normal left ventricular ejection fraction.

OBJECTIVES: At present, there are conflicting data on the ability of echocardiographic parameters to predict the exercise-induced elevation of left ventricular (LV) filling pressure. The purpose of the present study was to validate the ratio of early diastolic transmitral (E) to mitral annular velocity (e') obtained at peak exercise in its capacity to determine the exercise-induced elevation of pulmonary capillary wedge pressure (PCWP) and to reveal new noninvasive parameters with such capacity. METHODS: Sixty-one patients who had undergone heart transplantation with normal LV ejection fraction underwent simultaneous exercise echocardiography and right heart catheterization. RESULTS: In 50 patients with a normal PCWP at rest, exercise E/e' ≥8.5 predicted exercise PCWP ≥25 mmHg with a sensitivity of 64.3% and a specificity of 84.2% (area under the curve [AUC]=0.74). A comparable or slightly better prediction was achieved by exercise E/peak systolic mitral annular velocity (s') ≥11.0 (sensitivity 79.3%; specificity 57.9%; AUC=0.75) and exercise E/LV systolic longitudinal strain rate ≤-105 cm (sensitivity 78.9%; specificity 78.6%; AUC=0.87). Combined, exercise E/s' and exercise E/e' resulted in a trend toward a slightly more precise prediction (sensitivity 53.6%; specificity 89.5%; AUC=0.78) than did either variable alone. CONCLUSIONS: Exercise E/e', used as a sole parameter, is not sufficiently precise to predict the exercise-induced elevation of PCWP. Exercise E/s', E/LV systolic longitudinal strain rate or combinations of these parameters may represent further promising possibilities for predicting exercise PCWP elevation.

Reporting LDL cholesterol results by clinical biochemistry laboratories in Czechia and Slovakia to improve the detection rate of familial hypercholesterolemia.

Introduction: This survey aims to assess the implementation of recommendations from the European Atherosclerosis Society (EAS) and the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) by clinical biochemistry laboratories in Czechia and Slovakia in their policies for reporting low-density lipoprotein cholesterol (LDL-C) concentrations. Materials and methods: The web-based survey was distributed to all 383 Czech and Slovak clinical biochemistry laboratories that measure lipids by external quality assessment provider SEKK. A total of 17 single-answer questions were included. The questionnaire was focused on the detection and decision points in familial hypercholesterolemia (FH). All survey answers were taken into account. The laboratories followed the EFLM and EAS guidelines when they reported an interpretative comment considering FH diagnosis in adults. Results: A total of 203 (53%) laboratories answered. Only 5% of laboratories added interpretative comments considering FH diagnosis when LDL-C concentrations are above 5.0 mmol/L in adults, and 3% of laboratories added interpretative comments considering FH diagnosis when LDL-C concentrations are above 4.0 mmol/L in children. Only 7% of laboratories reported goals for all cardiovascular risk categories (low, moderate, high, very high). Non-HDL cholesterol concentrations were calculated by 74% of responders. A significant number (51%) of participants did not measure apolipoprotein B, and 59% of laboratories did not measure lipoprotein(a). Conclusions: Only a small portion of laboratories from Czechia and Slovakia reported high LDL-C results with interpretative comments considering FH diagnosis in adults, the laboratories did not follow the guidelines.

Genetic risk score in patients with the APOE2/E2 genotype as a predictor of familial dysbetalipoproteinemia.

BACKGROUND: Familial dysbetalipoproteinemia (FD) is an autosomal recessive (rarely dominant) inherited disorder that is almost exclusively associated with the apolipoprotein E gene (APOE) variability. Nonetheless, only a small proportion of APOE2/E2 subjects develop the phenotype for mixed dyslipidemia; the context of other trigger metabolic or genetic factors remains unknown. METHODS: One hundred and one patients with FD and eighty controls (all APOE2/E2 homozygotes; rs429358) were screened for 18 single-nucleotide polymorphisms (SNPs) within the genes involved in triglyceride metabolism. RESULTS: Two SNPs were significantly associated with the FD phenotype (rs439401 within APOE; P < 0.0005 and rs964184 within ZPR1/APOA5/A4/C3/A1 gene cluster; P < 0.0001). Unweighted genetic risk scores - from these two SNPs (GRS2), and, also, additional 13 SNPs with P-value below 0.9 (GRS15) - were created as an additional tool to improve the risk estimation of FD development in subjects with the APOE2/E2 genotype. Both GRS2 and GRS15 were significantly (P < 0.0001) increased in patients and both GRSs discriminated almost identically between the groups (P = 0.86). Subjects with an unweighted GRS2 of three or more had an almost four-fold higher risk of FD development than other individuals (OR 3.58, CI: 1.78-7.18, P < 0.0005). CONCLUSIONS: We identified several SNPs that are individual additive factors influencing FD development. The use of unweighted GRS2 is a simple and clinically relevant tool that further improves the prediction of FD in APOE2/E2 homozygotes with corresponding biochemical characteristics.

Depression as a prominent cause of sexual dysfunction in women with epilepsy.

The etiology of sexual dysfunction in patients with epilepsy is perceived as multifactorial, with seizure and medication effects being the most often discussed and analyzed factors. We used common statistical methods to evaluate the impact of type of epilepsy, antiepileptic medication, hormones, seizure control, and symptoms of depression and anxiety on sexual function in a group of 78 women with epilepsy. To assess sexual function, we used the Female Sexual Function Index (FSFI). To assess symptoms of depression and anxiety, we used the Beck Depression and Anxiety Inventories (BDI, BAI). Of all the observed factors, only BDI score was significantly correlated with FSFI score. There was no correlation between FSFI, hormonal levels, seizure frequency, and symptoms of anxiety. No differences were found between patients with focal and those with generalized epilepsies; between seizure-free and non-seizure-free patients; or in relation to the number and type of antiepileptic medications.