Correlations among different platelet aggregation pathways in a group of healthy volunteers.

Platelet aggregation is a complicated process mediated by different signaling pathways. As the process is highly complex and apparently redundant, the relationships between these pathways are not yet fully known. The aim of this project was to study the interconnections among seven different aggregation pathways in a group of 53 generally healthy volunteers aged 20 to 66 years. Platelet aggregation was induced with thrombin receptor activating peptide 6 (TRAP), arachidonic acid (AA), platelet activating factor 16 (PAF), ADP, collagen, thromboxane A2 analogue U46619 or ristocetin (platelet agglutination) ex vivo in fasting blood samples according to standardized timetable protocol. Additionally, some samples were pre-treated with known clinically used antiplatelet drugs (vorapaxar, ticagrelor or acetylsalicylic acid (ASA)). Significant correlations among all used inducers were detected (Pearson correlation coefficients (rP): 0.3 to 0.85). Of all the triggers, AA showed to be the best predictor of the response to other inducers with rP ranging from 0.66 to 0.85. Interestingly, the antiplatelet response to ticagrelor strongly predicted the response to unrelated drug vorapaxar (rP = 0.71). Our results indicate that a response to one inducer can predict the response for other triggers or even to an antiplatelet drug. These data are useful for future testing but should be also confirmed in patients.

What is the context?• Platelet activation is a complicated process with multiple signaling cascades involved.• A total of seven common platelet triggers (ADP, collagen, TRAP-6, PAF, arachidonic acid/AA/, ristocetin and U46619) were tested.• The process is dependent on many factors including sex, age, concomitant disease(s), pharmacotherapy.What is new?• There were significant correlations between all tested aggregatory cascades.• AA has the highest rate of response predictability in our heterogeneous generally healthy volunteer group.• There was no correlation between impedance aggregometry in whole blood and turbidimetric measurement with platelet-rich plasma.What is the impact?• The effect of antiplatelet drugs can be assessed from the reaction to different trigger(s) at least in this group of healthy patients.• Future studies must test these relationships in patients with different diseases.

Sex-Related Differences in Platelet Aggregation: A Literature Review Supplemented with Local Data from a Group of Generally Healthy Individuals.

The process of platelet aggregation is often influenced by several factors including sex and age. A literature review confirmed the existence of sex-related differences in platelet aggregation. Although 68 out of 78 papers found such differences, there are still some controversies regarding these differences, which can be due to multiple factors (age, trigger, concomitant disease, sample handling, etc.). These outcomes are discussed in line with novel results obtained from a local study, in which blood samples from a total of 53 overall healthy women and men with ages ranging from 20 to 66 years were collected. Aggregation was induced with seven different triggers (ristocetin, thrombin receptor activating peptide 6 [TRAP-6], arachidonic acid [AA], platelet-activating factor 16 [PAF-16], ADP, collagen, or thromboxane A2 analog U-46619) ex vivo. In addition, three FDA-approved antiplatelet drugs (vorapaxar, ticagrelor, or acetylsalicylic acid [ASA]) were also tested. In general, women had higher aggregation responses to some agonists (ADP, TRAP), as well as lower benefit from inhibitors (ASA, vorapaxar). The aggregatory responses to AA and TRAP decreased with age in both sexes, while responses to ADP, U-46619, and PAF were affected by age only in women. In conclusion, more studies are needed to decipher the biological importance of sex-related differences in platelet aggregation in part to enable personalized antiplatelet treatment.

The Impact of Convertase Subtilisin/Kexin Type 9 Monoclonal Antibodies with and without Apheresis on Platelet Aggregation in Familial Hypercholesterolemia.

BACKGROUND AND AIMS: It is well known that elevated cholesterol is associated with enhanced platelet aggregation and patients suffering from familial hypercholesterolemia (FH) have a high risk of thrombotic cardiovascular events. Although decreasing cholesterol level is associated with attenuation of platelet hyperactivity, there are currently no data on the effect of convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9ab) on platelet reactivity in FH. The aim of the study was to analyse the impact of different therapies including PCSK9ab on platelet aggregation in FH. METHODS: This study enrolled all 15 patients treated in the University Hospital Hradec Králové for FH. PCSK9ab have been administered in 12 of 15 patients while 8 patients were also undergoing lipid apheresis. Blood samples from all patients including pre- and post-apheresis period were tested for platelet aggregation triggered by 7 inducers, and the effect of 3 clinically used drugs (acetylsalicylic acid, ticagrelor and vorapaxar) was compared as well. RESULTS: Although apheresis decreased the reactivity of platelets in general, platelet responses were not different between non-apheresis patients treated with PCSK9ab and apheresis patients (post-apheresis values) with the exception of ristocetin. However, when compared to age-matched healthy population, FH patients had significantly lower platelet aggregation responses to 4 out of 7 used inducers and higher profit from 2 out of 3 used antiplatelet drugs even after exclusion of FH patients regularly receiving conventional antiplatelet treatment. CONCLUSION: This study showed for the first time the suitability of PCSK9ab treatment for reduction of platelet reactivity in FH patients.

Metformin -associated lactic acidosis.

Lactic acidosis is a feared complication of metformin therapy. In our article we describe 2 case reports of patients treated with metformin, who developed this complication. In the first case, which was fatal, cummulation of lactate was a result of acute kidney failure caused by diarrhea. In the second patient, lactic acidosis developed in the terrain of preexisting chronic kidney disease, when dyspepsia and decreased fluid intake caused progression into acute kidney failure. In this case, treatment of lactic acidosis was successful. Death of the first patient was probably caused by the presence of serious comorbidities and other complications which developed early after her addmission to intensive care unit. Lactic acidosis can be prevented by strict avoidance of metformin use in case of contraindications and interruption of its use during intercurrent disease.

Lipoprotein(a) - the cardiovascular risk factor: significance and therapeutic possibilities.

About 20 % of the population has raised Lp(a) concentrations and evidence suggests that high levels of Lp(a) are an independent cardiovascular risk factor. Both the European Society of Cardiology and the European Atherosclerosis Society recommend measuring Lp(a) values in intermediate to high-risk patients for risk stratification, as well as in patients already under statin treatment and with recurrent clinical events as a residual risk factor that calls for lipid-lowering therapy intensification. Strategies used to lower Lp(a) concentrations have either been partially disappointing in the past or lack cardiovascular outcome data. Therefore, Lp(a) has often been considered as a nonmodifiable cardiovascular risk factor. New and consistent data retrieved from the PCSK9 inhibitor trials now suggest that Lp(a) can be decreased effectively by roughly 30 %, while emerging data from apo(a) antisense therapy trials suggest that selective and potent Lp(a) reduction is a feasible treatment approach in the future. The impact of such decreases on the occurrence of cardiovascular outcomes, independent from LDL-C, could, if established, herald Lp(a) in the treatment of atherosclerosis. Key words: alirocumab - atherosclerosis - cardiovascular disease - evolocumab - hypercholesterolaemia - lipoprotein(a) - lipoprotein apheresis.

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.

Statin therapy in elderly patients.

Cardiovascular events occur most frequently in patients at higher age groups. The elderly suffer not only more advanced and complex changes of cardiovascular system but, also, other chronic conditions. Moreover, compared to middle-age, different therapeutic response is often observed due to changes of pharmaco-kinetics and -dynamics; these patients use other medications, which may trigger drug interactions. The situation is further complicated by non-adherence related to frequent cognitive impairment. On one hand the elderly enjoy the greatest absolute benefit from adequate cardiovascular treatment while on the other they might be more susceptible to adverse reactions. In spite of the fact statins represent preventative medications, they must be indicated cautiously taken into consideration comorbidities, frailty and disability occurring in advanced age. Frail and disabled patients have greater risk of statin adverse effects, however, even these patients have lower mortality rates while being on statins. In seniors with life expectancy exceeding 5 years statins, when indicated, bring unambiguously proven benefit and should be considered high-priority medications. Key words: atherosclerosis - cardiovascular disease - dyslipidemia - elderly - frailty - management - statins.

[The role of PCSK9-inhibitors and of lipoprotein apheresis in the treatment of homozygous and severe heterozygous familial hypercholesterolemia: A rivalry, or are things quite different?] / Postavení inhibitoru PCSK9 a lipoproteinové aferézy v lécbe homozygotní a závazné heterozygotní familiární hypercholesterolemie: Kdo z koho, nebo je to jinak?

PCSK9-inhibitors belong to the new class of hypolipidemic agents. They enhance catabolism of low density lipoprotein cholesterol (LDL-C) through inhibiting activity of proprotein convertase subtilisin/kexin type 9 (PCSK9). They are monoclonal antibodies (alirocumab, evolocumab etc). Under clinical development are also other types of PCSK9-inhibitors which act at a subcellular level. The treatment with PCSK9-inhibitors can be beneficially combined with lipoprotein apheresis (LA). If such treatment using PCSK9-inhibitors is possible with regard to an individual patients genotype, the combination of LA and PCSK9-inhibitors leads to slowing the space of LDL-C increase between individual procedures of apheresis and enables attaining of the lowest possible values of LDL-cholesterolemia for the longest possible period of time. Due to high efficiency of PCSK9-inhibitors lowering LDL-C, but also their lower cost as compared to therapeutic LA, PCSK9-inhibitors now take precedence over the use of extracorporeal lipoprotein apheresis which, nonetheless, still remains the final method for hypolipidemic treatment of patients with severe hypercholesterolemia, who are resistant to conventional therapy while not reaching the target lipid values and at high cardiovascular risk. They belong to extracorporeal elimination methodologies which remove low density lipoprotein (LDL) cholesterol from circulating blood. LA in combination with higher doses of statins and ezetimib currently represents the most efficient method of treatment of homozygous and statin-refractory heterozygous familial hypercholesterolemia (FH). Residual cardiovascular risk in these patients still remains high, in particular because, despite the aforementioned treatment, the target values for lipids according to present recommendations cannot be reached. The combination of LA with the new drugs is promising, primarily due to its potential for further lowering of LDL-cholesterolemia between the individual apheresis procedures. Preliminary results of the ongoing studies indicate that the new hypolipidemic drugs in combination with LA, or when used separately, will substantially enrich and improve the treatment of refractory FH.Key words: alirocumab - atherosclerosis - evolocumab - hypercholesterolemia - cardiovascular disease - lipoprotein apheresis.

[Severe familial hypercholesterolemia treatment]. / Lécba tezké familiární hypercholesterolemie.

Familial hypercholesterolemia (FH) represents the most frequent of inborn errors of metabolism. It is a group of disorders with a codominant mode of inheritance characterized by marked elevations of LDL-cholesterol as well as atherosclerotic cardiovascular disease risk. Clinical (phenotypic) picture of FH varies widely depending on genotype and concomitant risk factors. Identification of most seriously affected FH individuals is necessary for proper clinical management. The therapeutic approach must be complex and comprehensive. The corner stone of pharmacotherapy is high-intensity statin therapy usually combined with ezetimibe (possibly complemented with bile acid sequestrant). Even this multi-drug combination do not lead majority of patients to their treatment goals. Thus, combinations with other pharmacological (PCSK9 inhibitors, apoB-100 anti-sense therapy, MTP inhibition) and non-pharmacological (LDL-apheresis, liver transplantation) approaches is being used.Key words: ezetimibe - LDL-apheresis - lomitapide - mipomersen - PCSK9 inhibitors - severe familial hypercholesterolemia - 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.

[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).

[Position of lipoprotein apheresis in present]. / Postavení lipoproteinové aferézy v soucasnosti.

Lipoprotein apheresis (LA) is an effective treatment method the patients with severe hypercholesterolemia, resistant to the standard therapy. LA is an extracorporeal elimination technique, which specifically removes low density lipoprotein (LDL) cholesterol from the circulation. At present, lipoprotein apheresis, combined with high-dose statin and ezetimibe therapy, is the best available means of treating patients with homozygous and statin refractory heterozygous familial hypercholesterolaemia (FH). However, the extent of cholesterol-lowering achieved is often insufficient to meet the targets set by current guidelines. The recent advent of new classes of lipid-lowering agents provides new hope that the latter objective may now be achievable. These compounds act either by reducing low density lipoprotein (LDL) cholesterol production by inhibiting apolipoprotein B synthesis with an antisense oligonucleotide (mipomersen), or by inhibiting microsomal triglyceride transfer protein (lomitapid), or by enhancing LDL catabolism via monoclonal antibody-mediated inhibition of the activity of proprotein convertase subtilisin/kexin 9 (PCSK9-alirocumab, evolocumab etc). The promising is the combination of LDL-apheresis with new drugs, namely for its potential to further decrease of LDL-cholesterol between apheresis. Depending on the outcome of current trials, it seems likely that these compounds, used alone or combined with lipoprotein apheresis, will markedly improve the management of refractory FH.

[LDL-apheresis in the treatment familial hypercholesterolemia]. / LDL-aferéza v lécbe familiárních hyperlipoproteinemií

LDL-apheresis is an extracorporeal elimination technique, which specifically removes LDL-cholesterol from the circulation. There are six methods for the selective LDL-cholesterol removal these days. The main indications for LDL-apheresis are the diagnosis of homozygous familial hypercholesterolemia, heterozygous familial hypercholesterolemia which is refractory the standard care and intolerance of routine care, and also patients with lipoprotein(a) increase resistant to the farmacotherapy. There is still debate which LDL-cholesterolemia is indication for LDL-apheresis therapy, and the recommendation differs among various countries. Despite large randomized trials are missing, there are several good quality studies to conclude, that the beneficial cardiovascular effects of LDL-apheresis in severe hypercholesterolemia are important and beneficial.

Optimizing Recovery in Elderly Patients: Anabolic Benefits of Glucose Supplementation during the Rehydration Period.

BACKGROUND: Since many acutely admitted older adults display signs of dehydration, treatment using balanced crystalloids is an important part of medical care. Additionally, many of these patients suffer from chronic malnutrition. We speculated that the early addition of glucose might ameliorate the hospital-related drop of caloric intake and modify their catabolic status. METHODS: We included patients 78 years and older, admitted acutely for non-traumatic illnesses. The patients were randomized into either receiving balanced crystalloid (PlasmaLyte; group P) or balanced crystalloid enriched with 100 g of glucose per liter (group G). The information about fluid balance and levels of minerals were collected longitudinally. RESULTS: In the G group, a significantly higher proportion of patients developed signs of refeeding syndrome, i.e., drops in phosphates, potassium and/or magnesium when compared to group P (83.3 vs. 16.7%, p < 0.01). The drop in phosphate levels was the most pronounced. The urinalysis showed no differences in the levels of these minerals in the urine, suggesting their uptake into the cells. There were no differences in the in-hospital mortality or in the 1-year mortality. CONCLUSION: The short-term administration of balanced crystalloids with glucose induced an anabolic shift of electrolytes in acutely admitted older adults.

Head-to-head ex vivo comparison of clinically used direct anticoagulant drugs.

An imbalance in coagulation is associated with cardiovascular events. For prevention and treatment, anticoagulants, currently mainly xabans and gatrans, are used. The purpose of the present study was to provide a head-to-head comparison since there are no studies directly evaluating these novel anticoagulants. An additional aim was to find whether selected anthropological and biochemical factors can affect their anticoagulant properties as they are used in fixed doses. In this cross-sectional study, blood from 50 generally healthy donors was collected, and coagulation responses to dabigatran, argatroban, rivaroxaban, and apixaban, at a concentration of 1 µM, were analyzed. Heparin was used as a positive control. Prothrombin time (PT) expressed as international normalized ratio (INR) and activated partial thromboplastin time (aPTT) were measured and compared. Rivaroxaban was the most active according to PT/INR while argatroban according to aPTT. The ex vivo anticoagulant effect measured by INR correlated inversely with body mass index (BMI) in all four anticoagulants tested. Shortening of aPTT was associated with higher cholesterol and triglyceride levels. No sex-related differences were observed in response to the anticoagulant treatments. As this was an ex vivo study and pharmacokinetic factors were not included, the influence of BMI is of high therapeutic importance.

In vitro comparison of the effectiveness of various antimicrobial locks with taurolidine in the treatment and prevention of catheter-related bloodstream infections in patients receiving parenteral nutrition.

OBJECTIVES: To evaluate the effectiveness of various taurolidine solutions in the prevention and treatment of catheter-related bloodstream infections (CRBSIs) caused by the entire spectrum of microbes in patients receiving parenteral nutrition in a shorter period of time. METHODS: The in vitro method was used to test for eradication of biofilm. Different locks were used: TauroSept (2%), TauroLock (1.35%), TauroLock half concentration, and 3.5% taurolidine and tested on Staphylococcus (S.) epidermidis, S. aureus, S. hominis, methicillin-resistant S. aureus (MRSA), Pseudomonas (P.) aeruginosa (PSAE), multidrug-resistant P. aeruginosa (MR PSAE), vancomycin-resistant enterococci, Klebsiella pneumoniae producing carbapenemase (KPC), Klebsiella pneumoniae producing extended-spectrum beta-lactamase (KLPN ESBL), Candida (C.) albicans, and C. glabrata. Broviac catheters were incubated for growth of each organism and then incubated in lock solutions. Colony forming units (CFUs) were then counted after 30 min, 60 min, and 120 min of incubation. RESULTS: A statistically significant decrease in CFUs was observed after 30 min of taurolidine exposure for S. hominis, PSAE, KLPN ESBL, KLPN KPC, C. albicans, and C. glabrata; after 60 min of exposure for S. epidermidis, PSAE, MR PSAE, KLPN ESBL, KPC, C. albicans, and C. glabrata; and after 120 min of exposure for S. epidermidis, S. hominis, S. aureus, PSAE, MR PSAE, KLPN ESBL, KPC, C. albicans, C. glabrata. CONCLUSIONS: The application of taurolidine is effective in the treatment of CRBSIs. Taurolidine proved to be more effective against Gram-negative microorganisms during a 30-min exposure. Using 0.675% taurolidine is still effective. To achieve the required antimicrobial effect, the catheter must be sanitized for at least 2 h.

Long-Term LDL-Apheresis Treatment and Dynamics of Circulating miRNAs in Patients with Severe Familial Hypercholesterolemia.

Lipoprotein apheresis (LA) is a therapeutic option for patients with severe hypercholesterolemia who have persistently elevated LDL-C levels despite attempts at drug therapy. MicroRNAs (miRNAs), important posttranscriptional gene regulators, are involved in the pathogenesis of atherosclerosis. Our study aimed to monitor the dynamics of twenty preselected circulating miRNAs in patients under long-term apheresis treatment. Plasma samples from 12 FH patients (men = 50%, age = 55.3 ± 12.2 years; mean LA overall treatment time = 13.1 ± 7.8 years) were collected before each apheresis therapy every sixth month over the course of four years of treatment. Eight complete follow-up (FU) samples were measured in each patient. Dynamic changes in the relative quantity of 6 miRNAs (miR-92a, miR-21, miR-126, miR-122, miR-26a, and miR-185; all p < 0.04) during FU were identified. Overall apheresis treatment time influenced circulating miR-146a levels (p < 0.04). In LDLR mutation homozygotes (N = 5), compared to heterozygotes (N = 7), we found higher plasma levels of miR-181, miR-126, miR-155, and miR-92a (all p < 0.03). Treatment with PCSK9 inhibitors (N = 6) affected the plasma levels of 7 miRNAs (miR-126, miR-122, miR-26a, miR-155, miR-125a, miR-92a, and miR-27a; all p < 0.04). Long-term monitoring has shown that LA in patients with severe familial hypercholesterolemia influences plasma circulating miRNAs involved in endothelial dysfunction, cholesterol homeostasis, inflammation, and plaque development. The longer the treatment using LA, the better the miRNA milieu depicting the potential cardiovascular risk.

The Effect of 4-Methylcatechol on Platelets in Familial Hypercholesterolemic Patients Treated with Lipid Apheresis and/or Proprotein Convertase Subtilisin Kexin 9 Monoclonal Antibodies.

Elevated low-density lipoprotein (LDL) cholesterol levels lead to atherosclerosis and platelet hyperaggregability, both of which are known culprits of arterial thrombosis. Normalization of LDL cholesterol in familial hypercholesterolemia (FH) is not an easy task and frequently requires specific treatment, such as regularly performed lipid apheresis and/or novel drugs such as proprotein convertase subtilisin kexin 9 monoclonal antibodies (PCSK9Ab). Moreover, a high resistance rate to the first-line antiplatelet drug acetylsalicylic acid (ASA) stimulated research of novel antiplatelet drugs. 4-methylcatechol (4-MC), a known metabolite of several dietary flavonoids, may be a suitable candidate. The aim of this study was to analyse the antiplatelet effect of 4-MC in FH patients and to compare its impact on two FH treatment modalities via whole-blood impedance aggregometry. When compared to age-matched, generally healthy controls, the antiplatelet effect of 4-MC against collagen-induced aggregation was higher in FH patients. Apheresis itself improved the effect of 4-MC on platelet aggregation and blood from patients treated with this procedure and pretreated with 4-MC had lower platelet aggregability when compared to those solely treated with PCKS9Ab. Although this study had some inherent limitations, e.g., a low number of patients and possible impact of administered drugs, it confirmed the suitability of 4-MC as a promising antiplatelet agent and also demonstrated the effect of 4-MC in patients with a genetic metabolic disease for the first time.

Evolocumab is Initiated in Central and Eastern Europe at Much Higher LDL-C Levels Than Recommended in Guidelines: Results from the Observational HEYMANS Study.

Purpose: We examined clinical characteristics and low-density lipoprotein cholesterol (LDL-C) lowering in patients initiating evolocumab in real-world practice in a Central and Eastern European (CEE) cohort from the pan-European HEYMANS study. Methods: Patients from Bulgaria, Czech Republic, and Slovakia were enrolled at initiation of evolocumab (baseline) as per local reimbursement criteria. Demographic/clinical characteristics, lipid-lowering therapy (LLT) and lipid values were collected from medical records for ≤6 months before baseline and ≤30 months after evolocumab initiation. Results: Overall, 333 patients were followed over a mean (SD) duration of 25.1 (7.5) months. At initiation of evolocumab, LDL-C levels were markedly elevated in all three countries, with a median (Q1, Q3) LDL-C of 5.2 (4.0, 6.6) mmol/L in Bulgaria, 4.5 (3.8, 5.8) mmol/L in the Czech Republic, and 4.7 (4.0, 5.6) mmol/L in Slovakia. Within the first three months of evolocumab treatment, LDL-C levels were reduced by a median of 61% in Bulgaria, 64% in the Czech Republic, and 53% in Slovakia. LDL-C levels remained low throughout the remaining period of observation. The 2019 ESC/EAS guideline-recommended risk-based LDL-C goals were attained by 46% of patients in Bulgaria, 59% in the Czech Republic, and 43% of patients in Slovakia. LDL-C goal attainment was higher in patients receiving a statin ± ezetimibe-based background therapy (Bulgaria: 55%, Czech Republic: 71%, Slovakia: 51%) compared to those receiving evolocumab alone (Bulgaria: 19%, Czech Republic: 49%, Slovakia: 34%). Conclusion: In the HEYMANS CEE cohort, patients initiated on evolocumab had baseline LDL-C levels approximately three-fold higher than guideline-recommended thresholds for PCSK9i initiation. Risk-based LDL-C goal attainment was highest in patients receiving high-intensity combination therapy. Lowering the LDL-C reimbursement threshold for PCSK9i initiation would allow more patients to receive combination therapy, thus improving LDL-C goal attainment. Trial registration: ClinicalTrials.gov (NCT02770131; registration date: 27 April 2016).

Spatial and temporal trends in δ66Zn and 206Pb/207Pb isotope ratios along a rural transect downwind from the Upper Silesian industrial area: Role of legacy vs. present-day pollution.

Transect sampling is an under-exploited tool in isotope studies of atmospheric pollution. Few studies have combined Zn and Pb isotope ratios to investigate whether atmospheric pollution at a receptor site is dominated by a different anthropogenic source of each of these toxic elements. It has been also unclear whether pollution abatement strategies in Central Europe have already resulted in regionally well-mixed background isotope signature of atmospheric Zn and Pb. Zinc and lead isotope ratios were determined in snow collected along a rural transect downwind from the Upper Silesian industrial area (southern Poland). Spatial and temporal gradients in δ66Zn and 206Pb/207Pb ratios at four sites were compared with those of ore and coal collected in eight Czech and Polish mining districts situated at distances of up to 500 km. Snow pollution was extremely high 8 km from Olkusz in 2011 (1670 µg Zn L-1; 240 µg Pb L-1), sharply decreased between 2011 and 2018, and remained low in 2019-2021. Snow pollution was lower at sites situated 28-68 km from Olkusz. Across study sites, mean δ66Zn and 206Pb/207Pb ratios of snow were -0.13‰ and 1.155, respectively. With an increasing distance from Olkusz, the δ66Zn values first increased and then decreased, while the 206Pb/207Pb ratios first decreased and then increased. The δ66Zn values in snow plotted closer to those of Upper Silesian ores (-0.20‰) than to the δ66Zn values of Upper Silesian stone coal (0.52‰), showing predominance of smelter-derived over power-plant derived Zn pollution. The 206Pb/207Pb ratios of Upper Silesian coal (1.171) and Upper Silesian ores (1.180) were higher compared to those of snow. A206Pb/207Pb vs.208Pb/207Pb plot identified legacy pollution from leaded gasoline as the low-radiogenic mixing end-member. Across the transect sites, only the last sampling campaign exhibited a high degree of isotope homogenization for both Zn and Pb.