Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, such as alirocumab and evolocumab, effectively reduce LDL-C levels, improve cardiovascular outcomes, and are well tolerated in the treatment of heterozygous familial hypercholesterolemia (HeFH). Oxidative stress, increased in HeFH, leads to DNA damage, LDL oxidation (ox-LDL), and reduced total plasma antioxidant capacity, which promotes the development of atherosclerosis. The aim of the study was to assess whether treatment with PCSK9 inhibitors reduces ox-LDL, anti-ox-LDL antibodies, oxidative stress, and DNA damage, including 8-OH-Gua levels. The study included 40 patients with HeFH diagnosed clinically or genetically, and 33 healthy volunteers at low cardiovascular risk as controls. Blood samples were collected from all participants for lipid profile, Lp(a), oxidative stress markers (ox-LDL, 8-OHdG, anti-oxLDL antibodies), total antioxidant capacity of plasma (TAC), and DNA damage status (using the comet assay with repair enzymes). The study showed that treatment with PCSK9 inhibitors (alirocumab or evolocumab) in HeFH patients significantly improved lipid profiles and reduced levels of oxidative stress markers such as 8-OHdG and ox-LDL, while increasing levels of anti-ox-LDL and TAC. This therapy also significantly reduced purine and pyrimidine DNA damage, although not to the level observed in the control group. The efficacy of reducing DNA damage was greater with alirocumab, which could be related to higher baseline levels of Lp(a) and oxidative damage in these patients. Treatment with PCSK9 inhibitors in HeFH patients reduces oxidative stress and DNA damage, indicating additional non-lipid benefits that support their use in preventing atherosclerotic complications.

Ethanol consumption can modify both drug exposure and drug response. However, the clinical relevance of these interactions depends strongly on the timing and pattern of alcohol intake, the affected pharmacological pathway, the dosage form and organ reserve. This review summarizes current evidence on ethanol-drug interactions, particularly human crossover studies, phenotyping studies, cohort analyses and appropriate case reports. It distinguishes acute ethanol-drug co-exposure, chronic alcohol exposure, drug use during early abstinence after chronic drinking, and pharmacotherapy in alcohol-associated liver disease. Key mechanisms include ADH- and ALDH-dependent ethanol oxidation, acetaldehyde formation, NADH/NAD+ redox shift, CYP2E1 induction, carboxylesterase 1 (CES1) modulation, altered intestinal and hepatic first-pass handling, dose dumping from susceptible modified-release products, changes in protein binding in alcohol-associated liver disease, and ALDH inhibition with acetaldehyde accumulation in disulfiram-like reactions. At the molecular level, ethanol may promote acetaldehyde adduct formation with proteins and DNA, CYP2E1-driven reactive oxygen species generation, redox stress, intestinal barrier injury, and CES1-dependent transesterification of selected ester drugs. Acute ethanol intake mainly increases pharmacodynamic toxicity and causes short-term pharmacokinetic disturbances, including enhanced central nervous system depression, delayed gastric emptying, impaired glucose and lactate handling and altered hemodynamic responses. In contrast, chronic exposure, early abstinence and alcohol-associated liver disease are more often associated with hepatic enzyme and transporter remodeling, altered protein binding, reduced hepatic or renal reserve, and greater susceptibility to drug-related organ injury. The highest-risk scenarios involve older adults, polypharmacy, alcohol-associated liver disease, dehydration or acute illness, early abstinence, and the concurrent use of central nervous system depressants, glucose-lowering drugs, NSAIDs, antihypertensives, renally eliminated drugs or warfarin. Hence, ethanol exposure should be treated as a dynamic, context-dependent modifier factor that can acutely exacerbate pharmacodynamic toxicity, alter selected pharmacokinetic pathways and lower organ tolerance to drug-related injury.

Wprowadzenie Lipoproteina(a) [Lp(a)] to cząsteczka lipidowa podobna do cholesterolu lipoprotein o niskiej gęstości (LDL-C). Podwyższony poziom Lp(a) jest związany ze zwiększonym ryzykiem miażdżycy. Cel pracy Celem badania jest przesiewowa analiza poziomów Lp(a) u pacjentów przyjętych do Kliniki Chorób Wewnętrznych, niezależnie od tego, czy hospitalizacja była związana z przyczynami kardiologicznymi, czy niekardiologicznymi. Materiał i metody Materiały i Metody Badaniem objęto 104 pacjentów hospitalizowanych w Klinice Chorób Wewnętrznych i Farmakologii Klinicznej w okresie od 2 lipca 2021 r. do 3 grudnia 2021 r., z wyłączeniem osób przyjętych z powodu zakażenia SARS-CoV-2. Pacjentów analizowano pod kątem obecności miażdżycy, poziomu Lp(a) oraz innych parametrów laboratoryjnych. Podzielono ich na dwie grupy: pacjentów przyjętych z powodów kardiologicznych oraz pacjentów hospitalizowanych z innych przyczyn. Wyniki i wnioski Wyniki: Do grupy pacjentów przyjętych z powodów kardiologicznych zakwalifikowano 46 osób, natomiast do grupy hospitalizowanej z innych przyczyn – 58 osób. Analizując poziomy Lp(a) w obu grupach, stwierdzono, że u 14 z 46 pacjentów (30,4%) hospitalizowanych z powodów kardiologicznych występował podwyższony poziom lipoproteiny ≥75 nmol/l. W grupie pacjentów przyjętych z przyczyn niekardiologicznych podwyższone wartości Lp(a) stwierdzono u 13 z 58 osób (22,4%). Oprócz poziomu HDL nie stwierdzono istotnych różnic pomiędzy obiema grupami. Wnioski: Uzyskane wyniki podkreślają znaczenie powszechnego badania przesiewowego poziomu Lp(a), szczególnie u osób bez objawów miażdżycy, w celu identyfikacji osób zagrożonych jej rozwojem.

Abstract Background Pulse Wave Velocity (PWV) is an important parameter in assessing arterial stiffness and potent predictor of cardiovascular risk, however its clinical usage remains limited. Whereas there is a range of dedicated devices (based on oscillometric or tonometric methods) the inclusion of PWV evaluation to transthoracic echocardiography (TTE) may increase significally its application. Purpose Our aim was to compare PWV measured with oscillometry signed as aPWV with this parameter measured by TTE, signed as ePWV during one examination (within 15 minutes time) and to evaluate the correlations of these parameters with clinical and echocardiographic characteristics. Methods We included 56 patients (mean age 55 years; 65% female), who underwent both TTE with Doppler examination of flow in carotid and femoral artery and ePWV calculation as well as oscillometric measurement of aPVW in the right brachial artery. ePWV was calculated using Doppler spectra registered in the both carotid and femoral arteries as well as a distance between points of measurements as the distance divided by estimated pulse wave transit time (achieved with simultaneous ECG recording). Studied group was divided into low and high cardiovascular risk category according SCORE2 scale for the primary prevention. As a low risk group, LR, we accepted those with score ≤5% including to HR group also secondary prevention patients (high risk group, HR). Results Oscillometric measurements were obtained in 50 patients (aPWV feasibility 89%) and Doppler parameters in all patients (ePWV feasibility 100%). Intra- and interobserver agreement was good for all measurements with coefficients of variation < 15%. PWV parameters, measured by both methods, showed a significant positive correlation with rho = 0.675, p<0.0001 as well as a good discriminatory potential between LR and HR groups (Figure 1). The HR group was older had faster PWV as well as higher LAV, E/E' and IMT values and lower TAPSE (see Table). Moreover, significant correlation between ePWV value and carotid IMT was observed with coefficient rho = 0.576, p = 0.0017, whereas this correlation achieved rho = 0.419, p=0.047 for aPWV. Conclusions ePWV based on Doppler echocardiography is a safe and highly feasible method of PWV measurement, showing good correlation with oscillometric assessment and providing data reflecting well cardiovascular risk as well as IMT of carotid arteries. Table. Comparison between LR and HR groups. Table Legend: T (R-flow) – time from R wave to Doppler spectrum of flow, ePWV or aPWV – pulsed wave velocity assessed with echocardiography or automatically, IMT- intima media thickness, LAV- left atrial volume, E/E’ - early mitral inflow to early mitral annulus motion ratio, LV EF, left ventricular ejection fraction, FAC – fractional area change of the right ventricle, TAPSE- tricuspid annulus plane systolic motion, RV S’ – tricuspid annulus systolic motion with tissue Doppler imaging. aPWV with ePWV correlation in LR and HR Table. Comparison of LR and HR groups

Atherosclerosis is a systemic disease which involves not only the coronary vessels but also occurs in other vascular beds (e.g., cervical, cerebral, and peripheral vessels), increasing cardiovascular risk. One of the causes of atherosclerosis is lipid disorders. In addition, other diseases, such as diabetes, chronic kidney disease, or familial hypercholesterolemia, accelerate the development of multi-bed (multilevel) atherosclerosis. Such patients are often treated by physicians of various specialties, and in our country there is no integrated system for managing these patients and their further treatment. This frequently results in the inability to achieve the therapeutic goals for low-density lipoprotein cholesterol set by the guidelines despite the availability of modern therapy for the treatment of lipid disorders in our country. The presented expert position paper postulates modification of the treatment of patients with multi-bed atherosclerosis by strengthening cooperation between physicians of many specialties (cardiologists, diabetologists, nephrologists, vascular surgeons, pediatricians, etc.) to improve the effectiveness of treatment and better educate the medical community and the treated patients.

Heterozygous familial hypercholesterolemia (HeFH) is a common autosomal dominant genetic disease (1:250) characterized by elevated LDL-C. Patients with HeFH are at increased risk of premature atherosclerosis and have at least a 10-fold greater chance of cardiovascular disease (CVD). The present study examines the effect of PCSK9 inhibitor treatment (iPCSK9: arilocumab or evolocumab) on DNA damage in HeFH patients. Fifty-six patients were studied, with a normolipidemic group (control; n = 20) and patients with HeFH (study group; n = 36). DNA damage was determined by alkaline comet assay and PCSK9 protein level by ELISA. PCSK9i treatment was found to be associated with lower DNA damage, Lp(a), PCSK9, and lipid profile compared to before treatment. However, 16 of 36 patients still had Lp(a) values above 125 nmol/L, and reduced Lp(a) did not correlate with reduced DNA damage. Reduced PCSK9 demonstrated a moderately positive correlation (r = 0.48) with reduced DNA damage. PCSK9i therapy reduces the level of DNA damage in HeFH patients, regardless of the type of inhibitor. While our findings confirm that PCSK9 treatment can reduce DNA damage, the mechanism remains unclear.

PURPOSE:The influence of SGLT2 inhibitors (SGLT2i) on cholesterol accumulation in Human Aortic Smooth Muscle Cells (HAoSMCs) has not yet been evaluated. This study aimed to assess the effect of SGLT2 inhibitors on cholesterol accumulation in HAoSMCs. MATERIALS AND METHODS:HAoSMCs were treated with empagliflozin (1 and 10 ​μM), dapagliflozin (1 and 10 ​μM), and canagliflozin (1 and 10 ​μM), with or without cholesterol-methyl-β-cyclodextrin complex (cholesterol complex), for 144 ​h. Lipid accumulation was assessed using Oil Red O staining, and absorbance at 492 ​nm was measured to quantify lipid content. Relative absorbance values were calculated against a medium control. RESULTS:Incubation of HAoSMCs with 10 ​μg/ml cholesterol complex resulted in a significant increase (31.8 ​%) in absorbance compared to untreated cells (p ​< ​0.0001). The presence of SGLT2 inhibitors significantly reduced the absorbance to 9.8-18.2 ​% in comparison to 31.8 ​% cholesterol complex alone. This effect was statistically significant for empagliflozin at 1 ​μM and 10 ​μM (p ​= ​0.0497 and p ​= ​0.0026, respectively) and dapagliflozin at 1 ​μM and 10 ​μM (p ​= ​0.0286 and p ​= ​0.0009, respectively). Interestingly, for canagliflozin, statistical significance was observed only at the higher concentration of 10 ​μM (p ​= ​0.0057). CONCLUSION:SGLT2 inhibitors may have a protective effect against cholesterol complex accumulation in HAoSMCs. There were no significant differences between the doses and types of SGLT2 inhibitors; however, dapagliflozin and empagliflozin showed a significant effect regardless of the concentration, while canagliflozin only at higher concentration.

AIMS:Our aim was to assess the clinical and prognostic significance of the left ventricular (LV) hypercontractile phenotype (HP) in hypertrophic cardiomyopathy (HCM), which until now remains unclear. METHODS AND RESULTS:We enrolled 1533 HCM patients (age 51 ± 15 years, 965 males, 63%) with ejection fraction (EF) ≥ 50%, referred for rest transthoracic echocardiography (TTE) in 27 laboratories from 13 countries. Two-dimensional volumetric TTE assessment included LV outflow tract gradient (LVOTG), LV EF, and LV force (systolic blood pressure + LVOTG/ESV, mmHg/mL). HP was defined as the highest quartile of the force (> 7.32 mmHg/mL). Survival analysis was performed in a subset of 1200 patients with follow-up information. Compared with non-HP patients, HP showed higher heart rate (72 ± 14 vs. 67 ± 14 beats per minute, P < 0.001), lower stroke volume (50 ± 22 vs. 67 ± 22 mL, P < 0.001), larger left atrial volume index (44 ± 16 vs. 40 ± 16 mL/m2, P = 0.011) and higher coronary flow velocity in the mid-distal left anterior descending artery (n = 325, 41 ± 12 vs. 37 ± 14 cm/s, P = 0.021). Force was moderately related to LV EF (r = 0.48, P < 0.001) and weakly to LVOTG (r = 0.36, P < 0.001). During a median follow-up of 87 months (interquartile range 45-143 months), 131 all-cause deaths occurred. At multivariable Cox analysis, a force > 7.32 mmHg (the fourth quartile for analyzed patients) was associated with a hazard ratio of 1.44 (95% Confidence intervals 1.00-2.07) for all-cause death, independently of LVOTG and LV EF. CONCLUSION:HP in HCM is associated with a disadvantageous systemic, cardiac and coronary hemodynamic profile as well as lower survival in the long-term.

The recently observed increase in cardiovascular disease incidence in patients with chronic hepatitis C has contributed to hepatitis C virus (HCV) being considered a new, non-classical risk factor. HCV infection may also lead to the development of metabolic disorders, which play an important role in the development of cardiovascular diseases. The notable impact of HCV on the development of obesity, insulin resistance, diabetes, lipid disorders and fatty liver has led to metabolic disorders in the course of HCV infection being referred to as metabolic-viral syndrome. On the other hand, modern treatment of HCV infection with direct-acting antiviral drugs is extremely effective and safe, while drug interactions are the main potential limitation. This article presents expert recommendations for the diagnosis and treatment of heart disease and lipid disorders in HCV-infected patients.

Food components and herbal substances can inhibit or enhance the therapeutic effects of drugs, thus influencing their efficacy and safety. As relatively little in known of these interactions, the aim of this review is to shed further light on the potentially dangerous influences that food and herbs may have on cytochrome P450 enzyme (CYP) and monoamine oxidase (MAO) activity in the first stage of drug biotransformation. The review includes documented cases in which such interactions have led to health complications in patients. For example, fruit juices, such as grapefruit juice, cranberry juice, and pomegranate juice, have been found to interact with drugs, and to particularly inhibit CYP450 activity, and commonly used herbs are known to inhibit (e.g., Astragalus membranous) or induce (e.g., Hypericum perforatum) CYP enzymes involved in drug metabolism. CYP is also induced by polycyclic aromatic hydrocarbons (PAHs), found in grilled meat and tobacco smoke. The paper also discusses the toxic effects of tyramine, present in inter alia blue cheese, resulting from interactions with MAO-metabolised drugs. Most importantly, while the quantity of food and herbs consumed plays a significant role in the described drug interactions, it is possible for toxic effects to be observed even after the consumption of relatively small amounts. Patients are encouraged to consult a healthcare provider about any potential drug interactions that may occur when starting a new medication.

Abstract Background Covid-19 took an huge death-toll in the era of its pandemic widespread in scale of the whole world imposing a new and still not completely understood not resolved threat to public health. Beyond the severity of lungs affliction and the subsequent respiratory failure thromboembolic complications with their crucial form of pulmonary embolism (PE) are seen as responsible of this high numbers of fatalities. Aim We aim to find predictors of in hospital death in subgroup of patients with COVID-19 pneumonia diagnosed simultaneously with CT-angiography of pulmonary embolism. Methods Our group included 39 patients from 42 to 95 year old (mean age 67±13, 27 males and 12 females) hospitalized in Internal Disease and Clinical Pharmacology Department since October 2020 to June 2021 with the diagnosis of SARS COV2 pneumonia and pulmonary embolism detected with CT angiography during the analysed hospitalization. We compared clinical, laboratory and treatment data between group who died during hospitalization (G1) and those who survived the early period of at least 1 month after disease onset (G2). Results During hospitalization and in extended to 1 month follow-up 12 deaths occurred, 8 in men (30%) and 4 in women (33%), however this difference did not reach statistical significance and moreover women were older than men among all PE patients (73±12 vs 64±13 years respectively, p=0.049). The compared groups did not differ significantly according to age (although some trend to higher age in G1), the prevalence of hypertension, diabetes, chronic obstructive pulmonary disease as well as provided treatment including heparin, oxygen therapy, remdesivir, tocilizumab and dexamethasone or heart rate, creatinine, troponin or NT-proBNP level, see Table. They differ, however, according to IL-6 concentration significantly higher in group with fatal outcome (108 (77-240) vs 52 (41-98) pg/ml, p =0.0162) as well as according to surprisingly higher lymphocyte count (0.95 (0.75-1.55) vs 0.6 (0.4-0.7) count X 1000, p=0.0058). Both these parameter showed significant predictive value of early death in studied group with sensitivity of 75% for both parameters and specificity of 74% for IL-6 > 91 and 78% for lymphocytes above 700/µl.

INTRODUCTION:Recently, interest has been growing in lipoprotein(a) (Lp[a]) as an independent risk factor for cardiovascular diseases. European Society of Cardiology recommends a single measurement of Lp(a) concentration as a guide to determine cardiovascular risk group and appropriate treatment. Although initially assumed to be genetically determined, a growing number of reports indicate that Lp(a) concentration may change over time. OBJECTIVES:The aim of the study was to compare changes in the concentration of Lp(a) in patients with acute coronary syndrome (ACS) at the moment of ACS and 3 months later. PATIENTS AND METHODS:Forty patients with ACS were enrolled and divided into ST‑segment elevation myocardial infarction (STEMI) and non‑STEMI (NSTEMI) + unstable angina (UA) groups. The levels of lipids, C‑reactive protein, high‑sensitivity troponin T, N-terminal pro-B-type natriuretic peptide, and Lp(a) were determined using routine laboratory methods, with interleukin‑33 levels measured using an enzyme‑linked immunosorbent assay. RESULTS:Among all ACS patients, 9 (22.5%) had elevated Lp(a) levels (>75 nmol/l). This proportion was higher in the STEMI (n = 8; 35%) than NSTEMI+UA (n = 2; 13%) patients. All patients with ACS showed significantly higher serum Lp(a) levels 3 months after ACS. The Lp(a) level at the moment of ACS and 3 months later differed markedly in the STEMI patients (P = 0.03), all patients with ACS (P = 0.003), and NSTEMI+UA individuals (P = 0.003). CONCLUSION:Measuring Lp(a) level during ACS may be insufficient for accurate diagnosis and effective treatment, as its concentration increases 3 months post‑ACS. Therefore, ACS may be regarded as another nongenetic factor influencing Lp(a) concentration.

Atherosclerotic plaque instability increases the risk of stroke. As such, determining the nature of an instability atherosclerotic plaque may speed up qualification for carotid endarterectomy (CEA), thus reducing the risk of acute vascular events. The aim of the study was to determine the diagnostic value of oxidized LDL cholesterol (ox-LDL), matrix metalloproteinase 9 (MMP-9) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in serum as a prognostic markers of instability atherosclerotic plaques. Serum was collected from 67 patients who underwent CEA in accordance with the qualification criteria. The levels of ox-LDL, MMP-9 and 8-OHdG were assessed by ELISA. The predictive value of the markers was determined based on an ROC curve, and the cut-off points with the highest sensitivity and specificity were determined. Patients with unstable atherosclerotic plaque had significantly higher serum ox-LDL, MMP-9 and 8-OHdG values. It was found that in patients before CEA, ox-LDL >31.4 ng/mL was associated with an 82.5% probability of unstable atherosclerotic plaque, MMP-9 >113.1 ng/mL with 78.6%, and 8-OHdG >2.15 ng/mL with 64.7%. Multivariate regression analysis found ox-LDL to be an independent factor associated with plaque instability. Patients with unstable plaques tend to have higher serum levels of ox-LDL, MMP-9 and 8-OHdG compared to those with stable plaques. The optimal cut-off point for ox-LDL (AUC 0.86, p <0.0001) was 31.14 ng/mL, with 91.18% sensitivity and 78.79% specificity. The high sensitivity and specificity of ox-LDL suggests that it can be used as an independent marker of plaque instability.