Prognostic value of plasma secretoneurin concentration in patients with heart failure with reduced ejection fraction in one-year follow-up.

BACKGROUND: This is the first study to examine the clinical utility of measuring plasma secretoneurin (SN) levels in patients with heart failure with reduced ejection fraction (HFrEF), as a predictor of unplanned hospitalization, and all-cause mortality independently, and as a composite endpoint at one-year follow-up. METHODS: The study group includes 124 caucasian patients in New York Heart Association (NYHA) classes II to IV. Plasma SN concentrations were statistically analyzed in relation to sex, age, BMI, etiology of HFrEF, pharmacotherapy, clinical, laboratory and echocardiographic parameters. Samples were collected within 24 h of admission to the hospital. KEY RESULTS: In the 12-month follow-up, high SN levels were noted for all three endpoints. CONCLUSIONS: SN positively correlates with HF severity measured by NYHA classes and proves to be a useful prognostic parameter in predicting unplanned hospitalizations and all-cause mortality among patients with HFrEF. Patients with high SN levels may benefit from systematic follow-up and may be candidates for more aggressive treatment.

The Role of Selected Epigenetic Pathways in Cardiovascular Diseases as a Potential Therapeutic Target.

Epigenetics is a rapidly developing science that has gained a lot of interest in recent years due to the correlation between characteristic epigenetic marks and cardiovascular diseases (CVDs). Epigenetic modifications contribute to a change in gene expression while maintaining the DNA sequence. The analysis of these modifications provides a thorough insight into the cardiovascular system from its development to its further functioning. Epigenetics is strongly influenced by environmental factors, including known cardiovascular risk factors such as smoking, obesity, and low physical activity. Similarly, conditions affecting the local microenvironment of cells, such as chronic inflammation, worsen the prognosis in cardiovascular diseases and additionally induce further epigenetic modifications leading to the consolidation of unfavorable cardiovascular changes. A deeper understanding of epigenetics may provide an answer to the continuing strong clinical impact of cardiovascular diseases by improving diagnostic capabilities, personalized medical approaches and the development of targeted therapeutic interventions. The aim of the study was to present selected epigenetic pathways, their significance in cardiovascular diseases, and their potential as a therapeutic target in specific medical conditions.

Therapeutic Drug Monitoring of Direct Oral Anticoagulants in Patients with Extremely Low and High Body Weight-Pilot Study.

Phase III clinical trials for individual direct oral anticoagulants (DOACs) contained a limited representation of subjects with abnormal body weight, which were mostly limited to a BMI > 40 kg/m2, or body weight > 120 kg for obese subjects, and <50 kg for underweight subjects. Although low or high body weight is not a contraindication to DOACs therapy, it can significantly affect the safety and effectiveness of treatment. Due to the limited amount of clinical data on the use of DOACs in extremely abnormal weight ranges, optimal pharmacotherapy in this group of patients is a matter of controversy. The objective of this study was to evaluate the pharmacokinetics of DOAC properties in patients with abnormal body weight beyond the established cut-off points in the phase III studies for rivaroxaban, apixaban, and dabigatran. In total, 38 patients took DOACs for at least 12 months for non-valvular atrial fibrillation in 2019-2021. Blood samples were collected before the planned intake of the drug and 4 h after its administration. The determined concentrations of DOACs were statistically analyzed in relation to body weight, age, and eGFR (estimated Glomerular Filtration Rate). Among subjects taking apixaban, rivaroxaban, and dabigatran, the smallest representation of patients who achieved therapeutic concentrations were those treated with dabigatran. The population of people with abnormal body weight is a potential risk group of patients, in which some of them do not reach the therapeutic range of DOACs.

Prognostic Value of Plasma Catestatin Concentration in Patients with Heart Failure with Reduced Ejection Fraction in Two-Year Follow-Up.

The primary objective of the study was to evaluate the prognostic value of measuring plasma catestatin (CST) concentration in patients with heart failure with reduced ejection fraction (HFrEF) as a predictor of unplanned hospitalization and all-cause death independently and as a composite endpoint at 2-year follow-up. The study group includes 122 hospitalized Caucasian patients in NYHA classes II to IV. Patients who died during the 24-month follow-up period (n = 44; 36%) were significantly older on the day of enrollment, were more likely to be in a higher NYHA class, had lower TAPSE, hemoglobin concentration, hematocrit, and platelet count, higher concentrations of CST, NT-proBNP, troponin T, creatinine, and glucose, and higher red cell distribution width value and leukocyte and neutrocyte count than patients who survived the follow-up period. Plasma catestatin concentration increased with NYHA class (R = 0.58; p <0.001) and correlated significantly with blood NT-proBNP concentration (R = 0.44; p <0.001). We showed that higher plasma catestatin concentration increased the risk of all-cause death by more than five times. Plasma CST concentration is a valuable prognostic parameter in predicting death from all causes and unplanned hospitalization in patients with HFrEF.

MicroRNA and lncRNA as the Future of Pulmonary Arterial Hypertension Treatment.

Pulmonary hypertension (PH) is characterized by a progressive increase in pulmonary arterial pressure and pulmonary vascular resistance. In a short time, it leads to right ventricular failure and, consequently, to death. The most common causes of PH include left heart disease and lung disease. Despite the significant development of medicine and related sciences observed in recent years, we still suffer from a lack of effective treatment that would significantly influence the prognosis and prolong life expectancy of patients with PH. One type of PH is pulmonary arterial hypertension (PAH). The pathophysiology of PAH is based on increased cell proliferation and resistance to apoptosis in the small pulmonary arteries, leading to pulmonary vascular remodeling. However, studies conducted in recent years have shown that epigenetic changes may also lie behind the pathogenesis of PAH. Epigenetics is the study of changes in gene expression that are not related to changes in the sequence of nucleotides in DNA. In addition to DNA methylation or histone modification, epigenetic research focuses on non-coding RNAs, which include microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Preliminary research results give hope that targeting epigenetic regulators may lead to new, potential therapeutic possibilities in the treatment of PAH.

Inclisiran-Safety and Effectiveness of Small Interfering RNA in Inhibition of PCSK-9.

Dyslipidemia is listed among important cardiovascular disease risk factors. Treating lipid disorders is difficult, and achieving desirable levels of LDL-cholesterol (LDL-C) is essential in both the secondary and primary prevention of cardiovascular disease. For many years, statins became the basis of lipid-lowering therapy. Nevertheless, these drugs are often insufficient due to their side effects and restrictive criteria for achieving the recommended LDL-C values. Even the addition of other drugs, i.e., ezetimibe, does not help one achieve the target LDL-C. The discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) discovery has triggered intensive research on a new class of protein-based drugs. The protein PCSK9 is located mainly in hepatocytes and is involved in the metabolism of LDL-C. In the beginning, antibodies against the PCSK9 protein, such as evolocumab, were invented. The next step was inclisiran. Inclisiran is a small interfering RNA (siRNA) that inhibits the expression of PCSK9 by binding specifically to the mRNA precursor of PCSK9 protein and causing its degradation. It has been noticed in recent years that siRNA is a powerful tool for biomedical research and drug discovery. The purpose of this work is to summarize the molecular mechanisms, pharmacokinetics, pharmacodynamics of inclisiran and to review the latest research.

Soluble Guanylyl Cyclase Activators-Promising Therapeutic Option in the Pharmacotherapy of Heart Failure and Pulmonary Hypertension.

Endogenous nitric oxide (NO)-dependent vascular relaxation plays a leading role in the homeostasis of the cardiovascular, pulmonary, and vascular systems and organs, such as the kidneys, brain, and liver. The mechanism of the intracellular action of NO in blood vessels involves the stimulation of the activity of the soluble cytosolic form of guanylyl cyclase (soluble guanylyl cyclase, sGC), increasing the level of cyclic 3'-5'-guanosine monophosphate (cGMP) in smooth muscle and subsequent vasodilation. In recent years, a new group of drugs, soluble guanylyl cyclase stimulators, has found its way into clinical practice. Based on the CHEST-1 and PATENT-1 trials, riociguat was introduced into clinical practice for treating chronic thromboembolic pulmonary hypertension (CTEPH). In January 2021, the FDA approved the use of another drug, vericiguat, for the treatment of heart failure.

Implementation of recommendations on the check of risk factors for cardiovascular diseases in patients undergoing coronary re-interventions.

METHOD: The study involved 905 patients after coronary interventions, qualified for invasive diagnosis due to symptomatic coronary disease. AIM: The aim of this study was to check the implementation of recommendations on the control of risk factors for cardiovascular diseases in patients undergoing re-interventions. RESULTS: Compared to elderly persons, younger people more often increased their physical activity (62 vs. 65 years, p = 0.009), stopped smoking (61 vs. 65 years, p < 0.001) and reduced alcohol consumption (62 vs. 65 years, p = 0.001). People with secondary and higher education increased their physical activity more often than those with primary education (51%, 31% vs. 23%, p = 0.006). Men more often than women decided to limit their alcohol consumption (48% vs. 37%, p = 0.007). Patients with a history of acute coronary syndrome were more likely to quit smoking and reduce their alcohol consumption than those without such a history (47% vs. 37%, p = 0.003 and 42% vs. 34%, p = 0.020, respectively). Only 2% of the subjects achieved the recommended LDL cholesterol values. Forty-eight percent were qualified for reinvasive procedures on the coronary arteries. Less than half of the patients undertook health-promoting behaviors that required modification of existing habits. CONCLUSION: Age, gender, and education level influence pro-health behaviors. The majority of patients do not achieve the levels of LDL cholesterol and triglycerides consistent with the ESC guidelines in the secondary prevention of coronary disease. Inadequate check of risk factors may result in faster disease progression and coronary re-interventions.

Safety of PCSK9 inhibitors.

annually in Europe, 4 million people die from cardiovascular diseases, the main cause of which is atherosclerosis. In order to slow down the development of atherosclerotic plaques, the main therapeutic goal is to lower LDL cholesterol (LDL-C) level. Undoubtedly, statins are the basis of lipid-lowering therapy for many years. However, a European study shows that only 43% of statin-taking patients achieved their LDL-C targets. PCSK9 inhibitors are a new group of lipid-lowering drugs whose main point of action is the protein discovered in 2003 - the PCSK9 (proprotein convertase subtilisin/kexin 9). This protein is responsible for reducing the density of LDL receptors on the surface of hepatocytes, which increases the value of LDL-C. The discovery of this protein was soon after the basis for the start of research, thanks to which three monoclonal antibodies against PCSK9 were developed - evolocumab, alirocumab, bococizumab - and inclisiran, an inhibitor of PCSK9 synthesis in the liver. In addition to the mechanism of action of PCSK9 inhibitors, resulting in lowering LDL-C level, a number of pleiotropic mechanisms have also been identified, including effects on metabolic processes and inflammation. Until the registration and introduction of above-mentioned drugs into everyday clinical practice, many studies were carried out, in which, in addition to assessing the effectiveness of treatment, the safety and tolerability of the drug were also examined. The purpose of this review is to summarize information on the safety profile of PCSK9 inhibitors, which may help in making therapeutic decision.

Alcohol and Cardiovascular Diseases-Do the Consumption Pattern and Dose Make the Difference?

Excessive consumption of alcohol is not only a social problem, but it also significantly increases the morbidity and mortality rates of many societies. A correlation has been demonstrated between alcohol consumption and increased mortality from cancer, accidents and injuries, liver cirrhosis and other causes. Alcohol abuse increases the incidence of hemorrhagic stroke and the risk of ischemic stroke, induces serious arrhythmias, adversely affects blood pressure and damages the heart muscle. The dose and way of drinking alcohol play a crucial role in assessing whether this drink allows people to maintain health or whether it is a great health and social threat. The beneficial effects of low and moderate doses of alcohol on the occurrence of cardiovascular diseases have been shown in many population studies and meta-analyses in which the effect of U-shaped or J-shaped curves relating alcohol intake to cardiovascular mortality was observed, especially in ischemic heart disease. However, due to the fact that alcohol consumption is associated with many health hazards, it is not recommended to consume it as a preventive action of cardiovascular diseases. Moreover, recent studies suggest that association of low-to-moderate alcohol consumption with the reduction in cardiovascular risk is a result of lifestyle changes and that any reduction in alcohol consumption is in fact beneficial in terms of general health.

The importance of pharmacokinetics, pharmacodynamic and repetitive use of levosimendan.

Levosimendan was introduced into routine clinical practice in 2000, obtaining approval for the treatment of decompensation of severe chronic heart failure. Levosimendan increases the calcium sensitivity of contractile proteins by binding to myocardial troponin C (cTnC) in a calcium dependent manner. Apart from the mechanism of action of levosimendan, resulting directly in the improvement of heart function, a number of pleiotropic mechanisms have also been identified, including anti-inflammatory, antioxidant and anti-apoptotic effects. Pharmacokinetics of levosimendan is linear in a therapeutic dose range i.e. from 0.05 to 0.2 µg/kg/min. Therapeutic concentration of levosimendan is reached approximately 1 h after the start of intravenous infusion, and steady state is reached within 5 h after continuous infusion initiation. OR-1855 and OR-1896 are the only significant metabolites detected in the systemic circulation after administration of levosimendan. After a 24-hour infusion of levosimendan, the pharmacodynamic effect of the drug is observed for at least one week. Repetitive levosimendan infusions are safe and multiple infusions of levosimendan show a number of benefits. However, experience with multiple doses of levosimendan is scarce. The protocols of clinical trials conducted so far on repeated and intermittent infusions of levosimendan were developed subjectively and were based on the opinion of experts forming a given research team. There is still a need for more clinical research on the multidirectional effect of levosimendan in the group of patients with heart failure. The aim of this review was to summarize most relevant and up-to-date scientific data on pharmacokinetic and pharmacodynamic basis of levosimendan repetitive use in clinical practice that may assist in bedside decision making.

Beta-blockers in cardiac arrhythmias-Clinical pharmacologist's point of view.

ß-blockers is a vast group of antiarrhythmic drugs which differ in their pharmacokinetic and chemical properties. Some of them block ß-adrenergic receptors selectively while the others work non-selectively. Consequently, they reduce the influence of the sympathetic nervous system on the heart, acting negatively inotropic, chronotropic, bathmotropic and dromotropic. Although they have been present in medicine since the beginning of the 1960s, they still play a crucial role in the treatment of cardiac arrhythmias. They are also first-line group of drugs used to control the ventricular rate in patients with the most common arrhythmia-atrial fibrillation. Previous reports indicate that infection with SARS-CoV-2 virus may constitute an additional risk factor for arrhythmia. Due to the aging of the population in developed countries and the increase in the number of patients with cardiac burden, the number of people suffering from cardiac arrhythmias will increase in the upcoming years. As a result the role of above-mentioned beta-blockers will remain significant. Particularly noteworthy is propranolol-the oldest beta adrenergic antagonist, which in recent years has found additional applications due to its unique properties. In this article, we reviewed the accessible literature and summarized the current guidelines on the use of beta-blockers in the treatment of cardiac arrhythmias.

The Clinical Significance of Drug-Food Interactions of Direct Oral Anticoagulants.

Cardiovascular diseases are the most common cause of death in the world. For almost 60 years, vitamin K antagonists (VKAs) were the mainstay of anticoagulation therapy, but in recent years direct oral anticoagulants (DOACs) have become the anticoagulant treatment of choice. DOACs were initially considered drugs with no significant food interactions; however, clinical observations from daily practice have proved otherwise as interactions with food ingredients have been reported. Food, dietary supplements or herbs may contain substances that, when administered concomitantly with DOACs, can potentially affect the plasma concentration of the drugs. The aim of this paper was to evaluate the clinical significance of drug-food interactions of DOACs, such as dabigatran, rivaroxaban, apixaban, edoxaban and betrixaban. Patients treated with anticoagulants should avoid products containing St. John's wort and take special care with other food ingredients. As the interest in dietary supplements is on the rise, healthcare providers can contribute to the development of well-designed clinical trials on interactions between DOACs and food, and distribute sufficient knowledge about the proper use of these supplements among patients.

Treatment of Hypertension Because of Immunosuppressive Therapy After Solid Organ Transplantation-Pharmacological Approach.

ABSTRACT: Solid organs transplantation procedures have been performed for more than half a century. Growing knowledge of immune response and development of new immunosuppressive regimens guarantee more and more successful outcomes. However, many of the applied drugs lead to cardiovascular complications, the most frequent of which is hypertension. This article describes epidemiology, pathogenetic mechanisms, and treatment of hypertension induced by immunosuppressive medication. The main impact is focused on drugs belonging to the following groups: calcineurin inhibitors, the inhibitors of the mammalian target of rapamycin, and glucocorticosteroids. We analyze the mechanism of action of the main hypertensive drugs and their influence on the reversing hypertonic action of the immunosuppressive agents. In the absence of current guidelines addressing this problem, this article is an attempt to fill the gap, helping clinicians to choose proper medication.

Resveratrol and cardiovascular system-the unfulfilled hopes.

INTRODUCTION: Resveratrol is a natural polyphenolic compound with a stilbene structure endowed with multiple health-promoting effects. Among phenolic compounds, resveratrol is assigned a leading role in the health-promoting effects of red wine. METHODS: The aim of the study was to assess the effect of resveratrol on the cardiovascular system in the experimental and clinical studies conducted so far. Moreover, the paper discusses the results of the most recent meta-analyses assessing resveratrol's therapeutic effect on the cardiovascular system in humans. RESULTS: In animal and preclinical studies, resveratrol has demonstrated a wide physiological and biochemical spectrum of activity, including antioxidant, anti-inflammatory, antiplatelet, and anticoagulant activities, which translated into its health-promoting effects on the cardiovascular system. The performed meta-analyses allow to confirm such an impact, however, after the assessment with the use of the SYRCLE's tool, these studies are burdened with a high risk of bias, and the results are not clearly presented. CONCLUSION: Despite numerous articles and clinical studies, the convincing beneficial mechanisms of resveratrol as well as its health-promoting effects in cardiovascular diseases have not been clearly confirmed in humans. Therefore, there is a need for further clinical studies, especially randomized, double-blind, placebo-controlled trials to objectively confirm the possible health-promoting effects of this substance and to determine both the efficacy and safety, and possible therapeutic potential.

Catestatin as a New Prognostic Marker in Stable Patients with Heart Failure with Reduced Ejection Fraction in Two-Year Follow-Up.

Background and Purpose. The main goal of the study was to assess the usefulness of plasma concentrations of catestatin as a predictor of a composite endpoint (CE): unplanned hospitalization and death for all causes in patients with HFrEF in the midterm follow-up. Experimental Approach. The study group consisted of 52 Caucasian patients in NYHA classes II and III. The control group consisted of 24 healthy volunteers. The biomarkers, whose concentration was assessed before and after physical exertion as well as the variability of their concentration under the influence of the physical exertion, were NT-proBNP, troponin T, and catestatin. Key Results. During the 24-month follow-up period, 11 endpoints were recorded. The univariate analysis of the Cox proportional hazard model showed a statistically significant effect of all assessed CST concentrations on the occurrence of CE. In the 24-month follow-up, where the starting concentration of catestatin was compared with other recognized prognostic factors in HF, the initial concentration of catestatin showed statistical significance in CE prognosis as the only parameter tested. Conclusions. Plasma concentration of catestatin before and after physical exertion is a valuable prognostic parameter in predicting death from all causes and unplanned hospitalization in the group of patients with HFrEF in the 2-year follow-up.

The Interactions of Nintedanib and Oral Anticoagulants-Molecular Mechanisms and Clinical Implications.

Nintedanib is a synthetic orally active tyrosine kinase inhibitor, whose main action is to inhibit the receptors of the platelet-derived growth factor, fibroblast growth factor and vascular endothelial growth factor families. The drug also affects other kinases, including Src, Flt-3, LCK, LYN. Nintedanib is used in the treatment of idiopathic pulmonary fibrosis, chronic fibrosing interstitial lung diseases and lung cancer. The mechanism of action suggests that nintedanib should be considered one of the potential agents for inhibiting and revising the fibrosis process related to COVID-19 infections. Due to the known induction of coagulation pathways during COVID-19 infections, possible interaction between nintedanib and anticoagulant seems to be an extremely important issue. In theory, nintedanib could increase the bleeding risk, thrombosis and lead to thrombocytopenia. The data from clinical trials on the concomitant use of nintedanib and antithrombotic agents is very limited as this patient group was within the standard exclusion criteria. Nintedanib is an important therapeutic option, despite its interaction with anticoagulants. If anticoagulant therapy is necessary, the more effective and safer option is the concomitant administration of DOACs and nintedanib, especially when drug-monitored therapy will be used in patients at high risk of bleeding complications.

Are changes in heart rate, observed during dobutamine stress echocardiography, associated with a response to cardiac resynchronisation therapy in patients with severe heart failure? Results of a multicentre ViaCRT study.

BACKGROUND: According to current European Society of Cardiology guidelines for the diagnosis and treatment of heart failure (HF), cardiac resynchronisation therapy (CRT) is indicated in patients suffering from HF with reduced ejection fraction (EF) with significantly widened QRS complexes. The presence of vital myocardium proven by dobutamine stress echocardiography (DSE) is considered as a good prognostic factor for responsiveness to this treatment. Chronotropic incompetence is, on the other hand, a known factor of unfavourable outcome in HF. AIM: The aim of this study was to analyse the relationship between heart rate (HR) response during DSE and resultant changes in echocardiographic parameters determined prior to CRT and six weeks post-implantation of the CRT system. METHODS: The study included 72 men and 25 women with chronic HF and markedly deteriorated left ventricular (LV) sys-tolic function (EF < 35%). Low-dose DSE was performed prior to the CRT system implantation. Baseline echocardiographic parameters determined before CRT were compared to those measured six weeks after implantation. RESULTS: Implantation of the CRT system resulted in an improvement of LV systolic function. DSE showed a significant in-crease in HR, by 16.3 bpm on average. Patients with the least prominent increase in HR during DSE (< 7 bpm) presented with significantly greater end-diastolic LV dimension and volume, as well as with significantly lower EF than the subjects with the most evident increase in HR (> 24 bpm). Improvement in EF at six weeks was associated with lower baseline HR and its greater absolute and relative increase during DSE. Greater absolute increase in HR during DSE was also associated with more prominent decrease in systolic/diastolic LV volumes. CONCLUSIONS: Patients with better chronotropic response during DSE show significant improvement in LV parameters determined by echocardiography within six weeks of CRT. Chronotropic response to pharmacologic stress test may serve as a predictive factor in patients qualified for CRT.

Prognostic value of selected echocardiographic, impedance cardiographic, and hemodynamic parameters determined during right heart catheterization in patients qualified for heart transplantation.

The aim of the study was to verify prognostic value of selected echocardiographic (UKG), impedance cardiography (ICG), and right heart catheterization (RHC) parameters in systolic heart failure (HF). UKG, ICG, and RHC were performed in 46 patients with chronic HF with ejection fraction <35%. During a 1-year follow-up, composite endpoint (death or hospitalization due to HF exacerbation) was achieved by 23 (50.0%) patients. Analysis of receiver operating characteristic (ROC) curves identified UKG parameters: inferior vena cava diameter on inspiration (IVCinsp) >13 mm [area under curve (AUC), 0.791], right atrial (RA) >5.2 cm (AUC 0.710) and ventricular dimension (RVD) >3.5 cm (AUC 0.717), tricuspid annular plane systolic excursion (TAPSE) <17 mm (AUC 0.682), and its velocity (S'RV) <6.07 cm/s (AUC 0.716) as unfavorable prognostic factors. RHC parameters: low values of cardiac index (CI < 2.1 L/min; AUC 0.846) and high pulmonary capillary wedge pressure (PCWP > 24 mmHg; AUC 0.773) turned out to be the most accurate single predictors of worse outcome. Prognostic value of non-invasive parameters was improved due to the use of their composite measures: IVC% × TAPSE (<430%/mm; AUC 0.826), RVSP/TAPSE (>2.4 mmHg/mm; AUC 0.800), IVC% × SBP (>2097% mmHg; AUC 0.826), and RA × IVCinsp/S'RV (>11.8 cm s; AUC 0.839). In conclusion, composite measures based on non-invasive parameters, such as IVC%/TAPSE, RVSP/TAPSE and RA × IVCinsp/S'RV, may provide equally accurate prognosis as the invasive examination. PCWP and CI determined during RHC were the best individual predictors of the composite endpoint. In addition, echocardiographic parameters: RVD, RA, IVC, TAPSE, and S'RV are accurate predictors of the unfavorable outcome.