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.

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.

Aging Athlete's Heart: An Echocardiographic Evaluation of Competitive Sprint- versus Endurance-Trained Master Athletes.

BACKGROUND: Sports training triggers exercise-induced cardiac remodeling (EICR). Sprint- and endurance-trained master athletes are exposed to different hemodynamic stimuli accompanied by aging. The aim of this study was to compare EICR types in light of the Morganroth hypothesis, frequency of abnormalities, and relationships between cardiac traits and age. METHODS: In this observational cross-sectional study, echocardiographic examinations were conducted in 143 sprint-trained (age range, 36-83 years) and 114 endurance-trained (age range, 38-85 years) competitive master athletes. Structural and functional characteristics were compared with population reference values, and EICR types were identified. Athletic groups were compared using t tests and χ2 tests. Relationships with age were assessed using linear regression. RESULTS: In the sprint group, 51.0% of athletes had normal cardiac geometry (nonhypertrophic heart), 4.2% had eccentric hypertrophy, 36.4% had concentric remodeling, and 8.4% had concentric hypertrophy. In their endurance-trained peers, these proportions were 22.8%, 16.7%, 36.8%, and 23.7%, respectively. Many athletes in both groups had structural abnormalities, as assessed using population norms (up to ~81% for septal thickness) but their resting cardiac function was normal. The relationships of structural and functional cardiac characteristics with age were mostly weak to moderate and did not differ between training modalities. CONCLUSIONS: Even though many endurance- and sprint-oriented master athletes exceed population norms for cardiac structure, they do not go beyond the "gray zone" and preserve normal cardiac function. Therefore, physiologic adaptations, rather than pathologic abnormalities, are expected in aging but still active athletes. Inconsistent with the Morganroth hypothesis, EICR is shifted toward normal geometry in sprinters and toward concentric remodeling and hypertrophy in endurance runners. A better understanding of the mechanisms behind cardiac remodeling during aging is needed to adequately predict EICR types in master athletes.

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.

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.

Material-Oriented Shape Functions for FGM Plate Finite Element Formulation.

A four-noded finite element of a moderately thick plate made of functionally graded material (FGM) is presented. The base element is rectangular and can be extended to any shape using a transformation based on NURBS functions. The proposed 2D shape functions are consistent with the physical interpretation and describe the states of element displacement caused by unit displacements of nodes. These functions depend on the FGM's material parameters and are called material-oriented. The shape function matrix is based on a superposition displacement field of two plate strips with 1D exact shape functions. A characteristic feature of the proposed formulation is full coupling of the membrane and bending states in the plate. The analytical form of the stiffness matrix and the nodal load vector was obtained, which leads to the numerical efficiency of the formulation. The element has been incorporated into Abaqus software with the use of Maple program. The finite element shows good convergence properties for different FGM models in the transverse direction to the middle plane of the plate. During derivation of the 2D plate element the formally exact 1D finite element for transverse nonhomogeneous FGM plate strip was developed.

Soft and Stiff Simplex Tensegrity Lattices as Extreme Smart Metamaterials.

The present paper is dedicated to an evaluation of novel cellular metamaterials based on a tensegrity pattern. The materials are constructed from supercells, each of which consists of a number of simplex modules with different geometrical proportions. Mechanical properties of the metamaterial can be controlled by adjusting the level of self-equilibrated forces or by changing the properties of structural members. A continuum model based on the equivalence of strain energy of the 3D theory of elasticity with a discrete formulation is used to identify the qualitative properties of the considered metamaterials. The model allows the inclusion of nonlinearities related to the equations of equilibrium in actual configuration of the structure with self-equilibrated set of normal forces typical for tensegrities. The lattices are recognised as extreme metamaterials according to the eigensolution of the equivalent elasticity matrices of the continuum model. The six representative deformation modes are defined and discussed: stiff, soft and medium extensional modes and high (double) as well as low shear modes. The lattices are identified as unimode or nearly bimode according to the classification of extreme materials.

Smart Metamaterial Based on the Simplex Tensegrity Pattern.

In the present paper, a novel cellular metamaterial that was based on a tensegrity pattern is presented. The material is constructed from supercells, each of which consists of eight 4-strut simplex modules. The proposed metamaterial exhibits some unusual properties, which are typical for smart structures. It is possible to control its mechanical characteristics by adjusting the level of self-stress or by changing the properties of structural members. A continuum model is used to identify the qualitative properties of the considered metamaterial, and to estimate how the applied self-stress and the characteristics of cables and struts affect the whole structure. The performed analyses proved that the proposed structure can be regarded as a smart metamaterial with orthotropic properties. One of its most important features are unique values of Poisson’s ratio, which can be either positive or negative, depending on the applied control parameters. Moreover, all of the mechanical characteristics of the proposed metamaterial are prone to structural control.

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.

Bone morphogenetic protein 6-a possible new player in pathophysiology of heart failure.

Derangement of bone morphogenetic protein (BMP) signalling was observed in cardiovascular disorders. The present study assesses the diagnostic and prognostic value of BMP6 plasma concentration in chronic heart failure (CHF). 130 CHF patients and 32 controls participated in the study. BMP6 plasma level was measured at baseline. During 12-month follow-up death and hospitalisation with CHF exacerbation were recorded. BMP6 was significantly increased in CHF patients with highest concentration in most advanced disease. Individuals with pulmonary congestion or peripheral oedema had higher levels of BMP6 than isovolemic patients. BMP6 was not a predictor of all-cause mortality or CHF hospitalisation. BMP6 may be involved in pathophysiology of systolic CHF. BMP6 plasma level is related to the disease severity and signs of exacerbation.

Melanoma cell adhesion molecule as an emerging biomarker with prognostic significance in systolic heart failure.

BACKGROUND: Melanoma cell adhesion molecule (MCAM) is a marker of endothelial damage. MCAM diagnostic and prognostic value was assessed in chronic heart failure (CHF). MATERIALS & METHODS: 130 CHF patients and 32 controls were included in the study. Telephone follow-up lasted one year. End points were: death from all causes, and hospitalization with CHF exacerbation. RESULTS: MCAM was higher in patients than in controls (p = 0.01). Receiver operator curve analysis revealed that MCAM may serve as a predictor of death (area under the curve: 0.8404; p < 0.002). Patients with MCAM above 500 ng/ml had worse prognosis (p = 0.03). NT-proBNP and age were independent predictors of death in multivariate analysis. CONCLUSION: The increased MCAM indicates endothelial damage in CHF and may serve as a marker of worse prognosis in these patients.

Use of transthoracic impedance cardiography and tissue Doppler echocardiography in the cardiovascular assessment of atrial fibrillation patients subjected to electroversion.

BACKGROUND: Atrial fibrillation (AF) is the commonest complex cardiac arrhythmia, affecting approximately 2% of the general population. AIM: To describe cardiovascular changes in tissue Doppler echocardiography (TDE) and impedance cardiography (ICG) in AF patients subjected to cardioversion. METHODS: Forty-one patients (22 males and 19 females) with acute or persistent AF were examined by means of TDE and transthoracic ICG before electroversion, and then one week following the restoration of sinus rhythm. Additionally, the preand post-cardioversion serum levels of B-type natriuretic peptide (BNP) were determined. RESULTS: The restoration of sinus rhythm was reflected by a significant increase in the following ICG parameters (average changes are presented): stroke volume (+25 mL), stroke volume index (+11.8 m/m²), contractility index (+12.6/s), end-diastolic index (+12.3 mL/m²), acceleration index (+6/s²), and left ventricular ejection time (+56 ms). These changes were accompanied by a significant increase in the TDE parameters of tricuspid annular systolic velocity and mitral annular systolic velocities. Moreover, a significant decrease in early diastolic velocities was also observed following the restoration of sinus rhythm, along with significantly lower levels of BNP. CONCLUSIONS: Both TDE and ICG are modern, valuable diagnostic methods that complementarily explain changes occurring in the cardiovascular system of AF patients subjected to electroversion.

Short-term alcohol consumption may have detrimental effect on fibrinolysis and endothelial function: preliminary report of prospective randomised study.

BACKGROUND AND AIM: This study was designed to clarify the impact of the short-term consumption of different types of alcoholic beverages on haemostatic factors, C-reactive protein (hsCRP) and endothelin-1 (E-1) plasma levels. METHODS: The study group consisted of 57 healthy male volunteers, aged 20-29 years. Subjects were randomised to consume 300 mL of red wine, white wine, 12% ethanol, black currant juice or water for five days. Blood samples were collected for CRP, tissue type plasminogen activator antigen (t-PA:Ag), plasminogen activator inhibitor antigen (PAI-1:Ag) and E-1 at baseline, on day 2, and on day 6. RESULTS: A significant increase in PAI-1:Ag concentration was observed in the red wine drinking group (day 1: 44.98; day 2:56.86; day 6: 47.44 ng/mL; p = 0.05). A similar increase of E-1 level was found in the 12% ethanol group (day 1: 0.53; day 2:1.65; day 6: 1.11 fmol/mL; p = 0.01). Dividing the whole study group according to ethanol content of consumed beverages revealed significant changes in tPA:Ag, PAI-1:Ag and E-1 levels. In the alcohol drinking group, significant increases of PAI-1:Ag (day 1: 44.75; day 2: 54.07; day 6: 44.80 ng/mL; p < 0.05); tPA:Ag level (day 1: 3.65; day 2: 4.17; day 6: 5.03 ng/mL;p < 0.02) and E-1 (day 1: 0.42; day 2: 1.01; day 6: 0.97 fmol/mL; p < 0.002) were observed. CONCLUSIONS: Short-term alcohol consumption increases tPA:Ag, PAI:Ag and E-1 plasma levels. This effect may have an unfavourable impact on the fibrinolytic system and endothelial function.

[Severe tachycardiomyopathy and thrombus in the left atrial appendage--a case report]. / Zaawansowana kardiomiopatia tachyarytmiczna i przewlekla, oporna na leczenie skrzeplina w uszku lewego przedsionka.

We describe a case of severe left ventricular (LV) heart failure caused by tachycardiomyopathy with concomitant presence of unsolved thrombus in left atrial appendage despite effective oral anticoagulant treatment. Successful ablation of atrial flutter and atrioventricular nodal reentry tachycardia entailed resolution of heart failure symptoms and normalisation of LV function.

[The case of surgically treated severe thromboemboic pulmonary hypertension developing in the course of recurrent pulmonary embolism]. / Ciezkie zakrzepowo-zatorowe nadcisnienie plucne w przebiegu nawracajacej zatorowosci plucnej leczone operacyjnie.

A case of a patient with surgically treated progressive thromboembolic pulmonary hypertension in the course of recurrent pulmonary embolism resulting from deep vein thrombosis is presented. Acute embolic episode seems to have crucial role as an initiating factor triggering the cascade of unfavorable changes in pulmonary vasculature. The paper stresses the role of systematic clinical and echocardiographic control of patients after pulmonary embolism in order to diagnose developing complications as soon as possible. It would allow to introduce efficient treatment and improve prognosis.