The 'peptide for life' initiative in the emergency department study.

AIMS: Natriuretic peptide (NP) uptake varies in Emergency Departments (EDs) across Europe. The 'Peptide for Life' (P4L) initiative, led by Heart Failure Association, aims to enhance NP utilization for early diagnosis of heart failure (HF). We tested the hypothesis that implementing an educational campaign in Western Balkan countries would significantly increase NP adoption rates in the ED. METHODS AND RESULTS: This registry examined NP adoption before and after implementing the P4L-ED study across 10 centres in five countries: Bosnia and Herzegovina, Croatia, Montenegro, North Macedonia, and Serbia. A train-the-trainer programme was implemented to enhance awareness of NP testing in the ED, and centres without access received point-of-care instruments. Differences in NP testing between the pre-P4L-ED and post-P4L-ED phases were evaluated. A total of 2519 patients were enrolled in the study: 1224 (48.6%) in the pre-P4L-ED phase and 1295 (51.4%) in the post-P4L-ED phase. NP testing was performed in the ED on 684 patients (55.9%) during the pre-P4L-ED phase and on 1039 patients (80.3%) during the post-P4L-ED phase, indicating a significant absolute difference of 24.4% (95% CI: 20.8% to 27.9%, P < 0.001). The use of both NPs and echocardiography significantly increased from 37.7% in the pre-P4L-ED phase to 61.3% in the post-P4L-ED phase. There was an increased prescription of diuretics and SGLT2 inhibitors during the post-P4L-ED phase. CONCLUSIONS: By increasing awareness and providing resources, the utilization of NPs increased in the ED, leading to improved diagnostic accuracy and enhanced patient care.

Rationale and design of the ESC Heart Failure III Registry - Implementation and discovery.

AIMS: Heart failure outcomes remain poor despite advances in therapy. The European Society of Cardiology Heart Failure III Registry (ESC HF III Registry) aims to characterize HF clinical features and outcomes and to assess implementation of guideline-recommended therapy in Europe and other ESC affiliated countries. METHODS: Between 1 November 2018 and 31 December 2020, 10 162 patients with chronic or acute/worsening HF with reduced, mildly reduced, or preserved ejection fraction were enrolled from 220 centres in 41 European or ESC affiliated countries. The ESC HF III Registry collected data on baseline characteristics (hospital or clinic presentation), hospital course, diagnostic and therapeutic decisions in hospital and at the clinic visit; and on outcomes at 12-month follow-up. These data include demographics, medical history, physical examination, biomarkers and imaging, quality of life, treatments, and interventions - including drug doses and reasons for non-use, and cause-specific outcomes. CONCLUSION: The ESC HF III Registry will provide comprehensive and unique insight into contemporary HF characteristics, treatment implementation, and outcomes, and may impact implementation strategies, clinical discovery, trial design, and public policy.

Results of the trycort: Cohort study of add-on antihypertensives for treatment of resistant hypertension.

Although true treatment resistant hypertension is relatively rare (about 7.3% of all patients with hypertension), optimal control of blood pressure is not achieved in every other patient due to suboptimal treatment or nonadherence. The aim of this study was to compare effectiveness, safety and tolerability of various add-on treatment options in adult patients with treatment resistant hypertension The study was designed as multi-center, prospective observational cohort study, which compared effectiveness and safety of various add-on treatment options in adult patients with treatment resistant hypertension. Both office and home blood pressure measures were recorded at baseline and then every month for 6 visits. The study cohort was composed of 515 patients (268 females and 247 males), with average age of 64.7 ± 10.8 years. The patients were switched from initial add-on therapy to more effective ones at each study visit. The blood pressure measured both at office and home below 140/90 mm Hg was achieved in 80% of patients with add-on spironolactone, while 88% of patients taking this drug also achieved decrease of systolic blood pressure for more than 10 mm Hg from baseline, and diastolic blood pressure for more than 5 mm Hg from baseline. Effectiveness of centrally acting antihypertensives as add-on therapy was inferior, achieving the study endpoints in <70% of patients. Adverse drug reactions were reported in 9 patients (1.7%), none of them serious. Incidence rate of hyperkalemia with spironolactone was 0.44%, and gynecomastia was found in 1 patient (0.22%). In conclusion, the most effective and safe add-on therapy of resistant hypertension were spironolactone alone and combination of spironolactone and a centrally acting antihypertensive drug.

Primary antiphospholipid syndrome as a cause of impaired left ventricular diastolic function: experience from a Serbian cohort.

OBJECTIVES: Cardiovascular manifestations, encountered in antiphospholipid syndrome, may develop as a consequence of acquired thrombophilia mediated by antiphospholipid antibodies and accelerated atherosclerosis as well. Our study aims to assess the impairment of the left ventricular diastolic performance, as early evidence of myocardial involvement in primary antiphospholipid syndrome (PAPS). METHODS: We analysed 101 PAPS patients, with the average age of 47.70±13.14y. Anticardiolipin antibodies (aCL IgG/IgM), anti-ß2 glycoprotein-I (anti-ß2GPI IgG/IgM), and lupus anticoagulant (LAC) were determined. Abnormal cut-off values used for left ventricular diastolic dysfunction (LVDD) were septal E ́<7 cm/sec, lateral E ́ <10 cm/sec, average E/E ́ ratio >14, LA volume index (LAVI) >34 mL/m2, and peak tricuspid regurgitation velocity >2.8 m/sec. LVDD was present if more than half parameters were with abnormal values. The results were compared to 90 healthy, age and sex-matched controls. RESULTS: LVDD was significantly more prevalent in PAPS patients compared to healthy controls (24.8% vs. 2.2%, p=0.001). In PAPS patients, it was signi cantly related to age, body mass index, hyperlipidaemia, thromboses and LAC positivity (p=0.0001, p=0.008, p=0.039, p=0.001, p=0.047 respectively). Patients with PAPS had higher LAVI (29.76±6.40 ml/m2 vs. 26.62±7.8 ml/m2, p=0.012), higher isovolumic relaxation time, lower lateral É velocity and lower E/É ratio compared to controls (p=0.0001, p=0.020, p=0.038, respectively). In multivariate analysis, thromboses in PAPS were significant, and independent predictors of LVDD. CONCLUSIONS: Thrombotic PAPS patients are at higher risk of LVDD development. Strong action against standard atherosclerotic risk factors and adequate therapy regimes seems to be crucial to preserve good diastolic performance of the left ventricle in PAPS.

Potential drug-drug interactions associated with clinical and laboratory findings at hospital admission.

Background Drug-drug interactions represent one of the causes of adverse therapy outcomes through deteriorated efficacy or safety. However, the true extent of harm related to drug-drug interactions is not well established due to a lack of recognition and understanding. Objective The aim of this study was to investigate the association of potential drug-drug interactions with patients variables recorded at admission. Setting A cross-sectional correlation study was performed on the Cardiology ward of the University Clinical Hospital Center in Belgrade, Serbia. Method Data were retrospectively obtained from medical records and LexiInteract was used as the screening tool for potential drug-drug interactions. Main outcome measure Clinical and laboratory parameters recorded at the patients admission. Results A total of 351 patient records entered the analysis, with the mean age of 70 ± 10 years. The prevalence of potentially relevant drug-drug interactions was 61% (N = 213). After controlling for patient characteristics, nine potential drug-drug interactions were significantly associated with laboratory values outside the range and five potential drug-drug interactions with inadequate clinical parameter values. Potential drug-drug interactions were associated with abnormalities in blood count, metabolic parameters, electrolyte imbalance and renal function parameters. Association with inadequate control of systolic, diastolic blood pressure, as well as heart rhythm was also shown. Conclusion Drug-drug interactions were associated with patients clinical and laboratory findings. Our findings may assist in the identification of patients with increased likelihood of suboptimal therapy outcomes. Generating evidence through post-marketing drug-drug interactions research would lead to improvement in clinical decision-support systems, increased effectiveness and utilization in everyday clinical practice.

Glutathione Transferase P1 Polymorphism Might Be a Risk Determinant in Heart Failure.

Disturbed redox balance in heart failure (HF) might contribute to impairment of cardiac function, by oxidative damage, or by regulation of cell signaling. The role of polymorphism in glutathione transferases (GSTs), involved both in antioxidant defense and in regulation of apoptotic signaling pathways in HF, has been proposed. We aimed to determine whether GST genotypes exhibit differential risk effects between coronary artery disease (CAD) and idiopathic dilated cardiomyopathy (IDC) in HF patients. GSTA1, GSTM1, GSTP1, and GSTT1 genotypes were determined in 194 HF patients (109 CAD, 85 IDC) and 274 age- and gender-matched controls. No significant association was found for GSTA1, GSTM1, and GSTT1 genotypes with HF occurrence due to either CAD or IDC. However, carriers of at least one variant GSTP1∗Val (rs1695) allele were at 1.7-fold increased HF risk than GSTP1∗Ile/Ile carriers (p = 0.031), which was higher when combined with the variant GSTA1∗B allele (OR = 2.2, p = 0.034). In HF patients stratified based on the underlying cause of disease, an even stronger association was observed in HF patients due to CAD, who were carriers of a combined GSTP1(rs1695)/GSTA1 "risk-associated" genotype (OR = 2.8, p = 0.033) or a combined GSTP1∗Ile/Val+Val/Val (rs1695)/GSTP1∗AlaVal+∗ValVal (rs1138272) genotype (OR = 2.1, p = 0.056). Moreover, these patients exhibited significantly decreased left ventricular end-systolic diameter compared to GSTA1∗AA/GSTP1∗IleIle carriers (p = 0.021). Higher values of ICAM-1 were found in carriers of the GSTP1∗IleVal+∗ValVal (rs1695) (p = 0.041) genotype, whereas higher TNFα was determined in carriers of the GSTP1∗AlaVal+∗ValVal genotype (rs1138272) (p = 0.041). In conclusion, GSTP1 polymorphic variants may determine individual susceptibility to oxidative stress, inflammation, and endothelial dysfunction in HF.

Adverse drug reactions caused by drug-drug interactions in cardiovascular disease patients: introduction of a simple prediction tool using electronic screening database items.

Objective: Cardiovascular disease (CVD) drugs have been frequently implicated in adverse drug reaction (ADR)-related hospitalizations. Drug-drug interactions (DDIs) are common preventable cause of ADRs, but the impact of DDIs in the CVD population has not been investigated. Hence, the primary aim of the study was to identify DDIs associated with ADRs in CVD patients at hospital admission. The second aim was to develop a simple tool to identify high-risk patients for DDI-related adverse events. Methods: An observational study was conducted on the Cardiology Ward of University Clinical Hospital Center. Data were obtained from medical charts. A clinical panel identified DDIs implicated in ADRs, using LexiInteract database and Drug Interaction Probability Scale. Statistics were performed using PASW 22 (SPSS Inc.). Results: DDIs contributed to hospital admission with a total prevalence of 9.69%. DDI-related ADRs affected mainly cardiac function (heart rate or rhythm, 41.07%); bleeding and effect on blood pressure were equally distributed (17.86%). Non-cardiovascular ADRs were found in 23.21% of DDIs. After admission, 73% of the identified DDIs led to changes in prescription. Prediction ability of calculated DDI adverse event probability scores was rated as good (AUC = 0.80, p < .001). Conclusions: CVD patients are highly exposed to adverse DDIs; about one in ten patients hospitalized with CVD might have a DDI contributing to the hospitalization. Given the high prevalence of CVD, DDI-related harm might be a significant burden worldwide. Identification of patients with high DDI adverse event risk might ease the recognition of DDI-related harm and improve the use of electronic databases in clinical practice.

The prevalence and preventability of potentially relevant drug-drug interactions in patients admitted for cardiovascular diseases: A cross-sectional study.

AIM: The aim was to describe the type and prevalence of potentially relevant drug-drug interactions (pDDIs) in a population of patients admitted for cardiovascular diseases (CVD), and management strategies for reducing the occurrence of pDDIs. METHODS: A retrospective cross-sectional study was performed on Cardiology ward of University Clinical Hospital Center in Belgrade, Serbia. A total of 527 patients, with more than one prescription during hospital stay, were enrolled in this study. Data were obtained from medical records. LexiInteract was used as the screening tool. RESULTS: At least one potentially relevant pDDI was identified in 83.9% of patients. Occurrence was significantly more prevalent in patients with higher number of drugs, multimorbidity, longer length of stay, arrhythmia, heart failure, infectious and respiratory disease. About 13% of pDDIs exposures were accompanied with concurrent renal or liver disease, as an additional risk for DDI manifestation. Among CVD, patients with a history of myocardial infarction possessed the highest additional risk. The most common potential clinical outcome was the effect on cardiovascular system 48.5%, renal function and/or potassium 22.3%, bleeding 9.5%, impaired glucose control 6.8% and digoxin toxicity 4.6%. Main management strategies to avoid X or D class included using paracetamol instead of NSAID or alternative NSAID (38%), alternative antibiotic or antifungal (20.4%), H2 receptor antagonist instead of PPI (8.3%), avoiding therapeutic duplication (7.3%), and alternative HMG-CoA reductase inhibitor (7%). Heart rate, blood pressure, electrolytes/potassium and blood glucose could have been employed in monitoring for potential consequence of 72.2% C class pDDIs. CONCLUSIONS: Use of drug interaction screening tools can be beneficial risk mitigation strategy for potentially relevant pDDIs in CVD patients. DDI screening software could be linked to the patient's laboratory results or clinical data regarding renal or liver function, as an approach to reinforce DDIs alert quality.

Cardiopoietic cell therapy for advanced ischaemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial.

AIMS: Cardiopoietic cells, produced through cardiogenic conditioning of patients' mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort. METHODS AND RESULTS: This multinational, randomized, double-blind, sham-controlled study was conducted in 39 hospitals. Patients with symptomatic ischaemic heart failure on guideline-directed therapy (n = 484) were screened; n = 348 underwent bone marrow harvest and mesenchymal stem cell expansion. Those achieving > 24 million mesenchymal stem cells (n = 315) were randomized to cardiopoietic cells delivered endomyocardially with a retention-enhanced catheter (n = 157) or sham procedure (n = 158). Procedures were performed as randomized in 271 patients (n = 120 cardiopoietic cells, n = 151 sham). The primary efficacy endpoint was a Finkelstein-Schoenfeld hierarchical composite (all-cause mortality, worsening heart failure, Minnesota Living with Heart Failure Questionnaire score, 6-min walk distance, left ventricular end-systolic volume, and ejection fraction) at 39 weeks. The primary outcome was neutral (Mann-Whitney estimator 0.54, 95% confidence interval [CI] 0.47-0.61 [value > 0.5 favours cell treatment], P = 0.27). Exploratory analyses suggested a benefit of cell treatment on the primary composite in patients with baseline left ventricular end-diastolic volume 200-370 mL (60% of patients) (Mann-Whitney estimator 0.61, 95% CI 0.52-0.70, P = 0.015). No difference was observed in serious adverse events. One (0.9%) cardiopoietic cell patient and 9 (5.4%) sham patients experienced aborted or sudden cardiac death. CONCLUSION: The primary endpoint was neutral, with safety demonstrated across the cohort. Further evaluation of cardiopoietic cell therapy in patients with elevated end-diastolic volume is warranted.

El ácido úrico y la actividad de gammaglutamil transferasa se asocian a los índices de remodelado ventricular izquierdo en pacientes con insuficiencia cardiaca crónica / Uric acid and gamma-glutamyl transferase activity are associated with left ventricular remodeling indices in patients with chronic heart failure

Introducción y objetivos El ácido úrico y la gammaglutamil transferasa son indicadores pronósticos en la insuficiencia cardiaca crónica. No obstante, el mecanismo subyacente a la asociación observada entre ácido úrico, gammaglutamil transferasa y progresión y pronóstico de la insuficiencia cardiaca crónica sigue siendo en gran parte desconocido.MétodosSe estudió la asociación del ácido úrico y la gammaglutamil transferasa con la dilatación mediada por flujo y con los índices ecocardiográficos del remodelado cardiaco en 120 pacientes con insuficiencia cardiaca isquémica crónica. Para determinar la contribución independiente del ácido úrico y la gammaglutamil transferasa en la dilatación mediada por flujo y en los índices ecocardiográficos del remodelado, se construyó una serie de modelos de regresión lineal múltiple, basados en los factores de riesgo tradicionales y no tradicionales que influyen en estos parámetros. Resultados: El ácido úrico es un factor independiente predictivo de dilatación mediada por flujo, pero no la gammaglutamil transferasa. El ácido úrico se asocia a todos los índices ecocardiográficos de disfunción ventricular izquierda evaluados en tres modelos de regresión múltiple; también muestra correlación con los diámetros telesistólico (r = 0,337) y telediastólico (r = 0,340) y los volúmenes telesistólico (r = 0,321) y telediastólicos (r = 0,294) del ventrículo izquierdo (p = 0,001). La gammaglutamil transferasa es un factor independiente predictivo de los volúmenes telesistólico y telediastólico del ventrículo izquierdo tras introducir un ajuste por todas las variables. La gammaglutamil transferasa muestra correlación con los diámetros telesistólico (r = 0,238; p = 0,009) y telediastólico (r = 0,219; p = 0,016) y los volúmenes telesistólico (r = 0,359; p < 0,001) y telediastólico (r = 0,369; p = 0,001) del ventrículo izquierdo. Conclusiones: El ácido úrico y la actividad de gammaglutamil transferasa se asocian a los índices de remodelado ventricular izquierdo en pacientes con insuficiencia cardiaca isquémica crónica

Introduction and objectives Uric acid and gamma-glutamyl transferase are prognostic indicators in chronic heart failure. Nevertheless, the mechanism underlying the association between uric acid, gamma-glutamyl transferase, and chronic heart failure progression and prognosis remains largely unknown.MethodsThe association of uric acid and gamma-glutamyl transferase with flow-mediated dilation and echocardiographic indices of cardiac remodeling was addressed in 120 patients with chronic ischemic heart failure. To determine the independent contribution of uric acid and gamma-glutamyl transferase to the flow-mediated dilation and echocardiographic indices of remodeling, a series of multiple linear regression models, based on traditional and nontraditional risk factors impacting upon these parameters, were constructed.ResultsUric acid, but not gamma-glutamyl transferase, was an independent predictor of flow-mediated dilation. Uric acid was associated with all the echocardiographic indices of left ventricular in patients with chronic ischemic heart failure

Uric acid and gamma-glutamyl transferase activity are associated with left ventricular remodeling indices in patients with chronic heart failure.

INTRODUCTION AND OBJECTIVES: Uric acid and gamma-glutamyl transferase are prognostic indicators in chronic heart failure. Nevertheless, the mechanism underlying the association between uric acid, gamma-glutamyl transferase, and chronic heart failure progression and prognosis remains largely unknown. METHODS: The association of uric acid and gamma-glutamyl transferase with flow-mediated dilation and echocardiographic indices of cardiac remodeling was addressed in 120 patients with chronic ischemic heart failure. To determine the independent contribution of uric acid and gamma-glutamyl transferase to the flow-mediated dilation and echocardiographic indices of remodeling, a series of multiple linear regression models, based on traditional and nontraditional risk factors impacting upon these parameters, were constructed. RESULTS: Uric acid, but not gamma-glutamyl transferase, was an independent predictor of flow-mediated dilation. Uric acid was associated with all the echocardiographic indices of left ventricular dysfunction tested in 3 multiple-regression models. Uric acid correlated with left ventricular end-systolic diameter, left ventricular end-diastolic diameter, left ventricular end-systolic volume, and left ventricular end-diastolic volume (r = 0.337; r = 0.340; r = 0.321; r = 0.294; P = .001, respectively). Gamma-glutamyl transferase was an independent predictor of left ventricular end-systolic volume and left ventricular end-diastolic volume, after adjustment for all variables. Gamma-glutamyl transferase correlated with left ventricular end-systolic diameter, left ventricular end-diastolic diameter, left ventricular end-systolic volume, and left ventricular end-diastolic volume (r = 0.238, P = .009; r = 0.219, P = .016; r = 0.359, P < .001; r = 0.369, P = .001, respectively). CONCLUSIONS: Serum uric acid and gamma-glutamyl transferase levels are associated with left ventricular remodeling in patients with chronic ischemic heart failure.

Association between cardiac manifestations and antiphospholipid antibody type and level in a cohort of Serbian patients with primary and secondary antiphospholipid syndrome.

BACKGROUND: Antiphospholipid syndrome (APS, also known as Hughes syndrome) may manifest itself as a primary or secondary disease, most commonly with systemic lupus erythemathosus (SLE) and various cardiac manifestations. OBJECTIVES: To report the first results from the Serbian National Cohort study, which was started in January 2000. METHODS: Our study included 374 patients: 260 primary APS patients and 114 SLE patients with secondary APS. Antiphospholipid antibody (aPL) analysis included detection of anticardiolipin antibodies (aCL) (immunoglobulin G and M), beta2-glycoprotein 1, and lupus anticoagulant. Echocardiography was performed in all patients, and data on myocardial infarction, unstable angina, chronic cardiomyopathy and acute heart failure were collected. RESULTS: There were 30.7% secondary APS patients and 9.2% primary APS patients with pseudo-infective endocarditis (P = 0.0001). Cardiac manifestations were observed in 28.7% of patients who had more than one type of antibody (category I), in 24.1% with category IIa, in 23.1% with category IIb, and in 27.8% with category IIc (P = 0.78). Age was confirmed as a significant factor for cardiac manifestations in APS patients (52.3 and 43.3 years, respectively, P = 0.001). aCL IgG and IgM positivity was related to valvular changes in all APS patients and high levels of those antibodies increased the risk of these manifestations. CONCLUSIONS: Patients with secondary APS had a higher prevalence ofvalvular lesions, and some aPL types and high levels of aPL were risk factors for specific cardiac manifestations in APS patients.

Associations of GSTM1*0 and GSTA1*A genotypes with the risk of cardiovascular death among hemodialyses patients.

BACKGROUND: The presence of glutathione transferase (GST) M1 null genotype (GSTM1-null) in end-stage renal disease (ESRD) patients is associated with lower overall survival rate in comparison to those with GSTM1-active variants. We examined association between GSTM1 and GSTT1 deletion polymorphisms as well as SNPs in GSTA1/rs3957357 and GSTP1/rs1695 genes with overall and cause-specific cardiovascular mortality in ESRD patients. METHODS: Total of 199 patients undergoing hemodialysis were included in the study. Median value of time elapsed from dialysis initiation until the death, or the end of follow-up was 8 ± 5 years. The effect of GSTM1, GSTT1, GSTP1 and GSTA1 gene polymorphisms on predicting overall and specific cardiovascular outcomes (myocardial infarction, MI or stroke) was analyzed using Cox regression model, and differences in survival were determined by Kaplan-Meier. RESULTS: GSTM1-null genotype in ESRD patients was found to be independent predictor of overall and cardiovascular mortality. However, after false discovery rate and Bonferroni corrections this effect was lost. The borderline effect modification by wild-type GSTA1*A/*A genotype on associations between GSTM1-null and analyzed outcomes was found only for death from stroke. Homozygous carriers of combined GSTM1*0/GSTA1*A genotype exhibited significantly shorter time to death of stroke or MI in comparison with carriers of either GSTM1-active or at least one GSTA1*B gene variant. The best survival rate regarding cardiovascular outcome was found for ESRD patients with combined GSTM1-active and mutant GSTA1*B/*B genotype. CONCLUSIONS: Combined GSTM1*0/GSTA1*A genotypes might be considered as genetic markers for cardiovascular death risk in ESRD patients, which may permit targeting of preventive and early intervention.

Regional differences among female patients with heart failure from the Cardiac Insufficiency BIsoprolol Study in ELDerly (CIBIS-ELD).

BACKGROUND: The aim of our study was to examine regional differences in the demographics, etiology, risk factors, comorbidities and treatment of female patients with heart failure (HF) in the Cardiac Insufficiency BIsoprolol Study in ELDerly (CIBIS-ELD) clinical trial. METHODS AND RESULTS: One hundred and fifty-nine female patients from Germany and 169 from Southeastern (SE) Europe (Serbia, Slovenia and Montenegro) were included in this subanalysis of the CIBIS-ELD trial. Women comprised 54% of the study population in Germany and 29% in SE Europe. German patients were significantly older. The leading cause of HF was arterial hypertension in German patients, 71.7% of whom had a preserved ejection fraction. The leading etiology in SE Europe was the coronary artery disease; 67.6% of these patients had a reduced left ventricular ejection fraction (34.64 ± 7.75%). No significant differences were found in the prevalence of traditional cardiovascular risk factors between the two regions (hypertension, diabetes, hypercholesterolemia, smoking and family history of myocardial infarction). Depression, chronic obstructive pulmonary disease and malignancies were the comorbidities that were noted more frequently in the German patients, while the patients from SE Europe had a lower glomerular filtration rate. Compared with the German HF patients, the females in SE Europe received significantly more angiotensin converting enzyme inhibitors, loop diuretics and less frequently angiotensin receptor blockers and mineralocorticoid receptor antagonists. CONCLUSIONS: Significant regional differences were noted in the etiology, comorbidities and treatment of female patients with HF despite similar risk factors. Such differences should be considered in the design and implementation of future clinical trials, especially as women remain underrepresented in large trial populations.

c-FLIP does not correlate with response to immunochemotherapy treatment and outcome of patients with nodal diffuse large B-cell lymphoma.

UNLABELLED: Cellular FLICE-inhibitory protein (c-FLIP) is a critical anti-apoptotic regulator that inhibits apoptosis-inducing ligand, (TRAIL)-induced apoptosis as well as chemotherapy-triggered apoptosis in malignant cells. The present study was designed to investigate the clinical and prognostic significance of c-FLIP expression in patients with nodal diffuse large B-cell lymphoma (DLBCL) treated with immunochemotherapy. METHODS: We have analyzed lymph node biopsy specimens, obtained from 60 patients with newly diagnosed nodal DLBCL treated with immunochemotherapy (R-CHOP or R-EPOCH). The expression of c-FLIP was analyzed using the standard imunohistochemical method on formalin-fixed and routinely processed paraffin-embedded lymph node specimens and evaluated semi quantitavely as a percentage of tumor cells. RESULTS: c-FLIP immunoexpression (>50% positive tumor cells) has been found in 28 (46.7%) patients, and observed as cytoplasmic staining. There was not significant difference in c-FLIP immunoexpression between GCB and non-GCB subtype of DLBCL (P=0.639). Besides, c-FLIP immunoexpression had no significant association with IPI, "bulky" disease, extranodal localization, haemoglobin, Ki-67 immunoexpression or other clinico-pathological parameters. c-FLIP positivity has no significant influence on therapy response and survival in patients with DLBCL (P=0.562 and P=0.093, respectively). Patients with c-FLIP overexpression did not relapse more often that patients without expression of this apoptotic protein (P=0.365). CONCLUSION: Our results suggest that c-FLIP immunoexpression can not be used as a prognostic factor in patients with nodal DLBCL treated with immunochemotherapy.

The role of serum VCAM-1 and TNF-α as predictors of mortality and morbidity in patients with chronic heart failure.

BACKGROUND: To assess the prognostic significance of four inflammatory markers (TNF-α, high sensitive C-reactive protein (hs-CRP), intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1)) in chronic heart failure (CHF) patients with respect to individual outcomes, especially disease exacerbation and mortality. METHODS: Plasma adhesion molecules, ICAM-1, and VCAM-1, together with TNF-α and hs-CRP were determined in 120 CHF patients and 69 healthy controls. Endothelial function was also estimated by flow-mediated brachial artery dilatation. RESULTS: Increased levels of all investigated inflammatory markers were found in CHF patients compared to controls, with the rise more pronounced in New York Heart association (NYHA) functional IV class. Significant correlations were obtained for VCAM-1 and brain natriuretic peptide (r = 0.191; P = 0.038), as well as, ICAM-1 and endothelium-dependent vasodilatation (r = -0.235; P = 0.01). Kaplan-Meier analysis showed disease exacerbation in patients with TNF-α levels >2.78 pg/ml significantly shorter compared to those with TNF-α levels <2.78 pg/ml (log-rank test = 8.270; P = 0.004), while similar association was observed for patients with hs-CRP levels >4.76 mg/l (log-rank test = 5.052; P = 0.025) and VCAM-1 levels >1200 ng/l (log-rank test = 5.45; P = 0.020) with respect to mortality. Cox regression analysis demonstrated only VCAM-1 (HR = 4.7; 95% confidence interval (CI): 1.1-18.7; P = 0.030) as independent death predictor, while TNF-α was associated with disease exacerbation (HR = 8.2; 95%CI: 1.1-23.0; P = 0.045). CONCLUSIONS: VCAM-1 appears to be useful in risk stratification of CHF patients and in screening, to identify subjects at risk for heart failure related events.

Markers of oxidative damage and antioxidant enzyme activities as predictors of morbidity and mortality in patients with chronic heart failure.

BACKGROUND: Although the majority of previous findings unequivocally confirmed the existence of systemic oxidative stress in chronic heart failure (CHF) patients, data on prognostic potential of biomarkers of oxidative lipid and protein damage are limited. We aimed to address the relation of oxidative stress markers to severity and prognosis in CHF secondary to ischemic cardiomyopathy. METHODS AND RESULTS: Plasma malondialdehyde (MDA), protein thiol groups (P-SH), reactive carbonyl derivatives (RCD), together with glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities were determined in 120 CHF patients and 69 healthy controls. Increased lipid peroxidation (MDA) and oxidation of plasma proteins (RCD; P-SH) s well as downregulated GSH-Px activity were found in CHF patients compared with controls. Significant correlation was obtained only for RCD content and remodeling indices (LVEDV: r = 0.469, P = .008; LVESV: r = 0.452; P = .011). Cox regression analysis demonstrated only MDA (HR = 3.33; CI: 1.55-7.12; P = .002) as independent predictor of death, whereas SOD was associated with unstable angina pectoris (HR = 2.09; CI: 1.16-3.78; P = .011). CONCLUSIONS: In the course of CHF progression, carbonyl stress is implicated in the LV remodeling. Malondialdehyde level might be a useful parameter for monitoring and planning management of CHF patients.

Markers of oxidative damage in chronic heart failure: role in disease progression.

BACKGROUND: We aimed to study the relationship between markers of oxidative lipid or protein damage and ventricular remodeling and the validity of 8-epi-prostaglandin F(2alpha) (8-epi-PGF(2alpha)) as an indicator of disease severity in patients with ischemic chronic heart failure (CHF). PATIENTS AND METHODS: We enrolled four groups of 12 patients with varying CHF according to the New York Heart Association (NYHA) classification and 25 controls. Urinary 8-epi-PGF(2alpha) and plasma malondialdehyde and protein thiol (P-SH) groups were correlated with echocardiographic indices of remodeling. The reliability of isoprostanes was analyzed by a receiver operating characteristics (ROC) curve. RESULTS: NYHA class III and IV patients exhibited elevated 8-epi-PGF(2alpha) levels, increased malondialdehyde concentrations and decreased P-SH groups when compared to controls and NYHA I and II patients. 8-Epi-PGF(2alpha) and P-SH groups correlated significantly with indices of remodeling. The ROC curve drawn for 8-epi-PGF(2alpha) allowed us to differentiate NYHA class III and IV patients from NYHA class I and II patients with a sensitivity of 95.8% and specificity of 95.8% (cut off 0.84 ng/mg creatinine; area under curve 0.99; P < 0.001). CONCLUSIONS: Markers of oxidative damage are unlikely to play a significant role in early stages of CHF. However, they might become important in the course of CHF when their concentrations reach critical levels. Urinary 8-epi-PGF(2alpha) is a reliable indicator of symptomatic CHF.