Biomarker Phenotypes in Heart Failure with Preserved Ejection Fraction Using Hierarchical Clustering-A Pilot Study.

OBJECTIVES: We hypothesized the existence of distinct phenotype-based groups within the very heterogeneous population of patients of heart failure with preserved ejection fraction (HFpEF) and using an unsupervised hierarchical clustering applied to plasma concentration of various biomarkers. We sought to characterize them as "biomarker phenotypes" and to conclude differences in their overall characteristics. SUBJECTS AND METHODS: A cross-sectional study was conducted on 75 patients with HFpEF. An agglomerative hierarchical clustering was performed using the concentrations of cardiac remodeling biomarkers, BNP and cystatin C. RESULTS: According to the obtained heat map of this analysis, we concluded two distinctive biomarker phenotypes within the HFpEF. The "remodeled phenotype" presented with significantly higher concentrations of cardiac remodeling biomarkers and cystatin C (p < 0.001), higher prevalence of myocardial infarction (p = 0.047), STEMI (p = 0.045), atrial fibrillation (p = 0.047) and anemia: lower erythrocytes count (p=0.037), hemoglobin concentration (p = 0.034) and hematocrit (p = 0.046), compared to "non-remodeled phenotype". Echocardiography showed that patients within "remodeled phenotype" had significantly increased parameters of left ventricular remodeling: left ventricular mass index (p < 0.001), left ventricular mass (p = 0.001), diameters of the interventricular septum (p = 0.027) and posterior wall (p = 0.003) and function alterations, intermediate pauses duration >2.0 seconds (p < 0.006). CONCLUSION: Unsupervised hierarchical clustering applied to plasma concentration of various biomarkers in patients with HFpEF enables the identification of two biomarker phenotypes, significantly different in clinical characteristics and cardiac structure and function, whereas one phenotype particularly relates to patients with reduced ejection fraction. These findings imply distinct underlying pathophysiology within a unique cohort of HFpEF.

Cardiac Remodeling Biomarkers as Potential Circulating Markers of Left Ventricular Hypertrophy in Heart Failure with Preserved Ejection Fraction.

Soluble suppressor of tumorigenicity 2 (sST2), galectin-3, growth differentiation factor (GDF)-15 and syndecan-1 represent biomarkers of cardiac remodeling, involved in heart failure (HF) progression. We hypothesize that their plasma concentrations, together with brain natriuretic peptide (BNP), are different in HF stratified by ejection fraction (EF), demonstrating correlations with echocardiographic parameters that indicate left ventricular (LV) hypertrophy; LV mass index (LVMI) and posterior wall and septum diameters. HF patients (n = 77) were classified according to EF: reduced EF < 40% (HFrEF), mid-range EF = 40-49% (HFmrEF), preserved EF > 50% (HFpEF). We found that plasma concentrations of four cardiac remodeling biomarkers were highest in HFrEF and lowest in HFpEF, p < 0.001. In HFpEF, remodeling biomarkers independently correlated with LVMI: sST2 (p = 0. 002), galectin-3 (p < 0.001), GDF-15 (p = 0.011), and syndecan-1 (p = 0.006), whereas galectin-3 correlated after multivariable adjustments (p = 0.001). Independent correlates of septum and posterior wall diameters, in HFpEF, were sST2 (p = 0.019; p = 0.026), galectin-3 (p = 0.011; p = 0.009), GDF-15 (p = 0.007; p = 0.001), and syndecan-1 (p = 0.005; p = 0.002). In HFrEF, only sST2, adjusted, correlated with LVMI (p = 0.010), whereas BNP correlated with LVMI (p = 0.002) and EF (p = 0.001). GDF-15 correlated with diastolic dysfunction in HFpEF (p = 0.046) and HFrEF (p = 0.024). Cardiac remodeling biomarkers are potential circulating indicators of LV hypertrophy in HFpEF, which may ensure timely recognition of disease progression among high-risk patients.

Predictors of Cardiovascular Events in Hypertensive Patients with High Cardiovascular Risk.

Background and objectives: A long-term therapeutic strategy in hypertensive patients equally depends on measured arterial blood pressure values and total determined cardiovascular risk. The aim of the adequate hypertensive patient treatment is both the reduction in arterial blood pressure and the reduction of all preexisting modifiable risk factors, prevention of target organs damage, and adverse cardiovascular events. The aim of this study was to determine independent predictors of cardiovascular events in patients with hypertension and high cardiovascular (CV) risk, and whether the modifiable risk factors could affect long-term prognosis in the studied population. Materials and Methods: This prospective study included 142 hypertensive patients (65% females), mean age 63.1±8 years, with high CV risk. Each participant was followed for 6.2 years. Results: During the follow-up period, the incidence of non-fatal and fatal CV events was 19.7%, CV mortality 7%, and total mortality 9.9%. Our multivariate analysis showed that plaques in both carotid arteries (p = 0.042), diabetes mellitus (p = 0.042) and cholesterol at the beginning of the study (p = 0.016) were significantly associated with an increased risk of CV events. Patients' age (p = 0.009), intima-media thickness (p = 0.001) and diabetes mellitus (p = 0.042) were significantly associated with an increased risk of CV mortality, and age (p = 0.007) and cholesterol (p = 0.002) were independent variables significantly associated with increased total mortality rates. Conclusions: The results of the present study showed that the main predictors of adverse CV events in high-risk hypertensive patients were years of age, cholesterol levels, diabetes, intima-media thickness, and carotid arteries plaques.

Does HAS-BLED risk score underestimate the risk of bleeding in patients with triple antithrombotic therapy?

stroke or other thromboembolic complications in patients with atrial fibrillation (AF). On the other hand, dual antiplatelet therapy (aspirin plus P2Y12 inhibitor) represents a cornerstone in the treatment of acute coronary syndrome. Atrial fibrillation is relatively common in patients with coronary artery disease and patients who undergo primary percutaneous coronary interventions (PCI) with stent implantation. They should be on triple antithrombotic therapy (TAT): preferably direct oral anticoagulants (DOAC) plus aspirin plus clopidogrel as it prevents ischemic as well as thromboembolic events. Before introducing OAT in patients with AF we must assess the risk of future bleeding episodes as OAT can lead to some life-threatening bleeding events. The most common risk score used for that purpose is HASBLED score. HAS-BLED score is valuable, proven tool in assessing future bleeding events in patients with AF. Nevertheless, it does not make the difference between dual and triple antithrombotic therapy which can be of great importance in preventing bleeding events.

Mechanisms and pathways of anti-inflammatory activity of DPP-4 inhibitors in cardiovascular and renal protection.

Dipeptidyl peptidase-4 (DPP-4) cleaves N-terminal dipeptides, with Pro, Ala or Ser at the penultimate position, and, in that way, modulates biological activity of certain polypeptides. Due to its ubiquitous distribution, many pathological processes are associated with altered DPP-4 expression and activity. Besides the regulation of glucose metabolism, DPP-4 also exhibits many other systemic effects, and the inhibition of its activity might lead to cardiovascular and renal protection. Mechanisms underlying these protective effects of DPP-4 inhibition are ascribed to elevated bioavailability of its substrates, to impacts on mediators and signaling pathways that ameliorate cardiovascular and renal function through the suppression of oxidative stress, inflammation, fibrosis and apoptosis, improved endothelial function and tissue reparation. Inflammation contributes to and promotes progression of cardiovascular and renal disorders. Herein, we discuss cellular and molecular mechanisms mediating the anti-inflammatory activity of clinically used DPP-4 inhibitors in cardiovascular and renal protection.

Effects of Music Therapy on Endothelial Function in Patients With Coronary Artery Disease Participating in Aerobic Exercise Therapy.

Context • Pleasant music that evokes a positive emotional response may activate brain pathways of the insular cortex, central nucleus of the amygdala, and lateral hypothalamus, which are involved in the integration of emotional and ambient sensory input, with corresponding autonomic responses. Exercise training can improve endothelium-dependent vasodilatation, both in epicardial coronary vessels and in resistance vessels, for patients with coronary heart disease. Objective • The aim of the present study was to evaluate the effects on endothelial function when patients with stable coronary artery disease (CAD) listened to their favorite music. Design • The study was a randomized controlled trial. Setting • The study occurred at the Institute of Cardiology, Niska Banja, Faculty of Medicine, University of Nis (Nis, Serbia). Participants • Participants were 74 patients with stable CAD. Intervention • Participants were randomly assigned to 1 of 3 groups: (1) exercise training only (T) group (n = 33), (2) listening to music and exercise training (MT) group (n = 31), and listening to music only (M) group (n = 10). Participants in the T and MT groups received usual medical care and underwent 3 wk of supervised aerobic exercise training. In addition to the exercise training, participants in the MT group listened to their favorite music for 1.5 h every day. Participants in the M group received the usual medical care and listened to their favorite music for 1.5 h every day. Outcome Measures • At baseline and postintervention, outcomes were assessed through measurement of the changes in circulating blood markers of endothelial function-the stable end product of nitric oxide (NOx), asymmetric dimethylarginine, symmetric dimethylarginine, and xanthine oxidase-and through the results of submaximal or symptom-limited exercise test. Results • After 3 wk, the NOx significantly increased in both in MT and T groups, with P < .001 and P < .01, respectively. The level of NOx was associated with an improvement in exercise capacity, which increased in the T, MT, and M groups, with P < .001, P < .001, and P < .05, respectively. At the end of the study, the xanthine oxidase was significantly lower in the T, MT, and M groups, with P < .001 and P < .05, respectively. Conclusions • The patients with stable CAD significantly improved their endothelial function by listening to their favorite music in addition to participating in regular exercise training. Having a patient listen to his or her favorite music can be proposed as an additional nonpharmacologic intervention for improving a CAD patient's endothelial function. The music program should be adjusted individually to fit with a well-established training program for aerobic exercise, according to a patient's preferences.

Circulating purine compounds, uric acid, and xanthine oxidase/dehydrogenase relationship in essential hypertension and end stage renal disease.

Purine nucleotide liberation and their metabolic rate of interconversion may be important in the development of hypertension and its renal consequences. In the present study, blood triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP) breakdown pathway was evaluated in relation to uric acid concentration and xanthine dehydrogenase/xanthine oxidase (XDH/XO) in patients with essential hypertension, patients with chronic renal diseases on dialysis, and control individuals. The pattern of nucleotide catabolism was significantly shifted toward catabolic compounds, including ADP, AMP, and uric acid in patients on dialysis program. A significant fall of ATP was more expressed in a group of patients on dialysis program, compared with the control value (p<0.001), while ADP and AMP were significantly increased in both groups of patients compared with control healthy individuals (p<0.001), together with their final degradation product, uric acid (p<0.001). The index of ATP/ADP and ATP/uric acid showed gradual significant fall in both the groups, compared with the control value (p<0.001), near five times in a group on dialysis. Total XOD was up-regulated significantly in a group with essential hypertension, more than in a group on dialysis. The activity of XO, which dominantly contributes reactive oxygen species (ROS) production, significantly increased in dialysis group, more than in a group with essential hypertension. In conclusion, the examination of the role of circulating purine nucleotides and uric acid in pathogenesis of hypertension and possible development of renal disease, together with XO role in ROS production, may help in modulating their liberation and ROS production in slowing progression from hypertension to renal failure.

Population pharmacokinetics of bisoprolol in patients with chronic heart failure.

PURPOSE: The aim of the study was to develop a population pharmacokinetic (PK) model for clearance of bisoprolol in patients with congestive heart failure (CHF). METHODS: Parameters associated with the plasma concentrations of bisoprolol at steady-state were analyzed in 61 patients (mean age 66.21 ± 9.49 years; mean total body weight 8.90 ± 12.26 kg) with CHF using non-linear mixed-effect modeling (NONMEM). A validation set of 17 patients with heart failure was used to estimate the predictive performance of the pharmacokinetic model. RESULTS: The typical mean value for bisoprolol clearance (CL), estimated by the base model (without covariates), in our population was 11.4 l h(-1). In the full model, covariates such as bisoprolol total daily dose (DD) and creatinine clearance were included. The final regression model for the clearance of bisoprolol was the following: CL (l h(-1)) = 4.68 + 0.859 * DD. CONCLUSION: The derived PK model describes the clearance of bisoprolol in patients with CHF, showing that the total daily dose of bisoprolol is the most important covariate. This finding will provide the basis for future PK studies on beta blockers in this specific patient population and lead to better overall management of heart failure.

Sport-related differences in QT dispersion and echocardiographic parameters in male athletes.

The aim of this study was to compare QT dispersion (QTd) and echocardiographic parameters in male athletes competing across different sports (long-distance running, volleyball, football, powerlifting, and bodybuilding) and a control population. Significant moderate-strong differences (p < 0.001, [Formula: see text] = 0.52-0.71) were found in corrected QTd, intraventricular septal wall thickness (ISWT), posterior wall thickness (PWT), relative wall thickness (RWT) and LV (left ventricular) index between groups. Corrected QTd, ISWT, PWT, and RWT were significantly (p < 0.001) higher in powerlifters and bodybuilders compared to other athlete groups and controls. While all athlete groups displayed a significantly higher LV index (p < 0.05) compared to controls, corrected QTd was significantly lower (p < 0.001) only in long-distance runners, volleyball athletes, and football athletes compared to controls. Normal or eccentric LV hypertrophy (LVH) was observed in most long-distance runners (58% and 33%), volleyball athletes (50% and 50%), and football athletes (56% and 41%). In contrast, concentric LVH was observed in most powerlifters (58%) and bodybuilders (54%). Advanced LVH, predominantly concentric in nature, appears to be accompanied with increased QTd in powerlifters and bodybuilders. On the other hand, runners, volleyball athletes, and football athletes experienced LVH toward the upper threshold of the normal reference range alongside reduced QTd compared to other groups.

Exercise-induced B-lines for the diagnosis of heart failure with preserved ejection fraction: a two-centre study.

BACKGROUND: Diagnosis of heart failure with preserved ejection fraction (HFpEF) remains challenging despite the use of scores/algorithms. This study intended to assess the diagnostic value of exercise lung ultrasound (LUS) for HFpEF diagnosis. METHODS: We studied two independent case-control studies of HFpEF patients and control subjects undergoing different exercise protocols: (i) submaximal exercise stress echocardiography (ESE) with LUS performed by expert cardiologists (N = 116, HFpEF = 65.5%), and (ii) maximal cycle ergometer test (CET) (N = 54, HFpEF = 50%) with LUS performed by unexperienced physicians shortly trained for the study. B-line kinetics (i.e. peak values and their changes from rest) were assessed. RESULTS: In the ESE cohort, the C-index (95% CI) of peak B-lines for HFpEF diagnosis was 0.985 (0.968-1.000), whereas the C-index of rest and exercise HFA-PEFF scores (i.e. including stress echo findings) were < 0.90 (CI 0.823-0.949), and that of H2FPEF score was < 0.70 (CI 0.558-0.764). The C-index increase of peak B-lines on top of the above-mentioned scores was significant (C-index increase > 0.090 and P-value < 0.001 for all). Similar results were observed for change B-lines. Peak B-lines > 5 (sensitivity = 93.4%, specificity = 97.5%) and change B-lines > 3 (sensitivity = 94.7%, specificity = 87.5%) were the best cutoffs for HFpEF diagnosis. Adding peak or change B-lines on top of HFpEF scores and BNP significantly improved diagnostic accuracy. Peak B-lines showed a good diagnostic accuracy in the LUS beginner-led CET cohort (C-index = 0.713, 0.588-0.838). CONCLUSIONS: Exercise LUS showed excellent diagnostic value for HFpEF diagnosis regardless of different exercise protocols/level of expertise, with additive diagnostic accuracy on top of available scores and natriuretic peptides.

Plasma advanced oxidation products as an additional tool in assessment of post-infarction heart failure.

OBJECTIVE: To define which oxidative stress markers could be used as diagnostic tools in the assessment of post-infarction heart failure (HF). METHODS: This observational study enrolled patients with HF that were divided into three subgroups (ejection fraction [EF] ≥ 50%; EF 40-49%; EF < 40%) and age- and sex-matched healthy control subjects. The plasma concentrations of advanced oxidation protein products (AOPP), thiobarbituric acid reactive substances, catalase activity and free thiols were determined in all participants. RESULTS: The study enrolled 81 patients with HF and 68 healthy control subjects. There were significant differences in the values ​​of oxidative stress markers between patients and controls. Oxidative stress parameters did not differ between the subgroups of patients, except for AOPP, which was significantly higher in the EF < 40% group. Univariate and multivariate logistic regression analyses showed an association between AOPP and HF in the EF ≥ 50% group, while receiver operating characteristic (ROC) curve analysis identified a cut-off value of 60.89 µmol/l for AOPP. CONCLUSIONS: Based on the ROC curve analysis of AOPP and the higher significance in the multivariate analyses for patients with EF ≥ 50%, these current results suggest that AOPP could be a useful additional tool in the assessment of post-infarction HF.

Exercise-induced B-lines in heart failure with preserved ejection fraction occur along with diastolic function worsening.

AIMS: Pulmonary congestion during exercise assessed by lung ultrasound predicts negative outcome in patients with heart failure with preserved ejection fraction (HFpEF). We aimed at assessing predictors of exercise-induced pulmonary B-lines in HFpEF patients. METHODS AND RESULTS: Eighty-one I-II NYHA class HFpEF patients (65.0  ± 8.2 y/o, 56.8% females) underwent standard and strain echocardiography, lung ultrasound, and natriuretic peptide assessment during supine exercise echocardiography (baseline and peak exercise). Peak values and their changes were compared in subgroups according to exercise lung congestion grading (peak B-lines >10 or ≤10). Exercise elicited significant changes for all echocardiographic parameters in both subgroups [39/81 (48.1%) with peak B-lines >10; 42/81 (51.9%) with B-lines ≤10]. Peak values and changes of E-wave (and its derived indices) were significantly higher in patients with >10 peak B-lines compared with those with ≤10 B-line (all P-values <0.03), showing significant correlation with peak B-lines for all parameters; concomitantly, global longitudinal strain (GLS) and global strain rate (GSR) during systole (GSRs), early (GSRe) and late (GSRa) diastole, and isovolumic relaxation (GSRivr) were reduced in patients with B-lines >10 (all P-values <0.05), showing a negative correlation with peak B-lines. By adjusted linear regression analysis, peak and change diastolic parameters (E-wave, E/e', GSRivr, and E/GSRivr) and peak GLS were individually significantly associated with peak B-lines. By covariate-adjusted multivariable model, E/e' and GSRa at peak exercise were retained as independent predictors of peak B-lines, with substantial goodness of fit of model (adjusted R2 0.776). CONCLUSIONS: In HFpEF, development of pulmonary congestion upon exercise is mostly concomitant with exercise-induced worsening of diastolic function.

The Discriminatory Ability of Renalase and Biomarkers of Cardiac Remodeling for the Prediction of Ischemia in Chronic Heart Failure Patients With the Regard to the Ejection Fraction.

Background: Renalase has been implicated in chronic heart failure (CHF); however, nothing is known about renalase discriminatory ability and prognostic evaluation. The aims of the study were to assess whether plasma renalase may be validated as a predictor of ischemia in CHF patients stratified to the left ventricular ejection fraction (LVEF) and to determine its discriminatory ability coupled with biomarkers representing a range of heart failure (HF) pathophysiology: brain natriuretic peptide (BNP), soluble suppressor of tumorigenicity (sST2), galectin-3, growth differentiation factor 15 (GDF-15), syndecan-1, and cystatin C. Methods: A total of 77 CHF patients were stratified according to the LVEF and were subjected to exercise stress testing. Receiver operating characteristic curves were constructed, and the areas under curves (AUC) were determined, whereas the calibration was evaluated using the Hosmer-Lemeshow statistic. A DeLong test was performed to compare the AUCs of biomarkers. Results: Independent predictors for ischemia in the total HF cohort were increased plasma concentrations: BNP (p = 0.008), renalase (p = 0.012), sST2 (p = 0.020), galectin-3 (p = 0.018), GDF-15 (p = 0.034), and syndecan-1 (p = 0.024), whereas after adjustments, only BNP (p = 0.010) demonstrated predictive power. In patients with LVEF <45% (HFrEF), independent predictors of ischemia were BNP (p = 0.001), renalase (p < 0.001), sST2 (p = 0.004), galectin-3 (p = 0.003), GDF-15 (p = 0.001), and syndecan-1 (p < 0.001). The AUC of BNP (0.837) was statistically higher compared to those of sST2 (DeLong test: p = 0.042), syndecan-1 (DeLong: p = 0.022), and cystatin C (DeLong: p = 0.022). The AUCs of renalase (0.753), galectin-3 (0.726), and GDF-15 (0.735) were similar and were non-inferior compared to BNP, regarding ischemia prediction. In HFrEF patients, the AUC of BNP (0.980) was statistically higher compared to those of renalase (DeLong: p < 0.001), sST2 (DeLong: p < 0.004), galectin-3 (DeLong: p < 0.001), GDF-15 (DeLong: p = 0.001), syndecan-1 (DeLong: p = 0.009), and cystatin C (DeLong: p = 0.001). The AUC of renalase (0.814) was statistically higher compared to those of galectin-3 (DeLong: p = 0.014) and GDF-15 (DeLong: p = 0.046) and similar to that of sST2. No significant results were obtained in the patients with LVEF >45%. Conclusion: Plasma renalase concentration provided significant discrimination for the prediction of ischemia in patients with CHF and appeared to have similar discriminatory potential to that of BNP. Although further confirmatory studies are warranted, renalase seems to be a relevant biomarker for ischemia prediction, implying its potential contribution to ischemia-risk stratification.

The partnership between renalase and ejection fraction as a risk factor for increased cardiac remodeling biomarkers in chronic heart failure patients.

Objective: Heart failure (HF) represents a huge socio-economic burden. It has been demonstrated, experimentally, that renalase, a newly discovered protein, prevents cardiac hypertrophy and adverse remodeling, which is seen in HF. We postulated the following aims: to investigate associations of renalase with biomarkers of cardiac remodeling: galectin-3, soluble suppression of tumorigenicity, (sST2), growth differentiation factor 15 (GDF-15) and syndecan-1, myocardial stretch (BNP) and cardio-renal axis (cystatin C) in HF patients with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF) to determine whether renalase, in combination with left ventricular ejection fraction (LVEF), represents a risk factor for plasma elevation in biomarkers.Methods: We classified HF patients (n = 76) according to LVEF (preserved/reduced), applied a median plasma renalase (113 ng/mL) as a cut-off value (low/high) and created four subgroups of HF patients: HFpEF/low renalase (n = 19), HFrEF/low renalase (n = 19), HFrEF/high renalase (n = 32) and HFpEF/high renalase (n = 6). A control group (n = 35) consisted of healthy volunteers.Results: Plasma concentrations of evaluated biomarkers were determined using an ELISA technique and were highest in HF patients with reduced EF (p < .001, respectively), and renalase's positive correlations were obtained relating to all biomarkers: galectin-3 (r = 0.913; p < .001), sST2 (r = 0.965; p < .001), GDF-15 (r = 0.887; p < .001), syndecan-1 (r = 0.922; p < .001), BNP (r = 0.527; p < .001) and cystatin C (r = 0.844; p < .001) and strong and negative correlation with LVEF (r = -0.456, p < .001). Increased renalase, regardless of the EF (preserved/reduced), was shown to be an independent risk factor for an increase in all evaluated cardiac remodeling biomarkers, p < .001, respectively. However, increased renalase and reduced EF was the only independent risk factor for BNP and cystatin C elevation, p < .001, respectively. Results after multivariable adjustments (age/gender) were identical.Conclusion: When elevated plasma renalase and HF are present, regardless of EF being reduced or preserved, that represents a significant risk factor for increase in cardiac remodeling biomarker plasma concentrations. However, only elevated renalase and reduced EF demonstrated significance as a risk factor for BNP and cystatin C plasma elevation. Renalase may be considered a promising molecule for the improved predictive abilities of conventional biomarkers and is worthy of further investigation.

Prognostic Value of Dynamic Changes in Pulmonary Congestion During Exercise Stress Echocardiography in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Patients with heart failure (HF) with preserved ejection fraction (HFpEF) typically develop dyspnea and pulmonary congestion upon exercise. Lung ultrasound is a simple diagnostic tool, providing semiquantitative assessment of extravascular lung water through B-lines. It has been shown that patients with HFpEF develop B-lines upon submaximal exercise stress echocardiography; however, whether exercise-induced pulmonary congestion carries prognostic implications is unknown. This study aimed at evaluating the prognostic value of B-line assessment during exercise in patients with HFpEF. METHODS: Sixty-one New York Heart Association class I to II patients with HFpEF underwent standard echocardiography, lung ultrasound (28-scanning point method), and BNP (B-type natriuretic peptide) assessment during supine exercise echocardiography (baseline and peak exercise). The primary end point was a composite of cardiovascular death or HF hospitalization at 1 year. RESULTS: B-lines, E/e', and BNP significantly increased during exercise (P<0.001 for all). By multivariable analysis, both peak (hazard ratio, 1.50 [95% CI, 1.21-1.85], P<0.001), and change (hazard ratio 1.34 [95% CI, 1.12-1.62], P=0.002) B-lines were retained as independent predictors of outcome (hazard ratios per 1 B-line increment), along with BNP and E/e' ratio. Importantly, adding peak B-line on top of a clinical model significantly improved prognostic accuracy (C-index increase, 0.157 [0.056-0.258], P=0.002) and net reclassification (continuous net reclassification improvement, 0.51 [0.09-0.74], P=0.016), with similar results for B-line change. CONCLUSIONS: Detection of exercise-induced pulmonary congestion by lung ultrasound is an independent predictor of outcome in patients with HFpEF; its use may help refining the routine risk stratification of these patients on top of well-established clinical variables.

Design and development of novel therapeutics for coronary heart disease treatment based on cholesteryl ester transfer protein inhibition - in silico approach.

Cholesteryl ester transfer protein (CETP) belongs to the group of enzymes which inhibition have the application in the treatment of cardiovascular diseases. This study presents QSAR modeling for a set of compounds acting as CETP inhibitors based on the Monte Carlo optimization with SMILES notation and molecular graph-based descriptors, and field-based 3D modeling. A 3D QSAR model was developed for one random split into the training and test sets, whereas conformation independent QSAR models were developed for three random splits, with the results suggesting there is an excellent correlation between them. Various statistical approaches were used to assess the statistical quality of the developed models, including robustness and predictability, and the obtained results were very good. This study used a novel statistical metric known as the index of ideality of correlation for the final assessment of the model, and the results that were obtained suggested that the model was good. Also, molecular fragments which account for the increases and/or decreases of a studied activity were defined and then used for the computer-aided design of new compounds as potential CETP inhibitors. The final assessment of the developed QSAR model and designed inhibitors was done using molecular docking, which revealed an excellent correlation with the results from QSAR modeling.Communicated by Ramaswamy H. Sarma.

Impact of interval versus steady state exercise on nitric oxide production in patients with left ventricular dysfunction.

AIM: The aim of the present study was to assess the impact of the interval exercise training (IET) vs. steady state exercise training (SSET) on nitric oxide production, through changes of circulating blood markers of endothelial function, including stable end-products of nitric oxide (NOx) and S-nitrosothiols (RSNOs) in patients with left ventricular dysfunction (LVD). PATIENTS AND METHODS: The impact of the IET vs. SSET on NOx and RSNOs production was assessed in a total of 31 (25 male, 6 female) patients with LVD (ejection fraction <40%), who were admitted to our residential rehabilitation centre. Patients were randomised into an IET group (n=18; 15 min interval exercise sessions, 2 times daily) and an SSET group (n=13; 5-10 min steady state exercise sessions, 2 times daily), and exercised every day over a period of 3 weeks. The modified Saville-Griess method was used to determine NOx and RSNOs concentrations. RESULTS: A significant increase was observed both for NOx (P < 0.05) and RSNOs (P < 0.001) in the IET group, as well as for RSNOs in the SSET group (P < 0.001). Both training methods were observed to significantly improve exercise capacity, as demonstrated for increased workload (P < 0.001 and P < 0.05 for the IET and SSET groups, respectively) and duration (P < 0.001 and P < 0.01 for the IET and SSET groups, respectively) of the exercise stress test at the end of the study. CONCLUSION: The results of the present study have demonstrated an increased nitric oxide production and improved exercise capacity in patients with left ventricular dysfunction, who were engaged in an interval exercise programme for three weeks, and clearly indicated an advantage of interval compared to steady state training method for cardiovascular rehabilitation.

Population Pharmacokinetic Analysis of Bisoprolol in Patients with Stable Coronary Artery Disease.

BACKGROUND AND OBJECTIVES: Bisoprolol is a selective beta adrenergic antagonist commonly used in treatment of coronary artery disease (CAD). The aim of our analysis was to estimate and identify different factors that could affect bisoprolol clearance (CL) and develop a population pharmacokinetic model in patients with stable coronary artery disease (CAD). METHODS: Population pharmacokinetic analysis was performed by using sixty-six plasma concentrations from the same number of patients (mean age 60.26 ± 9.68 years; mean total body weight 80.37 ± 12.93 kg) with CAD. We examined the effects of various clinical and demographic parameters using nonlinear mixed-effect modeling (NONMEM) with ADVAN1 with TRANS2 subroutine. The pharmacokinetics of bisoprolol in patients with CAD were suitably defined by an oral one-compartment model. RESULTS: The typical mean value for bisoprolol CL, estimated by the base model, in the target population was 6.76 l/h. The only demographic covariate which affected bisoprolol pharmacokinetic variability was creatinine clearance (CLcr). The final model of bisoprolol clearance was described by following equation: CL (l/h) = 2.83 + 0.0385 × CLcr (ml/min). Validation of the final model was performed in a group of 17 patients using the validation set and bootstrapping analysis. CONCLUSIONS: These findings suggest that one of the causes of clearance of bisoprolol variability in patients with CAD is the difference in renal function.

Cross-talk between the dipeptidyl peptidase-4 and stromal cell-derived factor-1 in stem cell homing and myocardial repair: Potential impact of dipeptidyl peptidase-4 inhibitors.

Dipeptidyl peptidase-4 (DPP-4), glycyl-prolyl-naphthylamidase, is a serine protease that catalyzes the hydrolysis of various proline-containing polypeptides. It is involved in the inactivation of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), having in this way a profound influence on glucose metabolism. During organ damage, stromal and endothelial cells produce a chemokine known as stromal cell-derived factor-1 (SDF-1), a powerful chemoattractant of stem/progenitor cells. SDF-1 binds to a specific α-chemokine receptor (CXCR4) and can be degraded by proteases, including matrix DPP-4/CD26, presented in the circulation, or activated in injured tissues. DPP-4 inhibition has received considerable attention because of its significant therapeutic benefits in the regulation of insulin secretion and tissue insulin sensitivity, the regulation of tumor growth and metastasis, angiogenesis, tissue repair, especially after myocardial infarction, and regulation of endocrine function. Inhibition of circulating proteases appears to maintain the optimal endogenous SDF-1 concentration and may enhance homing of endothelial progenitor cells. In the present article, we present an overview of some basic facts about the role of DPP-4 in glucose homeostasis, the mechanism of its inhibition, and a brief summary of available DPP-4 inhibitors. Furthermore, since protection against the overactivity of proteases is important for restorating cardiac function and repair after myocardial damage, necrosis and apoptosis, we propose that administration of a DPP-4 inhibitor may also be beneficial following myocardial infarction by the prevention of cleavage of stem cell chemoattractant cytokine SDF-1.

The influence of type 2 diabetes mellitus on the frequency and complexity of ventricular arrhythmias and heart rate variability in patients after myocardial infarction.

Background/Aim: After myocardial infarction arrhythmic cardiac deaths are significantly more frequent compared to non-arrhythmic ones. The aim of the study was to investigate the influence of type 2 diabetes mellitus (T2DM) on the frequency and complexity of ventricular arrhythmias after myocardial infarction. Methods: The study included 293 patients, mean age 59.5 ± 9.21 years, who were at least six months after acute myocardial infarction with the sinus rhythm, without atrioventricular blocks and branch blocks. In the clinical group 95 (32.42%) patients were with T2DM, while 198 (67.57%) patients were without diabetes. All of the patients were subjected to the following procedures: standard ECG according to which the corrected QT dispersion (QTdc) was calculated, exercise stress test, and 24-hour holter monitoring according to which, the four parameters of time domain of heart rate variability (HRV) were analyzed: standard deviation of all normal RR intervals during 24 hours (SDNN), standard deviation of the averages of normal RR intervals in all five-minute segments during 24 hours (SDANN), the square root of the mean of the sum of the squares of differences between adjacent normal (RMS-SD), and percentage of consequtive RR intervals which differed for more than 50 ms during 24 hours (NN > 50 ms). Results: In patients after myocardial infarction, patients with T2DM had significantly higher percentage of frequent and complex ventricular arrhythmias compared to the patients without diabetes (p < 0.001). The patients with T2DM had significantly higher percentage of residual ischemia (p < 0.001), and arterial hypertension (p < 0.001), compared to patients without diabetes. The patients with T2DM had significantly lower values of HRV parameters: SDNN (p < 0.001); SDANN (p < 0.001); RMS-SD (p < 0.001), and NN > 50 ms (p < 0.001), and significantly higher values of QTdc (p < 0.001) compared to the patients without diabetes. Conclusion: The study showed that type 2 diabetes mellitus has significant influence on ventricular arrhythmias, HRV parameters and QT dispersion in patients after myocardial infarction.