Marie Tomandlová

Prognostic utility of biomarkers in predicting of one-year outcomes in patients with aortic stenosis treated with transcatheter or surgical aortic valve implantation.

Objectives The aim of the work was to find biomarkers identifying patients at high risk of adverse clinical outcomes after TAVI and SAVR in addition to currently used predictive model (EuroSCORE). Background There is limited data about the role of biomarkers in predicting prognosis, especially when TAVI is available. Methods The multi-biomarker sub-study included 42 consecutive high-risk patients (average age 82.0 years; logistic EuroSCORE 21.0%) allocated to TAVI transfemoral and transapical using the Edwards-Sapien valve (n = 29), or SAVR with the Edwards Perimount bioprosthesis (n = 13). Standardized endpoints were prospectively followed during the 12-month follow-up. Results The clinical outcomes after both TAVI and SAVR were comparable. Malondialdehyde served as the best predictor of a combined endpoint at 1 year with AUC (ROC analysis) = 0.872 for TAVI group, resp. 0.765 (p<0.05) for both TAVI and SAVR groups. Increased levels of MDA, matrix metalloproteinase 2, tissue inhibitor of metalloproteinase (TIMP1), ferritin-reducing ability of plasma, homocysteine, cysteine and 8-hydroxy-2-deoxyguanosine were all predictors of the occurrence of combined safety endpoints at 30 days (AUC 0.750–0.948; p<0.05 for all). The addition of MDA to a currently used clinical model (EuroSCORE) significantly improved prediction of a combined safety endpoint at 30 days and a combined endpoint (0–365 days) by the net reclassification improvement (NRI) and the integrated discrimination improvement (IDI) (p<0.05). Cystatin C, glutathione, cysteinylglycine, asymmetric dimethylarginine, nitrite/nitrate and MMP9 did not prove to be significant. Total of 14.3% died during 1-year follow-up. Conclusion We identified malondialdehyde, a marker of oxidative stress, as the most promising predictor of adverse outcomes during the 30-day and 1-year follow-up in high-risk patients with symptomatic, severe aortic stenosis treated with TAVI. The development of a clinical “TAVIscore” would be highly appreciated. Such dedicated scoring system would enable further testing of adjunctive value of various biomarkers.

The prediction role of indexes of circulating adipokines for common anthropometric and nutritional characteristics of obesity in the obese Central European population.

AIMS This study was designed to investigate the relationship between 8 selected adipokines (leptin, leptin receptor, adiponectin, agouti-related peptide, omentin, visfatin, adipsin and resistin), dietary composition and anthropometric parameters found in the Central European obese population. METHODS A total of 65 unrelated obese Central European Caucasian individuals were recruited for the study. Phenotypic measurements included weight, height, BMI, lean body mass, fat mass, body fat, waist and hip circumference, waist-hip ratio (WHR) and skinfold thickness. Participants completed standardized self-reported 7-day food records. Plasma levels of leptin, leptin receptor, adiponectin, agouti-related peptide (AgRP), resistin, adipsin, omentin and visfatin were examined using ELISA. RESULTS Multiple associations (weight, height, percentage of body fat, waist circumference, hip circumference, WHR and sum of skinfold thickness) with the circulation levels of the investigated adipokines were identified. Leptin-Leptin receptor (L-LR) levels were found to correlate with total energy intake and macronutrients while adipsin was found to strongly correlate with multiple adipokines. Furthermore, the L-LR index was found to constitute a more accurate description of the relationship between BMI and body weight than individual measurements and the Ag-LR index was found to strongly correlate with both anthropometric and dietary characteristics. CONCLUSION Following confirmation on larger population samples and on samples of different ethnicities, the reported adipokine indexes could become a useful tool for estimating nutritional status and predicting the body composition of specific patient groups.

Visfatin is secreted into the breast milk and is correlated with weight changes of the infant after the birth

INTRODUCTION Visfatin is a recently identified adipokine with numerous metabolic and immunoregulatory properties that has been implicated in the regulation of the white adipose tissue (WAT) and significant changes in visfatin levels were reported during pregnancy. The aim of the study was to investigate dynamics of visfatin levels in maternal serum and human breast milk during a 180-d period after the delivery. MATERIALS AND METHODS : Breast milk and venous blood samples were obtained from 24 healthy lactating women with uncomplicated, physiological pregnancy and appropriate-for-gestational age neonates and serum-milk sample duos were collected at the time of birth, at the 1-3, 12-14, 28-30, 88-90 and 178-180 postpartum. RESULTS Our study demonstrates that (1) visfatin is abundantly secreted into breast milk in humans, reaching approx. 100× higher concentrations compared to maternal serum; (2) visfatin concentrations in maternal serum show significant variations after the delivery and (3) visfatin concentration in colostrum could be used for prediction of the subsequent weight development (less/more severe weight loss during first 3 days after the birth) of the infant. DISCUSSION Our data suggest that visfatin could play an important role in regulation of adiposity of the infant after the birth.

The common polymorphism Val109Asp in the omentin gene is associated with daily energy intake in the Central-European population

Abstract Background Omentin is an adipokine expressed predominantly in visceral adipose tissue, with adipose tissue stromal cells being the main source. Very little is known about the relationship between the genetic variability of the omentin gene and pathophysiology of obesity, although omentin is believed to play an important role in visceral obesity development. The aim of the study was to investigate two common polymorphisms in the omentin gene (rs2274908 and rs2274907) and dietary composition and anthropometric parameters of obesity in the Central European population. Material and methods A total of 495 subjects were included into the study, they were further dividend into the non-obese, obese, and morbidly obese cohorts. Dietary habits were established using the 7-day food records and selected anthropometric parameters were measured. Results There were significant differences in genotype distributions of rs2274907 between the obese and morbidly obese cohorts (P = 0.01). In the multivariate modelling, the rs2274907 polymorphism expressed independent prediction role for the daily energy intake, independently on the age and gender (P = 0.03); the TT genotype associated with the lowest (7877 ± 2780 J/day) and the AA genotype with the highest (8764 ± 2467 J/day) average energy intake. The rs2274907 also significantly associated with the daily consumption of fat and proteins. Conclusion This is, so far, the first study to investigate the polymorphisms in the omentin gene in a large population cohort of obese and non-obese individuals. Based on our results, the rs2274907 polymorphism is associated with the daily energy intake as well as daily intake of fat and protein.

Prognostic Value of Pentraxin-3 Level in Patients with STEMI and Its Relationship with Heart Failure and Markers of Oxidative Stress

Objective. Pentraxin-3 (PTX3) appears to have a cardioprotective effect through a positive influence against postreperfusion damage. This study assesses the prognostic value of PTX3 level and its relationship with clinical parameters and markers of oxidative stress and nitric oxide metabolism in patients with ST-elevation myocardial infarction (STEMI). Methods. Plasma/serum levels of several biomarkers of inflammation and oxidative stress and nitrite/nitrate were assessed upon admission and 24 h after STEMI onset in patients treated by primary percutaneous coronary intervention. Results. ROC analysis showed that plasma PTX3 at 24 h was a strong predictor of 30-day and 1-year mortality and independent predictor of combined end-point of left ventricle dysfunction or mortality in 1 year. The inflammatory response expressed by PTX3 had a significant relationship with age, heart failure, infarct size, impaired flow in the infarct-related artery, and renal function and positively correlated with neopterin, TNF-α, 8-hydroxy-2′-deoxyguanosine, and nitrite/nitrate. Conclusions. Plasma PTX3 at 24 h after STEMI onset is a strong predictor of 30-day and 1-year mortality. PTX3 as a single biomarker is comparable with currently used scoring systems (TIMI or GRACE) or B-type natriuretic peptide. PTX3 is also an independent predictor of combined end-point of left ventricle dysfunction or mortality in 1 year.

Natriuretic peptides, nitrite/nitrate and superoxide dismutase have additional value on top of the GRACE score in prediction of one-year mortality and rehospitalisation for heart failure in STEMI patients — Multiple biomarkers prospective cohort study

BACKGROUND Blood-based biomarkers have a prognostic value in patients with myocardial infarction. The aim of our prospective observational cohort study was to evaluate the prognostic value of biomarkers of different pathophysiological pathways for the occurrence of 1-year all-cause mortality and hospitalisation due to acute heart failure. METHODS AND RESULTS In 593 patients with ST-segment elevation MI (STEMI) treated by primary PCI, biomarkers were evaluated at 24h after MI onset. A minimum of three-year follow-up was achieved in all patients. The combination of 1-year all-cause mortality and hospitalisation due to heart failure was the primary endpoint. A cohort for validation of our combined GRACE-natriuretic peptide (NP) score included 667 STEMI patients. The primary endpoint was reached in 9.3% of patients. Among 21 biomarkers, only B-type natriuretic peptide (BNP), NT-proBNP, superoxide dismutase and nitrite/nitrate, added to clinical GRACE score led to a significant increase in the area under the curve of C statistics, in comparison to GRACE alone (tested by Delongs test). Continuous net reclassification improvement and integrated discrimination index demonstrated an improved reclassification and discrimination of the GRACE model for SOD, BNP and NT-proBNP, and improved reclassification for nitrite/nitrate. Consistent results for this new combined prognostic model GRACE-NP were found also for a validation cohort. CONCLUSIONS The levels of NP have an additional value to the prognostic properties of the GRACE score for the prediction of the combined endpoint of one-year mortality or hospitalisation for AHF. Nitrite/nitrate and SOD are strong prognostic factors, even on top of the GRACE score.

Infectious Complications and Immune/inflammatory Response in Cardiogenic Shock Patients: A Prospective Observational Study

Introduction: Patients with cardiogenic shock (CS) are at a high risk of developing infectious complications; however, their early detection is difficult, mainly due to a frequently occurring noninfectious inflammatory response, which accompanies an extensive myocardial infarction (MI) or a postcardiac arrest syndrome. The goal of our prospective study was to describe infectious complications in CS and the immune/inflammatory response based on a serial measurement of several blood-based inflammatory biomarkers. Methods: Eighty patients with CS were evaluated and their infections were monitored. Inflammatory markers (C-reactive protein, procalcitonin, pentraxin 3, presepsin) were measured seven times per week. The control groups consisted of 11 patients with ST segment elevation myocardial infarction without CS and without infection, and 22 patients in septic shock. Results: Infection was diagnosed in 46.3% of patients with CS; 16 patients developed an infection within 48 h. Respiratory infection was most common, occurring in 33 out of 37 patients. Infection was a significant or even the main reason of death only in 3.8% of all patients with CS, and we did not find statistically significant difference in 3-month mortality between group of patients with CS with and without infection. There was no statistically significant prolongation of the duration of mechanical ventilation associated with infection. Strong inflammatory response is often in patients with CS due to MI, but we found no significant difference in the course of the inflammatory response expressed by evaluated biomarkers in patients with CS with and without infection. We found a strong relationship between the elevated inflammatory markers (sampled at 12 h) and the 3-month mortality: the area under the curve of receiver operating characteristic ranged between 0.683 and 0.875. Conclusion: The prevalence of infection in patients with CS was 46.3%, and respiratory tract infections were the most common type. Infections did not prolong statistically significantly the duration of mechanical ventilation and did not increase the prevalence of hospital mortality in this high-risk CS population. CS due to acute myocardial infarction was accompanied by a strong and highly variable inflammatory response, but it did not reach the intensity of the inflammatory response observed in patients with septic shock. An extensive immune/inflammatory response in patients with CS is linked to a poor prognosis.

Determination of asymmetric and symmetric dimethylarginines in human plasma by HPLC with electrochemical detection.

A new HPLC method was developed and validated for the determination of asymmetric and symmetric dimethylarginines and l-arginine in human plasma. After SPE and evaporation of the eluate, the samples were derivatised with an o-phthaldialdehyde reagent containing 3-mercaptopropionic acid. The derivatives formed were analysed by isocratic RP-HPLC with electrochemical detection at +320 mV. The mobile phase consisted of 50 mM phosphate buffer (pH 6.1) containing 10% v/v acetonitrile, the flow rate was 1 mL/min. The retention times of all compounds including monomethylarginine (internal standard) were <24 min. The LODs (S/N 3:1) were 0.012 μM for both dimethylarginines and 0.013 μM for L-arginine; the linearity of the method was from 0.1 to 20 μM for both dimethylarginines and from 1 to 200 μM for L-arginine. Absolute extraction recoveries measured for all analytes ranged from 85 to 88%.

Brain-derived neurotrophic factor and ciliary neurotrophic factor in maternal plasma and umbilical cord blood from pre-eclamptic and physiological pregnancies

The aim of the study was to investigate the circulating levels of ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) in maternal serum and umbilical cord blood from respective pregnancies in pre-eclampsia (PE) cases and a control cohort. A total of 12 pre-eclampsia cases and 34 healthy controls were enrolled and the maternal peripheral blood – umbilical cord blood duos, were examined for BDNF and CNTF levels. BNDF levels were significantly higher in umbilical cord blood from pre-eclamptic pregnancies; there was also significant difference between maternal plasma and umbilical cord blood levels of BDNF (p < 0.001) in the controls. The CNTF levels in umbilical cord blood (CNTF-UCB) were significantly higher in PE cases than in the controls (p = 0.03). Significant differences were observed in expression of BDNF and CNTF proteins in maternal peripheral blood and umbilical cord blood between pre-eclampsia cases and healthy controls.

Association of genetic variability in selected regions in visfatin (NAMPT) gene with anthropometric parameters and dietary composition in obese and non-obese Central-European population

AIMS Visfatin (NAMPT/PBEF) is a recently identified adipocytokine which harbors strong insulin-mimetic activity and was reported to be associated with obesity. However, nothing is known about whether visfatin is related to specific nutritional behavior which may result in obesity development. This is the first study focusing on genetic variability of the visfatin gene and its association with circulating visfatin, anthropometric parameters and dietary composition. MATERIALS AND METHODS We analyzed a total of 11 exons and adjacent non-coding regions of the NAMPT gene in 20 extremely obese Czech individuals (mean BMI 52.2±5.0 SD) using direct sequencing and a frequency of rs2302559 was established in the validation cohort of another 605 individuals with completed 7-day food records and complex anthropometric measurements. Serum levels of visfatin, leptin and leptin-receptor were measured in all sequenced individuals and in part of the validation cohort. RESULTS Three common polymorphisms were identified, two in non-coding regions (rs78411774 A/C, rs71564769 A/C) and one synonymous SNP in exon 7 (rs2302559 A/G). The rs2302559 showed significant correlation with visfatin serum level throughout the entire study cohort (p<0.001); there was a significant tendency toward higher visfatin levels in G allele carriers with GG homozygotes having the highest visfatin serum levels. Furthermore, a negative correlation was observed between visfatin and leptin serum level (p=0.01). No association between investigated SNPs and anthropometric parameters or native dietary composition was observed. CONCLUSION This is the first study to demonstrate that the rs2302559 polymorphism in the PBEF gene is related to circulating levels of visfatin. As the SNP is synonymous, we hypothesize it might be linked to another SNP in the PBEF gene which controls visfatin serum levels.