Lívia Jánoskuti

Red cell distribution width in heart failure: Prediction of clinical events and relationship with markers of ineffective erythropoiesis, inflammation, renal function, and nutritional state

OBJECTIVES The goal of this study was to independently validate the recent observations on the predictive role of red cell distribution width (RDW) for outcomes in chronic heart failure and to provide epidemiologic data on the biological correlates of RDW in heart failure (HF). Understanding the mechanism underlying this observation is unclear, largely hampered by the lack of epidemiologic studies demonstrating factors that are associated with anisocytosis in cardiovascular diseases. METHODS One hundred ninety-five patients (145 men, 50 women) with systolic HF were enrolled and followed up for a median of 14.5 months. Primary end points were all-cause mortality and hospital readmission due to worsening HF symptoms. A total of 19 clinical chemistry, hematology, and biochemical variables were considered for analysis together with clinical parameters in Cox proportional hazards and multiple regression models. RESULTS Red cell distribution width was found to be an N-terminal pro-brain natriuretic peptide independent predictor of all-cause mortality (adjusted HR 1.61 per 1 SD increase) in our study. Multiple correlations between biomarkers of ineffective erythropoiesis (serum iron, ferritin, and soluble transferrin receptor levels), inflammation and acute-phase reaction (interleukin-6, soluble tumor necrosis factor (TNF) receptor I and soluble TNF receptor II, C-reactive protein, and prealbumin concentrations), undernutrition (total cholesterol and albumin levels), and renal function were observed. In the multiple regression model, the strongest relationship for RDW was obtained with soluble transferrin receptor, soluble TNF receptor I, soluble TNF receptor II, and total cholesterol. CONCLUSIONS Here we validate the strong, independent prediction of morbidity and mortality in HF by RDW. The described correlations between RDW and inflammation, ineffective erythropoiesis, undernutrition, and impaired renal function may facilitate the understanding why this marker is associated with adverse outcomes in HF.

Interaction of serum 70-kDa heat shock protein levels and HspA1B (+1267) gene polymorphism with disease severity in patients with chronic heart failure

BackgroundCirculating heat shock protein 70 (Hsp70) is present in the circulation of healthy individuals and in patients with various disorders, including chronic heart failure (CHF). However, the source and routes of release of Hsp70 is only partially characterised in clinical samples.AimsThe purpose of this study was to study the clinical and biological correlates of Hsp70 in a CHF population and, for the first time, to investigate the association of HspA1B (also known as Hsp70-2) +1267 alleles with serum Hsp70 levels.MethodsA total of 167 patients (123 men, 44 women) with <45% left ventricular ejection fraction (LVEF) were enrolled; serum Hsp70 level was determined by enzyme-linked immunosorbent assay and HspA1B +1267 polymorphism by polymerase chain reaction–restriction fragment length polymorphism.ResultsIncreased Hsp70 levels were present in patients with severe CHF (NYHA III–IV) as compared to the group of NYHA I–II (p = 0.003). Hsp70 levels correlated with LVEF, NT-proBNP, serum bilirubin, aspartate aminotransferase, alanine aminotransferase, γGT (p < 0.05) concentrations in patients with severe CHF, although no correlation was observed between Hsp70 and CRP, TNF-α, or IL-6. HspA1B allele G was associated with higher Hsp70 levels (p = 0.001) in patients in NYHA IV class as compared to carriers of allele A.ConclusionsSerum Hsp70 levels were associated with disease severity in heart failure patients. An interaction with the presence of HspA1B +1267 allele G was observed for Hsp70 concentrations. Hsp70 correlates with markers of heart function and hepatic injury, but not with signs of inflammation.

Angiotensin II type 1 receptor gene polymorphism and mitral valve prolapse syndrome

BACKGROUND Mitral valve prolapse syndrome (MVPS), a term applied to patients who have a variety of symptoms, has been associated with autonomic or neuroendocrine dysfunction. Recent evidence suggests that effects of angiotensin II mediated by the angiotensin II type 1 (AT(1)) receptor are involved in modulation of cardiovascular autonomic control in human beings. Association of a genetic polymorphism (A-C(1166)) of the AT(1) gene with abnormal vasomotion and low blood pressure related to autonomic control has been reported recently. Because the role of this genetic variant in MVPS has not been studied, we performed a case-control study of the A-C(1166) variant in a group of 76 white subjects with MVPS. METHODS AND RESULTS All patients were genotyped by use of a mismatch polymerase chain reaction/Afl II restriction fragment length polymorphism analysis. Frequency of the C(1166) allele was 0.4 in patients with MVPS and 0.26 in control patients. The difference in genotype (chi square = 6.5; P <.05) and allele (chi square = 5.9; P =.02) frequencies between the groups was significant. The odds ratio in favor of carrying the C allele was 4 times greater for patients with MVP than for control patients (95% confidence interval 1.4 to 12.1). CONCLUSIONS The current results indicate that the A-C(1166) polymorphism of the angiotensin II type 1 receptor gene is associated with MVPS in the white population.

Levels of von Willebrand factor antigen and von Willebrand factor cleaving protease (ADAMTS13) activity predict clinical events in chronic heart failure

Decreased activity of ADAMTS13, the von Willebrand factor (VWF) cleaving protease, was recently reported in cardiovascular diseases and in hepatic failure. Chronic heart failure (CHF) is characterised by abnormalities of left ventricular function accompanied by the failure of the liver and dysregulation of endothelial activation. Therefore, the aim of our study was to measure ADAMTS13 activity in CHF, and determine the prognostic value of VWF and ADAMTS13 on major clinical events in CHF. ADAMTS13 activity (measured by FRETS-VWF73 substrate) was decreased in CHF (n = 152, left ventricular ejection fraction <45%), and it correlated negatively with B-type natriuretic peptide (BNP) NYHA (New York Heart Association) classes, markers of synthetic capacity of the liver and endothelial dysfunction (all p < 0.005). Both, high VWF:Ag levels (hazard ratio [HR] 1.52, 95% confidence interval [CI] 1.189-1.943), and low ADAMTS13/VWF:Ag ratios (HR 0.70, 95% CI 0.58-0.84) independently and significantly predicted short-term (1 year follow-up) clinical adverse events in heart failure (HF). Decreased activity of ADAMTS13 with concomitant high VWF:Ag levels is a significant independent predictor of clinical events in CHF. The levels of the two molecules may integrate the impaired synthetic capacity of the liver and the disturbed endothelial regulation and can therefore be a useful tool to predict clinical events in CHF.

Adrenomedullin and endothelin-1 are related to inflammation in chronic heart failure

Abstract.Background:Adrenomedullin (ADM) and endothelin-1 (ET-1) are novel promising peptide biomarkers in chronic heart failure (CHF). According to recent studies among their pleiotropic effect they play roles in the regulation of inflammation. The aim of the study was to measure the above mentioned two vasoactive peptides in parallel in a well characterized population of patients with CHF, and study their associations with inflammatory markers.Materials and methods:A total of 186 patients (138 male, 48 female) with <45% left ventricular ejection fraction (LVEF), and without acute inflammatory disease, were enrolled. Plasma midregional-proADM (MR-proADM) and C-terminal-proET-1 (CT-proET-1) were determined by a novel sandwich immunoluminomertic assay.Results:Increased MR-proADM and CT-proET-1 plasma levels were measured in patients with severe CHF (NYHA III-IV) as compared to the group of NYHA I-II (p<0.0001). MR-proADM and CT-proET-1 levels showed significant negative correlation with serum albumin and prealbumin levels (p≤0.0001), while positive correlations were found with levels of CRP, TNF-alpha, soluble TNF receptors and IL-6 (p≤0.0001). In multiple linear regression models after adjustments for several potential confounders (disease severity [LV-EF, NYHA classes, NT-proBNP], ion and water homeostasis [sodium and presence of peripheral oedema], renal function [serum creatine]) the relationship between ADM and albumin, CRP, soluble TNF receptors and between ET-1 and CRP, TNF receptors and IL-6 remained significant.Conclusions:Vasoregulation and inflammation may be connected in heart failure patients independently of the disease severity. The observed link may contribute to the understanding of the complex pathomechanism in CHF.

Anti-cholesterol antibodies (ACHA) in patients with different atherosclerotic vascular diseases and healthy individuals. Characterization of human ACHA

In animal experiments the protective role of anti-cholesterol antibodies (ACHA) in the development of atherosclerosis has been demonstrated. Despite the fact that ACHA are present in the serum of healthy humans, no data on the occurrence of these antibodies in human diseases are available. We determined serum concentrations of IgG type ACHA by an enzyme immunosorbent assay in 600 patients with atherosclerotic vascular diseases (86 patients with peripheral occlusive atherosclerosis, 146 patients with cerebrovascular diseases, 341 patients with severe coronary heart disease (CHD) who received aorto-coronary by-pass, 27 patients with myocardial infarction who did not undergo by-pass operation), in 57 patient controls (complaints of CHD, without coronarographic alterations) and in 218 healthy individuals. ACHA were present in the sera of all persons tested. No serum cofactor is needed for the binding of human ACHA to solid phase cholesterol, binding can be inhibited dose-dependently by LDL and even more strongly with LDL/VLDL preparations purified from human serum. ACHA levels were found to be considerably lower in patients with peripheral occlusive atherosclerosis and cerebrovascular diseases compared with the levels in healthy individuals. By contrast, the ACHA levels of patients with CHD were considerably higher. No differences in the IgG subclass distribution and binding efficiency of ACHA in the sera of CHD patients and controls were found. Thus, our present findings indicate that both low and high ACHA production may be associated with different atherosclerotic vascular diseases.

Copeptin (C-terminal pro Arginine-Vasopressin) is an Independent Long-Term Prognostic Marker in Heart Failure with Reduced Ejection Fraction

BACKGROUND The level of copeptin, a stable fragment of pro-arginine-vasopressin (AVP), correlates with disease severity. It is an established, short-term prognostic marker for patients with heart failure with reduced ejection fraction (HFREF). We aimed to examine the association between copeptin and long-term mortality. We also studied the clinical usefulness of copeptin as a prognostic biomarker by analysing the improvement of net reclassification. METHODS Copeptin concentrations were measured in a cohort of 195 consecutive patients with HFREF. Disease severity and clinical parameters were determined at baseline, and all-cause mortality was recorded after five-year follow-up. RESULTS One hundred and ten patients died during the five-year follow-up (five-year mortality rate: 0.56). Univariate analysis identified copeptin (HR 2.168 [95% CI 1.740-2.700]) as a predictor of mortality. The final, multivariable Cox survival model identified a number of independent predictors of death. These included higher NHYA functional class, previous MI, at least one hospitalisation for worsening HF (within the two years before inclusion into the study), elevated blood urea nitrogen, NT-proBNP-, and copeptin levels, as well as increased red blood cell distribution width, and decreased GFR. The addition of copeptin alone to the baseline predictive model (NT-proBNP only) resulted in a minor (8.21%) improvement, whereas the final, multivariable model showed a significant increase in net reclassification (10.26%, p=0.015). CONCLUSIONS These data indicate that copeptin is an independent long-term prognostic marker in HFREF, with possible clinical relevance for multimarker risk prediction algorithms.

Red cell distribution width: a powerful prognostic marker in heart failure

We read the recent paper by Al-Najjar et al. on the prognostic value of red cell distribution width (RDW) in heart failure (HF) with great interest. The authors have shown in a population of 1087 ambulatory patients with HF due to left ventricular systolic dysfunction that RDW is a potent prognostic marker of all-cause mortality and has similar prognostic power to that of NT-proBNP. Two important open questions were raised at the end of the manuscript: whether the effect of RDW is independent of erythropoietin (EPO) levels, and what are the mechanisms of elevated RDW values in HF. The authors suggested that this new information may lead to novel approaches in treatment. We have also published similar results showing the prognostic value of RDW in chronic HF that appear to be in parallel with the study of Al-Najjar et al. Besides showing the prognostic power of RDW for all-cause mortality in our cohort, we were able to show the same for rehospitalization due to worsening HF symptoms. Furthermore, according to our analysis, RDW has NT-proBNP-independent predictive power for clinical events in chronic HF. In addition, we also provided observational data about the laboratory correlates of RDW in chronic HF and described novel data for delineation of the underlying mechanisms behind this observation. According to our data, RDW values are strongly related to signs of ineffective erythropoiesis, inflammation, impaired renal function, and under nutrition. Higher RDW values were associated with significantly lower serum iron and ferritin levels and decreased transferrin saturation and also with increased soluble transferrin receptor levels. The strongest correlate of RDW was soluble transferrin receptor concentration in the multiple linear regression model. Thus, based on these observations, RDW seems to be a prominent marker of anaemia of chronic diseases complicated by iron deficiency in patients with chronic HF. Furthermore, high serum EPO levels were associated with high RDW values in our cohort, indicating that the bonemarrow effects of EPO may also be compromised. In response to the questions raised by Al-Najjar et al., we have now performed an analysis to evaluate whether the prognostic effect of RDW is independent of EPO levels. The results of our Cox regression models (Table 3 in our paper) after addition of EPO as a further covariate suggest that the prognostic power of RDW is independent of EPO levels (for all-cause mortality HR 1.586 (95% CI 1.288–1.951; x 13.165 and P , 0.0001; for all-cause mortality or HF hospitalization HR 1.424 (95% CI 1.153–1.757; x 8.65 and P 1⁄4 0.003). Taken together, the results of these two recent independent studies in combination with the pioneering work of Felker et al. have now convincingly shown that future HF prognostic models should utilize RDW, a test available as part of the complete blood count. The effectiveness of this marker may lie, as supported by our observational data, on its relationship with ineffective red cell production, inflammation, impaired renal function, and under nutrition.

High levels of C‐reactive protein with low total cholesterol concentrations additively predict all‐cause mortality in patients with coronary artery disease

Background This study aimed to investigate independent and additive predictive effects of raised C‐reactive protein (CRP) levels and decreased total cholesterol levels on mortality in patients with chronic coronary artery disease (CAD). Low total cholesterol (TC) levels are associated with worsened survival in chronic and acute diseases. Elevated CRP level is an important predictor of vascular events and mortality in patients with CAD. Potential inhibition of immune activation by circulating lipoproteins could be a link between cholesterol and inflammatory markers.

Glutathione S-Transferase Enzyme Polymorphisms in a Hungarian Myelodysplasia Study Population

GSTM1, GSTT1 and GSTP1 Ile105Val that are members of the GST gene family encode for Phase II drug/xenobiotic metabolizing enzymes, primarily with detoxifying function, and are polymorphic in humans. GSTM1 and GSTT1 homozygous deletion genotypes do not express the enzymes. It has been hypothesised that individuals with homozygous deletion of the GSTM1 and/or GSTT1 gene may have lower detoxification capacity towards genotoxic agents therefore those individuals may be at increased risk of myelodysplastic syndrome which is a preleukemic condition. Genetic polymorphism of GSTM1, GSTT1 and GSTP1 Ile105Val was investigated in a case–control study in a Hungarian patient population comprising 86 patients with myelodysplastic syndrome and 99 hospital-based controls. There were no statistically significant differences between cases and controls for the GSTM1, GSTT1 and GSTP1 Ile105Val genotype frequencies for any of the three genes separately and in various combinations. This suggests that these genetic polymorphisms may not be strong risk factors, if any, for myelodysplastic syndrome.