Zsolt Förhécz

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.

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.

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.

Red cell distribution width as predictive marker in CHF: Testing of model performance by reclassification methods

those on twice-weekly HD (HR = 0.64). Two limitations are noted. First, this was a prospective singlecenter study with a small number of participants and limited followup. Second, we failed to randomly allocate ESRD patients to thriceweekly HD or twice-weekly HD. In conclusion, thrice-weekly HD patients may be associated with increased risk of CVD, compared with those with twice-weekly HD. Our results have important clinical implications due to the global epidemic of ESRD and the escalating financial burden of RRT. We thank all staffs in our HD center for contributing to data collection, excellent patient care, etc.

Long-Term Survival and Apolipoprotein A1 Level in Chronic Heart Failure: Interaction With Tumor Necrosis Factor α −308 G/A Polymorphism

BACKGROUND Apolipoprotein A1 (ApoA1), a major constituent of high-density lipoprotein (HDL), has antiinflammatory and antioxidative properties and plays a prognostic role in chronic heart failure (CHF). Despite increased tumor necrosis factor α (TNFα) levels being linked to worse outcome of HF, the results are ambiguous about the association of functionally active 308 promoter polymorphism of the TNFα gene. The aims of our study were to investigate the association of ApoA1 and TNFα levels with mortality and to evaluate potential interaction between these factors and TNFα -308 polymorphism. METHODS Together with several parameters ApoA1, TNFα levels and TNFα-308 polymorphism were determined in a cohort of 195 patients with CHF who were followed for 5 years. RESULTS Low ApoA1 and high TNFα levels were associated with more severe disease, and ApoA1 showed the strongest relationship with HDL, total cholesterol, C-reactive protein, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). TNFα -308 A carriers had significantly higher ApoA1 levels than wild-type (GG) patients (1.41 ± 0.268 vs 1.29 ± 0.324 g/L; P = .007), whereas levels of TNFα were the same in these groups. Decreased ApoA1 levels were significant predictors of 5-year mortality (NT-proBNP-adjusted HR for 1 decile decrease in ApoA1 level was 1.10 (P = .011). Interaction was found between the ApoA1 level and TNFα -308 polymorphism, because in patients with GG haplotype the adverse effect of low ApoA1 level on survival was more prevalent. CONCLUSIONS Lower ApoA1 levels were strongly associated with adverse outcome in CHF patients in a TNFα -308 polymorphism dependent manner. These observations support the complex involvement of malnutrition and inflammation in the pathogenesis of CHF.