Tímea Gombos

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.

Strong complement activation after acute ischemic stroke is associated with unfavorable outcomes

OBJECTIVE According to data from animal models, complement activation plays a major role in the brain injury after acute ischemic stroke. Scarce findings are, however, available on the detection of complement activation products in stroke patients. METHODS We have measured plasma levels of the five complement activation products (C1rC1sC1inh, C4d, C3a, C5a and SC5b-9) in samples of 26 patients with ischemic stroke upon admission. Twenty-six patients with severe carotid atherosclerosis served as patient controls. RESULTS Levels of two activation products (SC5b-9 and C4d)) were significantly elevated in the plasma of stroke patients, SC5b-9 levels, exhibited significant positive correlation with the clinical severity of stroke, the severity of neurological deficit, as well as with the level of functional disability. CONCLUSION These findings suggest that complement activation plays an active role in the development of brain infarct. The measurement of complement activation products might help to determine the clinical prognosis after acute ischemic stroke. Furthermore, there is potential usefulness of complement modulating therapy in ischemic stroke.

Increased plasma von Willebrand factor antigen levels but normal von Willebrand factor cleaving protease (ADAMTS13) activity in preeclampsia

The activity of ADAMTS13, the von Willebrand factor (VWF) cleaving protease is low in several conditions, including HELLP (haemolysis, elevated liver enzymes, and low platelet count) syndrome. As HELLP syndrome develops in most cases on the basis of preeclampsia, our aim was to determine whether plasma ADAMTS13 activity is decreased in preeclampsia. Sixty-seven preeclamptic patients, 70 healthy pregnant women and 59 healthy non-pregnant women were involved in this case-control study. Plasma ADAMTS13 activity was determined with the FRETS-VWF73 assay, while VWF antigen (VWF:Ag) levels with an enzyme-linked immunosorbent assay. The multimeric pattern of VWF was analyzed by SDS-agarose gel electrophoresis. There was no significant difference in plasma ADAMTS13 activity between the preeclamptic and the healthy pregnant and non-pregnant groups (median [25-75 percentile]: 98.8 [76.5-112.8] %, 96.3 [85.6-116.2] % and 91.6 [78.5-104.4] %, respectively; p > 0.05). However, plasma VWF:Ag levels were significantly higher in preeclamptic patients than in healthy pregnant and non-pregnant women (187.1 [145.6-243.1] % versus 129.3 [105.1-182.8] % and 70.0 [60.2-87.3] %, respectively; p < 0.001). The multimeric pattern of VWF was normal in each group. Primiparas had lower plasma ADAMTS13 activity than multi-paras (92.6 [75.8-110.6] % versus 104.2 [92.1-120.8] %; p = 0.011). No other relationship was found between clinical characteristics, laboratory parameters and plasma ADAMTS13 activity in either study group. In conclusion, plasma ADAMTS13 activity is normal in preeclampsia despite the increased VWF:Ag levels. However, further studies are needed to determine whether a decrease in plasma ADAMTS13 activity could predispose preeclamptic patients to develop HELLP syndrome.

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.

Early complement activation follows eversion carotid endarterectomy and correlates with the time of clamping of the carotid artery

BACKGROUND Complement activation plays an important role in ischemia/reperfusion (I/R) injury. The objective of the present study was to detect the presence and mechanism of complement activation in patients who underwent carotid endarterectomy (CEA). METHODS Complement activation products C1rsC1-inhibitor, C4d, C3a and SC5b-9 and concentrations of C-reactive protein (CRP) were measured in samples serially taken from 16 patients with eversion CEA and 10 with carotid artery stenting (CAS) in the first 24h post-surgery/intervention. MBL2 genotypes were also determined. RESULTS In patients with CEA an intense increase in C3a levels were observed immediately after surgery (p<0.001), accompanied by a slight elevation in SC5b-9 levels (p<0.05). C3a levels remained elevated until 4h post-surgery, compared with the baseline values and with CAS patients. Peak C3a levels correlated with the time of carotid clamping (r=0.5921, p=0.02). No significant changes were detected in C1rsC1-inhibitor or C4d levels following CEA, and we found no association between the generation of C3a and MBL2 genotypes or CRP levels. Complement activation was not present in patients with CAS. CONCLUSIONS Early complement activation follows CEA and correlates with the time of I/R injury. The lack of C4d generation suggests the role of the alternative and not the lectin pathway in the process.

Association between estrogen receptor α gene polymorphisms and early restenosis after eversion carotid endarterectomy and carotid stenting

OBJECTIVE Our aim was to identify the role of PvuII and XbaI polymorphisms of the ESR1 (estrogen receptor alpha) gene in the occurrence of early restenosis after carotid endarterectomy and carotid artery stenting. METHODS In a non-randomized prospective study we analysed blood samples from 172 patients (105 men) with severe stenosis of the internal carotid artery, using the PCR-RFLP method. Patients were treated either by carotid endarterectomy (n=82) or carotid artery stenting (n=90), and were followed-up by ultrasonography with a median follow-up time of 12 months (7.32-14.65 months). Conventional laboratory parameters were also recorded. Restenosis (>50%) rates were compared between patients carrying different genotypes and risk factors were calculated by using multivariate logistic regression. RESULTS Allelic frequencies were similar between sexes (C/T allele, 0.40/0.60 and 0.43/0.57; p=0.67; G/A allele, 0.35/0.65 and 0.32/0.68; p=0.65; in men and women, respectively). Significantly higher restenosis rate was observed in patients homozygous for the A-allele of the XbaI polymorphism as compared to carriers of AG and GG genotypes (23.4% vs. 10.5%, p=0.02). TT and TC genotypes of the PvuII polymorphism were also associated with greater restenosis rate, as compared with genotype CC (19.3% vs. 3.1%, p=0.02). Associations for both polymorphisms were more expressed in women and in CEA patients. At multivariate analysis, T-A haplotype was a predictor of restenosis in the whole patient cohort (adjusted odds ratio, 7.85; 95% CI, 1.01-60.98). CONCLUSION Presence of A and T alleles (of the XbaI and PvuII polymorphisms, respectively) were associated with higher incidence of carotid restenosis, while the presence of G and C alleles (of the XbaI and PvuII polymorphisms, respectively) were associated with lower incidence of carotid restenosis.