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.

Multiple Valvular Complications of Hypereosinophilic Syndrome.

Endomyocardial fibrosis (EMF) is the most common cardiac abnormality in hyeperosinophilic syndrome (HES), sometimes complicated with mitral valve disease. Mitral valve disease without ventricular manifestation is very rare, however. Case reports link HES to prosthetic valve thrombosis (PVT), but the optimal type of prosthetic valve in HES is not known. Herein is reported the case of a young female HES patient with secondary mitral valve degeneration and severe regurgitation. A mechanical prosthetic valve was implanted six months after she was diagnosed with HES, but despite anticoagulation and antiplatelet therapy she developed PVT three months later. Partially successful thrombolysis was followed by biological prosthetic valve implantation, with no further complications during the subsequent four years. The eosinophil count and treatment for HES was basically unchanged during the follow up period, following the initiation of treatment. Based on these findings it is suggested that, in HES, the implantation of a biological prosthetic valve might be preferable over a mechanical valve.

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.

Association of ficolin-3 with severity and outcome of chronic heart failure.

BACKGROUND: Inflammatory mechanisms involving complement activation has been shown to take part in the pathophysiology of congestive heart failure, but the initiating mechanisms are unknown. We hypothesized that the main initiator molecules of the lectin complement pathway mannose-binding lectin (MBL), ficolin-2 and ficolin-3 were related to disease severity and outcome in chronic heart failure. METHODS AND RESULTS: MBL, ficolin-2 and ficolin-3 plasma concentrations were determined in two consecutive cohorts comprising 190 patients from Hungary and 183 patients from Norway as well as controls. Disease severity and clinical parameters were determined at baseline, and all-cause mortality was registered after 5-years follow-up. In univariate analysis a low level of ficolin-3, but not that of MBL or ficolin-2, was significantly associated with advanced heart failure (New York Heart Association Class IV, p<0.001 for both cohorts) and showed inverse correlation with B- type natriuretic peptide (BNP) levels (r = -0.609, p<0.001 and r = -0.467, p<0.001, respectively). In multivariable Cox regression analysis, adjusted for age, gender and BNP, decreased plasma ficolin-3 was a significant predictor of mortality (HR 1.368, 95% CI 1.052-6.210; and HR 1.426, 95% CI 1.013-2.008, respectively). Low ficolin-3 levels were associated with increased complement activation product C3a and correspondingly decreased concentrations of complement factor C3. CONCLUSIONS: This study provides evidence for an association of low ficolin-3 levels with advanced heart failure. Concordant results from two cohorts show that low levels of ficolin-3 are associated with advanced heart failure and outcome. The decrease of ficolin-3 was associated with increased complement activation.

Elevated extracellular HSP70 (HSPA1A) level as an independent prognostic marker of mortality in patients with heart failure.

Predicting the survival of a patient with heart failure (HF) is a complex problem in clinical practice. Our previous study reported that extracellular HSP70 (HSPA1A) correlates with markers of heart function and disease severity in HF, but the predictive value of HSP70 is unclear. The goal of this study was to analyze extracellular HSP70 as predictive marker of mortality in HF. One hundred ninety-five patients with systolic heart failure were enrolled and followed up for 60 months. By the end of follow-up, 85 patients were alive (survivors) and 110 died (nonsurvivors). HSP70 (measured by ELISA in the serum) was elevated in nonsurvivors, compared with survivors (0.39 [0.27-0.59] vs. 0.30 [0.24-0.43] ng/ml, respectively, p = 0.0101). In Kaplan-Meier survival analysis higher HSP70 levels above median were associated with a significantly increased mortality. In multivariable survival models, we show that HSP70 level above the median is an age-, sex-, body mass index-, creatinine-, and NT-proBNP-independent predictor of 5-year mortality in HF. Extracellular HSP70 could prove useful for estimating survival in patients with HF.

Complement anaphylatoxin C3a as a novel independent prognostic marker in heart failure.

OBJECTIVES: The purpose of this study was to evaluate complement activation in a heart failure cohort. Based on their powerful biological activity, we hypothesized that the levels of anaphylatoxin C3a are related to pathological signs and outcomes in heart failure. DESIGN, SETTING AND PATIENTS: Complement activation products C3a and SC5b9 were determined in 182 consecutive CHF patients (single centre, prospective cohort study), with a left ventricular ejection fraction <45%. Mortality and re-hospitalisation due to the progression of CHF were assessed after a median follow-up of 14 months. INTERVENTIONS: None. RESULTS: In the univariate analysis, high level of anaphylatoxin C3a was significantly associated with clinical events (p < 0.0001), whereas SC5b9 showed a tendency of association (p = 0.094). In multivariable Cox analysis, adjusted for age, NT-proBNP, diastolic blood pressure, body mass index (BMI), haemoglobin and creatinine levels, C3a was a significant predictor of HF-related re-hospitalization or death (HR 1.189 per 1-SD increase, 95% CI 1.023-1.383), and of cardiovascular events or death (HR 1.302, CI 1.083-1.566). C3a was strongly associated with the presence of peripheral oedema, inflammatory markers (CRP, prealbumin, IL-6, sTNFRI, sTNFRII), heat-shock protein 70 levels and endothelial activation markers (von-Willebrand factor and endothelin-1). CONCLUSIONS: Results of the present study showed that complement activation is strongly linked to unfavourable outcomes in heart failure. High levels of anaphylatoxin C3a predicted re-hospitalization, cardiovascular events and mortality in adjusted survival model. Increased C3a levels were associated with biomarkers of acute-phase reaction, inflammation, cellular stress response, endothelial-cell activation and oedematous complications independently from disease severity.

Serum soluble E-selectin and NT-proBNP levels additively predict mortality in diabetic patients with chronic heart failure.

BACKGROUND: Neuroendocrine activation with endothelial dysfunction is a key pathophysiological process in chronic heart failure (CHF). Although increased soluble E-selectin (sE-selectin) levels predict adverse events in several forms of cardiovascular disease, there are only scarce data on its predictive value in CHF. The aim of our study was to investigate whether sE-selectin is a useful predictor of mortality in CHF patients and whether its predictive power is additive to that of NT-proBNP. METHODS: Plasma levels of sE-selectin were measured by ELISA in 192 CHF patients with clinical systolic heart failure. The study population was followed up for 14.9 months on average; 46 patients died during this period. RESULTS: Levels of sE-selectin were significantly higher in non-surviving patients than in survivors (p = 0.005) and significantly correlated with the following inflammatory markers: CRP (r = 0.242, p = 0.001), TNF-α (r = 0.201, p = 0.005), TNF-RII (r = 0.207, p = 0.004), and IL-6 (r = 0.339, p < 0.0001). According to Cox regression analysis of the prediction power of sE-selectin for all-cause mortality, high sE-selectin levels independently and significantly predicted short-term mortality in CHF (HR 1.47, 95% CI 1.103-1.956). Furthermore, sE-selectin predicted mortality in CHF patients with concomitant diabetes mellitus, as well as simultaneously elevated sE-selectin and NT-proBNP levels additively predicted mortality. CONCLUSIONS: This study demonstrated a weak correlation of sE-selectin level with inflammatory markers and prediction of short-term mortality in diabetic CHF patients. Elevated serum sE-selectin levels and concomitantly increased NT-proBNP concentrations have additive predictive power in CHF. This suggests that parallel activation of various pathophysiological pathways confers increased risk of adverse outcome in CHF.

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.

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.

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

BACKGROUND: Circulating 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. AIMS: The 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. METHODS: A 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. RESULTS: Increased 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, gammaGT (p < 0.05) concentrations in patients with severe CHF, although no correlation was observed between Hsp70 and CRP, TNF-alpha, 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. CONCLUSIONS: Serum 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.

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.

Unique presentation of hypereosinophilic syndrome: recurrent mitral prosthetic valve thrombosis without endomyocardial disease.

Hypereosinophilic syndrome (HES) is defined as a prolonged, unexplained peripheral eosinophilia in a patient presenting with end-organ damage. The heart is frequently involved, resulting in eosinophilic endomyocardial disease, which is characterized by mural thrombus formation and endocardial fibrosis. Thromboembolic complications in HES are mediated by material released from eosinophilic granules. Herein is reported the case of a patient who presented, 15 years after valve replacement with a mechanical prosthesis, with clinical signs of recurrent prosthetic valve thrombosis that was caused by missed hypereosinophilia. The unique feature of the case was that the mitral prosthetic valve obstruction was the result of an eosinophilic thrombus, though no tissue infiltration or inflammation had been detected by random biopsy of the left ventricular myocardium. After nine years of effective treatment of HES there were no cardiac or extracardiac complications.

Endothelin-1 and cardiac function in anthracycline-treated patients: a 1-year follow-up.

Anthracyclines are widely used chemotherapeutic agents in the treatment of lymphomas known to induce cardiomyopathy in more than 20% of patients. There is increasing experimental evidence that cardiac endothelial cells regulate cardiac performance and that endothelin-1 (ET-1) is a central substance in this regulatory mechanism. Twenty (seven male, aged 20-68 years) patients with Hodgkin's or non-Hodgkin's lymphoma treated with anthracycline were followed-up for 1 year. At baseline, after cessation of anthracycline treatment and at 1 year, the plasma ET-1 level was measured by enzyme-linked immunosorbent assay and cardiac function was estimated by echocardiographic measurement of the ejection fraction, the E/A ratio and the deceleration time. The ET-1 level decreased significantly after therapy (5.47 +/- 3.34 pg/mL versus 3.44 +/- 0.69 pg/mL, P < 0.02), and remained significant at 1 year (3.43 +/- 0.57 pg/mL, P < 0.008). The ejection fraction (57.80 +/- 4.73% versus 48.05 +/- 5.65%, P < 0.0001) and the E/A ratio (1.35 +/- 0.40 versus 1.15 +/- 0.40, P < 0.01) decreased, and the deceleration time (177.00 +/- 44.96 ms versus 209.50 +/- 66.25 ms, P < 0.04) increased significantly after therapy, showing that both systolic and diastolic left ventricular performance were deteriorated. Compared with the baseline, the same significant changes were found at 1 year (ejection fraction, 50.65 +/- 8.87%, P < 0.0007; E/A ratio, 1.10 +/- 0.34, P < 0.003; deceleration time, 223.25 +/- 46.85 ms, P < 0.002). The decrease of the ET-1 concentration might be a result of anthracyclines' direct cytotoxic effect and the decreasing level of ET-1 may play a role in the ejection fraction reduction. The results of 1-year follow-up suggest that, although anthracycline toxicity occurs shortly after treatment, the undesirable effect remains.