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.

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.

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.

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.

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.