GDF-15 Is Associated with Cancer Incidence in Patients with Type 2 Diabetes.

BACKGROUND: Diabetes has been linked epidemiologically to increased cancer incidence and mortality. Growth differentiation factor 15 (GDF-15) is increased in patients with diabetes and has recently been linked to the occurrence of cancer. We investigated whether circulating GDF-15 concentrations can predict the incidence of malignant diseases in a diabetic patient cohort already facing increased risk for cancer. METHODS: We prospectively enrolled a total of 919 patients with type 2 diabetes and no history of malignant disease, who were clinically followed up for 60 months. GDF-15, N-terminal pro-B-type natriuretic peptide and troponin T were measured at baseline; an additional 4 cardiovascular biomarkers were determined for a subpopulation (n = 259). Study end point was defined as the first diagnosis of any type of cancer during the follow-up period. RESULTS: During a median follow-up of 60 months, 66 patients (7.2%) were diagnosed with cancer. Baseline circulating GDF-15 concentrations were higher in patients that developed cancer over the follow-up period when compared to cancer-free patients. Increased GDF-15 concentrations were significantly associated with cancer incidence [crude hazard ratio (HR) per 1-IQR (interquartile range) increase 2.13, 95% CI 1.53-2.97, P < 0.001]. This effect persisted after multivariate adjustment with an adjusted HR of 1.86 (95% CI 1.22-2.84; P = 0.004). Among the 4 additionally tested cardiovascular markers in the subpopulation, only troponin T and C-terminal proendothelin-1 showed a significant association with future cancer incidence with unadjusted HRs of 1.71 (95% CI 1.28-2.28, P < 0.001) and 1.68 (95% CI 1.02-2.76, P = 0.042), respectively. CONCLUSIONS: Increased circulating concentrations of GDF-15 are associated with increased cancer incidence in patients with type 2 diabetes.

Outcome of conservative management vs. assist device implantation in patients with advanced refractory heart failure.

BACKGROUND: In patients with advanced refractory heart failure (HF) cardiac transplantation (HTX), conservative medical management and the implantation of a ventricular assist device (VAD) represent valuable options. The determination of the best therapeutic destination strategy for the individual patient remains a challenge. The aim of this study was to assess the clinical outcome in advanced refractory HF patients either managed conservatively receiving optimal contemporary medical therapy ('conservative'), or who who underwent pulsatile flow VAD ('pVAD') or continuous-flow VAD ('contVAD') implantation. MATERIALS AND METHODS: A total of 118 patients with INTERMACS profile >1 at baseline, who died, or fully completed a 24-month follow-up free from HTX were included into this retrospective analysis. All-cause mortality at 24 months was assessed and compared between the three groups. RESULTS: Fifty (42%) patients were managed conservatively, 25 (21%) received a pVAD and 43 (36%) a contVAD. NT-proBNP values were comparable between the three groups (median 4402 (IQR 2730-13390) pg/mL, 3580 (1602-6312) pg/mL and 3693 (2679-8065) pg/mL, P = 0·256). Mean survival was 18·6 (95% CI 16·2-21·0) months for patients managed conservatively, 7·0 (3·9-10·0) for pVAD and 20·5 (18·2-22·8) for contVAD (overall log-rank test P < 0·001). Conservatively managed patients spent a mean of 22·4 (95% CI 22·1-22·8), pVAD 17·7 (15·4-20·1) and contVAD 21·6 (21·2-22·1) months out of hospital (conservative vs. pVAD P < 0·001; conservative vs. contVAD P = 0·015; pVAD vs. contVAD P < 0·001). CONCLUSIONS: In accordance with the literature, contVAD resulted in a significantly better clinical outcome than pVAD implantation. However, conservative management with current optimal medical therapy appears to remain a valuable option for patients with advanced HF.

Association of endostatin with mortality in patients with chronic heart failure.

BACKGROUND: Experimental data imply that in decompensated heart failure (HF), the anti-angiogenic factor endostatin is increased. This study aimed to investigate whether the angiogenesis inhibitor endostatin is related to the risk of all-cause mortality in a prospective cohort study of chronic HF patients. METHODS: In this prospective observational cohort study, endostatin serum concentrations were determined in patients with chronic HF. Mortality data were recorded during a median follow-up of 31 months. RESULTS: One fifty one patients were included. The overall mortality rate was 20%. Baseline endostatin concentrations > 245 ng/mL were associated with higher risk of all-cause mortality [HR 8·7 (95% CI 2·5-30·0); P = 0·001] in the multivariate analysis as compared to endostatin concentrations ≤ 245 ng/mL. When both endostatin and NT-proBNP were above the calculated cut-off of 245 ng/mL and 2386 pg/mL, respectively, the prognostic utility of both biomarkers increased [HR 40·8 (95% CI 4·7-354·6); P = 0·001] compared with values lower than the cut-offs. CONCLUSIONS: Serum endostatin concentrations are independently associated with all-cause mortality. Furthermore, combination of endostatin and NT-proBNP discriminates patients at high risk.

Impact of tricuspid regurgitation on survival in patients with chronic heart failure: unexpected findings of a long-term observational study.

AIMS: Tricuspid regurgitation (TR) is common in patients with chronic heart failure (CHF) but its prognostic impact is unclear. METHODS AND RESULTS: A total of 576 consecutive patients with CHF were prospectively included. The impact of moderate and severe (significant) TR on the combined endpoint death/heart transplantation/left ventricular-assist device implantation was assessed. Patients were followed for 5.8 ± 4.2 (maximum 14.4) years. Kaplan-Meier analysis showed a worse outcome of patients with significant TR (P < 0.0001). By multivariable analysis, amino terminal pro B-type natriuretic peptide (NT-proBNP) (P = 0.0028), systolic left ventricular function (LVF) (P = 0.0014), serum sodium, NYHA functional class, systolic blood pressure, right atrial size (all P = 0.0001), but not TR were significantly related with the outcome. However, as soon as the strong interaction between TR and LVF was included in the model, significant TR determined outcome as well (P = 0.0059). Therefore, in a second analysis patients were stratified for LVF. In patients with mildly or moderately impaired LVF, TR was significantly related with the outcome (HR: 1.368, CI: 1.070-1.748, P = 0.0125), whereas in patients with severely depressed LVF it was not (P = 0.1401). As a proof of concept, we additionally stratified patients according to serum NT-proBNP concentrations. In patients with NT-proBNP concentrations below the median (≤ 280 fmol/mL), TR was related with the outcome (HR: 2.512, CI: 1.127-5.597, P = 0.0242) but it was not in patients with NT-proBNP concentrations above the median (P = 0.3935). CONCLUSION: The prognostic impact of TR depends on the severity of CHF. While TR was significantly related with excess mortality in mild to moderate CHF, it provided no additive value in advanced disease when compared with established risk factors.

Inorganic phosphate and FGF-23 predict outcome in stable systolic heart failure.

BACKGROUND: Recent studies show associations between inorganic phosphate and risk of heart failure in the general population as well as between fibroblast growth factor 23 (FGF-23) and outcome in coronary heart disease. This study was carried out to assess whether circulating levels of inorganic phosphate and FGF-23, a new central hormone in mineral bone metabolism, predict outcome in systolic heart failure. MATERIALS AND METHODS: Ninety-nine consecutive outpatients with systolic heart failure were enrolled. Mean (SD) age was 61 years (11), mean left ventricular ejection fraction (LVEF) was 33% (10), 82 patients were men, median estimated creatinine clearance was 83 mL/min (Q(1) -Q(3) 58-106), median NTproBNP level was 803 pg/mL (Q(1) -Q(3) 404-2757), median inorganic phosphate was 1·12 mM (Q(1) -Q(3) 1·02-1·22), median FGF-23 was 39·02 pg/mL (Q(1) -Q(3) 32·45-55·86) and median follow-up was 35 months. Associations between inorganic phosphate, FGF-23 and endpoints were assessed using Cox regression analyses. RESULTS: Inorganic phosphate and FGF-23 levels were significantly higher (P < 0·001 and P = 0·009) in patients reaching the combined endpoint of cardiac hospitalization or death. FGF-23 (ln) predicted all-cause mortality (hazard ratio (HR) 5·042, P = 0·032) in a model adjusted for age, gender, estimated creatinine clearance, LVEF, New York Heart Association (NYHA) stage and NTproBNP level. Inorganic phosphate predicted heart failure hospitalization (HR 26·944, P = 0·021), cardiac hospitalization (HR 16·016, P = 0·017) and the combined endpoint (HR 13·294, P = 0·015) in models adjusted for the same co-variables. CONCLUSION: The results of this study demonstrate the independent prognostic value of inorganic phosphate and FGF-23 in heart failure even in the context of established risk markers.

Cost analysis and cost-effectiveness of NT-proBNP-guided heart failure specialist care in addition to home-based nurse care.

BACKGROUND: Heart failure management programmes have been shown to reduce re-hospitalizations. We recently investigated a new disease management programme comparing usual care (UC) to home-based nurse care (HNC) and a HNC group in which decision-making was based on NT-proBNP levels (BNC). As re-hospitalization is the main contributing economic factor in heart failure expenditures, we hypothesized that this programme might be able to reduce costs and could be conducted cost effectively compared to UC. METHODS: One hundred and ninety congestive heart failure patients, who were included in a randomized trial to receive UC, HNC or BNC at discharge, were analysed in a cost-effectiveness model. Different models were applied to perform analysis of all medical costs, and the costs per year survived were chosen as an effectiveness parameter. RESULTS: Per patient costs because of heart failure treatment in the UC and the BNC group were € 7109 ± 11,687 and € 2991 ± 4885 (P=0·027), respectively. Corrected for death as a competing risk, the costs in the UC group were € 7893 ± 11,734 and were reduced by BNC to €3148 ± 4949 (P=0·012). Considering costs because of all-cause re-hospitalizations, calculated costs per year survived after discharge were € 19,694 ± 26,754 for UC, € 14,262 ± 25 330 for HNC (P > 0·05) and € 8784 ± 14,728 for BNC (t-test-based contrast P=0·015). In all models calculated, HNC was cost neutral. CONCLUSIONS: NT-BNP-guided heart failure specialist care in addition to home-based nurse care is cost effective and cheaper than standard care, whereas HNC is cost neutral.

Repeat measurements of glycated haemoglobin A(1c) and N-terminal pro-B-type natriuretic peptide: divergent behaviour in diabetes mellitus.

BACKGROUND: Patients with diabetes mellitus have a substantially increased risk of developing cardiovascular disease. However, the absolute risk greatly varies not only among patients, but the risk profile for an individual patient may also change over time. We investigated the prognostic role of repetitive measurements of Glycated haemoglobin A(1c) (HbA(1c) ) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with longstanding diabetes. MATERIALS AND METHODS: For this prospective, observational study data from 544 consecutive patients were collected between 2005 and 2008. HbA(1c) and NT-proBNP were measured at baseline and after 1 year. The median observation period was 40 months. Endpoints were all-cause mortality, cardiac, cardiovascular and all-cause hospitalizations. RESULTS: N-terminal pro-B-type natriuretic peptide concentrations significantly increased from 230 ± 385 to 280 ± 449 pg mL(-1) (P < 0·001); during the same time, HbA(1c) significantly decreased from 7·6 ± 1·5 to 7·3 ± 1·2 (P < 0·001). NT-proBNP was the best baseline predictor in a Cox regression model consisting of NT-proBNP, HbA(1c) , age, gender and duration of diabetes for all endpoints (P < 0·001). NT-proBNP at follow-up was the best predictor for the remaining period (P < 0·001, all endpoints). HbA(1c) at baseline and follow-up was predictive for all-cause hospitalizations (P = 0·005 both). In a third model that investigated the plasticity of both markers, changes in HbA(1c) concentration had no predictive value, but a change of NT-proBNP concentration was highly predictive (P = 0·025 all-cause mortality, P < 0·001 all other endpoints). CONCLUSIONS: N-terminal pro-B-type natriuretic peptide and HbA(1c) concentrations significantly diverged over a 1-year period. NT-proBNP was the most potent predictor of outcome at baseline and follow-up, and changes in NT-proBNP concentrations were linked to an altered risk profile, unlike changes in HbA(1c) levels.

NT-proBNP and cardiac events in older diabetic patients.

NT-proBNP is an excellent predictor of adverse events in patients with diabetes mellitus. Due to an aging population it is of interest to determine whether NT-proBNP can predict cardiac events with equal precision in subgroups with different ages. 1395 outpatients with diabetes mellitus were recruited for this prospective observational study. NT-proBNP, renal function, lipid status and other demographic variables were measured at baseline. The cohort was divided into three groups: Group I (609 patients under 60 years of age), group II (634 patients ranging from 60-75) and group III (152 patients older than 75). Patients were followed during a mean observation period of 11 months, 75 patients reached the defined endpoint, which was unplanned hospitalization due to a cardiac event. Mean age was 60 ± 30 years, mean HbA(1c) was 7.6% and mean NT-proBNP was 242 ± 437 pg/ml. In a multiple Cox regression model, age (hazard ratio (HR) 11.18, p < 0.01) and the absence of a cardiac disease (HR 0.49, p < 0.01) were important variables for short-term prognosis. The addition of the logarithm of NT-proBNP provided independent prognostic information (HR 1.81 p < 0.01) and significantly increased the explained variance of the model (χ(2 )= 22.93; d.f. = 1; p < 0.01). More importantly, the predictive power of this model was similar in different age-groups. The prognostic information of NT-proBNP was not influenced by age and this biomarker remained a reliable predictor of short-term cardiac events in patients with diabetes mellitus aged 75 years or older.

Prognostic value of emerging neurohormones in chronic heart failure during optimization of heart failure-specific therapy.

BACKGROUND: Serial measurements of neurohormones have been shown to improve prognostication in the setting of acute heart failure (HF) or chronic HF without therapeutic intervention. We investigated the prognostic role of serial measurements of emerging neurohormones and BNP in a cohort of chronic HF patients undergoing increases in HF-specific therapy. METHODS: In this prospective study we included 181 patients with chronic systolic HF after an episode of hospitalization for worsening HF. Subsequently, HF therapy was gradually increased in the outpatient setting until optimized. We measured copeptin, midregional proadrenomedullin, C-terminal endothelin-1 precursor fragment, midregional proatrial natriuretic peptide, and B-type natriuretic peptide before and after optimization of HF therapy. The primary endpoint was all-cause mortality at 24 months. RESULTS: Angiotensin-converting enzyme/angiotensin receptor blocker and beta-blockers were increased significantly during the 3-month titration period (P < 0.0001 for both). In a stepwise Cox regression analysis adjusted for age, sex, glomerular filtration rate, diabetes mellitus, and ischemic HF, baseline and follow-up neurohormone concentrations were predictors of the primary endpoint as follows (baseline hazard ratios): copeptin 1.92, 95% CI 1.233-3.007, P = 0.004; midregional proadrenomedullin 2.79, 95% CI 1.297-5.995, P = 0.009; midregional proatrial natriuretic peptide 2.05, 95% CI 1.136-3.686, P = 0.017; C-terminal endothelin-1 precursor fragment 2.24, 95% CI 1.133-4.425, P = 0.025; B-type natriuretic peptide 1.46, 95% CI 1.039-2.050, P = 0.029. CONCLUSIONS: In pharmacologically unstable chronic HF patients, baseline values and follow-up measures of copeptin, midregional proadrenomedullin, C-terminal endothelin-1 precursor fragment, midregional proatrial natriuretic peptide, and B-type natriuretic peptide were equally predictive of all-cause mortality. Relative change of neurohormone values was noncontributory.

Electrical optimization of cardiac resynchronization in chronic heart failure is associated with improved clinical long-term outcome.

BACKGROUND: Cardiac resynchronization therapy (CRT) is an established treatment option for symptomatic chronic heart failure (CHF) patients with pharmacological baseline therapy, but not all patients benefit from device therapy. One reason for this may be inadequate device settings. In real-world practice, echocardiographic evaluation of atrioventricular (AV) delay is not performed in a high proportion of patients, as the effect of electrical optimization of CRT is an issue open for investigation. MATERIALS AND METHODS: We performed a retrospective observational study analysing the effect of AV-interval evaluation with echocardiography on long-term [32 (23?43) months] clinical outcome in 205 CHF patients. A stepwise Cox regression model including a co-morbidity score, failed AV-interval evaluation, satisfactory device function after the first implantation attempt, failure to reach 100% of the recommended renin-angiotensin system inhibitor and beta-blocker dose at follow-up and CRT device implantation compared with CRT in combination with an implanted cardioverter defibrillator (ICD) was applied. RESULTS: In the total study cohort, 124 (60.5%) patients had reached the primary combined endpoint death or cardiac hospitalization and 59 (28.8%) had died. Cox regression analysis revealed that failed AV-interval evaluation [HR = 1.72 (1.19-2.49), P = 0.004] non-optimized CHF pharmacotherapy dosages [HR = 2.12 (1.32-3.42), P = 0.002], the presence of a CRT/ICD combination device [HR = 1.87 (1.28-2.71), P = 0.001] and satisfactory device function after the first implantation attempt [HR = 0.44 (0.25-0.77), P = 0.004] were associated with the primary endpoint. CONCLUSION: Echocardiographic evaluation of the AV-interval in patients with CRT was independently associated with improved clinical outcome, impacting on daily clinical practice of HF patient care.

Relationships between cardiac resynchronization therapy and N-terminal pro-brain natriuretic peptide in patients with heart failure and markers of cardiac dyssynchrony: an analysis from the Cardiac Resynchronization in Heart Failure (CARE-HF) study.

AIMS: The Cardiac Resynchronization in Heart Failure (CARE-HF) study showed that cardiac resynchronization therapy (CRT) reduces mortality in HF patients with markers of dyssynchrony. Plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) might predict which patients benefit most from CRT. We evaluated whether the prognostic value of NT-proBNP was influenced by CRT and the effects of CRT stratified according to NT-proBNP. METHODS AND RESULTS: A total of 813 patients were enrolled in CARE-HF. Baseline log-transformed NT-proBNP independently predicted all-cause mortality, sudden death, and death from pump failure. In a multivariable model including log-transformed NT-proBNP, assignment to CRT remained independently associated with better prognosis without evidence of interaction. Stratifying patients according to the median NT-proBNP and to CRT treatment allocation, all-cause mortality was 12% if or= median + CRT, and 51% if >or= median + control group. There was no evidence of a difference in the relative effect of CRT across different values of NT-proBNP. CONCLUSION: NT-proBNP retains its prognostic value in HF patients with CRT. Deploying CRT before the patients have reached end-stage HF may maximize the benefit of treatment.

Prognostic value of apoptosis markers in advanced heart failure patients.

AIMS: Apoptosis plays an important role in the progression of heart failure (HF). The purpose of this study was to assess whether the pro-apoptotic molecules apoptosis-stimulating fragment (FAS, CD95/APO-1) and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) predict event-free survival of HF patients. METHODS AND RESULTS: We assayed soluble (s)FAS and sTRAIL levels in 351 patients with advanced HF. During the median follow-up time of 16 months, 175 patients (50%) experienced the composite endpoints: rehospitalization and death. The hazard increased with sFAS concentrations, with a hazard ratio of 2.3 comparing fourth and first quartiles. This association remained significant after adjustment for B-type natriuretic peptide (BNP) and other risk factors in a Cox regression model (P = 0.014). Patients with high sFAS but low BNP had a comparable event-free survival rate with those with elevated BNP only (P = 0.78). Conversely, high sTRAIL concentrations were related to a better prognosis. Particularly, the risk of mortality dropped by 70% in the fourth quartile of sTRAIL (P = 0.001, multivariable Cox regression model). CONCLUSION: sFAS is an independent risk predictor in advanced HF patients. It may be of particular value for the identification of high-risk patients in addition to BNP. Conversely, sTRAIL appears to be protective and could be an interesting therapeutic agent.

B-type natriuretic peptide predicts benefit from a home-based nurse care in chronic heart failure.

BACKGROUND: Home-based nurse care (HBNC) can reduce adverse events in patients with chronic heart failure. However, which patients really benefit from such an intervention remains unclear. We investigated if B-type natriuretic peptide (BNP), a strong prognostic marker in chronic heart failure, can predict benefit from HBNC. METHODS AND RESULTS: After discharge from heart failure hospitalization, 96 patients were randomized to either HBNC for 12 months or usual care. The combined endpoint of death or heart failure hospitalization was evaluated after 12 and 24 months. The median value of BNP (267 pg/mL) was used as a cutoff value to predict benefit from the HBNC. HBNC reduced the endpoint after 12 (P = .013) and 24 months (P = .033, relative risk [RR] (95% confidence intervals): 0.42 [0.20-0.78] and 0.55 [0.31-0.98], respectively). This benefit from HBNC was dependent on BNP. In patients with supramedian BNP, the endpoint was significantly reduced after 12 (P = .002) and 24 months (P = .003, RR: 0.39 [0.20-0.76] and 0.50 [0.30-0.83], respectively), whereas in patients with inframedian BNP no significant changes occurred. CONCLUSIONS: A high BNP can predict benefit from HBNC in patients with chronic heart failure and may assist in selecting patients for such an intervention.

Prognostic value of plasma midregional pro-adrenomedullin and C-terminal-pro-endothelin-1 in chronic heart failure outpatients.

AIMS: The identification of chronic heart failure (CHF) patients at high risk of adverse outcome remains a challenge. New peptides are emerging that may give additional information. In CHF patients, endothelin (ET) levels predict mortality risk. Adrenomedullin has been shown to predict mortality in ischaemic heart failure, but not in unselected or non-ischaemic CHF patients. Moreover, ADM and ET have never been assessed in one model. The aim of the present study was to assess the prognostic value of midregional-pro-adrenomedullin (MR-proADM) and C-terminal-pro-endothelin-1 (CT-proET-1) in outpatients with CHF. METHODS AND RESULTS: We measured plasma MR-proADM and CT-proET-1 levels in 786 consecutive CHF outpatients and compared them with B-type natriuretic peptide (BNP) levels. At 24-month follow-up, 233 patients had died. A stepwise forward Cox regression model with age, sex, estimated glomerular filtration rate, NYHA > II, left ventricular ejection fraction (LVEF), MR-proADM, CT-proET-1, and BNP as possible predictors revealed that MR-proADM levels [hazard ratio (HR) = 1.77, P < 0.001] in addition to age (HR = 1.02, P = 0.004), ejection fraction (HR = 0.98, P = 0.004), and NYHA > II (HR = 1.86, P < 0.001) were predictors of death at 24 months. When the analysis was repeated dependent on NYHA-stage, MR-proADM (HR = 2.12, P < 0.001) and LVEF (HR = 0.96, P = 0.006) were significant markers, but only in patients with mild/moderate CHF. CONCLUSION: Our data suggest that MR-proADM may be an important prognostic humoral marker, especially in mild/moderately symptomatic and non-ischaemic CHF patients.

Chronic heart failure leads to an expanded plasma volume and pseudoanaemia, but does not lead to a reduction in the body's red cell volume.

Aims Chronic heart failure (CHF) is frequently associated with a decreased haemoglobin level, whereas the mechanism remains largely unknown. Methods and results One hundred consecutive CHF patients without anaemia or renal dysfunction based on non-cardiac reasons were enrolled. We explored determinants of anaemia (as iron parameters, erythropoietin, hepcidin and kidney function) including red cell volume (RCV) (by a 51 Cr assay) as well as related markers and plasma volume. The influence of each factor on haemoglobin concentrations was determined in a multiple regression model. Mean haemoglobin concentrations were 11.7 +/- 0.8 mg/dL in anaemic CHF patients and 14.4 +/- 1.2 mg/dL in non-anaemic patients. Corrected reticulocytes were lower in anaemic patients (35.1 +/- 15.7 vs. 50.3 +/- 19.2 G/L, P = 0.001), but the RCV was not reduced (1659.3 +/- 517.6 vs. 1826.4 +/- 641.3 mL, P = 0.194). We found that plasma volumes were significantly higher in anaemic CHF patients (70.0 +/- 2.4 vs. 65.0 +/- 4.0%, P < 0.001). Plasma volume was the best predictor of haemoglobin concentrations in the regression model applied (B = -0.651, P < 0.001, R(2) = 0.769). Conclusion Haemodilution appears to be the most potent factor for the development of low haemoglobin levels in patients with CHF. Our data support an additional independent, but minor influence of iron deficiency on haemoglobin concentrations in CHF patients.

NT-proBNP has a high negative predictive value to rule-out short-term cardiovascular events in patients with diabetes mellitus.

AIMS: This study evaluated the predictive value of NT-proBNP for patients with diabetes mellitus and compared the prognostic aptitude of this neurohumoral marker to traditional markers of cardiovascular events. METHODS AND RESULTS: A prospective observational study was conducted in 631 diabetic patients. The composite endpoint consisted of unplanned hospitalization for cardiovascular events or death within the observation period of 12 months. Of all variables analysed (age, gender, history of hypertension, ischaemic heart disease/any cardiac disease, smoking, duration of diabetes, body mass index, blood pressure, New York Heart Association-class, Dyspnoea score, Minnesota Living with Heart Failure Questionnaire, LDL-cholesterol, HbA(1c), creatinine, glomerular filtration rate), the logarithm of NT-proBNP gave the most potent information in a stepwise Cox regression analysis (P < 0.0001). Bootstrapping with 500 samples supports this result in 95% samples. The negative predictive value of a normal value (<125 pg/mL) of NT-proBNP for short-term cardiovascular events in diabetic patients is 98%. CONCLUSION: We have demonstrated a strong and independent correlation between NT-proBNP and short-term prognosis of cardiovascular events for patients with diabetes mellitus. With a high negative predictive value it can identify individuals who are not at intermediate risk for cardiovascular events. NT-proBNP proved to be of higher predictive value than traditional cardiovascular markers, in this unselected cohort.

Prognostic value of sequential measurements of amino-terminal prohormone of B-type natriuretic peptide in ambulatory heart failure patients.

BACKGROUND: We evaluated the prognostic value of sequential NT-proBNP values in ambulatory heart failure patients after discharge, investigating whether the current value or the recent percent change is more important. METHODS AND RESULTS: In 166 patients, NT-proBNP was measured at discharge from heart failure hospitalisation and three months later. The combined endpoint of death or heart failure rehospitalisation was evaluated after a maximum of 18 months or at follow-up closure. During a mean observation time of 14+/-4 months, 63 patients (38%) reached the endpoint. In multiple Cox analysis, NT-proBNP three months after discharge (NT-proBNP-3Mo) and NT-proBNP percent change (NT-proBNP-%change) were the only independent predictors of the endpoint among various clinical and laboratory variables. After definition of a high- (n=83, 57% endpoints) and a low-NT-proBNP patient subgroup (n=83, 19% endpoints) according to the median NT-proBNP-3Mo (1751 pg/ml), NT-proBNP-%change was the strongest predictor in the high-NT-proBNP subgroup. In the low-NT-proBNP subgroup, NT-proBNP-3Mo was the only independent predictor. CONCLUSIONS: In ambulatory heart failure patients, the prognostic value of sequential NT-proBNP measurements depends on the magnitude of the current NT-proBNP value. Recent percent changes in NT-proBNP provide important prognostic information in patients with high NT-proBNP but not in patients with low NT-proBNP.

Plasma NT-proBNP increases in response to LPS administration in healthy men.

Circulating levels of B-type natriuretic peptide (BNP) and NH(2)-terminal-proBNP (NT-proBNP) increase in response to volume overload and help in the differential diagnosis of acute heart failure. Elevated plasma BNP levels are observed also in sepsis and do not always correspond to left ventricular dysfunction. Here, we investigated plasma NT-proBNP fluctuations in response to human bacterial endotoxinemia, an experimental model of systemic infection and inflammation. Escherichia coli endotoxin (LPS) (2 ng/kg) was administered to 10 healthy volunteers in a randomized, placebo-controlled, cross-over design. Plasma NT-proBNP, C-reactive protein (CRP), COOH terminal pro-endothelin-1 (CT-proET-1), and midregional-pro-adrenomedullin (MR-proADM) were measured at hourly intervals for 6 h. LPS administration induced a continuous increase in plasma NT-proBNP that reached peak values after 6 h (40.7 +/- 7.9 vs. 16.1 +/- 3.2 pg/ml in placebo days, mean +/- SE; P = 0.023). The profile of changes in NT-proBNP correlated to changes in body temperature (P < 0.001), heart rate (P = 0.005), CRP (P < 0.001), and CT-proET-1 (P = 0.008), but not to blood pressure values. Our results demonstrate that plasma NT-proBNP increases in a model of systemic infection/inflammation in healthy men with normal heart function. This finding emphasizes the necessity to consider concomitant infections when interpreting elevated circulating NT-proBNP concentrations.

Comparative evaluation of B-type natriuretic peptide, mid-regional pro-A-type natriuretic peptide, mid-regional pro-adrenomedullin, and Copeptin to predict 1-year mortality in patients with acute destabilized heart failure.

BACKGROUND: The aim of the present study was to evaluate the capability B-type natriuretic peptide (BNP) as a prognostic marker in patients with acute destabilized heart failure in comparison with mid-regional pro-A-type natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin (MR-proADM), and the C-terminal part of the arginine vasopressin prohormone (Copeptin). METHODS AND RESULTS: BNP, MR-proANP, MR-proADM, and Copeptin plasma concentrations were obtained in 137 patients with acute destabilized heart failure attending a tertiary care hospital. The end point was defined as all-cause mortality, and the study participants were followed for 365 days. Of the 137 patients enrolled, 41 died and 96 survived during follow-up. ROC curve analysis showed that the areas under curve for the prediction of 1-year mortality were similar for BNP (0.716; 95% CI 0.633-0.790), MR-proANP (0.725; 95% CI 0.642-0.798), MR-proADM (0.708; 95% CI 0.624-0.782), and Copeptin (0.688; 95% CI 0.603-0.764). Using tercile approaches, Kaplan-Meier curve analyses demonstrated that the predictive value of all four analytes for survival probability was comparable (log-rank test for trend, P < .001 for each). In multivariable Cox proportional-hazards regression analyses, increased BNP, MR-proANP, MR-proADM, and Copeptin plasma concentrations were the strongest predictors of mortality. CONCLUSION: BNP is considered an established prognostic marker for heart failure patients. The present study provides evidence that MR-proANP, MR-proADM, and Copeptin measurements might have similar predictive properties compared with BNP determinations for one-year all-cause mortality in acute destabilized heart failure.