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BACKGROUND: ProBNP, the precursor peptide to BNP and NT-proBNP (NP), circulates in patients with chronic heart failure (HF) and appears to be the predominant form of NP. This heterogeneity may confound interpretation of NP concentrations. The aim of this study was to evaluate the response to therapy and prognostic influence of proBNP in a cohort of patients admitted to hospital for decompensated HF. METHODS: We prospectively evaluated 40 Class III-IV patients who received clinically-indicated nesiritide infusions as part of their care. Blood was drawn before, during, and post-infusion, and assayed for proBNP, BNP, and NT-proBNP. RESULTS: All biomarkers were increased at baseline consistent with HF. ProBNP and NT-proBNP demonstrated significant reductions in response to therapy (42% and 18% post-infusion, respectively). In the patients who experienced post-hospital mortality (40% at 6 months), baseline proBNP and BNP concentrations were significantly lower than in survivors. This paradoxical finding may be explained by the end-stage nature of this patient cohort possibly experiencing exhaustion of their NP systems. CONCLUSIONS: Circulating concentrations of proBNP are increased in decompensated HF and similar to NT-proBNP are reduced in response to acute therapy. Paradoxically and similar to BNP, baseline proBNP concentrations were lower in post-hospital non-survivors. While hypothesis generating, the results of this study support a role for proBNP in monitoring therapy and predicting short-term outcome. These findings need to be confirmed in a patient cohort without nesiritide therapy and more moderate HF.

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BACKGROUND: Brain natriuretic peptide (BNP), N-terminal proBNP (NT-proBNP) and to a lesser extent prohormone proBNP are recognized as biochemical markers of left ventricular dysfunction. In renal failure, interpretation of natriuretic peptide remains unclear, as natriuretic peptide levels may be not only be dependent on cardiac function and dimensions but also on renal function, fluid volume and removal by dialysis procedure including hemodiafiltration (HDF). The purpose of this study was (i) to assess BNP, NT-proBNP and proBNP levels and their correlation with clinical and echocardiographic data in chronic hemodialysis patients, and (ii) to investigate basal level alteration following HDF. METHODS: Baseline clinical and echocardiographic parameters were collected in 31 dialysis patients without evidence of cardiac failure. Pre- and post-HDF BNP, NT-proBNP and proBNP concentrations were measured. Correlations between echocardiographic measurements and basal circulating peptides, between changes in peptide values and changes in fluid volume after HDF were investigated. RESULTS: Baseline plasmatic levels were elevated (BNP=517+/-840 pg/mL, NT-proBNP=5340+/-6132 pg/mL and proBNP=3569+/-4683 pg/mL) and correlated with left auricular diameter and left ventricular mass index. HDF session induced a significant decrease of 39%, 59% and 36% for BNP, NT-proBNP and proBNP levels, respectively. This decrease was not correlated to post-HDF fluid removal or weight decrease. Correlation between BNP and proBNP was stronger (r(2)=0.88) than between NT-proBNP and proBNP (r(2)=0.54). CONCLUSIONS: Despite their elimination, BNP, NT-proBNP and proBNP could be potential markers of left ventricular remodeling in chronic renal failure patients on hemodialysis. According to these results, their cut-off values, however, need to be re-evaluated.

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OBJECTIVES: The aim of this study was to establish the diagnostic sensitivity of combinations of well-selected monoclonal antibodies (mAbs) against cardiac troponin I (cTnI) to allow an earlier rule-in of acute coronary syndrome (ACS) patients. DESIGN AND METHODS: Using several combinations of mAbs, four new experimental cTnI immunoassays were evaluated to analyze plasma samples from 62 patients suffering from angina (16/62), patients having a chest pain of extracardiovascular origin (19/62) and ACS without ST elevation (NSTE-ACS) (27/62). RESULTS: Assay 2, which relies on a capture mAb directed against the central part of cTnI and two conjugated mAbs directed against the N-ter region, provided the best clinical sensitivity. In 11 out of 27 patients with NSTE-ACS, it detected an early rise of cTnI within 0 and 1 h upon admission, contributing to the detection of 53% of samples found to be negative by the reference AccuTnI Assay upon admission (Beckman Coulter), thereby reducing the delay in diagnosis. CONCLUSIONS: Assay 2 can identify early cTnI elevation in NSTE-ACS, possibly facilitating the rule-in procedure for these patients once the assay is automated.

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BACKGROUND: B-Type natriuretic peptide (BNP1-32) as well as the N-terminal fragment of the prohormone containing residues 1-76 (NT-proBNP1-76), both cleavage products of the precursor proBNP1-108, are reported to be powerful markers for prognosis and risk stratification of heart failure. However, the intact precursor also circulates in the bloodstream. Assays for the detection of these cleavage products have been developed, but most of these assays may overestimate the concentrations of the cleavage products because they also measure the precursor form. It is therefore important to develop an immunoassay that specifically measures solely proBNP1-108 in plasma. METHODS: After carefully designing the peptide used to immunize mice, we selected a specific monoclonal antibody (mAb Hinge76) that recognizes the cleavage site of proBNP1-108, an epitope present only in the precursor form. mAb Hinge76 recognizes recombinant proBNP1-108 in a dose-dependent manner, without any significant cross-reactivity with either recombinant NT-proBNP1-76 or synthetic BNP1-32. By combining mAb Hinge76 with a polyclonal antibody directed against BNP1-32, we were able to set up a proBNP1-108-specific sandwich immunoassay able to confirm the presence of proBNP1-108 in blood samples. RESULTS: From a cohort of 50 healthy persons and 170 patients with congestive heart failure (CHF), our assay was able to differentiate healthy individuals from CHF patients (P <0.005). Interestingly, plasma proBNP1-108 concentrations were correlated with New York Heart Association classification. Moreover, a close relationship between proBNP1-108 and BNP1-32 concentrations may exist, as a good correlation (r2= 0.89) was obtained when their respective concentrations were compared. CONCLUSION: mAb Hinge76 is the first proBNP1-108-specific mAb produced that allows accurate estimation of proBNP1-108 concentrations in plasma.

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OBJECTIVE: To determine the predominant form in which cardiac troponin I circulates in the bloodstream of unstable angina patients. DESIGN AND METHODS: The cardiac troponin I forms released in the bloodstream of 25 patients suffering from unstable angina were examined by using three immunoenzymatic assays: the total cTnI assay for detection of free and complexed cTnI, the IC-TIC assay for detection of the IC and TIC troponin complexes, and the IT-TIC assay for detection of the IT and TIC troponin complexes. RESULTS: Approximately 60% of patients with unstable angina had at least one positive value in the total cTnI assay or in the IC-TIC assay. Our results demonstrated that the predominant cardiac troponin I form circulating in the bloodstream of patients with unstable angina was the IC complex. Free cTnI, IT, and/or TIC forms were seldom found, the frequency of IT and/or TIC complexes being higher than that observed previously in patients with acute myocardial infarction. CONCLUSIONS: The release pattern of cTnI in patients suffering from unstable angina is similar to that previously observed in patients with acute myocardial infarction, i.e., a predominance of the IC complex.

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