Influence of Glycosylation on Diagnostic and Prognostic Accuracy of N-Terminal Pro–B-Type Natriuretic Peptide in Acute Dyspnea: Data from the Akershus Cardiac Examination 2 Study

Abstract

BACKGROUND The N-terminal part of pro–B-type natriuretic peptide (NT-proBNP) is glycosylated, but whether glycosylation influences the diagnostic and prognostic accuracy of NT-proBNP measurements is not known. METHODS We measured NT-proBNP concentrations of 309 patients with acute dyspnea by use of standard EDTA tubes and EDTA tubes pretreated with deglycosylation enzymes. The primary cause of dyspnea was classified as heart failure (HF) or non-HF, and the diagnosis was adjudicated by 2 independent physicians. We collected information on all-cause mortality during follow-up. RESULTS In all, 142 patients (46%) were diagnosed with HF. NT-proBNP concentrations in nondeglycosylated samples distinguished HF patients from patients with non-HF related dyspnea [median 3588 (quartiles 1–3 1578–8404) vs 360 (126–1139) ng/L, P < 0.001], but concentrations were markedly higher in samples pretreated with deglycosylation enzymes (total NT-proBNP) [7497 (3374–14 915) vs 798 (332–2296) ng/L, P < 0.001]. The AUC to separate HF patients from patients with non-HF related dyspnea was 0.871 (95% CI 0.829–0.907) for total NT-proBNP compared with 0.852 (0.807–0.890) for NT-proBNP measurements in standard EDTA plasma. During a median follow-up of 816 days, 112 patients (36%) died. Both NT-proBNP and total NT-proBNP concentrations were associated with mortality in separate multivariate models, but only total NT-proBNP concentrations provided added value to the basic risk model of our dataset as assessed by the net reclassification index: 0.24 (95% CI 0.003–0.384). There was a graded increase in risk across total NT-proBNP quartiles, in contrast with the results for NT-proBNP measurements. CONCLUSIONS NT-proBNP concentrations were higher, and diagnostic and prognostic accuracy was improved, by pretreating tubes with deglycosylation enzymes.

Specificity of B-Type Natriuretic Peptide Assays: Cross-Reactivity with Different BNP, NT-proBNP, and proBNP Peptides

“…There are interindividual differences in NT-proBNP and proBNP glycosylation patterns in patients with and without heart failure and therefore current NT-proBNP immunoassays underestimate "true" NT-proBNP concentrations. Assessment of deglycosylated NT-proBNP concentrations also has been shown to improve the diagnostic and prognostic accuracy in patients with dyspnea, which suggests the antibody configurations used in NTproBNP assays could be improved if glycosylated peptides were also detected (27 ).…”

Mid-regional pro-adrenomedullin in patients with acute dyspnea: Data from the Akershus Cardiac Examination (ACE) 2 Study

“…Akershus University Hospital, a Norwegian teaching hospital with a catchment area of approximately 460 000 subjects, and the details of the study has previously been reported [15].…”

“…We used a standardized questionnaire to collect relevant data from the patients and the physicians in the ED as previously reported [15]. Analogous to previous studies on patients with acute dyspnea [2][3][4], the ED physicians were asked to assess the probability of acute HF being the main cause of dyspnea from 0% (highly unlikely) to 100% (very likely) after their initial assessment of the patient and prior to results of NT-proBNP testing.…”

“…We calculated C statistics by combining MR-proADM on top of the other variables that were significantly associated with mortality in the multivariate Cox regression models (basic model). Furthermore, we also calculated the net reclassification index (NRI) [20] by adding MR-proADM concentrations to the basic model as previously reported [15]. All analyses were considered statistically significant at the threshold value of p<0.05.…”

B-Type Natriuretic Peptide as a Therapeutic Strategy: Opportunities and Pitfalls

“…Glycosylated proBNP 1-108 also seems to represent the major form by means of which BNP immunoreactivity is released from cardiomyocytes, both in disease states and in healthy subjects. Thus, in addition to influencing the diagnostic and prognostic accuracy of the commercially available NT-proBNP assay (ProBNP assay, Roche Diagnostics, Penzberg, Germany) [6], glycosylation of proBNP 1-108 could have implications for the clinical relevance of the results by Chang et al [2 ]as limited endogenous BNP 1-32 may actually be available in healthy subjects and in patients with cardiovascular disease. Moreover, and also important for the clinical relevance of their study, the proportion of intact BNP 1-32 in patients appears to be very low because BNP 1-32 molecules are truncated from the C-terminal end [reviewed in [5]].…”