Amino-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) Testing - Recent Lessons Learned

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Abstract

The use of natriuretic peptide testing has dramatically risen recently, in recognition of the value of these blood tests for assisting in the evaluation of patients with suspected heart failure (HF). B-type natriuretic peptide (BNP) is formed as a consequence of production of a 108-amino-acid precursor peptide that is synthesized within the cardiomyocyte; this 'pro-BNP108' is subsequently cleaved at the time of release of the peptide by the cardiomyocyte into two fragments: the 32-aminoacid BNP, and the 76-amino-acid amino-terminal portion (NT-proBNP). BNP has numerous biologic effects in the body, including induction of diuresis and natriuresis, vasodilation, and downregulation of the renin-angiotensin-aldosterone system. These effects bespeak of the potential usefulness of measurement of BNP or NT-proBNP in disease states such as HF.

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The first US Food and Drug Administration (FDA)- approved BNP assay became available in 2001. Subsequently, automated assays for NT-proBNP received approval in 2002 and, since then, testing for the natriuretic peptides has been shown to be exceptionally useful for numerous clinical applications, including the evaluation of the patient complaining of dyspnea, as elevated concentrations of these markers have been shown to be present in patients with acute HF, a diagnosis that is typically difficult to secure using standard clinical methods.

Since the earliest experiences with BNP and NT-proBNP, much has been learned about the utility of these tests for evaluation of patients with suspected or proven HF.

Comparing BNP with NT-proBNP
Analytical Differences
As would be expected, the analytical methods for testing both BNP and NT-proBNP differ considerably, and as such it is not surprising that considerable differences between the two markers exist with respect to optimal methods for their testing. It has been shown that recoverable levels of BNP fall rapidly after phlebotomy,1 which likely reflects on-going activity of neutral endopeptidases in the blood sample or activation of the kallikrein system in the tube within which the blood sample is collected.2 Indeed, a recent study using exquisitely accurate mass spectral techniques actually demonstrated that among HF patients with extremely high concentrations of 'BNP32'(as assessed by a point-ofcare immunoassay for the marker), no detectable intact BNP actually existed in the samples. This disturbing finding raises the concern that what is actually measured by BNP methods is a mixture of varying chain lengths of BNP, as well as potentially other cross-reactive species from the natriuretic peptide family of markers. In contrast, NT-proBNP is remarkably stable after release, and the methods for its measurement are highly precise another major problem for several methods of BNP measurement.
Clinical Differences
In general, the clinical information that is gained by measurement of either BNP or NT-proBNP is largely similar; results of head-to-head comparisons of the markers demonstrate similar utilities in unselected populations of patients with suspected HF. Some noteworthy differences between BNP and NT-proBNP do exist, however.

In head-to-head comparisons, while both BNP and NTproBNP had similar sensitivity and specificity for evaluation of symptomatic patients, Mueller and colleagues demonstrated that NT-proBNP had superior sensitivity to BNP for the detection of those patients with asymptomatic left ventricular (LV) dysfunction. This has serious ramifications, as the detection of patients with asymptomatic or early forms of HF has recently been emphasized by the American Heart Association (AHA). Furthermore, recent data suggest that up to 21% of symptomatic patients with established chronic HF may demonstrate BNP values below 100pg/ml, currently the only cut-off identified for use for BNP (which was based on data from acutely dyspneic patients in the emergency department (ED) setting). Indeed, a source of concern is that no optimal cut-off for use of BNP in office-based evaluation has been established for the identification of asymptomatic structural heart disease or longitudinal evaluation of patients with established HF. For NTproBNP, clinical studies demonstrate significant utility of a cut-off of 125pg/ml for patients <75 years of age and 450pg/ml for patients =75 years of age for the out-patient evaluation of patients with suspected HF (see Table 1)./>/>/>/>/>/>/>/>/>/>

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