Secretion of prohormone of B-type natriuretic peptide, proBNP1-108, is increased in heart failure

Abstract

Objectives: Using a novel, specific assay for proBNP(1-108), this study tested the hypotheses that proBNP(1-108) is secreted by both nonfailing and failing human hearts and that proBNP(1-108) secretion is increased in failing hearts.

Background: The prohormone of B-type natriuretic peptide (proBNP(1-108)) is a 108-amino acid peptide produced primarily by the heart and cleaved into biologically active BNP(1-32) and the biologically inactive NT-proBNP(1-76). It is unknown to what extent increased cardiac proBNP1-108 secretion compared to reduced peripheral processing is responsible for elevated proBNP(1-108) levels in patients with heart failure (HF) compared to subjects without HF.

Methods: The transcardiac gradient of proBNP(1-108) was determined by collecting arterial blood and blood from the coronary sinus (CS). Samples from subjects without overt heart disease (n = 9) were collected during cardiac catheterization after coronary artery disease had been excluded. Samples from HF patients (n = 21) were collected during implantation of a biventricular pacemaker. ProBNP(1-108) was measured with a new assay. Values are medians (25th/75th percentiles).

Results: The gradient of proBNP(1-108) across the nonfailing hearts was 8 (2/20) ng/l (aorta: 15 [1/25] ng/l; CS: 24 [8/41] ng/l; p = 0.018). The transcardiac gradient of proBNP(1-108) in the failing hearts was 326 (96/482) ng/l (arterial: 381 [201/586] ng/l; CS: 709 [408/1,087] ng/l; p<0.001). The transcardiac gradient was greater in failing than nonfailing hearts (p = 0.001).

Conclusions: ProBNP(1-108) is secreted by nonfailing and failing human hearts, but more so in the latter. It remains to be established where peripheral processing of proBNP(1-108) occurs and how this is affected by disease.

Keywords: biomarker; heart failure; natriuretic peptides; proBNP(1-108).

Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

Schematic of proBNP1–108 and two of its derivatives, NTproBNP1–76 and BNP1–32 (which is proBNP77–108). Two putative enzymes involved in proBNP cleavage are corin and furin. The specific proBNP1–108 assay (Bio-Rad, Hercules, CA, USA) uses a capture antibody directed against the hinge region, i.e. region in which proBNP1–108 is cleaved into bioactive BNP1–32 and inactive NTproBNP1–76. There is a monoclonal detection antibody directed against BNP1–32 epitopes. Thus, the proBNP1–108 assay only detects uncleaved proBNP forms.

Figure 2

ProBNP1–108 immunoreactivity of normal human plasma spiked with various proBNP1–108 derivatives and proBNP1–108. Except for when proBNP1–08 was added (far right), none of the added proBNP1–108 derivatives had proBNP1–108 immunoreactivity different from unspiked plasma (far left).

Figure 3

ProBNP1–108 secretion in subjects without HF. Left graph: lines show individual subjects. Right graph: bars show median, 25th and 75th percentile (A). ProBNP1–108 secretion in patients with HF. Left graph: lines show individual subjects. Right graph: bars show median, 25th and 75th percentile (B).

Figure 4

Transcardiac gradients of proBNP1–108 secretion in subjects with non-failing and failing hearts. Left graph: Scatter plot shows individual subjects. Right graph: bars show median, 25th and 75th percentile (A). Scatter plot shows individual transcardiac proBNP1–108 gradients in subjects with and without HF in relation to age. Age was not the major determinant of the transcardiac gradient, but rather HF was (B).