Biochemistry of B-type natriuretic peptide - where are we now?

Background: The discovery of the cardiac endocrine function more than 25 years ago was a breakthrough for the implementation of a routine laboratory marker of heart failure. The heart secretes two different natriuretic peptides with similar biological effects. B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) emerged as the superior diagnostic markers compared to circulating A-type natriuretic peptide (ANP) and proANP derived peptide forms. However, the biochemistry with the processing and metabolism of proBNP, NT-proBNP and BNP with their impact on BNP quantification are still incompletely understood. Methods: Published data and own results were used. Results: This review shows that the present understanding of the biochemistry of BNP and its circulating forms is far from complete. The regulation of BNP secretion occurs mainly at the level of gene transcription with only minor stores of proBNP and processed BNP 1-32 within cardiomyocytes. proBNP is believed to be split into BNP 1-32 and NT-proBNP 1-76 mainly upon secretion, although limited amounts of processed BNP have also been described in the secretory granules of atrial cardiomyocytes. proBNP can be also detected in the circulation and exists as a monomer. There is no evidence for relevant processing of proBNP into BNP 1-32 and NT-proBNP in the circulation. Only small amounts of the intact hormone BNP 1-32 appear to circulate in plasma, there are no known BNP binding proteins. The major circulating BNP forms appear to be split products of BNP 1-32, but are still not sufficiently characterized. Dipeptidylpeptidase IV degrades BNP 1-32 to BNP 3-32 at its N-terminal end. NT-proBNP appears to be rapidly truncated at both ends as well. proBNP and NT-proBNP are glycosylated to a variable degree. BNP and NT-proBNP are extracted by the kidneys to a comparable extent. In contrast to BNP, the biological half-life of NT-proBNP in humans is still not known. The current commercial BNP assays do not significantly cross-react with NT-proBNP and vice versa. However, BNP as well as NT-proBNP assays cross-react with proBNP to a varying extent. Conclusions: The better characterization of circulating proBNP, BNP, and NT-proBNP forms is necessary to define the relevant standard for assay standardization. Until then, assays should be designed to detect the total amount of the circulating analyte to achieve optimal sensitivity. The identification of possible disease effects on proBNP, BNP, and NT-proBNP metabolism could pave the way for the development of more disease specific assays in the clinical setting.