Analytical Issues with Natriuretic Peptides - has this been Overly Simplified?

Abstract

Natriuretic peptides (NPs) were first described as cardiac biomarkers more than two decades ago. Since that time, numerous studies have confirmed NPs' diagnostic and prognostic utilities as biomarkers of myocardial function. However, we must now admit that despite the NPs' relatively long period of use in clinical practice, our understanding of the biochemistry and the variety of circulating forms of NPs, as well as of their potential as biomarkers, remains far from being complete and comprehensive. The highly complex nature and wide diversity of circulating forms of NPs make their accurate measurements in plasma far more complex than initially believed. A highly simplistic view of the NPs' use is that elevated values of NPs indicate the severity of heart failure and thus reflect the prognosis. However, as shown by a variety of studies, deep understanding of how the NP system works will be required for correct interpretation of test results in routine practice of cardiovascular disease. In this review, we summarize the recent advances in understanding of the complexity of the NP system and discuss related analytical issues, which open new horizons, as well as challenges for clinical diagnostics.

Keywords: ANP; BNP; NT-proBNP; glycosylation; immunoassay; natriuretic peptide; proBNP; processing.

Figure 1. The primary structures of human ANP, BNP, and CNP

Similar residues are marked by a green background. The ring structure is formed by a disulfide bridge between two cysteine residues.

Figure 2

The known main degradation sites of BNP by the action of DPP IV, NEP and IDE

Figure 3. The scheme of proBNP maturation and processing with the suggested inhibitory effect of O-glycans bound to the Thr₇₁ on processing efficiency

Seven potential sites of O-glycosylation are marked as dark diamonds (34). The potential N- and C-terminal sites of proteolytic degradation as well as the ones located within the ring structure of BNP (proBNP) are marked by red arrows. Adapted with modifications from (40).

Figure 4. Antibodies and standard materials used in commercial BNP immunoassays

Adapted with modifications from: http://www.ifcc.org/media/102208/NP%20Assay%20Table%20C%20SMCD%20vJuly_2011.pdf.

Figure 5

Schematic representation of proBNP-specific assays designed by HyTest and Bio-Rad. Seven potential O-glycosylation sites within the proBNP sequence are marked with dark diamonds (34)