Analytical Issues with Natriuretic Peptides – Has This Been Overly Simplified? Alexander G
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In this issue: Cardiac Markers. The World is Changing – Are We Ready? Analytical issues with natriuretic peptides – has this been overly simplified? Alexander G. Semenov, Alexey G. Katrukha HyTest Ltd., Turku, Finland ARTICLE INFO ABSTRACT Corresponding author: Natriuretic peptides (NPs) were first described as -car Alexander G. Semenov diac biomarkers more than two decades ago. Since HyTest Ltd. Intelligate, 6th floor that time, numerous studies have confirmed NPs’ Joukahaisenkatu 6 diagnostic and prognostic utilities as biomarkers of 20520 Turku, Finland myocardial function. However, we must now admit Phone: +358 405855037 Fax: +358 25120909 that despite the NPs’ relatively long period of use in E-mail: [email protected] clinical practice, our understanding of the biochemis- try and the variety of circulating forms of NPs, as well Key words: ANP, BNP, glycosylation, immunoassay, as of their potential as biomarkers, remains far from natriuretic peptide, NT-proBNP, being complete and comprehensive. The highly com- proBNP, processing plex nature and wide diversity of circulating forms of Acknowledgments: NPs make their accurate measurements in plasma far We are grateful to Dr. Alexander B. Postnikov more complex than initially believed. A highly sim- for the constructive criticism and helpful plistic view of the NPs’ use is that elevated values of comments in the preparation of this manuscript. NPs indicate the severity of heart failure and thus re- flect the prognosis. However, as shown by a variety of studies, deep understanding of how the NP sys- tem works will be required for correct interpretation of test results in routine practice of cardiovascular disease. In this review, we summarize the recent ad- vances 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. Page 189 eJIFCC2016Vol27No3pp189-207 Alexander G. Semenov, Alexey G. Katrukha Analytical issues with natriuretic peptides – has this been overly simplified? Abbreviations (in alphabetical order) blood pressure, showing involvement in the aar: amino acid residues; maintenance of blood pressure, water, and ADHF: acute decompensated heart failure; electrolyte balance in organisms (3). The two AHF: acute heart failure; peptides, ANP and BNP, have been shown to ANP: atrial natriuretic peptide; display very similar physiological activities and BNP: brain natriuretic peptide; under normal conditions are mainly produced cGMP: cyclic GMP; in the atria. Both peptides are known to reduce CNP: C-type natriuretic peptide; vascular resistance and increase both diuresis DPP IV: dipeptidyl peptidase IV; and sodium excretion, reducing systemic blood FDA: Food and Drug Administration; pressure (4-6). IDE: insulin-degrading enzyme; The third member of the NP family, C-type na- HF: heart failure; triuretic peptide (CNP), was isolated shortly -af mAb: monoclonal antibody; ter the discovery of ANP and BNP (7). However, MI: myocardial infarction; in contrast to ANP and BNP, which are mainly NEP: neutral endopeptidase (neprilysin); produced in the myocardium, CNP is predomi- NPR-A: natriuretic peptide receptor A; nantly produced in the central nervous system NPR-B: natriuretic peptide receptor B; and vascular endothelium and acts as a para- NPR-C: natriuretic peptide receptor C; crine factor (8). This member of the NP family NT-proANP: N-terminal fragment of proANP; was not shown to have much value as biomark- NT-proBNP: N-terminal fragment of proBNP; er of cardiovascular complications. As a result, proANP: ANP precursor; CNP did not attract much interest and was not proBNP: BNP precursor; introduced to routine clinical practice. SES-BNP: Single Epitope Sandwich BNP immunoassay. All 3 members of the NP family share a common structural feature – a ring structure consisting in humans of 17 amino acid residues (aar) and formed by an intramolecular disulfide bond. It is BACKGROUND thought to be essential for mediating receptor binding and the biological activity of NPs (Fig. 1). Natriuretic peptides (NPs) belong to a family of structurally and functionally related circu- Two types of natriuretic peptide receptors (NPRs), lating peptides involved in maintaining cardio- NPR-A and NPR-B, are responsible for most of renal homeostasis. The finding that the heart the physiological effects of NPs. The binding of not only reacts to the humoral stimulus but NPs to these guanylyl cyclase-coupled recep- actively participates in maintaining the fluid tors leads to an increase in cGMP, resulting in and salt balance by producing physiologically natriuresis, vasorelaxation, diuresis, inhibition active compounds emerged with the discov- of the renin-angiotensin-aldosterone system, ery of atrial natriuretic peptide (ANP) and later enhanced myocardial relaxation, inhibition of of B-type natriuretic peptide (BNP) (1, 2). This fibrosis and hypertrophy, promotion of cell sur- new concept of the heart as an endocrine or- vival, and inhibition of inflammation (reviewed gan was introduced in 1981, when de Bold et al. in (9)). Another type of NPR, NPR-C, lacking the showed that the intravenous injection of atrial guanylyl cyclase domain, is responsible for clear- extracts into rats led to an increase in sodium ance and possibly involved in regulation of the chloride and fluid excretion and a decrease in cell proliferation (reviewed in (10)). Page 190 eJIFCC2016Vol27No3pp189-207 Alexander G. Semenov, Alexey G. Katrukha Analytical issues with natriuretic peptides – has this been overly simplified? Figure 1 The primary structures of human ANP, BNP, and CNP D R M I K S R BNP (32 aar) S G S F S C G S P K M V Q G S G L G C K V L R R H D R D R M I L I R G K G G L A S ANP (28 aar) G Q CNP (22 aar) G M F S F S C G C G L L S L R R S S G G L S K G G C C N S F R Y Similar residues are marked by a green background. The ring structure is formed by a disulfide bridge between two cysteine residues. The expression and secretion of ANP and BNP (FDA) for acute congestive HF (ACHF). However, increase significantly in pathological states ac- questions regarding the efficiency and safety of companied by stretching of the heart cham- nesiritide diminished its use. Neseritide is cur- bers, volume overload, and ischemic injury, rently considered to be safe, but with little ben- such as heart failure (HF) and myocardial in- eficial effect (19). farction (MI) (11-13). Because the increase As mentioned above, ANP and BNP share many in their production and release in circulation common features and may be expected to is associated with the cardiac pathologies have similar or even equal value as biomark- caused by pressure or volume overload, it was ers. However, BNP was shown to have greater suggested that these peptides may be used as in vitro stability and superior diagnostic perfor- biochemical markers of HF. The diagnostic and mance compared with ANP, and therefore BNP prognostic utility of ANP and BNP was later and its related peptides have emerged as the confirmed in a large number of studies (re- preferred candidates for the diagnosis of HF, as viewed in (14, 15)). well as other clinical applications. Recent inter- Considering the beneficial physiological ac- national guidelines recommend its use for the tivities of NPs in HF, recombinant forms of diagnosis, risk stratification, and follow-up of ANP and BNP were introduced as therapeutic patients with chronic or acute HF (15, 20). As agents for the treatment of this disease (16-18). a consequence, the data regarding BNP-related Recombinant human ANP (carperitide) was ap- peptides are currently more comprehensive proved in Japan in 1995 for intravenous adminis- that the data regarding ANP. In this review, we tration in patients with acute heart failure (AHF) will focus mostly on the analytical issues relat- and acute decompensated heart failure (ADHF). ed to BNP, as this member of the NP family is Later, in 2001, recombinant BNP (nesiritide) was more interesting and important from a clinical approved by the Food and Drug Administration perspective. Page 191 eJIFCC2016Vol27No3pp189-207 Alexander G. Semenov, Alexey G. Katrukha Analytical issues with natriuretic peptides – has this been overly simplified? SYNTHESIS AND SECRETION OF ANP as coat antibodies along with monoclonal rat antibodies specific to the fragment 73-90 of ANP is translated from its gene as a 151-ami- proANP (25). no acid prepropeptide, preproBNP, that is stored in atrial granules (21). It is secreted SYNTHESIS AND SECRETION OF BNP and cleaved to a mature peptide, ANP, in re- sponse to atrial stretching or stimulation by The BNP gene encodes a 134-amino acid prep- angiotensin II, endothelin, as well as sympa- roBNP precursor, which is converted to 108-ami- thetic stimulation. After cleavage of the signal no acid proBNP by the cleavage of a 26-amino peptide (a common element of all secretory acid signal peptide (26). Interestingly, a frag- proteins, which is responsible for addressing ment of preproBNP signal peptide (17-26 AAR) the protein to a secretory pathway) from the was shown to be present in the blood of normal 151-amino acid preproANP, the precursor pro- individuals and patients with acute MI and was ANP is further processed by atrial convertase suggested as a circulating biomarker of cardiac corin to produce two circulating peptides, ANP ischemia and MI, with some possible advan- 1-28 and the N-terminal fragment NT-proANP tages over currently used biomarkers such as 1-98 (22). The processing of proANP is consid- creatine kinase-MB, myoglobin, and troponins ered to occur at the time of secretory granule (27). Similarly, a fragment of preproANP signal release. peptide (16-25 aar) was shown by the same re- NT-proANP is also cleaved, forming 3 fragments search group to have some potential as an isch- that exhibit physiological activity: proANP 1-30 emic biomarker (28).