Deconvolution Analysis of Cardiac Natriuretic Peptides During Acute Volume Overload

Abstract

Abstract-Cardiac natriuretic peptides, especially amino terminal pro-Brain Natriuretic Peptide (NT-proBNP), are emerging as powerful circulating markers of cardiac function. However, the in vivo secretion and elimination (t 1 ⁄2) of these peptides during acute volume overload have not been studied. We present the first report of the secretion and elimination of cardiac natriuretic peptides, based on deconvolution analysis of endogenous ovine plasma levels measured by specific radioimmunoassay. Four normal, conscious sheep underwent rapid right ventricular pacing (225 bpm) for 1 hour to stimulate acute cardiac natriuretic peptide release. Plasma samples and right atrial pressure measurements were taken at regular intervals 30 minutes before, during, and 4 hours after pacing. Baseline right atrial pressure significantly increased (Pϭ0.02) during the 1 hour of pacing in association with a prompt increase in plasma BNP (Pϭ0.03), atrial natriuretic peptide (Pϭ0.01), and NT-proBNP (Pϭ0.02). Deconvolution analysis showed that the t 1 ⁄2 of NT-proBNP (69.6Ϯ10.8 minutes) was 15-fold longer than BNP (4.8Ϯ1.0 minutes). Despite sustained increases in atrial pressure, cardiac secretion of natriuretic peptides (particularly atrial natriuretic peptide) fell during the pacing period, suggesting a finite source of peptide for secretion. Size-exclusion high-performance liquid chromatography revealed NT-proBNP to be a single immunoreactive peak, whereas BNP comprised at least 2 immunoreactive forms. These findings, especially the prompt secretion of BNP and the prolonged t 1 ⁄2 of NT-proBNP, clarify the metabolism of BNP forms and help to explain the diagnostic value of NT-proBNP measurement as a sensitive marker of ventricular function. Key Words: heart failure Ⅲ natriuretic peptides Ⅲ myocytes Ⅲ metabolism I ncreases in circulating volume and cardiac filling pressures promote increased secretion of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) from mammalian cardiac myocytes. ANP is synthesized and stored in the atria, whereas BNP is released from the ventricle. 1,2 ProANP is the dominant storage form in mammalian cardiac extracts 3 and is cleaved during secretion into 2 fragments, ANP [4][5][6] In contrast, myocytes contain either proBNP alone or a complex ratio of proBNP, BNP,3 suggesting that the mechanism responsible for cardiac processing of proBNP differs from that of proANP. Circulating ANP is rapidly cleared by specific clearance receptor (NPR-C) and enzymatic (neutral endopeptidase, NEP) pathways 10 -12 in contrast to 8,9,13 which is slowly metabolized and accumulates in plasma at concentrations 10-to 50-fold those of ANP. 13 Whereas BNP is cleared from the circulation by NPR-C and NEP at variable rates across species, 1,14 the absolute and proportional increment of NTproBNP in clinical and experimental heart failure 15-18 exceeds that of BNP.The growing recognition of the value of plasma levels of BNP and NT-proBNP as markers of left ventricular function 17 and prognosis after myocardial infarcti...

Natriuretic Peptides and Analytical Barriers

“…NT-proBNP has no known biologic activity. Despite the 1:1 stoichiometric ratio, the molar plasma concentration of NT-proBNP is higher than the concentration of BNP likely because NTproBNP has slower clearance from the circulation (17 ). ProBNP in nonprocessed form is found in healthy individuals and patients with HF (18 ).…”

“…Of interest, in that study, glycosylation had no impact. In addition, assays specific to the amino terminus (amino acids [11][12][13][14][15][16][17] are less susceptible to BNP cleavage by neprilysin than epitopes specific for amino acids 14 -21. Currently it is not clear how BNP and NT-proBNP concentrations are affected by treatment with LCZ696 in different conditions.…”

The diagnostic and prognostic value of brain natriuretic peptides in adults with a systemic morphologically right ventricle or Fontan-type circulation

“…NT-proBNP has a longer half-life compared to that of BNP [25], and this might indicate that it better reflects long-term cardiac status and thus might correlate better with the clinical variables.…”

Breed Differences in Natriuretic Peptides in Healthy Dogs

“…NT‐proANP is further cleaved into 3 segments; proANP 1‐30, 31‐67, and 68‐98 24. All segments can be analyzed,3, 4, 6, 8, 17, 18, 25 but the N‐terminal segments have been found to have longer half‐lives and may, therefore, be better suited as diagnostic tools 11, 26, 27, 28, 29. Furthermore, midregional proANP, such as proANP 31‐67, has been shown to have high biological stability, potentially because of a lower risk of fragmentation compared to proANP 1‐98 27…”