B-type Natriuretic Peptide Molecular Forms and Their Convertases in Heart Failure

Whereas numerous studies have examined the cardiac tissue content and secretion of atrial natriuretic peptide (ANP), the response of brain natriuretic peptide (BNP) in states of experimental cardiac overload is less well documented. Our recent partial cloning of the ovine BNP gene has enabled us to study changes in cardiac tissue concentration, together with tissue and circulating molecular forms of ANP and BNP, in response to cardiac overload induced by rapid ventricular pacing (n = 7) and aortic coarctation (n = 6). In normal sheep, although highest levels of BNP were found in atrial tissue (15-fold those of the ventricle), the BNP/ANP concentration ratio in the ventricles was 10- to 20-fold higher than the ratio calculated for atrial tissue. Compared with normal sheep, significant depletion of both ANP and BNP concentrations within the left ventricle occurred after rapid ventricular pacing. Size exclusion and reverse phase HPLC analysis of atrial and ventricular tissue extracts from normal and overloaded sheep showed a single peak of high molecular weight BNP consistent with the proBNP hormone. In contrast, immunoreactive BNP extracted from plasma drawn from the coronary sinus was all low molecular weight material. Further analysis of plasma BNP using ion exchange HPLC disclosed at least 3 distinct immunoreactive peaks consistent with ovine BNP forms 26-29 amino acid residues in length. These findings show that BNP is stored as the prohormone in sheep cardiac tissues and that complete processing to mature forms occurs at the time of secretion. The capacity to process the prohormone at secretion is not impaired by chronic heart failure.

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Diversity of molecular forms of plasma brain natriuretic peptide in heart failure--different proBNP-108 to BNP-32 ratios in atrial and ventricular overload

Heart ◽

10.1136/hrt.2009.178392 ◽

2009 ◽

Vol 96 (6) ◽

pp. 432-439 ◽

Cited By ~ 31

Author(s):

T. Nishikimi ◽

N. Minamino ◽

M. Ikeda ◽

Y. Takeda ◽

K. Tadokoro ◽

...

Keyword(s):

Heart Failure ◽

Brain Natriuretic Peptide ◽

Natriuretic Peptide ◽

Molecular Forms ◽

Plasma Brain Natriuretic Peptide

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Changes of molecular forms of atrial natriuretic peptide after treatment for congestive heart failure

Klinische Wochenschrift ◽

10.1007/bf01726925 ◽

1988 ◽

Vol 66 (15) ◽

pp. 675-681 ◽

Cited By ~ 11

Author(s):

F. Marumo ◽

T. Kurosawa ◽

S. Takeda ◽

Y. Katoh ◽

N. Hasegawa ◽

...

Keyword(s):

Heart Failure ◽

Congestive Heart Failure ◽

Atrial Natriuretic Peptide ◽

Natriuretic Peptide ◽

Molecular Forms ◽

Atrial Natriuretic

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Prognostic Role of Molecular Forms of B-Type Natriuretic Peptide in Acute Heart Failure

Clinical Chemistry ◽

10.1373/clinchem.2016.265140 ◽

2017 ◽

Vol 63 (4) ◽

pp. 880-886 ◽

Cited By ~ 14

Author(s):

Toru Suzuki ◽

M Zubair Israr ◽

Liam M Heaney ◽

Minoru Takaoka ◽

Iain B Squire ◽

...

Keyword(s):

Heart Failure ◽

Natriuretic Peptide ◽

Poor Prognosis ◽

Adverse Outcome ◽

Survival Rates ◽

Molecular Forms ◽

Spearman Correlation ◽

Prognostic Role ◽

All Cause Mortality

Abstract BACKGROUND B-type natriuretic peptide (BNP) molecular forms 5-32, 4-32, and 3-32 are known to be present in the circulation of heart failure (HF) patients. This study investigated the prognostic role of circulating BNP molecular forms on risk prediction for patients with acute HF. METHODS BNP molecular forms were measured in plasma using an immunocapture MALDI-TOF–mass spectrometry (MS) method. Associations of molecular BNP forms with adverse outcome of all-cause mortality (death) and a composite of all-cause mortality and rehospitalization due to HF (death/HF) at 6 months and 1 year were investigated. RESULTS BNP molecular forms 5-32, 4-32, and 3-32 were detected in 838 out of 904 patient samples. BNP molecular forms were all able to independently predict death and death/HF at 6 months and 1 year. BNP 5-32 was the superior form with strongest predictive qualities for death at 6 months [adjusted hazard ratio (HR) 1.31, P = 0.005] and 1 year (adjusted HR 1.29, P = 0.002) and death/HF at 1 year (adjusted HR 1.18, P = 0.011). BNP 5-32, 4-32, and 3-32 showed decreased survival rates across increasing tertiles of circulating concentrations (P ≤ 0.004). BNP molecular forms showed prognostic ability comparable with conventional BNP measurements across all end points (P = 0.002–0.032 vs P = 0.014–0.039, respectively) and reduced associations with renal dysfunction (blood urea; Spearman correlation rs = 0.187–0.246 vs rs = 0.369, respectively). CONCLUSIONS BNP molecular forms, notably BNP 5-32, showed association with poor prognosis at 6 months and 1 year in patients with acute HF. This is the first study reporting the prognostic ability of molecular BNP forms in HF patients and demonstrated comparable qualities to conventional BNP measurements.

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Exposing the High Heterogeneity of Circulating Pro B-Type Natriuretic Peptide Fragments in Healthy Individuals and Heart Failure Patients

Clinical Chemistry ◽

10.1093/clinchem/hvaa130 ◽

2020 ◽

Vol 66 (9) ◽

pp. 1200-1209 ◽

Cited By ~ 1

Author(s):

Benno Amplatz ◽

Bettina Sarg ◽

Klaus Faserl ◽

Angelika Hammerer-Lercher ◽

Johannes Mair ◽

...

Keyword(s):

Heart Failure ◽

Natriuretic Peptide ◽

Isotope Labeling ◽

High Resolution Mass Spectrometry ◽

Molecular Forms ◽

Peptide Fragments ◽

Naturally Occurring ◽

Current Thinking ◽

Processing Modes ◽

Molecular Complexity

Abstract Background The high molecular complexity of variably O-glycosylated and degraded pro B-type natriuretic peptide (proBNP) derived molecular forms challenges current immunoassays. Antibodies used show pronounced differences in cross-reactivities with these circulating fragments, which still need to be better characterized on a molecular level. To pave the way for advanced quantitative assays in the future, it is critical to fully understand these circulating forms. Methods Plasma samples were collected from 8 heart failure (HF) patients and 2 healthy controls. NT-proBNP and proBNP were purified by immunoprecipitation and analyzed by nano-flow liquid chromatography coupled to high-resolution mass spectrometry. Fragments formed during proteolysis in solution digestion were distinguished from naturally occurring peptides by using an 18O stable isotope labeling strategy. Results We detected 16 previously unknown circulating fragments of proBNP peptides (9 of which are located in the N-terminal and 7 in the C-terminal region), revealing a more advanced state of degradation than previously known. Two of these fragments are indicative of either unidentified processing modes or a far-reaching C-terminal degradation (or a combination thereof) of the precursor proBNP. Conclusions Our results further restrict ideal target epitopes for immunoassay antibodies and expand the current thinking of diversity, degradation, and processing of proBNP, as well as the distribution of circulating forms.

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Superiority of proatrial natriuretic peptide in the prognostic power in patients with acute decompensated heart failure on hospital admission: comparison with B-type natriuretic peptide and other natriuretic peptide forms

Open Heart ◽

10.1136/openhrt-2019-001072 ◽

2019 ◽

Vol 6 (2) ◽

pp. e001072

Author(s):

Seiji Takashio ◽

Hiroyuki Takahama ◽

Toshio Nishikimi ◽

Tomohiro Hayashi ◽

Chiaki Nagai-Okatani ◽

...

Keyword(s):

Heart Failure ◽

Adverse Events ◽

Hospital Admission ◽

Natriuretic Peptide ◽

Acute Decompensated Heart Failure ◽

Decompensated Heart Failure ◽

Left Ventricular ◽

Molecular Forms ◽

Lv Function ◽

Prognostic Power

AimsThere are significant differences in how atrial (A-type) and B-type natriuretic peptide (ANP and BNP) are secreted and metabolised, but there is little information available about the relative clinical significance of the two peptides. The aim of the present study was to investigate: (1) the association between the circulating level of each ANP molecular form and patient clinical background and (2) their prognostic power for patients with acute decompensated heart failure (ADHF).MethodsWe used specific chemiluminescence enzyme immunoassays to prospectively evaluate the levels of six bioactive molecular forms of ANP (pro-ANP, β-ANP and total ANP) and BNP (pro-BNP, N-terminal pro-BNP (NT-pro-BNP) and total BNP) in plasma samples collected from 173 patients with ADHF on their hospital admission.ResultsWe found that pro-ANP levels were strongly associated with left ventricular (LV) size and ejection fraction (p<0.001), but were not associated with left atrial size. Percent pro-ANP ([pro-ANP/total ANP]x100) was also associated with LV size and function. During the follow-up term (median: 469 days), composite adverse events (all causes of death or rehospitalisation for HF) occurred in 67 patients (38.7 %). Pro-ANP was significantly associated with composite adverse events even after adjusting by estimated glomerular filtration rate (eGFR) (p<0.05). In contrast, NT-pro-BNP was not independent of eGFR in the multivariate analysis.ConclusionCirculating levels of pro-ANP are strongly associated with LV function and clinical outcomes of patients with ADHF. These findings suggest that during the acute phases of HF, pro-ANP has a prognostic power comparable with NT-pro-BNP independently of renal function.

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