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Departments of
1
Clinical Biochemistry and
2
Cardiovascular Laboratory, Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark.
3 Department of Cardiology, Frederiksberg Hospital, DK-2000 Frederiksberg, Denmark.
aAddress correspondence to this author at: Department of Clinical Biochemistry, Rigshospitalet, 9 Blegdamsvej, DK-2100 Copenhagen, Denmark. Fax 45-35454640; e-mail JPG{at}dadlnet.dk.
Background: Measurement of cardiac natriuretic peptides or their precursors in plasma appears promising in the diagnosis of heart failure. However, the currently available assays to measure pro-B-type natriuretic peptide (proBNP)-derived peptides have produced grossly discrepant results.
Methods: We treated plasma with trypsin before assay and used in the assay an antibody specific for a processing-independent epitope of human proBNP. We then determined the total concentration of proBNP and its products in healthy volunteers and heart-failure patients.
Results: The antiserum produced (no. 98192) required an intact proBNP NH2 terminus for binding and displayed a high titer, index of heterogeneity, and binding affinity, implying that the RIA was monospecific and highly sensitive. Preanalytical tryptic treatment of plasma cleaved proBNP forms to release the N-terminal 1–21 fragment. Furthermore, enzymatic treatment of plasma also was efficient in avoiding nonspecific interference from plasma proteins, making it an expedient alternative to extraction. In healthy individuals, the total proBNP concentrations increased with age from 2.0 pmol/L (range, 0–15 pmol/L; ages 51–65 years) to 22 pmol/L (range, 3–40 pmol/L; ages 66–88 years; P <0.0001). The increase in plasma proBNP in the elderly, however, also seems to reflect the prevalence of cardiac disease. Plasma concentrations in patients with heart failure were all markedly increased [median, 89 pmol/L (range, 29–659) vs 1.0 pmol/L (range, 0–16) in age-matched controls; P <0.0001].
Conclusions: The processing-independent analysis measures the total proBNP product irrespective of the degree of proBNP processing. The results show that proBNP and its products circulate in low picomolar concentrations in healthy individuals.
The following articles in journals at HighWire Press have cited this article:
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  E. E. Niederkofler, U. A. Kiernan, J. O'Rear, S. Menon, S. Saghir, A. A. Protter, R. W. Nelson, and U. Schellenberger Detection of Endogenous B-Type Natriuretic Peptide at Very Low Concentrations in Patients With Heart Failure Circ Heart Fail, November 1, 2008; 1(4): 258 - 264. [Abstract] [Full Text] [PDF]
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 J. P. Goetze, U. Dahlstrom, J. F. Rehfeld, and U. Alehagen Impact of Epitope Specificity and Precursor Maturation in Pro-B-Type Natriuretic Peptide Measurement Clin. Chem., November 1, 2008; 54(11): 1780 - 1787. [Abstract] [Full Text] [PDF]
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 M. Damgaard, J. P. Goetze, P. Norsk, and N. Gadsboll Altered sodium intake affects plasma concentrations of BNP but not proBNP in healthy individuals and patients with compensated heart failure Eur. Heart J., November 2, 2007; 28(22): 2726 - 2731. [Abstract] [Full Text] [PDF]
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M. Nybo, M. Benn, R. Mogelvang, J. S. Jensen, P. Schnohr, J. F. Rehfeld, and J. P. Goetze Impact of Hemoglobin on Plasma Pro-B-Type Natriuretic Peptide Concentrations in the General Population Clin. Chem., November 1, 2007; 53(11): 1921 - 1927. [Abstract] [Full Text] [PDF]
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 R. Mogelvang, J. P. Goetze, P. Schnohr, P. Lange, P. Sogaard, J. F. Rehfeld, and J. S. Jensen Discriminating Between Cardiac and Pulmonary Dysfunction in the General Population With Dyspnea by Plasma Pro-B-Type Natriuretic Peptide J. Am. Coll. Cardiol., October 23, 2007; 50(17): 1694 - 1701. [Abstract] [Full Text] [PDF]
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T. Borglum, J. F. Rehfeld, L. B. Drivsholm, and L. Hilsted Processing-Independent Quantitation of Chromogranin A in Plasma from Patients with Neuroendocrine Tumors and Small-Cell Lung Carcinomas Clin. Chem., March 1, 2007; 53(3): 438 - 446. [Abstract] [Full Text] [PDF]
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J. P. Goetze, R. Mogelvang, L. Maage, H. Scharling, P. Schnohr, P. Sogaard, J. F. Rehfeld, and J. S. Jensen Plasma pro-B-type natriuretic peptide in the general population: screening for left ventricular hypertrophy and systolic dysfunction Eur. Heart J., December 2, 2006; 27(24): 3004 - 3010. [Abstract] [Full Text] [PDF]
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I. Giuliani, F. Rieunier, C. Larue, J.-F. Delagneau, C. Granier, B. Pau, M. Ferriere, M. Saussine, J.-P. Cristol, A.-M. Dupuy, et al. Assay for Measurement of Intact B-Type Natriuretic Peptide Prohormone in Blood Clin. Chem., June 1, 2006; 52(6): 1054 - 1061. [Abstract] [Full Text] [PDF]
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 M. Damgaard, P. Norsk, F. Gustafsson, J. K. Kanters, N. J. Christensen, P. Bie, L. Friberg, and N. Gadsboll Hemodynamic and neuroendocrine responses to changes in sodium intake in compensated heart failure Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2006; 290(5): R1294 - R1301. [Abstract] [Full Text] [PDF]
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K. G. Halse, M. L.S. Lindegaard, J. P. Goetze, P. Damm, E. R. Mathiesen, and L. B. Nielsen Increased Plasma Pro-B-Type Natriuretic Peptide in Infants of Women with Type 1 Diabetes Clin. Chem., December 1, 2005; 51(12): 2296 - 2302. [Abstract] [Full Text] [PDF]
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S. J. Nielsen, J. F. Rehfeld, F. Pedersen, J. Kastrup, R. Videbaek, and J. P. Goetze Measurement of Pro-C-Type Natriuretic Peptide in Plasma Clin. Chem., November 1, 2005; 51(11): 2173 - 2176. [Full Text] [PDF]
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A. Lev-Sagie, B. Bar-Oz, L. Salpeter, D. Hochner-Celnikier, I. Arad, and A. Nir Plasma Concentrations of N-Terminal Pro-B-Type Natriuretic Peptide in Pregnant Women near Labor and during Early Puerperium Clin. Chem., October 1, 2005; 51(10): 1909 - 1910. [Full Text] [PDF]
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S. Paterna, P. Di Pasquale, G. Parrinello, E. Fornaciari, F. Di Gaudio, S. Fasullo, M. Giammanco, F. M. Sarullo, and G. Licata Changes in Brain Natriuretic Peptide Levels and Bioelectrical Impedance Measurements After Treatment With High-Dose Furosemide and Hypertonic Saline Solution Versus High-Dose Furosemide Alone in Refractory Congestive Heart Failure: A Double-Blind Study J. Am. Coll. Cardiol., June 21, 2005; 45(12): 1997 - 2003. [Abstract] [Full Text] [PDF]
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F. S. Apple, M. Panteghini, J. Ravkilde, J. Mair, A. H.B. Wu, J. Tate, F. Pagani, R. H. Christenson, A. S. Jaffe, and on Behalf of the Committee on Standardization of M Quality Specifications for B-Type Natriuretic Peptide Assays Clin. Chem., March 1, 2005; 51(3): 486 - 493. [Abstract] [Full Text] [PDF]
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 J. P. Goetze, J. F. Rehfeld, R. Videbaek, L. Friis-Hansen, and J. Kastrup B-type natriuretic peptide and its precursor in cardiac venous blood from failing hearts Eur J Heart Fail, January 1, 2005; 7(1): 69 - 74. [Abstract] [Full Text] [PDF]
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M. Ala-Kopsala, J. Magga, K. Peuhkurinen, J. Leipala, H. Ruskoaho, J. Leppaluoto, and O. Vuolteenaho Molecular Heterogeneity Has a Major Impact on the Measurement of Circulating N-Terminal Fragments of A- and B-Type Natriuretic Peptides Clin. Chem., September 1, 2004; 50(9): 1576 - 1588. [Abstract] [Full Text] [PDF]
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J. P. Goetze Biochemistry of Pro-B-Type Natriuretic Peptide-Derived Peptides: The Endocrine Heart Revisited Clin. Chem., September 1, 2004; 50(9): 1503 - 1510. [Abstract] [Full Text] [PDF]
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J. P. Goetze, W. Yongzhong, J. F Rehfeld, E. Jorgensen, and J. Kastrup Coronary angiography transiently increases plasma pro-B-type natriuretic peptide Eur. Heart J., May 1, 2004; 25(9): 759 - 764. [Abstract] [Full Text] [PDF]
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C. Hall Essential biochemistry and physiology of (NT-pro)BNP Eur J Heart Fail, March 15, 2004; 6(3): 257 - 260. [Abstract] [Full Text] [PDF]
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S. A. Jortani, S. D. Prabhu, and R. Valdes Jr Strategies for Developing Biomarkers of Heart Failure Clin. Chem., February 1, 2004; 50(2): 265 - 278. [Abstract] [Full Text] [PDF]
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 W Jimenez and V Arroyo Origins of cardiac dysfunction in cirrhosis Gut, October 1, 2003; 52(10): 1392 - 1394. [Full Text] [PDF]
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J H Henriksen, J P Gotze, S Fuglsang, E Christensen, F Bendtsen, and S Moller Increased circulating pro-brain natriuretic peptide (proBNP) and brain natriuretic peptide (BNP) in patients with cirrhosis: relation to cardiovascular dysfunction and severity of disease Gut, October 1, 2003; 52(10): 1511 - 1517. [Abstract] [Full Text] [PDF]
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M. Rauh and A. Koch Plasma N-Terminal Pro-B-Type Natriuretic Peptide Concentrations in a Control Population of Infants and Children Clin. Chem., September 1, 2003; 49(9): 1563 - 1564. [Full Text] [PDF]
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J. P. Goetze, J. Kastrup, and J. F Rehfeld The paradox of increased natriuretic hormones in congestive heart failure patients: Does the endocrine heart also fail in heart failure? Eur. Heart J., August 2, 2003; 24(16): 1471 - 1472. [Full Text] [PDF]
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U. Alehagen, G. Lindstedt, H. Eriksson, and U. Dahlstrom Utility of the Amino-Terminal Fragment of Pro-Brain Natriuretic Peptide in Plasma for the Evaluation of Cardiac Dysfunction in Elderly Patients in Primary Health Care Clin. Chem., August 1, 2003; 49(8): 1337 - 1346. [Abstract] [Full Text] [PDF]
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O. W. Nielsen, T. A. McDonagh, S. D. Robb, and H. J. Dargie Retrospective analysis of thecost-effectiveness of using plasmabrain natriuretic peptide inscreening for left ventricularsystolic dysfunction in the general population J. Am. Coll. Cardiol., January 1, 2003; 41(1): 113 - 120. [Abstract] [Full Text] [PDF]
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J. Mair Role of Cardiac Natriuretic Peptide Testing in Heart Failure Clin. Chem., July 1, 2002; 48(7): 977 - 978. [Full Text] [PDF]
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