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Proteomics and Protein Markers |
Departments of1
Physiology and 2
Pharmacology and Toxicology, Biocenter Oulu, University of Oulu, Oulu, Finland.
3 Department of Internal Medicine, Kuopio University Hospital, Kuopio, Finland.
4 Department of Pediatrics, Helsinki University Hospital, Helsinki, Finland.
aAddress correspondence to this author at: Department of Physiology, Faculty of Medicine, PO Box 5000, University of Oulu, Oulu, FIN-90014 Finland. Fax 358-8-5375320; e-mail olli.vuolteenaho{at}oulu.fi.
Background: The N-terminal fragments of A- and B-type natriuretic peptides (NT-proANP and NT-proBNP) are powerful markers of cardiac function. The current assays require refinement with regard to standardization with native calibrators and the ability to detect the actual circulating forms.
Methods: The following peptides were prepared with recombinant methods: NT-proANP, NT-proBNP, proBNP1–108, and Tyr0-proBNP77–108. Fifteen peptides of 13–22 amino acids, spanning the sequences of NT-proANP and NT-proBNP, were prepared by solid-phase peptide synthesis. Two immunoassays for NT-proANP and four for NT-proBNP were set up, each with a different epitope specificity. The assays were applied for the measurement of NT-proANP and NT-proBNP in healthy individuals and in patients with acute myocardial infarction. The circulating molecular forms were analyzed by gel-filtration and reversed-phase HPLC.
Results: According to the HPLC analyses, circulating NT-proANP consists mainly of the full-length peptide, with some degradation at both ends. In contrast, circulating NT-proBNP is very heterogeneous. Most immunoreactive NT-proBNP is significantly smaller in size than NT-proBNP1–76, with truncation at both termini. The smallest fragments can be detected by assays directed at the central part of NT-proBNP only; assays directed at the ends gave 30–40% lower values. Despite the difference, the various assays correlated reasonably well with each other (r2 = 0.77–0.85). In patients with acute myocardial infarction, NT-proANP and NT-proBNP concentrations were 1.8–2.3 and 4.2–4.5 times higher than in healthy individuals. The development of heart failure further increased the concentrations.
Conclusions: Molecular heterogeneity of the circulating forms causes a serious risk of preanalytical errors in assays for NT-proBNP and, to a lesser extent, NT-proANP. The development of a sandwich assay for NT-proBNP would be especially challenging. The most robust and reliable assays use antibodies directed at the central portions of NT-proANP or NT-proBNP.
The following articles in journals at HighWire Press have cited this article:
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  S. Q. Khan, O. Dhillon, D. Kelly, I. B. Squire, J. Struck, P. Quinn, N. G. Morgenthaler, A. Bergmann, J. E. Davies, and L. L. Ng Plasma N-Terminal B-Type Natriuretic Peptide as an Indicator of Long-Term Survival After Acute Myocardial Infarction: Comparison With Plasma Midregional Pro-Atrial Natriuretic Peptide: The LAMP (Leicester Acute Myocardial Infarction Peptide) Study J. Am. Coll. Cardiol., May 13, 2008; 51(19): 1857 - 1864. [Abstract] [Full Text] [PDF]
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 M G Nicholls, C M Frampton, and T G Yandle BNP: not just for heart failure Heart, January 1, 2008; 94(1): 6 - 7. [Full Text] [PDF]
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 J. J. Ronkainen, O. Vuolteenaho, and P. Tavi Calcium-Calmodulin Kinase II Is the Common Factor in Calcium-Dependent Cardiac Expression and Secretion of A- and B-Type Natriuretic Peptides Endocrinology, June 1, 2007; 148(6): 2815 - 2820. [Abstract] [Full Text] [PDF]
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 V.-P. Ronkainen, J. J. Ronkainen, S. L. Hanninen, H. Leskinen, J. L. Ruas, T. Pereira, L. Poellinger, O. Vuolteenaho, and P. Tavi Hypoxia inducible factor regulates the cardiac expression and secretion of apelin FASEB J, June 1, 2007; 21(8): 1821 - 1830. [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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 P. Belluardo, A. Cataliotti, L. Bonaiuto, E. Giuffre, E. Maugeri, P. Noto, G. Orlando, G. Raspa, B. Piazza, L. Babuin, et al. Lack of activation of molecular forms of the BNP system in human grade 1 hypertension and relationship to cardiac hypertrophy Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1529 - H1535. [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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J. A. Laukkanen, S. Kurl, M. Ala-Kopsala, O. Vuolteenaho, H. Ruskoaho, K. Nyyssonen, and J. T. Salonen Plasma N-terminal fragments of natriuretic propeptides predict the risk of cardiovascular events and mortality in middle-aged men Eur. Heart J., May 2, 2006; 27(10): 1230 - 1237. [Abstract] [Full Text] [PDF]
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A. Gegenhuber, J. Struck, W. Poelz, R. Pacher, N. G. Morgenthaler, A. Bergmann, M. Haltmayer, and T. Mueller Midregional Pro-A-Type Natriuretic Peptide Measurements for Diagnosis of Acute Destabilized Heart Failure in Short-of-Breath Patients: Comparison with B-Type Natriuretic Peptide (BNP) and Amino-Terminal proBNP Clin. Chem., May 1, 2006; 52(5): 827 - 831. [Abstract] [Full Text] [PDF]
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 A. M. Hawkridge, D. M. Heublein, H. R. Bergen III, A. Cataliotti, J. C. Burnett Jr., and D. C. Muddiman Quantitative mass spectral evidence for the absence of circulating brain natriuretic peptide (BNP-32) in severe human heart failure PNAS, November 29, 2005; 102(48): 17442 - 17447. [Abstract] [Full Text] [PDF]
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D. L. Crimmins Human N-Terminal proBNP Is a Monomer Clin. Chem., June 1, 2005; 51(6): 1035 - 1038. [Full Text] [PDF]
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M. Ala-Kopsala, H. Ruskoaho, J. Leppaluoto, L. Seres, R. Skoumal, M. Toth, F. Horkay, and O. Vuolteenaho Single Assay for Amino-Terminal Fragments of Cardiac A- and B-Type Natriuretic Peptides Clin. Chem., April 1, 2005; 51(4): 708 - 718. [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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