CLINICAL RESEARCH: HEART FAILURE AND BNP
Evidence for Functional Heterogeneity of Circulating B-Type Natriuretic Peptide
Faquan Liang, MD, PhD*,
Jessica O’Rear*,
Ute Schellenberger, PhD*,
Lungkuo Tai, PhD*,
Michael Lasecki*,
George F. Schreiner, MD, PhD*,
Fred S. Apple, PhD ,
Alan S. Maisel, MD ,
N. Stephen Pollitt, PhD* and
Andrew A. Protter, PhD*,*
* Scios, Inc., Fremont, California
Hennepin County Medical Center and University of Minnesota School of Medicine, Minneapolis, Minnesota
Veteran’s Affairs Medical Center, San Diego, California.
Manuscript received March 14, 2006;
revised manuscript received October 5, 2006,
accepted October 10, 2006.
* Reprint requests and correspondence: Dr. Andrew A. Protter, Scios, Inc., 6500 Paseo Padre Parkway, Fremont, California 94555. (Email: andyprotter{at}mac.com).
Objectives: These studies describe molecular forms of circulating B-type natriuretic peptide (BNP) as well as their biological activity.
Background: Increased circulating levels of immunoreactive BNP correlate with the severity of heart failure and are considered a sensitive biomarker. However, little is known about the molecular forms of circulating BNP and their biological activity.
Methods: Western blot analysis was used to characterize immunoreactive BNP species in heart failure plasma. Recombinant proBNP was assessed for reactivity in commercially available BNP assays and cell activity by cyclic guanosine monophosphate production in vascular cells.
Results: Heart failure plasma contained both low- (LMW-BNP) and high-molecular-weight (HMW-BNP) forms. The LMW-BNP migrated similarly to a 32-amino acid BNP standard, whereas HMW-BNP, when deglycosylated, was similar to deglycosylated recombinant proBNP. Recombinant proBNP and BNP were equally recognized by the Triage BNP assay (Biosite, San Diego, California). Furthermore, recombinant proBNP and BNP were both recognized by the Advia Centaur BNP test (Bayer Diagnostics, Tarrytown, New York), but only recombinant proBNP was recognized by the Elecsys NTproBNP assay (Roche Diagnostics, Indianapolis, Indiana). Recombinant proBNP exerted significantly less biological activity than BNP on human endothelial and vascular smooth muscle cells. Comparison of effective concentration (50%) values indicates that proBNP is 6- to 8-fold less potent than BNP in these human cells.
Conclusions: This study demonstrates that proBNP, constituting a substantial portion of immunoreactive BNP in heart failure plasma, possesses significantly lower biological activity than the processed 32-amino acid hormone. These results implicate a discordance in heart failure between the high circulating levels of immunoreactive BNP and hormone activity, suggesting that some patients may be in a state of natriuretic peptide deficiency.
|
Abbreviations and Acronyms
| | BNP = B-type natriuretic peptide | | cGMP = cyclic guanosine monophosphate | | CHO = Chinese hamster ovary | | EC50 = effective concentration (50%) | | HF = heart failure | | HMW = high molecular weight | | NPRA = natriuretic peptide receptor A |
|
Related Article
-
Heart Failure: A State of Brain Natriuretic Peptide Deficiency or Resistance or Both!
- Horng H. Chen
J. Am. Coll. Cardiol. 2007 49: 1089-1091.
[Full Text]
[PDF]
This article has been cited by other articles:
|
|
|
|
 
H. Rosjo and T. Omland
Glycosylated natriuretic peptides: the cardiologist's new sweetheart?
Heart,
January 15, 2012;
98(2):
95 - 96.
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Nishikimi, M. Ikeda, Y. Takeda, T. Ishimitsu, I. Shibasaki, H. Fukuda, H. Kinoshita, Y. Nakagawa, K. Kuwahara, and K. Nakao
The effect of glycosylation on plasma N-terminal proBNP-76 levels in patients with heart or renal failure
Heart,
January 15, 2012;
98(2):
152 - 161.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. P. Goetze
B-Type Natriuretic Peptide: From Posttranslational Processing to Clinical Measurement
Clin. Chem.,
January 1, 2012;
58(1):
83 - 91.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. M. Dickey and L. R. Potter
ProBNP1-108 Is Resistant to Degradation and Activates Guanylyl Cyclase-A with Reduced Potency
Clin. Chem.,
September 1, 2011;
57(9):
1272 - 1278.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Clerico, A. Giannoni, S. Vittorini, and C. Passino
Thirty years of the heart as an endocrine organ: physiological role and clinical utility of cardiac natriuretic hormones
Am J Physiol Heart Circ Physiol,
July 1, 2011;
301(1):
H12 - H20.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. G. Semenov, K. R. Seferian, N. N. Tamm, M. M. Artem'eva, A. B. Postnikov, A. V. Bereznikova, A. N. Kara, N. A. Medvedeva, and A. G. Katrukha
Human Pro-B-Type Natriuretic Peptide Is Processed in the Circulation in a Rat Model
Clin. Chem.,
June 1, 2011;
57(6):
883 - 890.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. M. Tonne, J. M. Campbell, A. Cataliotti, S. Ohmine, T. Thatava, T. Sakuma, F. Macheret, B. K. Huntley, J. C. Burnett Jr, and Y. Ikeda
Secretion of Glycosylated Pro-B-Type Natriuretic Peptide from Normal Cardiomyocytes
Clin. Chem.,
June 1, 2011;
57(6):
864 - 873.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. L. Miller, M. A. Phelps, C. M. Wood, U. Schellenberger, A. Van Le, R. Perichon, and A. S. Jaffe
Comparison of Mass Spectrometry and Clinical Assay Measurements of Circulating Fragments of B-Type Natriuretic Peptide in Patients With Chronic Heart Failure
Circ Heart Fail,
May 1, 2011;
4(3):
355 - 360.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Macheret, G. Boerrigter, P. McKie, L. Costello-Boerrigter, B. Lahr, D. Heublein, S. Sandberg, Y. Ikeda, A. Cataliotti, K. Bailey, et al.
Pro-B-Type Natriuretic Peptide1-108 Circulates in the General Community: Plasma Determinants and Detection of Left Ventricular Dysfunction
J. Am. Coll. Cardiol.,
March 22, 2011;
57(12):
1386 - 1395.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Emdin, C. Passino, and A. Clerico
Natriuretic Peptide Assays Revisited: Do We Need Pro-B-Type Natriuretic Peptide?
J. Am. Coll. Cardiol.,
March 22, 2011;
57(12):
1396 - 1398.
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. L. Dries
Process Matters: Emerging Concepts Underlying Impaired Natriuretic Peptide System Function in Heart Failure
Circ Heart Fail,
March 1, 2011;
4(2):
107 - 110.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. S. Maisel, N. Katz, H. L. Hillege, A. Shaw, P. Zanco, R. Bellomo, I. Anand, S. D. Anker, N. Aspromonte, S. M. Bagshaw, et al.
Biomarkers in kidney and heart disease
Nephrol. Dial. Transplant.,
January 1, 2011;
26(1):
62 - 74.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Ichiki, B. K. Huntley, D. M. Heublein, S. M. Sandberg, P. M. McKie, F. L. Martin, M. Jougasaki, and J. C. Burnett Jr.
Corin Is Present in the Normal Human Heart, Kidney, and Blood, with Pro-B-Type Natriuretic Peptide Processing in the Circulation
Clin. Chem.,
January 1, 2011;
57(1):
40 - 47.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Chen, S. Sen, D. Young, W. Wang, C. S. Moravec, and Q. Wu
Protease corin expression and activity in failing hearts
Am J Physiol Heart Circ Physiol,
November 1, 2010;
299(5):
H1687 - H1692.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. T. Maeder, J. A. Mariani, and D. M. Kaye
Hemodynamic Determinants of Myocardial B-Type Natriuretic Peptide Release: Relative Contributions of Systolic and Diastolic Wall Stress
Hypertension,
October 1, 2010;
56(4):
682 - 689.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Ichiki and J. C. Burnett Jr
A New Signal From B-Type Natriuretic Peptide in ST-Elevation Myocardial Infarction: What Does It Mean for B-Type Natriuretic Peptide and Innovative Diagnostics?
Circulation,
July 20, 2010;
122(3):
229 - 232.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. G. Semenov, N. N. Tamm, K. R. Seferian, A. B. Postnikov, N. S. Karpova, D. V. Serebryanaya, E. V. Koshkina, M. I. Krasnoselsky, and A. G. Katrukha
Processing of Pro-B-Type Natriuretic Peptide: Furin and Corin as Candidate Convertases
Clin. Chem.,
July 1, 2010;
56(7):
1166 - 1176.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Dong, S. Chen, J. Yang, L. He, P. Liu, D. Zheng, L. Li, Y. Zhou, C. Ruan, E. Plow, et al.
Plasma Soluble Corin in Patients With Heart Failure
Circ Heart Fail,
March 1, 2010;
3(2):
207 - 211.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. L. Dries, B. Ky, A. H. B. Wu, J. E. Rame, M. E. Putt, and T. P. Cappola
Simultaneous Assessment of Unprocessed ProBNP1-108 in Addition to Processed BNP32 Improves Identification of High-Risk Ambulatory Patients With Heart Failure
Circ Heart Fail,
March 1, 2010;
3(2):
220 - 227.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. O. Xu-Cai and Q. Wu
Molecular forms of natriuretic peptides in heart failure and their implications
Heart,
March 1, 2010;
96(6):
419 - 424.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Nishikimi, N. Minamino, M. Ikeda, Y. Takeda, K. Tadokoro, I. Shibasaki, H. Fukuda, Y. Horiuchi, S. Oikawa, T. Ieiri, et al.
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,
March 1, 2010;
96(6):
432 - 439.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. E. Rame, S. W. Tam, D. McNamara, M. Worcel, M. L. Sabolinski, A. H. Wu, and D. L. Dries
Dysfunctional Corin I555(P568) Allele Is Associated With Impaired Brain Natriuretic Peptide Processing and Adverse Outcomes in Blacks With Systolic Heart Failure: Results From the Genetic Risk Assessment in Heart Failure Substudy
Circ Heart Fail,
November 1, 2009;
2(6):
541 - 548.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Moertl, R. Berger, J. Struck, A. Gleiss, A. Hammer, N. G. Morgenthaler, A. Bergmann, M. Huelsmann, and R. Pacher
Comparison of Midregional Pro-Atrial and B-Type Natriuretic Peptides in Chronic Heart Failure: Influencing Factors, Detection of Left Ventricular Systolic Dysfunction, and Prediction of Death
J. Am. Coll. Cardiol.,
May 12, 2009;
53(19):
1783 - 1790.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Mair
Clinical Significance of Pro-B-Type Natriuretic Peptide Glycosylation and Processing
Clin. Chem.,
March 1, 2009;
55(3):
394 - 397.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. G. Semenov, A. B. Postnikov, N. N. Tamm, K. R. Seferian, N. S. Karpova, M. N. Bloshchitsyna, E. V. Koshkina, M. I. Krasnoselsky, D. V. Serebryanaya, and A. G. Katrukha
Processing of Pro-Brain Natriuretic Peptide Is Suppressed by O-Glycosylation in the Region Close to the Cleavage Site
Clin. Chem.,
March 1, 2009;
55(3):
489 - 498.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Lourenco, J. P. Araujo, A. Azevedo, A. Ferreira, and P. Bettencourt
The cyclic guanosine monophosphate/B-type natriuretic peptide ratio and mortality in advanced heart failure
Eur J Heart Fail,
February 1, 2009;
11(2):
185 - 190.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. L. Miller, K. A. Hartman, D. E. Grill, J. C. Burnett Jr, and A. S. Jaffe
Only Large Reductions in Concentrations of Natriuretic Peptides (BNP and NT-proBNP) Are Associated with Improved Outcome in Ambulatory Patients with Chronic Heart Failure
Clin. Chem.,
January 1, 2009;
55(1):
78 - 84.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Ronco, M. Haapio, A. A. House, N. Anavekar, and R. Bellomo
Cardiorenal Syndrome
J. Am. Coll. Cardiol.,
November 4, 2008;
52(19):
1527 - 1539.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
P. Ray, S. Delerme, P. Jourdain, and C. Chenevier-Gobeaux
Differential diagnosis of acute dyspnea: the value of B natriuretic peptides in the emergency department
QJM,
November 1, 2008;
101(11):
831 - 843.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
A. Cataliotti, H. H. Chen, J. A. Schirger, F. L. Martin, G. Boerrigter, L. C. Costello-Boerrigter, K. D. James, K. Polowy, M. A. Miller, N. B. Malkar, et al.
Chronic Actions of a Novel Oral B-Type Natriuretic Peptide Conjugate in Normal Dogs and Acute Actions in Angiotensin II-Mediated Hypertension
Circulation,
October 21, 2008;
118(17):
1729 - 1736.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. N. Tamm, K. R. Seferian, A. G. Semenov, K. S. Mukharyamova, E. V. Koshkina, M. I. Krasnoselsky, A. B. Postnikov, D. V. Serebryanaya, F. S. Apple, M. M. Murakami, et al.
Novel Immunoassay for Quantification of Brain Natriuretic Peptide and Its Precursor in Human Blood
Clin. Chem.,
September 1, 2008;
54(9):
1511 - 1518.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. S. Jaffe
Key Issues in the Developing Synergism between Cardiovascular Imaging and Biomarkers
Clin. Chem.,
September 1, 2008;
54(9):
1432 - 1442.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. M. Mills
Learning to Use a Biomarker: More About B-Type Natriuretic Peptide
J. Am. Coll. Cardiol.,
June 17, 2008;
51(24):
2336 - 2338.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. W. Waldo, J. Beede, S. Isakson, S. Villard-Saussine, J. Fareh, P. Clopton, R. L. Fitzgerald, and A. S. Maisel
Pro-B-Type Natriuretic Peptide Levels in Acute Decompensated Heart Failure
J. Am. Coll. Cardiol.,
May 13, 2008;
51(19):
1874 - 1882.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. C. Burnett Jr and J. Korinek
The Tumultuous Journey of Nesiritide: Past, Present, and Future
Circ Heart Fail,
May 1, 2008;
1(1):
6 - 8.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. M. Hawkridge, D. C. Muddiman, D. M. Hebulein, A. Cataliotti, and J. C. Burnett Jr.
Effect of Plasma Protein Depletion on BNP-32 Recovery
Clin. Chem.,
May 1, 2008;
54(5):
933 - 934.
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. N. Luckenbill, R. H. Christenson, A. S. Jaffe, J. Mair, J. Ordonez-Llanos, F. Pagani, J. Tate, A. H. B. Wu, R. Ler, and F. S. Apple
Cross-Reactivity of BNP, NT-proBNP, and proBNP in Commercial BNP and NT-proBNP Assays: Preliminary Observations from the IFCC Committee for Standardization of Markers of Cardiac Damage
Clin. Chem.,
March 1, 2008;
54(3):
619 - 621.
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. B. Daniels and A. S. Maisel
Natriuretic Peptides
J. Am. Coll. Cardiol.,
December 18, 2007;
50(25):
2357 - 2368.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W.H. W. Tang and G. S. Francis
The Year in Heart Failure
J. Am. Coll. Cardiol.,
December 11, 2007;
50(24):
2344 - 2351.
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
D. Heublein, B. Huntley, G. Boerrigter, A. Cataliotti, S. Sandberg, M. Redfield, and J. C. Burnett Jr
Response to Do Commercially Available Assay Kits for B-Type Natriuretic Peptide Measure Pro-BNP1-108, as Well as BNP1-32?
Hypertension,
November 1, 2007;
50(5):
e164 - e164.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Maisel
Biomarkers in Heart Failure: Does Prognostic Utility Translate to Clinical Futility?
J. Am. Coll. Cardiol.,
September 11, 2007;
50(11):
1061 - 1063.
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. S. Apple, A. H.B. Wu, A. S. Jaffe, M. Panteghini, R. H. Christenson, NACB COMMITTEE MEMBERS, R. H. Christenson, F. S. Apple, C. P. Cannon, G. Francis, et al.
National Academy of Clinical Biochemistry and IFCC Committee for Standardization of Markers of Cardiac Damage Laboratory Medicine Practice Guidelines: Analytical Issues for Biomarkers of Heart Failure
Circulation,
July 31, 2007;
116(5):
e95 - e98.
[Full Text]
[PDF]
|
|
|
|
|
|
|
W.H. Wilson Tang, G. S. Francis, D. A. Morrow, L. K. Newby, C. P. Cannon, R. L. Jesse, A. B. Storrow, R. H. Christenson, COMMITTEE MEMBERS, R. H. Christenson, et al.
National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Clinical Utilization of Cardiac Biomarker Testing in Heart Failure
Circulation,
July 31, 2007;
116(5):
e99 - e109.
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. H. Chen
Heart Failure: A State of Brain Natriuretic Peptide Deficiency or Resistance or Both!
J. Am. Coll. Cardiol.,
March 13, 2007;
49(10):
1089 - 1091.
[Full Text]
[PDF]
|
|
|
|
