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.
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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 |
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