EDITORIAL COMMENT
Learning to Use a BiomarkerMore About B-Type Natriuretic Peptide*
Roger M. Mills, MD, FACC*,1
Scios Inc., Mountain View, California.
* Reprint requests and correspondence: Dr. Roger M. Mills, Medical Affairs, Scios Inc., 1900 Charleston Road, Mountain View, California 94043. (Email: rmills{at}scius.jnj.com).
"Human beings, who are almost unique in having the ability to learn from the experience of others, are also remarkable for their apparent disinclination to do so." Douglas Adams, Last Chance to See (1)
Learning to interpret immunoreactive B-type natriuretic peptide (iBNP) levels in heart failure can be compared to putting together a jigsaw puzzle. The report from Nishii et al. (2) in this issue of the Journal gives us an important new piece. The authors report a single-center observational study of 83 Japanese patients with dilated cardiomyopathy who remained clinically stable for at least 6 months after an episode of decompensated heart failure. They followed the subjects for another 18 months or until death or readmission. In this highly selected population, the B-type natriuretic peptide (BNP) level at 6 months post-discharge was a strong predictor of subsequent outcomes, with a cut-point of 190 pg/ml separating those with improved left ventricular systolic function and a low rate of readmission from those who were subsequently rehospitalized for heart failure. Since the biomarker puzzle is coming together so rapidly, and with so many investigators contributing, a brief overview of our current understanding of BNP and the data supporting its importance as a cardiac biomarker should help to place these new findings in context.
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Brief Review of BNP
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Short-term regulation of total body salt and water balance requires the coordinated interaction of brain, heart, blood vessels, and kidneys to set dietary intake and renal excretion of salt and water within parameters that maintain cardiac filling pressures and organ perfusion. The renin-angiotensin-aldosterone-sympathetic axis and the natriuretic peptide system serve to respectively promote or inhibit salt and water retention. For animals in an aqueous environment, both systems are important. In contrast, in land-dwelling mammals, the renin-angiotensin-aldosterone-sympathetic axis system is strikingly physiologically dominant. Although by 1981, the work of DeBold et al. (3) clearly pointed to the existence of natriuretic hormones, the structure of BNP was not defined until 1988 (4); our understanding of natriuretic peptides has progressed dramatically since.
Under normal conditions, myocyte stretch constitutes the primary stimulus for natriuretic peptide release (5). Recent data suggest that the mechanisms for processing the large natriuretic peptide prohormone, proBNP, to the small active 32-amino-acid molecule BNP may be overwhelmed by the sustained pressure-volume overload of chronic heart failure. Both Western blot (6) and sophisticated mass spectroscopy studies (7) (Ute Schellenberger, personal communication, September 2007) confirm that proBNP and other related large molecules, which have little or no physiologic activity, make up a large amount of the substances measured by commercially available immunoassays for BNP in clinical heart failure patients. Nonetheless, ample clinical data confirm that measurement of iBNP provides an extraordinarily useful biomarker of cardiac stress.
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Biomarker Data in Heart Failure
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As individuals progress from asymptomatic good health to highly symptomatic heart failure, the threshold level for iBNP levels associated with increased risk rises. In the Framingham Offspring study, Wang et al. (8) studied 3,346 subjects without heart failure. B-type natriuretic peptide levels above the 80th percentile values of 20.0 pg/ml for men and 23.3 pg/ml for women "were associated with multivariable-adjusted hazard ratios of 1.62 for death (p = 0.02), 1.76 for a first major cardiovascular event (p = 0.03), 1.91 for atrial fibrillation (p = 0.02), 1.99 for stroke or transient ischemic attack (p = 0.02), and 3.07 for heart failure (p = 0.002)" (8).
In the BNP (Breathing Not Properly) multinational study, Maisel et al. (9) studied 1,586 adult patients with dyspnea. Using a receiver-operator characteristic curve analysis, they reported, "A B-type natriuretic peptide cutoff value of 100 pg/ml had a sensitivity of 90%, a specificity of 76%, and an accuracy of 83% for differentiating congestive heart failure from other causes of dyspnea" (9).
Fonarow et al. (10) and the ADHERE (Acute Decompensated Heart Failure National Registry) investigators retrospectively analyzed admission BNP levels and subsequent mortality in 48,629 patients. "Quartiles (Q) of BNP were Q1 (<430 pg/ml), Q2 (430 to 839 pg/ml), Q3 (840 to 1,729 pg/ml), and Q4 ( 1,730 pg/ml)." "There was a near-linear relationship between BNP and in-hospital mortality: Q1 (1.9%), Q2 (2.8%), Q3 (3.8%), and Q4 (6.0%), p < 0.0001" (10).
After inpatient therapy for an episode of acute heart failure, iBNP cutoff values for increased risk fall again. Logeart et al. (11) studied 223 subjects in a derivation/validation study. The pre-discharge iBNP level was the best predictor of subsequent death or readmission. "Using the predischarge BNP level (as a continuous variable and after adjustment for covariables), similar results were obtained for: 1) death or re-admission at 1 month (hazard ratio 1.17 [1.06 to 1.28], p = 0.002); and 2) re-admission at 6 months (hazard ratio 1.25 [1.16 to 1.34], p < 0.001) ... a BNP level of 350 ng/l was found to have the best compromise between sensitivity and specificity for predicting death or re-admission at 6 months" (11).
The STARS (Plasma Brain Natriuretic Peptide Guided Therapy to Improve Outcome in Heart Failure) investigators (12) enrolled 220 subjects at least 1 month after hospitalization with symptomatic heart failure in a trial of BNP-guided versus clinical management. They found "In the BNP group, mean plasma BNP levels significantly decreased during follow-up from 352 ± 260 pg/ml at baseline to 284 ± 180 pg/ml at 3-month follow-up (p = 0.03)" (12). This was "associated with a lower risk of death related to heart failure or hospital stay related to heart failure than the usual strategy based on clinical expertise" (12).
Now, Nishii et al. (2) have added yet another piece of data, from stable nonischemic patients at 6 months after discharge, showing 190 pg/ml as a risk cutoff. These subjects represent an extremely low-risk group. They had relatively low iBNP levels at discharge from hospital and were stable for 6 months in New York Heart Association functional class I to II on oral therapy. Even in this low-risk group, relatively higher versus relatively lower iBNP levels effectively differentiated patients at increased subsequent risk.
The broad outlines of a picture have emerged, as shown in Figure 1. "Cutoff values" for a high-risk BNP level in the general population, in those at risk for heart failure, or recognized heart failure patients vary across a wide spectrum of values depending on clinical context. Skeptics will decry this as too confusing. Proponents will point out the marvelous range of utility that iBNP offers, including long-term risk assessment, emergency diagnosis, short-term and longer-term prognosis, and objectively guided therapy. Using iBNP data as a tool, however, requires making the effort to understand it.
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Figure 1 Biomarker Data in HF
Cutpoints for immunoreactive B-type natriuretic peptide (iBNP) levels associated with increased risk, progressing from asymptomatic individuals to dyspneic patients, then to admission, discharge, 1 month post-discharge, and 6 months post-discharge. ACC/AHA = American College of Cardiology/American Heart Association; ADHF = acute decompensated heart failure; HF = heart failure; NYHA = New York Heart Association.
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For clinician-investigators, the more important question remains unanswered. Now that we can identify patients at increased risk across a wide spectrum of cardiovascular disease, can we intervene with drugs, devices, or improved care strategies, or all of these, to effectively change the dismal natural history of the heart failure syndrome? With a better understanding of iBNP, we have a new tool in hand to plan better heart failure treatment trials; the challenge now is to skillfully execute them.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
1 The author is a full-time employee of Scios Inc.
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References
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1. Adams D, Carwardine M. Last Chance to SeeNew York, NY: Harmony Books; 1991.2. Nishii M, Inomata T, Takehana H, et al. Prognostic utility of B-type natriuretic peptide assessment in stable low-risk outpatients with nonischemic cardiomyopathy after decompensated heart failure J Am Coll Cardiol 2008;51:2329-2335.[Abstract/Free Full Text] 3. DeBold AJ, Borenstein HB, Veress AT, et al. A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats Life Sci 1981;28:89-94.[CrossRef][Web of Science][Medline] 4. Sudoh T, Kangawa K, Minamino N, Matsuo H. A new natriuretic peptide in porcine brain Nature 1988;332:78-81.[CrossRef][Medline] 5. Ramos H, DeBold AJ. Gene expression, processing, and secretion of natriuretic peptides: physiologic and diagnostic implications Heart Failure Clinics 2006;2:255-268.[CrossRef][Medline] 6. Liang F, O'Rear J, Schellenberger U, et al. Evidence for functional heterogeneity of circulating B-type natriuretic peptide J Am Coll Cardiol 2007;49:1071-1078.[Abstract/Free Full Text] 7. Hawkridge AM, Heublein DM, Berger 3rd HR, Cataliotti A, Burnett Jr JC. Quantitative mass spectral evidence for the absence of circulating brain natriuretic peptide (BNP-32) in severe human heart failure Proc Natl Acad Sci U S A 2005;102:17442-17447.[Abstract/Free Full Text] 8. Wang TJ, Larson MG, Levy D, et al. Plasma natriuretic peptide levels and the risk of cardiovascular events and death N Engl J Med 2004;350:655-663.[Abstract/Free Full Text] 9. Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure N Engl J Med 2002;347:161-167.[Abstract/Free Full Text] 10. Fonarow GC, Peacock WF, Phillips CO, et al. Admission B-type natriuretic peptide levels and in-hospital mortality in acute decompensated heart failure J Am Coll Cardiol 2007;49:1943-1950.[Abstract/Free Full Text] 11. Logeart D, Thabut G, Jourdain P, et al. Predischarge B-type natriuretic peptide assay for identifying patients at high risk of re-admission after decompensated heart failure J Am Coll Cardiol 2004;43:635-641.[Abstract/Free Full Text] 12. Jourdain P, Jondeau G, Funck F, et al. Plasma brain natriuretic peptide guided therapy to improve outcome in heart failure: the STARS-BNP multicenter study J Am Coll Cardiol 2007;49:1733-1739.[Abstract/Free Full Text]
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