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B-Type Natriuretic Peptide: The Level and the Drug— Partners in the Diagnosis and Management of Congestive Heart Failure Over the past 100 years, cardiovascular disease has become a leading cause of morbidity and mortality worldwide. A tremendous increase in incidence and prevalence of heart failure has been observed in the United States. The cost of managing heart failure itself is $56 billion a year, 70% of which is due to hospitalization. Although we have made tremendous advances in our understanding of the pathophysiology and treatment of congestive heart failure, the diagnosis of the disease still remains difficult. Unfortunately, the signs and symptoms of congestive heart failure are nonspecific. The recognition of the role of B-type natriuretic peptide as an objective marker for the diagnosis, severity, and prognosis of acute coronary syndromes and congestive heart failure was truly a breakthrough for clinicians and patients faced with cardiovascular disease. Also, the high levels of endogenous B-type natriuretic peptide may be released as a “distress hormone”; that is, these levels are no longer effective in maintaining the balance of vasoconstriction and vasodilation. Hence it makes intuitive and practical sense that giving back B-type natriuretic peptide in the form of exogenous nesiritide might restore neurohormonal homeostasis. Therefore, lately there has been a lot of interest shown in the use of recombinant B-type natriuretic peptide as a drug. This article reviews the literature concerning the use of these peptides in a variety of clinical scenarios and the use of recombinant B-type natriuretic peptide in decompensated heart failure. (CHF. 2004;10(1 suppl 1):3–27) 2004 CHF, Inc. ©

O

ver the past 100 years, cardiovascular disease (CVD) has become a leading cause of morbidity and mortality worldwide. At the beginning of the last century, CVD accounted for less than 10% of all deaths worldwide. Due to the drastic increase in CVD risk factors such as obesity and diabetes and the use of disease-modifying agents like angiotensin-converting enzyme (ACE) inhibitors and β blockers that improve survival rate after acute myocardial infarction (and subsequent development of congestive heart failure [CHF], at the beginning of the 21st century CVD now accounts for nearly one half of all deaths in the developed world and 25% in the developing world. By 2020, CVD will be the cause of 25 million deaths each year and will surpass infectious disease as the world’s leading cause of death and disability. Figure 1 shows the increasing incidence and prevalence of heart failure in the United States. According to

the Centers for Disease Control and Prevention, in the United States alone about 950,000 Americans die of CVD each year and CVD accounts for nearly 40% of all deaths, which amounts to one death every 33 seconds. It is a leading cause of death for both men and women and although more common among people aged 65 years or older, the number of sudden deaths from heart disease among people aged 15– 34 years has increased. Also, about 61 million Americans (almost one fourth of the population) live with CVD, of which 4.7 million are symptomatic heart failure patients. This number is expected to increase to an estimated 10 million in 2037, which makes coronary artery disease a leading cause of premature, permanent disability in the US workforce.1,2 There are almost 6 million hospitalizations each year due to CVD, including heart failure. The cost of heart disease and stroke in the United States in 2003 is projected to

almost match the federal budget deficit—a staggering $351 billion, including health care expenditures and lost productivity from death and disability. The cost of heart failure itself is $56 billion a year, 70% of which is due to hospitalization. In a study of 17,000 survivors of hospitalization for heart failure it was shown that almost half were readmitted within 6 months and close to 16% were readmitted at least twice.3

Pathophysiology of Heart Failure and the Natriuretic Peptide Family

Heart failure begins with myocardial injury, usually secondary to myocardial infarction, ischemia, hypertension, or other etiologies. The activation of ensuing physiologic compensatory mechanisms has been well documented. These mechanisms include activation of the renin-angiotensin-aldosterone system (RAAS), natriuretic

Vikas Bhalla, MD; Scott Willis, BS; Alan S. Maisel, MD, FACC From the Division of Cardiology and General Internal Medicine, and the Departments of Medicine and Nursing, Veterans Affairs Medical Center, and the University of California, San Diego, CA Address for correspondence: Alan S. Maisel, MD, VAMC, Cardiology 111-A, 3350 La Jolla Village Drive, San Diego, CA 92161 E-mail: [email protected]

BNP as a Diagnostic Tool and a Drug

January • February • 2004 • Supplement 1

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Congestive Heart Failure (ISSN 1527-5299) is published bimonthly (Feb., April, June, Aug., Oct., Dec.) by CHF, Inc., Three Parklands Drive, Darien, CT 06820-3652. Copyright ©2004 by CHF, Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in Congestive Heart Failure do not necessarily reflect those of the Editor and Publisher. For copies in excess of 25 or for commercial purposes, please contact Sarah Howell at [email protected] or 203.656.1711 x106.

12 Heart Failure Patients in US (millions)

10

• More deaths from heart failure than from all forms of cancer combined

10

8

• 4.7 million symptomatic patients; estimated 10 million in 2037

6

• Incidence: About 550,000 new cases/year

4.7

4

3.5

2

• Prevalence is 1% between the ages of 50 and 59, progressively increasing to >10% over age 80

0 2000

1991

2037*

Figure 1. The increasing incidence and prevalence of heart failure in the United States. *Data from J AM Geriatric Soc. 1997;45:968–974.1 Adapted from 2001 Heart and Stroke Statistical Update.2 1

H2 N 1 H2 N

Leu Arg Arg 5

Gly

Ser Ser Asn Ser 25 Phe Arg Tyr

Pro Lys

ANP 28 AA (atria)

Ser

HOOC

Ser

Gly Arg

Phe

Gln Gly

Gly

Gly

Ile

15

Lys Val

Gly Gly Ser Gln 20

Leu

Ala

HOOC

28

Gly

Ser

Arg

Cys 23 Leu

Val

Met Asp

Cys 7

BNP 32 AA (ventricles)

Met

Arg Lys

Phe Cys 10

Cys 26

25

Gly Leu

Arg Arg

H2 N

15 Met Asp

CNP 53-, 22 AA (endothelium)

Gly

10

Leu Ser Lys

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Arg Ile Ser

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5

HOOC

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Leu Lys

Leu Asp

Phe Cys

Arg

Cys

Ile

Gly Leu

20

Gly 15 Gly Ser Met

Ser

His 32

NP-A

NP-B

NP-C

Figure 2. The common 17-amino-acid ring structure of atrial (A-type) natriuretic peptide (ANP), B-type Natriuretic Peptide (BNP), and C-type natriuretic peptide (CNP). NP=natriuretic peptide

peptide system, sympathetic nervous system (SNS), endothelins, and other neurohormonal factors. Thus, cardiorenal, hemodynamic, and neurohormonal factors all play a role in the pathogenesis of heart failure.4 Activation of these compensatory mechanisms leads to progressive worsening of left ventricular function in part by increasing remodeling and overall work of the heart. The development of heart failure is complicated by a complex balance between vasodilatory and vasoconstrictive influences. Natriuresis, diuresis, and vasodilatory mechanisms work to relieve stress on the heart, but are 4

essentially overwhelmed by the RAAS, SNS, and endothelins, leading to peripheral vasoconstriction and hemodynamic alterations. The end result is progressive deterioration of heart function with worsened symptoms of heart failure (i.e., dyspnea, peripheral edema, tachycardia, and volume overload). All three major natriuretic peptides share a common 17-amino-acid ring structure; atrial (A-type) natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are of myocardial cell origin, and C-type natriuretic peptide (CNP) is of endothelial origin5–7 (Figure 2). All three peptides are secreted in an

BNP as a Diagnostic Tool and a Drug

attempt to correct the vasoconstrictive, sodium retaining, antidiuretic, and antifibrotic effects caused by the neurohormonal imbalance (Figure 3).

Mechanism of Action

The natriuretic peptides exert their action through binding to high-affinity receptors mainly on endothelial cells, vascular smooth muscle cells, and other target cells (Figure 4). Three distinct natriuretic peptide receptors (NPRs) known as NPR A, NPR B, and NPR C have been identified in mammalian tissues. 8 NPR A and NPR B are structurally similar, with a 44% homology in the ligand binding domain. 9,10 A single membrane-spanning portion bridges the intracellular and extracellular segments of these receptors. Both types of receptors utilize a cyclic guanosine monophosphatesignaling cascade.11 NPR B is mostly found in the brain, whereas NPR A is more commonly located in large blood vessels.11 Both receptor types are also found in the adrenal glands and kidneys. NPR A binds preferentially to ANP, but also binds to BNP. On the other hand, CNP is the natural ligand for B receptors.11 BNP is cleared from the circulation through two distinct mechanisms: endocytosis and enzymatic degradation by endopeptidases 9 (Figure 5). NPR C binds to all members of the natriuretic peptide family with equal affinity. When a ligand-receptor complex forms, the complex undergoes receptor-mediated endocytosis. The C-type receptors are recycled to the cellular membrane, and the various natriuretic peptides are degraded to building blocks. The second mechanism to remove natriuretic peptides from plasma involves zinc-containing endopeptidases. These enzymes are present in renal tubules and vascular endothelial cells. They chew and degrade natriuretic peptides among other proteins.

January • February • 2004 • Supplement 1

Congestive Heart Failure (ISSN 1527-5299) is published bimonthly (Feb., April, June, Aug., Oct., Dec.) by CHF, Inc., Three Parklands Drive, Darien, CT 06820-3652. Copyright ©2004 by CHF, Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in Congestive Heart Failure do not necessarily reflect those of the Editor and Publisher. For copies in excess of 25 or for commercial purposes, please contact Sarah Howell at [email protected] or 203.656.1711 x106.

Physiologic Effects of BNP

BNP is a potent natriuretic, diuretic, and vasorelaxant peptide. It coordinates fluid and electrolyte homeostasis through its activity in the central nervous system and peripheral tissue. BNP promotes vascular relaxation and lowers blood pressure, particularly in states of hypervolemia. It inhibits sympathetic tone, the renin-angiotensin axis, and synthesis of vasoconstrictor molecules such as catecholamines, angiotensin II, aldosterone, and endothelin-1.11 An improvement in central hemodynamics, including the cardiac index, in patients with CHF is achieved through suppression of myocyte proliferation, cardiac growth, and compensatory hypertrophy of the heart.11 Its renal effects include increasing glomerular filtration rate (GFR) and enhancing sodium excretion. BNP reinforces the diuretic effects through suppressing centers for salt appetite and it counteracts sympathetic tone via its action in the brainstem.11 The major source of plasma BNP is the cardiac ventricles. This is unlike ANP, whose major storage sites include both the atria and ventricles.12 Figure 6 shows the structure of proBNP, BNP, and N-terminal natriuretic peptide NTBNP. Unlike ANP, which is mainly released from its storage granules in response to atrial wall tension, BNP (as the nucleic acid sequence of the preproBNP gene with high turnover of mRNA suggests) is synthesized in bursts by increased gene expression owing to stretch stimulus to the ventricular wall13 as preproBNP (132 amino acids) and then released in direct proportion to ventricular volume expansion and pressure overload from ventricular myocytes as a 76 amino acid N-terminal fragment (NT-BNP) and a 32 amino acid active hormone (BNP).14–16 Since ANP is stored in granules and released episodically, a minor stimulus, like exercise, can trigger the release of significant amounts of ANP into the bloodstream.17 In contrast, BNP levels show only minor changes with vigor-

Renin-angiotensinaldosterone system

Natiuretic peptides • Natiuretic • Diuretic

• Sodium retaining

• Vasodilating

• Antidiuretic

• Renin and aldosterone inhibiting

• Vasoconstricting • Fibrosis

• Antifibrotic

Figure 3. The neurohormonal imbalance in heart failure

Sympathoinhibitory

ET inhibiting Vasodilating

ANP BNP ANP BNP

Antifibrotic Lusitropic

ANP

BNP ANP BNP

CNP ANP

Aldosterone inhibiting

BNP Natriuretic Renin inhibiting

Antiproliferative

Figure 4. The receptor distribution of natriuretic peptide receptors. ET=endothelin; ANP=A-type natriuretic peptide; BNP=B-type natriuretic peptide

ous exercise, making it unlikely that a normal patient would be classified as having CHF based on a BNP level obtained after activity.18 This suggests that BNP may be a more sensitive and specific indicator of ventricular disorders than other natriuretic peptides.14,19 BNP levels accurately reflect the decompensated state of circulatory congestion.16,20 BNP has been found to be an independent predictor of high left ventricular (LV) end-diastolic pressure and is more useful than ANP or other neurohormones for assessing mortality in patients with chronic

BNP as a Diagnostic Tool and a Drug

CHF.10 The half-life of BNP is 22 minutes, and prior studies have established that BNP can accurately reflect pulmonary capillary wedge pressure changes every 2 hours.21,22

Natriuretic Peptide Family as Cardiac Neurohumoral Markers

As mentioned, heart failure is characterized by complicated neurohormonal alterations.23,24 Increased levels of vasoconstrictor neurohumoral factors, such as norepinephrine, renin, endothelin-1, interleukin-6, and tumor

January • February • 2004 • Supplement 1

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Congestive Heart Failure (ISSN 1527-5299) is published bimonthly (Feb., April, June, Aug., Oct., Dec.) by CHF, Inc., Three Parklands Drive, Darien, CT 06820-3652. Copyright ©2004 by CHF, Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in Congestive Heart Failure do not necessarily reflect those of the Editor and Publisher. For copies in excess of 25 or for commercial purposes, please contact Sarah Howell at [email protected] or 203.656.1711 x106.

GC-A GTP

?

BNP

cGMP

Biological effects

?

Neutral endopeptidase

Clearance receptor Figure 5. The mechanisms of B-type natriuretic peptide (BNP) clearance from blood. GC-A=guanylate cyclase A receptor GTP=guanosine triphosphate; cGMP=cyclic guanosine monophosphate

necrosis factor α, have been found to have significant prognostic value in CHF, suggesting an important role of vasoconstrictors in the pathogenesis of the disorder.14,25-28 Even though pharmacologic modulation of these factors has led to improvements in cardiac function in some cases, relying on these factors to monitor therapy has proved impractical.29,30 Levels of neurohormones and cytokines, such as tumor necrosis factor α and interleukin-6, have wide ranges, assay stability issues, and may vary considerably over time.31 The recognition of the role of BNP as an objective marker for the

diagnosis, severity, and prognosis of acute coronary syndromes and CHF was truly a breakthrough for clinicians and patients faced with CVD.

Historical Perspective of Natriuretic Peptide Levels

Table I summarizes the development of the natriuretic peptides. Henry and Pearce 32 were the first to describe natriuretic response after balloon stretch of the canine left atrium. A quarter of a century later, de Bold et al. 33 injected homogenized atrial tissue into rats and noted a potent natriuretic response.

PreproBNP 134

126-aa signal sequence

ProBNP1-108

N-terminal ProBNP1-76

↑ WALL STRESS

BNP77-108 t 1/2 = 18 min

Natriuresis ↑ lusitropy

Vasodilatation ↓ RAAS

Figure 6. The structure of proBNP, BNP, and N-terminal proBNP. BNP=B-type natriuretic peptide; RAAS=renin-angiotensin-aldosterone system

6

BNP as a Diagnostic Tool and a Drug

Subsequently, in 1984, the structure of ANP was identified by Kangawa et al.34 In 1988, Sudoh et al.35 isolated a compound from pig brain tissue that caused natriuretic and diuretic responses similar to ANP. Although they coined the term “brain (Btype) natriuretic peptide” for this peptide, the primary site of BNP synthesis was found to be the ventricular myocardium. 17,36 In 1990, Sudoh et al.37 again isolated a member of the natriuretic peptide family, also from pig brain tissue, and called it CNP. Subsequently, CNP tissue was found to be structurally distinct from ANP and BNP and is known to express to a much greater extent in the central nervous system and vascular tissues than in the heart. 38 The first approved assay for BNP was introduced by Biosite Inc. in 2000. This a of point-of-care platform that could be used in the emergency room or laboratory. The following year, nesiritide (recombinant BNP) was approved for treatment of patients with decompensated heart failure. Bayer Diagnostics released the first fully automated BNP assay in 2003, moving BNP testing into the high volume hospital and reference laboratory setting. Bayer launched their BNP assay on the ACS:180 in January of 2004. Results are extremely close to those seen with the ADVIA Centaur assay and may provide an alternative BNP assay for the lower volume core laboratory marketplace (Figure 7). Although BNP assays are not all exactly alike, the outcome of the various studies can be extrapolated across all BNP assays.

Role of BNP Levels in the Diagnosis of CHF in Emergency Department Settings

Although we have made tremendous advances in our understanding of the pathophysiology and treatment of CHF, diagnosis of the disease still remains difficult. For the acutely ill

January • February • 2004 • Supplement 1

Congestive Heart Failure (ISSN 1527-5299) is published bimonthly (Feb., April, June, Aug., Oct., Dec.) by CHF, Inc., Three Parklands Drive, Darien, CT 06820-3652. Copyright ©2004 by CHF, Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in Congestive Heart Failure do not necessarily reflect those of the Editor and Publisher. For copies in excess of 25 or for commercial purposes, please contact Sarah Howell at [email protected] or 203.656.1711 x106.

Table I. The B-Type Natriuretic Peptide (BNP) Story 1956 Henry and Pierce32 described natriuretic response to balloon stretch of atrium 1981 de Bold33 injected homogenized atrial tissue into rats and noted a potent natriuretic response 1984 Kangawa et al.34 identified structure of ANP 1988 Sudoh et al.35 isolated BNP from porcine brain tissue 1988 Early work began to synthesize recombinant ANP and BNP 1991 Mukoyama* et al. demonstrated that BNP is a normal cardiac hormone secreted primarily by the ventricles 1992 Kohno et al.** found hypertensive patients with LVH had higher BNP levels 1993 Multiple reports of elevated BNP levels in CHF 1996 Yamamoto✝ found BNP had superior performance compared with the other natriuretic peptides when measured in systolic dysfunction, LVH, and diastolic dysfunction 1997 Cowie et al.✝✝ confirmed BNP could be used to diagnose CHF in the primary care setting 1998 McDonagh‡ demonstrated BNP was superior to the other natriuretic peptides in the clinical diagnosis of CHF (n=1653) 2000 Biosite, Inc. introduced BNP (point-of-care) 2001 Nesiritide (Natrecor) was introduced in the US market as an IV treatment for decompensated CHF 2002 Maisel et al.,45 in Breathing Not Properly study, demonstrated utility of BNP point-of-care assay in diagnosis of CHF 2003 Bayer Diagnostics introduced laboratory-based BNP assay 2004

Bayer Diagnostics introduces BNP on their benchtop ACS:180 analyzer for lower volume laboratories

ANP=A-type natriuretic peptide; BNP=B-type natriuretic peptide; LVH=left ventricular hypertrophy; CHF=congestive heart failure; NT-proBNP=N-Terminal proBNP; ANP=A-type natriuretic peptide; BNP=B-type natriuretic peptide; LVH=left ventricular hypertrophy; CHF=congestive heart failure; NT-proBNP=N-Terminal proBNP; *Mukoyama M, Nakao K, Hosoda K, et al. Brain natriuretic peptide as a novel cardiac hormone in humans. Evidence for an exquisite dual natriuretic peptide system, atrial natriuretic peptide and brain natriuretic peptide. J Clin Invest. 1991;87(4):1402-1412; **Kohno M, Horio T, Yoshiyama M, et al. Accelerated secretion of brain natriuretic peptide from the hypertrophied ventricles in experimental malignant hypertension. Hypertension. 1992;19(2):206-211; ✝Yamamoto K, Burnett JC Jr, Jougasaki M, et al. Superiority of brain natriuretic peptide as a hormonal marker of ventricular systolic and diastolic dysfunction and ventricular hypertrophy. Hypertension. 1996;28(6):988-994. ✝✝Cowie MR, Struthers AD, Wood DA, et al. Value of natriuretic peptides in assessment of patients with possible new heart failure in primary care. Lancet. 1997;350(9088):1349-1353; ‡McDonagh TA, Robb SD, Murdoch DR, et al. Biochemical detection of left-ventricular systolic dysfunction. Lancet. 1998; 351(9095):9-13.

patient presenting to the emergency department with dyspnea, an incorrect diagnosis could place him or her at risk for both morbidity and mortality.39 Therefore, the emergency department diagnosis of CHF needs to be rapid and accurate. Unfortunately, the signs and symptoms of CHF are nonspecific.40 A helpful history is not often obtainable in an acutely ill patient, and dyspnea, a key symptom of CHF, may also be a nonspecific finding in the elderly or obese patient in whom comorbidity with respiratory disease and physical deconditioning are common.41 Routine laboratory values, electrocardiograms, and x-rays are also not accurate enough to always make the appropriate diagnosis.39-42 Table II illustrates data from Dao et al.43 who evaluated the clinical signs and symp-

Table II. How Good Are Our Tools for Heart Failure (HF) Diagnosis? VARIABLE SENSITIVITY SPECIFICITY ACCURACY History of HF 62 94 80 Dyspnea 56 53 54 47 88 72 Orthopnea Rales 56 80 70 S3 20 99 66 JVD 39 94 72 Edema 67 68 68 Adapted from J Am Coll Cardiol. 2001;37:379–385.43

toms of 250 patients presenting with acute dyspnea. Thus, it is difficult for clinicians to differentiate patients with CHF from other diseases like pulmonary disease on the basis of routinely available laboratory tests. The BNP immunoassay has all the earmarks of the ideal tool for detecting CHF in patients who present with dys-

BNP as a Diagnostic Tool and a Drug

pnea—especially in the critical care setting. Davis and colleagues44 measured levels of the natriuretic hormones ANP and BNP in 52 patients presenting with acute dyspnea. They found that admission plasma BNP concentrations more accurately reflected the final diagnosis than did ejection fraction levels or ANP plasma concentrations.

January • February • 2004 • Supplement 1

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Congestive Heart Failure (ISSN 1527-5299) is published bimonthly (Feb., April, June, Aug., Oct., Dec.) by CHF, Inc., Three Parklands Drive, Darien, CT 06820-3652. Copyright ©2004 by CHF, Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in Congestive Heart Failure do not necessarily reflect those of the Editor and Publisher. For copies in excess of 25 or for commercial purposes, please contact Sarah Howell at [email protected] or 203.656.1711 x106.

4500 4000 3500

ACS:180 pg/mL

3000 2500 2000 1500 1000 500 0 -500 -500

y = 1.0301x - 0.1023

500

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Centaur pg/mL

Figure 7. Comparison of 730 samples run on the ACS:180 BNP analyzer vs. ADVIA Centaur analyzer (Bayer HealthCare LLC, Tarrytown, NY). The correlation coefficient is 1.00. Table III. Other Factors That Account for High B-Type Natriuretic Peptide Levels Age Renal failure Myocardial infarction Acute coronary syndrome Right sided congestive heart failure Cor pulmonale: 200–500 pg/mL Primary pulmonary hypertension: 300–500 pg/mL Acute pulmonary embolism: 150– 500 pg/mL

Dao et al.43 were the first to use the BNP assay to evaluate 250 patients presenting to an emergency department with the chief complaint of dyspnea. Physicians assigned to the unit were asked to make an

assessment of the probability (low, medium, or high) for each CHF patient and were blinded to the results of BNP measurements. The finding that BNP levels were the strongest predictor of those who had CHF spurred the Breathing Not Properly study, the first large-scale, multinational prospective study using BNP levels to evaluate the cause of dyspnea. In this study of 1586 patients who came to the emergency department with acute dyspnea, patients’ BNP levels were measured upon arrival, and the emergency department physicians (blinded to levels) were asked to assess the probability of the patient having CHF.45 Two independent cardiologists also blinded to the BNP levels later reviewed all clinical data

Table IV. When Will Congestive Heart Failure Present Without B-Type Natriuretic Peptide Elevations? Flash pulmonary edema 400–500 pg/mL. It again demonstrates that BNP is not a stand-alone test, especially in the setting of mid-range BNP levels. Figure 13 shows data that suggest that the presence of hypertension, diabetes, renal insufficiency, and chronic obstructive pulmonary disease can influence the level of BNP in patients with heart failure. This is most likely related to the influence of these disorders on the severity of heart failure rather than a direct effect, since such an effect was not seen in control subjects. The presence of these concomitant disorders does not diminish the utility of the test in distinguishing patients with heart failure from those without heart failure (Figure 13). Figure 14 shows data from Morrison et al.49 who were able to show that rapid testing of BNP could help differentiate pulmonary from cardiac etiologies of dyspnea. Some types of pulmonary disease, such as cor pulmonale, lung cancer, and pulmonary embolism, have elevated BNP levels, but these are not usually elevated to the extent as in patients with dyspnea from CHF. In a substudy of Breathing Not Properly,50 it was demonstrated that of 417 subjects with a history of asthma or chronic obstructive pulmonary disease without a history of CHF, 21% (87 patients) were found to have newly discovered CHF. Only 37% were identified in the emergency department while a BNP >100 pg/ mL identified 93%. Because BNP levels have been a useful surrogate of wedge pressure and are useful in differentiating heart failure from lung disease, they may be of value in differentiating noncardiogenic from cardiogenic pulmonary edema.51 BNP levels were obtained in 35 patients with acute respiratory distress syndrome (ARDS) and from 42 patients hospitalized for severe dys-

BNP = 100 (pg/mL)

BNP = 125 (pg/mL)

BNP = 150 (pg/mL)

0.6

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Final Diagnosis Heart Failure

Final Diagnosis Not Heart Failure

BNP ≥100 pg/mL “Test Positive”

673

227

BNP < 100 pg/mL “Test Negative”

71

615 Specificity

Sensitivity

= 73%

= 90%

Positive predictive value=75%

Negative predictive value=90%

0.0 0.0

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1-Specificity Figure 8. Illustrates the specificity, sensitivity, and accuracy of a B-type natriuretic peptide (BNP) cutoff value of 100 pg/mL for differentiating congestive heart failure from other causes of dyspnea.

pnea with the diagnosis of CHF. The median BNP level in patients with CHF of 773 pg/mL was significantly higher than patients with ARDS (123 pg/mL (p