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(Chest. 2004;125:652-668.)
© 2004 American College of Chest Physicians

Brain Natriuretic Peptide in the Management of Heart Failure*

The Versatile Neurohormone

Simon de Denus, MSc(Pharm){dagger}; Chantal Pharand, PharmD and David R. Williamson, MSc(Pharm)

* From the Philadelphia College of Pharmacy (Mr. de Denus), University of Sciences of Philadelphia, Philadelphia, PA; and Faculty of Pharmacy (Dr. Pharand and Mr. Williamson), Université de Montréal and Hôpital du Sacré-Coeur de Montréal, Montréal, QC, Canada. {dagger} As part of his fellowship training, Mr. de Denus has served as a coinvestigator in Acute Decompensated Heart Failure Registry (ADHERE), which was sponsored by Scios, the manufacturer of Natrecor.

Correspondence to: David R. Williamson, MSc(Pharm), Assistant Professor, Faculté de Pharmacie, Université de Montréal, Hôpital du Sacré-Coeur de Montréal, 5400 Blvd Gouin Ouest, Montréal, QC, H4J 1C5 Canada; e-mail: david.williamson{at}umontreal.ca


   Abstract
TOP
 Abstract
Introduction
 BNP
 BNP as a Diagnostic...
 BNP as a Prognostic...
 BNP as a Marker...
 Emerging Roles of BNP
 Conclusions
 References
 
Brain natriuretic peptide (BNP), also called B-type natriuretic peptide, is a member of a family of structurally related hormones, the natriuretic peptides. Current data suggest that measurement of BNP plasma concentrations is a useful tool in the diagnosis of acute heart failure in patients presenting to an emergency department with acute dyspnea. Furthermore, BNP constitutes a promising new marker of prognosis after an acute coronary syndrome episode and in patients with chronic heart failure. Nesiritide, the human recombinant form of BNP, is a new vasodilator used in the treatment of acute heart failure that has several potential advantages over current drug therapy.

Key Words: brain natriuretic peptide • congestive heart failure • nesiritide


   Introduction
TOP
 Abstract
 Introduction
BNP
 BNP as a Diagnostic...
 BNP as a Prognostic...
 BNP as a Marker...
 Emerging Roles of BNP
 Conclusions
 References
 
Brain natriuretic peptide (BNP), also called B-type natriuretic peptide, is a member of a family of structurally related hormones, the natriuretic peptides. This family also includes atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP). It has recently gained a lot of popularity as a potential marker for congestive heart failure. In addition, clinical studies using recombinant BNP (nesiritide) as a treatment strategy in the management of heart failure have been published. Hence, the purpose of this article is to review the usefulness of BNP as a biological marker and the usefulness of its applications in the management of congestive heart failure.

Articles were selected from those listed on MEDLINE from 1966 to February 2003 using the terms brain natriuretic peptide, B-type natriuretic peptide, and nesiritide. The bibliographies of all articles retrieved during the literature search subsequently were studied for articles that may have been missed during the computerized literature search.


   BNP
TOP
 Abstract
 Introduction
 BNP
BNP as a Diagnostic...
 BNP as a Prognostic...
 BNP as a Marker...
 Emerging Roles of BNP
 Conclusions
 References
 
BNP, a 32-amino acid protein, was first isolated from porcine brain.1 As opposed to ANP and CNP, the BNP amino acid sequence varies greatly among species.2 3 At physiologic concentrations, these neurohormones play a complex role on body fluid homeostasis and vascular tone.4 To date, the following three natriuretic peptide receptors (NPRs) have been identified: NPR-A; NPR-B; and NPR-C. NPR-A and NPR-B are members of the guanylyl cyclase receptor family and mediate the biological activities of the natriuretic peptides by the synthesis and intracellular accumulation of cyclic guanosine 3',5'-monophosphate.5 NPR-C is a clearance receptor for circulating natriuretic peptides and lacks guanylate cyclase activity.6 Circulating natriuretic peptides also are metabolized by neutral endopeptidase into inactivated fragments.5 The relative binding affinity of natriuretic peptides to NPRs is illustrated in Table 1 .5


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  		Table 1. Relative Affinity of NPRs to Natriuretic Peptides*

 
In humans, BNP is mainly secreted from the heart, and mostly from the ventricles in both healthy individuals and patients with congestive heart failure.7 Unlike BNP, ANP secretion comes mainly from the atria in healthy individuals, and from both the atria and the ventricles in patients with congestive heart failure. BNP seems to be the only natriuretic peptide that is specific to the ventricles.8 9 The precursor of BNP, pro-BNP is stored in secretory granules in myocytes. After being synthesized in the ventricle, pro-BNP is cleaved by a protease into its biologically active form, BNP, and N-terminal (NT)-proBNP, the 76-amino acid, the biologically inactive amino portion of pro-BNP.10 Compared to BNP, NT-proBNP has a longer half-life than the active form of BNP (ie, 60 to 120 min vs 15 to 20 min) and is not affected by the administration of exogenous BNP like nesiritide. Finally, animal studies have demonstrated that the gene expression and the ventricular secretion of BNP occur more rapidly than those of ANP in an acute overload, suggesting that BNP may play a role as an "emergency" neurohormone against overload. As a result, BNP could be considered superior to ANP as a potential diagnostic marker of acute heart failure.11

In healthy subjects without any cardiovascular disease, BNP levels vary according to sex and age.12 13 Female subjects demonstrate higher plasma concentrations than male subjects, while BNP levels increase in both sexes with advancing age. This suggests that gender and age should be taken into consideration when defining a normal reference range of BNP for a given patient (Table 2 ).12 13


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  		Table 2. Impact of Gender and Age on Normal Reference BNP Levels Using the Point-of-Care BNP Test*

 
From a physiologic standpoint, BNP has an important role in congestive heart failure as a counterregulatory hormone to angiotensin II, norepinephrine, and endothelin because it decreases the synthesis of some of these neurohormones and acts like a balance vasodilator (Fig 1 ). Furthermore, as a result of its hemodynamic effect and its direct tubular action, BNP has natriuretic and diuretic effects. The molecular biology and the physiologic properties of natriuretic peptides and their receptors have been reviewed elsewhere,4 5 6 and the reader is invited to consult these publications for further information.



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  		Figure 1. Physiology of BNP in congestive heart failure.4 5 6 8 10 Following increased ventricular wall tension or stretch, pro-BNP synthesis in the ventricle is increased. Pro-BNP is cleaved by a protease to NT-proBNP (ie, the inactive fragment) and BNP. BNP is the biologically active fragment of pro-BNP. The exact role of the various neurohormones on BNP synthesis secretion remains to be clearly established. ET-1 = endothelin-1; NE = norepinephrine.

 
Compared to other neurohormones, plasma BNP concentration correlates in a superior way with pulmonary capillary wedge pressure, left ventricular end-diastolic pressure, and left ventricular ejection fraction in patients with systolic dysfunction.8 9 14 15 Many studies have shown that in patients with systolic dysfunction, BNP concentration increases with the clinical severity of the disease, as assessed by the New York Heart Association classification. Preliminary data also have demonstrated that BNP could become a powerful predictor of decreased exercise capacity as measured by exercise oxygen uptake in patients with chronic heart failure (CHF).16 Interestingly, other studies have demonstrated that BNP concentrations also are increased in patients with diastolic dysfunction and left ventricular hypertrophy.17 18 19 This indicates that BNP release is increased as left ventricular function deteriorates, and that both increased wall stretch (ie, increased volume) and increased tension (ie, increased filling pressures) are responsible for this increased secretion.

Because heart failure is a common and costly condition with poor prognosis, new cost-effective strategies must be developed to diagnose heart failure in patients who already have the disease or in those who are at risk of developing it. These strategies could enable early treatment and could prevent, or at least delay, progression to end-stage heart failure. In this respect, BNP plasma levels have the potential to become a practical marker of left ventricular dysfunction in clinical practice.


   BNP as a Diagnostic Tool
TOP
 Abstract
 Introduction
 BNP
 BNP as a Diagnostic...
BNP as a Prognostic...
 BNP as a Marker...
 Emerging Roles of BNP
 Conclusions
 References
 
Acute Care Setting
In patients presenting to an emergency department with acute dyspnea, a rapid and accurate diagnosis is indispensable in providing adequate treatment. Unfortunately, the signs and symptoms of congestive heart failure are often nonspecific.20 Although echocardiography is considered to be the "gold standard" for the diagnosis of left ventricular dysfunction, it is not readily available in all institutions, it is of limited availability in an urgent care setting, and it represents a costly intervention. Therefore, a rapid and accurate blood test for congestive heart failure would constitute a useful addition to the existing diagnostic tools.

Three preliminary studies have evaluated and demonstrated the usefulness of BNP as a potential diagnostic marker of heart failure in patients presenting with acute dyspnea in the emergency department (Table 3 ).21 22 23 Davis et al22 evaluated the usefulness of BNP for diagnosing acute decompensated heart failure in 52 patients presenting with acute dyspnea. In this study, BNP was a better diagnostic marker of heart failure than ANP and left ventricular ejection fraction. However, a major limitation of this study was that a time-consuming radioimmunoassay method was used, thus limiting its value in an acute setting. Nonetheless, these results prompted further research21 23 using a rapid (ie, 15 min) point-of-care test for BNP (Triage BNP test; Biosite Diagnostic Inc; San Diego, CA).21 24 This self-processing fluorescence immunoassay test can quantify BNP by simply adding ethylenediaminetetraacetic acid-anticoagulated whole blood or plasma to the BNP test device, which then is inserted into the metering device for the test. The detection of the assay is 5 to 1,300 pg/mL, with a coefficient of variation for intraassay precision of 9.5 to 13.9% and interassay variation of 10 to 14.8%.25 The point-of-care BNP test has been shown to have a good correlation with the more time-consuming Shiono radioimmunoassay test (Shionogi; Osaka, Japan) [R2 = 0.92],26 but demonstrates more variation.13 This makes the BNP test an acceptable diagnostic test. However, this test is of limited usefulness for clinical research compared to the radioimmunoassay, which has demonstrated less variation and a wider detection range.


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  		Table 3. Studies Evaluating BNP as a Diagnostic Marker of Heart Failure or Left Ventricular Dysfunction*

 
Although the results from these studies were impressive, they were performed largely in male veterans and needed confirmation from larger multicenter trials before measurement of plasma BNP levels in the urgent-care setting become the standard of care. The prospective, blinded Breathing Not Properly trial27 has now corroborated the data obtained in these smaller studies. In that trial, which included 1,586 patients presenting to the emergency department with a primary complaint of shortness of breath, a BNP plasma level of 100 pg/mL measured by a fluorescence immunoassay had an accuracy of 83.4% to diagnose acute heart failure, as determined by two cardiologists blinded to the BNP plasma levels. A level of 50 pg/mL had a negative predictive value of 96%, again demonstrating that a low BNP plasma level can be used to rule out heart failure in such a setting. Patients with a diagnosis of decompensated heart failure had a mean (± SD) BNP concentration of 675 ± 450 pg/mL, whereas patients with a history of left ventricular dysfunction without decompensated heart failure had a mean BNP concentration of 346 ± 390 pg/mL, and patients without heart failure had a mean BNP concentration of 110 ± 225 pg/mL. In a subsequent analysis of the trial,28 it was demonstrated that the addition of BNP at a cutoff of 100 pg/mL would have increased the accuracy of the emergency department physician’s diagnosis from 74.0 to 81.5% for patients believed to have a high probability of decompensated heart failure. Figure 2 illustrates the capacity of BNP to distinguish between heart failure and other causes of dyspnea in this study. The calculated area under the curve (AUC) of 0.91 compares well with that of the prostate-specific antigen and is far superior to that of Papanicolaou smears or mammography.27 In a multiple logistic regression analyses of factors used in the diagnosis of heart failure in dyspneic patients, a value for BNP of 100 pg/mL was shown to be the strongest independent predictor of congestive heart failure and to increase the combined explanatory power of the history, signs, symptoms, radiologic findings, and laboratory findings.



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  		Figure 2. Receiver-operating characteristic AUC for various cutoff levels of BNP to differentiate between dyspnea due to congestive heart failure and dyspnea due to other causes in the Breathing Not Properly Multinational Study27 (copyright 2002 Massachusetts Medical Society; all rights reserved; reprinted with permission).

 
A recent single-center trial29 conducted in 163 patients compared the diagnostic value of plasma BNP measurement to Doppler echocardiography in patients presenting to the emergency department with severe dyspnea. Similarly to previous trials, a BNP cutoff of 80 pg/mL had a high negative predictive value (93%), while a cutoff of > 300 pg/mL had the highest accuracy (88%) [Table 3 ]. A "restrictive" mitral inflow pattern (defined as an E-wave/A-wave ratio of > 2, or between 1 and 2 with an E-wave deceleration time of < 130 ms, or a deceleration time of < 130 ms alone in the presence of atrial fibrillation) demonstrated an accuracy of 91% in the 138 patients with assessable Doppler echocardiography findings. Both BNP and Doppler echocardiography added predictive value to clinical variables. A BNP level between 80 and 300 pg/mL had an inferior diagnostic value. In these patients, a restrictive mitral pattern proved to be useful in confirming or ruling out a diagnosis of heart failure.

Therefore, the measurement of BNP levels constitutes an important new addition to the diagnostic tools that are available in patients presenting with acute dyspnea, particularly to exclude the diagnosis of decompensated heart failure. Using the point- of-care BNP test mentioned above (Triage), physicians can rapidly rule out decompensated heart failure when low BNP concentrations (ie, < 80 to 100 pg/mL) are measured, whereas high BNP values can confirm a diagnosis of decompensated heart failure.30 Intermediate values (100 to 400 pg/mL) may not be accurate to confirm a diagnosis of decompensated heart failure, particularly in elderly women (Table 2) . Furthermore, such values may only reflect left ventricular dysfunction without decompensation, as illustrated by the mean BNP concentration (346 ± 390 pg/mL) reported in the BNP trial for patients with left ventricular dysfunction without decompensated heart failure.27 In patients with intermediate BNP values, other potential causes for BNP increases (eg, cor pulmonale, pulmonary embolism,23 or heart failure without exacerbation) should be considered in the interpretation of the BNP concentration and excluded.30 It is important to stress that clinical judgement should always prevail and that the interpretation of BNP levels should always take into account the global evaluation of a patient. Although the use of this test will in many cases only confirm the diagnosis of heart failure, current data28 have indicated that the addition of BNP concentrations to clinical variables can markedly improve the diagnostic accuracy of decompensated heart failure.

Primary Care Setting
In the primary care setting, heart failure is also commonly misdiagnosed.31 Such misdiagnoses can lead to an unacceptable delay in the treatment of heart failure and to excessive referrals for evaluating left ventricular function by echocardiography or radionuclide ventriculography, leading to increased health-care costs. Preliminary data17 have shown that in a selected population undergoing cardiac catheterization, plasma BNP level measurements could be used to evaluate the need for echocardiography to evaluate left ventricular function. Therefore, many investigators have hypothesized that plasma BNP levels could be used as a screening test for left ventricular dysfunction in the primary care setting in patients who are suspected of having left ventricular dysfunction.

The results of several trials26 32 33 34 35 36 conducted in various settings evaluating the potential usefulness of BNP as a biochemical marker of heart failure support this conclusion, although using a lower threshold value may be more appropriate to rule out heart failure in the primary care setting (Table 3) . Those trials highlighted the superiority of BNP over other neurohormones to detect left ventricular function. Patients with low BNP concentrations (ie, < 40 to 50 pg/mL) could be rapidly ruled out from having left ventricular dysfunction, while patients with high BNP concentrations could be referred for further workup to evaluate left ventricular function. Again, a higher discriminatory value may be needed in women and elderly patients. This strategy would result in a decrease in unnecessary referrals for left ventricular function evaluation in patients with symptoms that are suggestive of heart failure and could translate reduced costs.37

However, definitive conclusions as to what is the optimal threshold value are difficult to reach because various threshold values of BNP concentrations and definitions of heart failure were used in past studies. Moreover, in some studies,26 34 36 BNP was used to detect both diastolic and systolic dysfunction, whereas in others32 33 BNP was used only for systolic dysfunction. Elevated BNP concentrations do not differentiate between diastolic and systolic heart failure,38 which explains why the diagnostic accuracy of BNP concentrations is increased when both types of ventricular dysfunction are evaluated. This is well-illustrated in a study by Krishnaswamy et al,36 which demonstrated a superior receiver operating characteristic AUC comparing the sensitivity and specificity of BNP and the echocardiographic diagnosis of both systolic and diastolic dysfunction (AUC, 0.95; 95% confidence interval [CI], 0.93 to 0.97) compared to the echocardiographic diagnosis of systolic dysfunction only (AUC, 0.82; 95% CI, 0.77 to 0.86) or diastolic dysfunction only (AUC, 0.66; 95% CI, 0.61 to 0.72). Future trials should assess the diagnostic role of BNP for both systolic and diastolic ventricular dysfunction. Because there is no uniform definition for a diagnosis of diastolic dysfunction, some authors have even suggested that an elevated BNP concentration in patients with normal systolic function may become a valuable noninvasive way to diagnose diastolic heart failure.39 The definition of systolic dysfunction in these trials should be in agreement with that used in clinical trials, which is generally an ejection fraction of <= 40%. Use of an improper definition, could result in the exclusion of patients with mild systolic dysfunction who have been shown to benefit from pharmacologic therapy with agents such as angiotensin-converting enzyme (ACE) inhibitors and ß-blockers.

The use of BNP13 35 40 and NT-BNP10 also has been investigated as a screening tool in the general population for the detection of left ventricular dysfunction, but with conflicting results. Whether this was secondary to discrepancies between the populations studied remains to be determined. Data from a cross-sectional study41 suggested that a BNP concentration threshold of 50 pg/mL might be efficacious for identifying various cardiac abnormalities, such as atrial fibrillation or flutter, and valvular diseases, and that BNP could be used as an efficient mass screening technique for heart diseases.

At the present time, the use of BNP in the primary care setting seems to be more promising as a tool to rule out heart failure in patients suspected of having left ventricular dysfunction and not as a mass screening tool. Future trials are needed before the use of BNP can be recommended in the primary care setting to determine the most accurate threshold value to rule out left ventricular dysfunction (systolic and diastolic) according to gender and age.13


   BNP as a Prognostic Marker
TOP
 Abstract
 Introduction
 BNP
 BNP as a Diagnostic...
 BNP as a Prognostic...
BNP as a Marker...
 Emerging Roles of BNP
 Conclusions
 References
 
Left ventricular ejection fraction is a prognostic marker of mortality after acute myocardial infarction and in CHF.42 43 Because plasma BNP concentrations correlate well with left ventricular ejection fraction, many have suggested8 14 44 that measuring BNP levels in patients after an acute myocardial infarction or with heart failure could become a valuable, noninvasive, easy-to-obtain marker of prognosis.

Preliminary data on the secreting patterns of BNP after ST-elevation myocardial infarction showed an increase in BNP levels on hospital admission, which peaked at about 16 h.45 Further analysis showed that the time course of BNP levels could be classified into the following two distinct patterns: a monophasic pattern, with one peak approximately 16 h after hospital admission; and a biphasic pattern, with peaks at 16 h and 5 days after hospital admission. The biphasic pattern of secretion was associated with the worst Killip classification, anterior myocardial infarction, and decreased left ventricular function 4 weeks after experiencing myocardial infarction, when compared to the monophasic pattern. This suggests that high BNP concentrations in the days following an acute myocardial infarction may predict a higher risk of ventricular remodeling and a depressed ventricular function. This hypothesis is supported by the work of others46 and suggests that these patients should be targeted to receive aggressive therapy to reduce ventricular remodeling, such as ACE inhibitors and ß-blockers. The initial rapid increase in BNP level also suggests that the synthesis and secretion of BNP may be related to myocardial necrosis, local mechanical stress, or both, and not only to ventricular dysfunction. Experimental data have suggested47 that increased BNP synthesis originates from both infracted and noninfarcted regions of the ventricle. Many preliminary studies45 48 49 50 51 have demonstrated that plasma BNP levels provide prognostic information that supplements conventional clinical, biochemical, neurohormonal, echocardiographic, and radionuclide ventriculographic evaluation methods (Table 4 ).


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  		Table 4. Studies of BNP as a Prognostic Marker After an ACS Episode or in Heart Failure*

 
Data from a retrospective analysis of the glycoprotein IIb/IIIa inhibition with Orbofiban in Patients with Unstable coronary Syndromes-Thrombolysis in Myocardial Infarction (TIMI) 16 trial,52 53 has confirmed that BNP could become a valuable prognostic marker in patients with various types of acute coronary syndrome (ACS). The 10-month mortality rate increased across increasing quartiles of baseline BNP levels before and after adjustment for other independent risks of death, including age, troponin I levels, presence of heart failure, presence of renal failure, and ST deviation (Table 4) . The association between mortality rate at 10 months and BNP concentration quartile was significant regardless of the type of ACS. Furthermore, increasing BNP levels remained predictive of the 10-month mortality rate even in patients without troponin I level elevation, suggesting that the prognostic information provided by BNP was independent of myocardial necrosis.54 These findings were confirmed in a substudy of the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-TIMI 18 study,55 which included patients with non-ST-elevation ACS. Finally, similar data for NT-proBNP were observed in a single-center observational study.56 This study also suggested that different thresholds for predicting adverse outcome according to the different types of ACS may be more appropriate than using a single value. Because no routine measurement of left ventricular function was performed in the first two aforementioned trials,53 55 more data are required, as a left ventricular dysfunction may have been a confounder to the prognostic importance of BNP in these patients. Further studies also should evaluate whether obtaining repeated BNP or NT-BNP plasma values during the index hospitalization would provide any further prognostic information.

The prognostic value of BNP and NT-proBNP levels also has been assessed in patients with CHF. Several small studies have demonstrated that BNP levels in this context provide prognostic information that supplements conventional clinical, neurohormonal, invasive, and noninvasive evaluations. Selected studies are presented in Table 4 .57 58 59 60 61 62 63 Interestingly, BNP seems to be a good predictor not only of death from pump failure, but also from sudden death,64 thereby suggesting that this neurohormone might become a useful tool in selecting patients who may benefit from an implantable cardioverter-defibrillator. Data from these preliminary studies have now been supported by the analysis of large clinical trials58 63 (Table 4) . Furthermore, current data have suggested that changes in BNP concentrations over time also may be a useful marker of prognosis in patients who have been treated for CHF.63 Patients with decreasing BNP concentrations would be at a low risk of experiencing an adverse event, while patients with an increasing BNP level would have a higher risk of experiencing an adverse cardiac event.63 Taken together, this body of evidence suggests that the measurement of BNP concentrations eventually could be used in identifying patients with CHF who require aggressive monitoring and treatment.

Preliminary data61 also have suggested that obtaining a BNP level at the time of hospital admission for a patient presenting with acute decompensated heart failure also may be of use in predicting outcome (Table 4) . Hence, measuring BNP in a patient who presents to the emergency department could be used not only as a diagnostic tool, but also as a prognostic tool in patients in whom acute decompensated heart failure has been diagnosed.

Cheng et al65 also evaluated the prognostic value of BNP in patients hospitalized for decompensated heart failure using a rapid bedside fluorescence immunoassay test (Biosite Diagnostic Inc; San Diego, CA), but they also measured plasma BNP levels daily. The authors hypothesized that BNP levels would predict outcome (ie, death during hospitalization or within 30 days after hospital discharge, or hospital readmission for heart failure within 30 days after hospital discharge). This single-center study included 72 male veterans who had been admitted for congestive heart failure with a New York Heart Association class III or IV determination were included. BNP levels were obtained within 24 h of hospital admission and then daily until hospital discharge or death. Patients who died or were readmitted to the hospital within 30 days tended to have an increase in BNP concentrations during hospitalization (increase, 239 ± 233 pg/mL) compared to patients with successful treatment, who showed a decrease in BNP levels (decrease, 216 ± 69 pg/mL; p < 0.05). By univariate analysis, the BNP level that was measured last was strongly associated with patients experiencing one of the prespecified outcomes (p < 0.0001). Larger trials are required to confirm these findings before the daily measuring of BNP levels becomes part of clinical practice in patients with acute decompensated heart failure.

These studies and others49 66 67 have demonstrated that BNP could constitute an important new marker of prognosis in patients with CHF, as current data have suggested that its use increases the prognostic information obtained by clinical, biochemical, echocardiographic, or invasive methods. Future trials need to corroborate the findings of previously published reports and to define clearly a threshold for identifying patients that are at higher risk of an adverse event. The data regarding the use of plasma BNP as a marker of prognosis in patients with acute decompensated heart failure is at this point insufficient and requires confirmation by larger studies before it can be incorporated into clinical practice. Furthermore, additional data are required before the measurement of BNP becomes part of clinical practice in patients with ACS, more precisely, clear thresholds according to ACS to predict outcome and whether any particularly therapeutic intervention provides any particular benefit to these high-risk patients.


   BNP as a Marker for Tailored Therapy
TOP
 Abstract
 Introduction
 BNP
 BNP as a Diagnostic...
 BNP as a Prognostic...
 BNP as a Marker...
Emerging Roles of BNP
 Conclusions
 References
 
ACE inhibitors, ß-blockers, and spironolactone all have been demonstrated to reduce mortality and morbidity in patients experiencing congestive heart failure.68 69 70 71 72 73 These agents, along with diuretics, constitute the cornerstone of treatment for congestive heart failure.74 Although these agents reduce mortality in the overall population, interpatient variability, whether racial74 75 76 or genetic,77 78 precludes uniform dosing and may not allow equal benefit in all individuals.

Current heart failure treatment strategies do not take into account the plasma concentration of neurohormones, even though several of these substances have been shown to be independent markers of left ventricular ejection fraction and mortality in patients with heart failure.57 79 80 However, several studies have evaluated the effect of drugs used in the management of heart failure on BNP levels. Compared to placebo, ACE inhibitors, angiotensin II receptor blockers, and their combination were shown to reduce BNP levels in a dose-dependent manner in the acute phase and after long-term therapy in patients with left ventricular dysfunction.81 82 83 84 85 86 87 88 This decrease in BNP levels probably resulted from a beneficial reduction in cardiac ventricular filling pressure and cardiac remodeling produced by the inhibition of the renin-angiotensin system.

Reductions in BNP levels also were reported following long-term treatment with ß-blockers, while a temporary increase in BNP levels was observed in the short term,89 90 91 92 although some studies have shown discrepancies.71 The decrease in BNP levels observed with ß-blocker therapy has been shown92 to correlate with improvement in left ventricular ejection fraction. Moreover, in a retrospective analysis of the Australia-New Zealand Heart Failure Group,58 patients with increased baseline BNP levels showed the greatest benefits from carvedilol. Therefore, more definitive data regarding the impact of ß-blockers are needed.

Spironolactone administration also has resulted in a significant decrease in BNP levels.93 94 The impact of digoxin therapy on BNP levels has not been extensively studied. One dose of IV deslanoside, a digitalis glycoside, was shown to increase BNP levels.95 The mechanism for this increase is uncertain. To date, the impact of digoxin on BNP levels has not been evaluated in patients with heart failure.

Based on the hypothesis that BNP plasma levels could reflect the level of therapeutic success, a preliminary study by Murdoch et al96 sought to determine whether titration of vasodilator therapy, specifically ACE inhibitors, according to BNP levels could be of value in optimizing individual treatment in patients with heart failure. Although results showed some favorable hemodynamic trends, few conclusions could be drawn from this small underpowered study.

In a larger study by Troughton et al,97 69 patients with mild-to-moderate heart failure (ie, mean left ventricular ejection fraction, 27%) who had been hospitalized for decompensated heart failure were randomized, in a double-blind fashion, to treatment guided either by plasma NT-proBNP, or by clinical assessment alone, after an initial stabilization. Treatment was intensified to reduce NT-proBNP levels to < 200 pmol/L in the BNP group and to obtain clinically compensated heart failure in the clinical group. The mean follow-up period was 9.6 months. The primary end point of total cardiovascular events (ie, cardiovascular death, hospital admission, or outpatient decompensated heart failure) was significantly lower in the BNP group than in the clinical group (19 vs 54 events; p = 0.02). One death occurred in the BNP group, and seven deaths occurred in the clinical group (p = 0.06). The time to first event analyzed by Kaplan-Meier curves showed significant divergence by 6 months (p = 0.034). Although the results from this study are impressive, a larger scale trial would need to be performed to confirm this promising new avenue of treatment before such tailored therapy becomes the standard of care. Emerging data also have suggested that such a strategy may be helpful in the treatment of acute decompensated heart failure.98


   Emerging Roles of BNP
TOP
 Abstract
 Introduction
 BNP
 BNP as a Diagnostic...
 BNP as a Prognostic...
 BNP as a Marker...
 Emerging Roles of BNP
Conclusions
 References
 
Preliminary data have suggested that BNP could be a useful marker of right ventricular dysfunction and outcome in patients with pulmonary hypertension,99 100 101 congenital heart disease,102 pulmonary embolism,103 and chronic respiratory diseases.104 105 106 In addition, BNP concentrations could become a potential marker of efficacy following pulmonary thromboendarterectomy101 107 or vasodilator therapy in patients with chronic thromboembolic pulmonary hypertension107 and primary pulmonary hypertension,100 or in identifying patients with pulmonary embolism at high risk of right ventricular failure, who require more aggressive monitoring and treatment.103 Further data are needed before considering measuring BNP concentrations in these settings. Furthermore, data are required to know whether or not BNP will be of any clinical relevance in these patients if left ventricular dysfunction is present. Other potential uses of measuring plasma BNP levels could be the detection of early cardiotoxicity of certain drugs like the antineoplastic agent antracycline108 109 and the prediction of outcome in patients following a heart transplantation.110

BNP as a Drug
Nesiritide (Natrecor; Scios; Sunnyvale, CA) is the human recombinant form of BNP and produces the same actions as endogenous BNP. It has been evaluated and is indicated in patients with acute heart failure who have dyspnea at rest or with minimal activity.111 Preliminary studies in patients with heart failure showed that the IV administration of nesiritide produces dose-dependent vasodilatation,112 113 114 115 which is mediated by the activation of the cyclic guanosine 3',5'-monophosphate-coupled receptor NPR-A that is present on the surface of vascular smooth muscle cells.4 Nesiritide is an arterial and venous vasodilator, as demonstrated by a decrease in both pulmonary capillary wedge pressure and peripheral vascular resistance, although significant arterial vasodilatation is seen only at high doses (Table 5 ).112 113 115 116 117 This results in an increase in stroke volume and cardiac index. Because nesiritide does not increase heart rate, does not have any positive inotropic effect, and may produce a vasodilatory effect on epicardial vessels, it probably has a beneficial effect on myocardial oxygen consumption.118 It has a rapid onset of action after bolus administration (< 15 min) and a short half-life (bicompartmental model: t1/2{alpha} = 10 min; t1/2ß = 15 min), which allow easy titration.113 116 117


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  		Table 5. Hemodynamic Changes From Clinical Trials of Nesiritide in Patients With Acute CHF*

 
Nesiritide infusion also decreases plasma aldosterone levels while producing no effect on renin levels, which suggests a direct inhibitory effect on the adrenal glands.112 119 This is in contrast with nitroprusside, which has recently been shown98 to increase aldosterone levels in patients with acute heart failure. At physiologic levels, IV infusion of BNP produces a sympathoinhibitory effect, while the sympathetic nervous activity is not affected by therapeutic doses, despite an anticipated reflex sympathetic increase secondary to a decrease in filling and arterial pressures.120 IV administration of nesiritide also decreases plasma levels of endothelin-1.121 In addition, BNP increases urine volume and sodium excretion, effects that are more pronounced in patients with congestive heart failure than in healthy subjects and results in a diuretic-sparing effect.112 Whether these effects are secondary to improved hemodynamics, a direct action, aldosterone suppression or a combination of these effects remains to be established.

Few studies with clinical end points have been published with nesiritide. Published trials were mainly powered to assess hemodynamic response and symptom relief with nesiritide. IV nesiritide was demonstrated to improve symptoms in patients with acute decompensated heart failure compared to placebo112 116 and to a similar extent than commonly used vasoactive agents112 such as nitroglycerin.116 As seen with other vasodilators, symptom relief is probably due in part to a decrease in mitral regurgitation following a decrease in left ventricular end-diastolic volume, and an increase in forward stroke volume resulting in a decrease in regurgitation flow and volume.122 123

Subsequent analysis of two of these trials110 112 124 revealed that nesiritide produced less sustained ventricular tachycardia (p = 0.014), nonsustained ventricular tachycardia (p = 0.029), and cardiac arrest (p = 0.011) than dobutamine,125 and that nesiritide may improve survival compared to the latter (dobutamine, 31%; nesiritide [0.015 µg/kg/min] 18% [p < 0.05]; dobutamine vs nesiritide [0.03 µg/kg/min], 24%; difference not significant).126

Current dosing recommendations are based on those used in the multicenter Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) trial.116 In this trial, 489 patients with dyspnea at rest and hospitalized for acutely decompensated heart failure were randomized to nesiritide, nitroglycerin, or placebo in addition to standard therapy in a double-blind fashion.116 Randomized patients were stratified according to the use of a right heart catheter (n = 246) or not (n = 243). Patients included in the catheterized group were randomized to placebo, IV nitroglycerin (at a dose determined by the investigator), nesiritide fixed-dose (a bolus of 2 µg/kg followed by an infusion of 0.01 µg/kg/min), or nesiritide adjustable-dose. In this latter group, the same initial regimen as in the fixed-dose arm was used. Additional dose increments of a bolus of 1 µg/kg followed by an increase in infusion rate of 0.005 µg/kg/min with a maximum infusion rate of 0.03 µg/kg/min could be performed following the first 3 h and at an interval of 3 h if the systolic BP was >= 100 mm Hg and pulmonary capillary wedge pressure was >= 20 mm Hg. Noncatheterized patients were randomized in a similar manner, except there was no nesiritide adjustable-dose group. Higher doses should be avoided because of the increased risk of hypotension.115 In both groups, patients treated with placebo were randomized to nesiritide fixed-dose or nitroglycerin after 3 h. Nesiritide had hemodynamic effects similar to nitroglycerin, with the exception of a lower decrease in pulmonary capillary wedge pressure. This may be the result of improper dosing of nitroglycerin in this trial as the mean dose was only 42 µg/min in catheterized patients after 3 h and 29 µg/min in noncatheterized patients. No difference in improvement of dyspnea was seen compared to that with nitroglycerin in the overall population. Although not powered to measure such end points, nesiritide therapy resulted in no benefit regarding the 7-day or 6-month mortality rate compared to nitroglycerin therapy. Treatment with nesiritide is very well-tolerated, with hypotension being the only significant adverse drug reaction.

Therefore, nesiritide has revealed itself as a unique agent in the management of decompensated heart failure. Unlike nitroglycerin, its use has not been associated with tolerance to its hemodynamic effects, although experience is limited with infusion lasting > 72 h (6% of patients in the VMAC trial received nesiritide for > 72 h). Compared to nitroprusside, the use of nesiritide is not accompanied by an increased risk of thiocyanate or cyanide toxicity in patients with renal or hepatic dysfunction, respectively, and nesiritide seems to have a more positive effect on neurohormonal activation.98 112 Finally, the hemodynamic improvements seen with nesiritide therapy are not secondary to increases in intracellular cyclic AMP and calcium, as has been seen with the use of positive inotropes such as dobutamine, and therefore the use of nesiritide does not result in any increased risk of ventricular arrhythmias.125

No guidelines currently exist regarding the treatment of acute decompensated heart failure. Diuretic agents, as a monotherapy or in combination, are generally considered to be the cornerstone of the treatment of fluid-overloaded patients.127 128 The use of IV vasodilators and positive inotropes in combination with diuretics also has been recommended in selected patients.127 128 Despite this, the impact on clinical outcome of agents used in the management of decompensated heart failure, other than symptom relief and improving hemodynamic parameters, remains unclear. Similar data are also lacking regarding nesiritide. Therefore, despite its uniqueness, prospective data demonstrating an improved clinical outcome are needed to justify the increased cost of nesiritide in the management of acute decompensated heart failure, particularly in view of the disappointing results of the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events,129 which showed no benefit for the use of omapatrilat, a drug with both ACE-inhibiting properties and neutral endopeptidase-inhibiting properties, the enzyme responsible for the breakdown of natriuretic peptides, compared to enalapril in the long-term management of heart failure.


   Conclusions
TOP
 Abstract
 Introduction
 BNP
 BNP as a Diagnostic...
 BNP as a Prognostic...
 BNP as a Marker...
 Emerging Roles of BNP
 Conclusions
References
 
BNP, a natriuretic peptide, is produced and released from the ventricles in response to increased wall stretch and tension. The measurement of BNP concentrations has become a useful tool in the diagnosis of acute heart failure in patients presenting to an emergency department with acute dyspnea. Its role in the primary care setting remains to be clearly established. Because BNP does not differentiate between systolic and diastolic dysfunction and does not provide any information regarding valvular integrity or function, it is important to underline that BNP will not replace the need to perform echocardiography, but rather will serve as a complementary tool. In the future, BNP concentrations also could become an important marker of prognosis for patients with congestive heart failure or those who have experienced an ACS episode, and could become a new avenue in tailoring therapy in patients with heart failure. Finally, nesiritide, the human recombinant form of BNP, has become a new tool in the armamentarium for the management of acute heart failure that demonstrates several potential advantages over current drug therapies. There is a need for additional data on clinical outcome (ie, mortality, rehospitalization, and length of stay) to justify the increased cost related to the use of nesiritide in the management of patients with decompensated heart failure.


   Footnotes
 
Abbreviations: ACE = angiotensin-converting enzyme; ACS = acute coronary syndrome; ANP = atrial natriuretic peptide; AUC = area under the curve; BNP = brain natriuretic peptide; CHF = chronic heart failure; CI = confidence interval; CNP = C-type natriuretic peptide; NPR = natriuretic peptide receptor; NT = N-terminal; TIMI = Thrombolysis in Myocardial Infarction; VMAC = Vasodilation in the Management of Acute Congestive Heart Failure

Received for publication December 26, 2002. Accepted for publication March 31, 2003.


   References
TOP
 Abstract
 Introduction
 BNP
 BNP as a Diagnostic...
 BNP as a Prognostic...
 BNP as a Marker...
 Emerging Roles of BNP
 Conclusions
 References
 

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