VIEWPOINT
Measuring plasma B-type natriuretic peptide in heart failure
Good to go in 2004?
Richard J. Rodeheffer, MD*
Division of Cardiovascular Diseases, Mayo Clinic and Foundation, Rochester, MinnesotaUSA
Manuscript received July 22, 2003;
revised manuscript received February 23, 2004,
accepted March 2, 2004.
* Reprint requests and correspondence: Dr. Richard J. Rodeheffer, Division of Cardiovascular Diseases, Mayo Clinic, 200 First Street, SW, Rochester, Minnesota 55905 (Email: rodeheffer.richard{at}mayo.edu).
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Abstract
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Elevated plasma brain natriuretic (BNP) concentrations correlate with increased cardiac filling pressures. Therefore, increased BNP has been proposed as a marker for asymptomatic ventricular dysfunction, as an aid in the diagnosis of cardiac dyspnea, as an end point to assess the efficacy of heart failure therapy, and as a prognostic marker in heart failure. An understanding of the utility of BNP requires an appreciation of the sensitivity, specificity, and diagnostic accuracy of BNP in each of these clinical situations. At this time, there is strong evidence for the value of BNP in the evaluation of dyspnea of uncertain cause. Further population studies will need to be performed to refine the application of BNP to community cohorts and to determine its clinical value and cost-effectiveness as a screening tool in the early diagnosis of ventricular dysfunction. To make optimal use of BNP for the assessment of heart failure therapy and prognosis in individual patients, physicians will require additional information on the biological variability of BNP. Studies comparing the sensitivity, specificity, and predictive value of the available BNP and N-terminal pro-BNP assays need to be conducted in each of these clinical settings.
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Abbreviations and Acronyms
| | ANP = atrial natriuretic peptide | | AUC = area under the receiver operating curve | | BNP = B-type natriuretic peptide | | CHF = congestive heart failure | | EF = ejection fraction | | LV = left ventricular | | LVD = left ventricular dysfunction | | NT-proBNP = N-terminal pro-B-type natriuretic peptide |
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Discovery of the cardiac peptides in the 1980s renewed our appreciation of the heart as an endocrine organ (1). It also opened a new area of cardiovascular-renal physiology, raising hope for further diagnostic and therapeutic progress in the management of heart failure. This viewpoint will focus on potential diagnostic utility of the natriuretic peptides, particularly that of B-type, or brain, natriuretic peptide (BNP).
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Physiology
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Atrial natriuretic peptide (ANP) and BNP are members of a structurally related family of peptides that are produced and released from cardiac myocytes (2,3). In healthy patients, ANP is produced primarily in the atria and BNP primarily in the ventricles. In patients with failing hearts, peptide production increases and becomes more generalized throughout the myocardium (4,5). Increased cardiac filling pressure is a potent stimulus for peptide secretion (Fig. 1) (6–9). The pro-peptide itself circulates (10). It is also cleaved into the biologically active fragment (C-BNP)and the N-terminal pro-B-type natriuretic peptide (NT-proBNP), both of which are measurable in plasma (10–12).
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Figure 1 Schematic diagram depicting the mechanism by which cardiac secretion of natriuretic peptides serves to maintain intravascular volume homeostasis. ANP = atrial natriuretic peptide; BNP = B-type natriuretic peptide; LA = left atrium; RA = right atrium; LVEDP = left ventricular end-diastolic pressure; RAAS = renin-angiotensin-aldosterone system; RVEDP = right ventricular end-diastolic pressure.
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During the mid-1980s the positive correlation between atrial pressures and plasma natriuretic peptide concentration was described, allowing peptide measurements to be considered as surrogates for atrial pressure measurement. Increased ANP release was shown to occur within minutes of an increase in atrial pressure (8). Conversely, ANP and BNP were shown to fall as atrial pressure decreased in response to heart failure treatment (13,14).
Both ANP and BNP were determined to have potent natriuretic, diuretic, vasodilator, and antimitotic properties that served to counterbalance the volume retaining, vasoconstrictive, and ventricular remodeling effects of renin-angiotensin-aldosterone system activation. The natriuretic peptides are counter-regulatory hormones that are thought to play a role in the stabilization of circulatory function during the early stages of the progression of ventricular dysfunction (15–17).
The ability of plasma ANP to distinguish asymptomatic left ventricular dysfunction (LVD) from normal ventricular function was appreciated as early as 1986 (Fig. 2) (7). Although initial efforts focused on ANP and N-terminal ANP as markers for ventricular dysfunction, BNP was eventually shown to have greater sensitivity and specificity for both systolic and diastolic dysfunction (18–20). Consequently, most recent studies have used BNP or NTproBNP.
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Figure 2 Plasma atrial natriuretic peptide (ANP) concentrations in normal subjects, asymptomatic cardiovascular (CV) disease subjects with normal or elevated pulmonary capillary wedge pressures (PCW), and symptomatic heart failure patients (CHF) with elevated PCW pressure. (Adapted, with permission, from Burnett JC Jr., Kao PC, Hu DC, et al. Atrial natriuretic peptide elevation in congestive heart failure in the human. Science 1986;231:1145–7.)
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Peptide and assay considerations
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Important evolving issues include the choice of which peptide to measure and the method of measuring it. During the 1990s research laboratories developed radioimmunoassays for c-terminal BNP, many using BNP antibodies produced by Shionogi (Osaka, Japan) or Peninsula (Belmont, California). Recently, a BNP assay based on the Shionogi antibody has been introduced in an automated platform format that is applicable to hospital clinical laboratories (Bayer Diagnostics, Tarrytown, New Jersey). In addition, a point-of-care immunofluorometric assay, designed to perform single BNP measurements quickly, has been approved to aid in heart failure diagnosis (Biosite, San Diego, California). Finally, an assay for the N-terminal component of BNP, NT-proBNP, has also been introduced (Roche Diagnostics, Indianapolis, Indiana). Still other versions of these assays are in development.
These assays have different characteristics, and their relative performance has only begun to be evaluated (21,22). In some laboratories the Shionogi assay method produces higher BNP concentrations than the Biosite point-of-care assay (23). The NT-proBNP has a longer plasma half-life than BNP, and its plasma concentrations are considerably higher (11,12,21,22). Data from Roche Diagnostics describe an NT-proBNP assay precision of 1.8% at high concentrations (800 pmol/l) and 2.7% at low concentrations (20.7 pmol/l), with a lower limit of detection of 0.6 pmol/l (21–23). A report comparing the Biosite, Bayer, and Roche assays showed that the automated systems (Bayer for BNP and Roche for NT-proBNP) demonstrated the smallest coefficient of analytic variation, just below 2% (22). The variation in analytic assay performance, however, was overwhelmed by substantial biologic variability (22). Among healthy subjects whose BNP was measured bi-weekly, the intra-individual variation was 33% to 59% over time, although this variation takes place largely within a low normal range. Among heart failure patients, the intraindividual coefficient of variation of the Biosite BNP assay was 24%. Heart failure patients sampled every 2 h during a 24-h period manifested a 77% significant serial change variation in BNP concentration (22). The absolute magnitude of baseline BNP and of serial variation in BNP is influenced by the degree of circulatory decompensation. Although normal or well-compensated heart failure patients with low BNP concentrations may manifest serial variation of small absolute magnitude, further studies are needed to assess the magnitude of biologic variation in poorly compensated patients so that clinicians will be able to interpret the significance of BNP change in the patients in whom it would be of greatest value (24,25). Although the longer plasma half-life and lower biological variability for NT-proBNP suggest that it could be a better marker for detecting serial changes in BNP secretion within individuals, even NT-proBNP manifests such biologic variation that only large changes in concentration within an individual are likely to be clinically significant (21,22).
Few data are available on comparative performance of these assays in clinical decision-making. In a study using the Biosite point-of-care BNP assay, the Roche NT-proBNP assay, and manually performed research laboratory assays in a cohort of 205 dyspneic patients, the commercial assays compared favorably with the validated research laboratory assays (21). Using optimal cutoff thresholds, the specificity of the assays for dyspnea due to heart failure was 70% to 89% and was highest for the NT-proBNP assay. Sensitivity ranged from 80% to 94% and was highest for the point-of-care Biosite assay system (21). Optimal sensitivity and negative predictive value enhance the ability of the point-of-care assay to rapidly exclude heart failure with a high degree of confidence. The NT-proBNP assay, with its slightly greater specificity and higher positive predictive value for heart failure diagnosis, as well as its longer plasma half-life, may be of greater value in other settings, such as monitoring individual response to therapy, where optimal specificity is desired. Further studies are needed to determine which peptide most accurately reflects ventricular filling pressure in a reproducible, economic, and efficient fashion.
Appropriate reference ranges for each assay must be established. In persons free of cardiovascular disease, plasma BNP and NT-proBNP increase with advancing age and are higher in women than men (23,26). Among normal subjects, higher heart rate is inversely correlated with BNP and NT-proBNPconcentration (26). Adjusting the normal range for age and gender, rather than using a single cutoff value for all persons, will be important for optimal test interpretation. Other clinical conditions that could affect concentrations, such as obesity or atrial arrhythmias, also need to be evaluated. Although limited data are available on BNP in renal failure, current observations suggest that renal failure without concomitant left ventricular hypertrophy is not associated with elevated BNP (27,28). The association between BNP and left ventricular hypertrophy has also been observed in hypertensives (29). Further studies are needed to evaluate the effect of renal failure on NT-proBNP.
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Assessing test performance
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The literature on peptide markers has relied on Bayesian analysis to generate estimates of test sensitivity, specificity, positive and negative predictive values, and receiver operating curves. Published studies have applied these methods to different types of patient cohorts, used different assay systems to detect different clinical end points, and emphasized different threshold peptide concentrations for positive/negative test interpretation (30).
Test performance depends on the assay used, on the threshold chosen to separate "normal" from "abnormal," and on whether the prevalence of the clinical feature of interest (e.g., ejection fraction [EF] <35% or diastolic dysfunction) is low (e.g., <10%), medium (30% to 50%), or high (>60%). If the condition has a low prevalence in the study population, the discriminatory test will tend to have a better negative ("rule out") predictive value than positive predictive value. Raising the discriminatory threshold for a positive test will improve specificity and reduce sensitivity. In some clinical situations (e.g., where the disease is rapidly lethal and the consequences of missing the diagnosis are grave) a low discriminatory threshold with high sensitivity is desired even if it results in a greater number of false positives. In other situations (e.g., a research setting in which one is trying to identify a pure cohort with a specific clinical condition), the discriminatory threshold may need to be raised to optimize specificity and minimize false positives.
The fact that several variables affect sensitivity and specificity analyses makes it challenging to compare published studies. In an attempt to apply a common measure of overall test performance, this review will rely on the area under the receiving operating curve (AUC) as the most effective way to express the overall potential diagnostic value of the test in a particular type of patient cohort. Sensitivity, specificity, and predictive values will be expressed at the discriminatory threshold value that provides the greatest overall test accuracy, i.e., the "optimal" discriminatory value. Discussion of specific threshold values, which vary across studies, will be avoided (Tables 1 to 3) (30).
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Potential applications of an lvd marker
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The BNP assay has several potential diagnostic uses: 1) screening populations to identify asymptomatic ventricular dysfunction; 2) assisting in the diagnosis of patients with nonspecific symptoms (e.g., dyspnea); 3) monitoring the effectiveness of heart failure therapy; and 4) estimating prognosis. Each topic will be considered separately.
BNP concentration and ventricular function.
Three investigations have attempted to establish the relationship between plasma BNP and ventricular function in patients referred for echocardiography (Table 1) (31–33). In the first study, in which the end point of EF <45% was found in 11% of the cohort, the AUC was 0.79 and only the negative predictive value ("rule out" function) of BNP was high enough (96%) to make BNP a useful discriminator (31). In the second study, which used a broader end point of EF <50% or Doppler evidence of diastolic dysfunction, the end point prevalence was 47% in the cohort; the AUC was higher at 0.96 and was associated with good sensitivity (86%) and excellent specificity (98%) (32). The third study attempted to detect diastolic dysfunction only, which was found in 40% of the patient cohort; the AUC was 0.92, and BNP showed good specificity (98%) and positive predictive value (96%) (33).
In summary, studies of patient cohorts referred for echocardiography show that high BNP concentration is associated with abnormal ventricular function. It is apparent that BNP has good negative predictive ("rule out") value when the prevalence of the end point of interest in the cohort is low (e.g., 5% to 10%). When the end point prevalence is higher (e.g., 40% to 60%), the positive predictive ("rule in") value is improved at the expense of a somewhat poorer negative predictive value. It should be noted that such referral populations usually have a higher prevalence of ventricular dysfunction than would non-referral cohorts.
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Screening
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During the 1990s a growing appreciation of the progressive nature of ventricular dysfunction led to an emphasis on early detection and therapeutic intervention to attenuate the evolution to overt heart failure. Recent community studies show that half or more of persons with ventricular systolic and diastolic dysfunction are asymptomatic (20,34–39). Although echocardiography can identify the early stages of ventricular dysfunction, its widespread application in populations is impractical and fiscally prohibitive. An inexpensive blood test that would identify persons having preclinical ventricular dysfunction would be an attractive method of selecting persons in whom echocardiographic evaluation could be more cost-effective. This use of BNP is analogous to the surveillance use of cervical pap smears or serum prostate-specific antigen to screen for occult malignancy (37,38).
A diagnostic marker for occult ventricular dysfunction might be measured in all members of a community, whether they seek medical attention or not. Alternatively, the test might be applied to persons who seek medical attention for health maintenance checks-ups, diagnosis of symptoms, or treatment of a known disorder. Such self-selected clinic cohorts are epidemiologically distinct from population-based community cohorts and consist of persons at higher likelihood of having disease.
Community screening.
In community populations, approximately 75% of systolic dysfunction and 50% of moderate-to-severe diastolic dysfunction in community populations are clinically undetected (20,34–36). Community LVD screening, however, presents significant challenges because the condition to be detected has a relatively low prevalence, approximately 1% to 2% for EF  40% and 7% for moderate-to-severe diastolic LVD (pseudonormal or restrictive Doppler pattern) (20,36) (Table 2).
The Framingham investigators focused on BNP to identify persons with EF 50%, EF 40%, and increased LV mass. (20) Because of the relatively low prevalence of these three conditions (5.6%, 2.2%, and 4.8%, respectively) the AUCs were suboptimal, ranging from 0.56 to 0.85, and only the negative predictive ("rule out") values were high enough (93% to 98%) to have potential utility (Table 2). They also determined that the small incremental value of BNP, when added to other commonly available clinical data, made it unlikely that BNP would be a useful community-screening tool.
Data from a population-based community cohort of 2,042 persons  45 years old from Olmsted County, Minnesota, confirm the limited sensitivity and specificity of BNP for both asymptomatic systolic and diastolic ventricular dysfunction (Table 2) (39). Using a likelihood ratio analysis approach, an elevated BNP predicted a 3.8:1 likelihood of EF 40%. Conversely, a low BNP yielded a 0.1:1 likelihood of EF 40%. Because of the low prevalence of EF 40% (1.1%), most of those with elevated BNP would actually be false positives. Indeed, analyses showed that if echocardiograms were obtained only in those with elevated BNP, 24% of the population would require an echocardiogram and 96% of these echocardiograms would show EF >40% (i.e., they would be false positives). Furthermore, the "cost" of this approach is that 10% of cases of asymptomatic EF 40% would be missed (i.e., they would be false negatives).
Another effort to apply BNP screening in a 1,242 person community population in Glasgow attempted to identify persons with EF 30%, a condition occurring in 3.2% of their cohort (Table 2) (40). The Glasgow investigators emphasized the impressive 98% negative predictive value of the test in excluding an EF 30% and proposed that plasma BNP could be a useful "rule out" maneuver when applied to community populations. In a subsequent analysis, they used clinical features (symptoms, blood pressure, electrocardiogram [ECG]) to identify subgroups at "low" and "high" risk of low EF (41). Models were constructed using BNP as the screening test that would determine which persons would proceed to echocardiography for definitive evaluation. When BNP concentration was added to the clinical risk group information, the number of echocardiograms needed to detect one case of systolic dysfunction was reduced from 17 to 12 among high-risk patients. This suggests that a strategy of combining clinical risk factors and BNP concentration to identify candidates for echocardiography could improve the cost-effectiveness of case detection in community populations.
A community-screening study in rural Japan posed a broader clinical question, i.e., whether BNP can identify persons with a range of subclinical cardiovascular disorders (atrial fibrillation, previous myocardial infarction, valve disease, hypertensive ventricular hypertrophy, atrial septal defect, or cor pulmonale) (Table 2) (42). In screening 1,098 persons, 3.6% of whom had one of the heart diseases of interest, BNP was 90% sensitive and 96% specific for identifying structural heart disease. The excellent negative predictive value of 99% was emphasized, and the AUC was 0.97. The incremental value of measuring plasma BNP in addition to standard screening tools (physical examination, ECG, and chest radiography) was not assessed.
Again, for community screening, the diagnostic value of BNP depends greatly on the community prevalence of the condition, or range of conditions, one is attempting to detect. The BNP may be more cost effective when used to screen, as in the Japanese study, for a range of subclinical cardiac disorders, rather than a specific level of ventricular systolic or diastolic dysfunction (43). Ultimately, the value of community screening will depend upon the cost of case identification balanced against the savings in quality and duration of life in those patients who receive early therapy based on population screening strategies. To keep the issue in perspective, it is useful to recall that the use of serum prostate-specific antigen in prostate cancer detection has taken more than two decades to reach its current level of refinement and there remains controversy about its value (44,45). Indeed, two large prospective studies are currently underway to assess the effectiveness of such screening on prostate cancer outcome. Similar efforts will be necessary to evaluate the cost-effectiveness of community screening with BNP or with a combination of plasma markers and other clinical variables.
Clinic screening.
BNP also has been used in patients who sought participation in a multiphasic health screening program (Table 2) (46). In this clinic setting, where the prevalence of a cardiac disease end point was 2.7% (previous myocardial infarction, valve disease, hypertensive heart disease, or atrial fibrillation), BNP was more specific (92%) than sensitive (85%), and the AUC was 0.94, suggesting that BNP could be useful for identifying clinic patients with these forms of subclinical heart disease.
A similar but somewhat more focused multicenter study of 1,050 tertiary hospital inpatients and outpatients showed that BNP was capable of discriminating heart failure patients from patients without heart failure with an AUC of 0.93, the test again showing better specificity than sensitivity (47). Although this number appears to be reasonably good test performance, it is not clear how participating patients in this study were selected.
In summary, clinic or hospital-based screening focuses on patient cohorts with low or moderate disease prevalence, where BNP shows good negative predictive value. Before it can be broadly recommended for office or hospital screening, further studies are needed to demonstrate that patient subgroups can be identified in whom screening with BNP is cost-effective.
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Using BNP to assist in the diagnosis of congestive heart failure (CHF) in symptomatic patients
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A commonclinical dilemma is that of assigning the cause of dyspnea or exercise intolerance in persons who may have cardiac and noncardiac (e.g., pulmonary)disease. Several publications have addressed the diagnostic value of BNP in this situation (Table 3).
Among symptomatic outpatients referred by primary care practitioners to a cardiology clinic for possible new onset heart failure, 29% were eventually determined to have heart failure. In this setting, the AUC was 0.96, suggesting that BNP may have diagnostic utility in patients suspected to have heart failure (Table 3) (48). In a similar primary practice cohort, the use of NT-proBNP improved heart failure diagnosis accuracy by 21%, whereas repeat clinical evaluation without knowledge of NT-proBNP improved diagnosis by only 8% (49).
Several studies have focused on emergency room evaluation of acutely dyspneic patients (50–54). The first effort to use natriuretic peptides in the diagnosis of 52 acutely dyspneic hospitalized patients, 62% of whom were determined to have heart failure, found BNP to be superior to ANP; BNP was 93% sensitive and 90% specific for identifying a cardiac cause of dyspnea; the AUC was not reported (50). Another emergency room study of 163 patients with acute severe dyspnea in the absence of myocardial infarction, 71% of whom were found to have heart failure, showed an AUC of 0.93, a sensitivity of 88%, and specificity of 87%, suggesting a high degree of test accuracy in this clinical context (51). A similar analysis was performed in 321 emergency room patients evaluated for dyspnea, 42% of whom were ultimately confirmed to have heart failure (52). In this study a rapid point-of-care BNP assay distinguished cardiac from pulmonary dyspnea with an AUC of 0.96, 86% sensitivity, 98% specificity, 98% positive predictive value, and 83% negative predictive value. On the basis of these promising findings, the use of BNP in emergency room triage was expanded to a multicenter study of 1,586 dyspneic patients, 47% of whom were found to have CHF; it demonstrated an AUC of 0.91, 85% sensitivity, 83% specificity, 83% positive predictive value, and 85% negative predictive value when the optimal BNP discriminatory value was used (53). When compared with the Framingham clinical CHF diagnostic criteria, plasma BNP provided independent and additive diagnostic information and improved diagnostic accuracy from 73% to 84%. BNP appears to be more useful in discriminating cardiac from noncardiac dyspnea than in distinguishing systolic from non-systolic ventricular dysfunction (54).
These studies suggesting improved emergency room diagnostic accuracy have led to evaluation of the impact of BNP measurement on the efficiency of patient management (55). In a controlled trial of 452 dyspneic emergency room patients, the use of BNP in clinical decision-making reduced the need for hospital admission (from 85% to 75%), the need for intensive care (from 24% to 15%), and reduced the length of hospitalization (from 11 days to 8 days).
Finally, an emergency room cohort of 205 dyspneic patients, 34% of whom had CHF, was evaluated with several different BNP assay systems (21). Both the point-of-care BNP assay and the NT-proBNP assay had satisfactory AUCs of 0.89. At its optimal discriminatory concentration, the point-of-care BNP assay showed 77% sensitivity, 84% specificity, 71% positive predictive value, and 88% negative predictive value. The NT-proBNP assay was 80% sensitive, 87% specific, with a positive predictive value of 76%, and a negative predictive value of 89%. These data suggest that the two assays, when used at their "optimal" discriminatory points, are comparable in ruling out CHF in an emergency room setting where roughly one third of patients in fact have heart failure.
In summary, there is good evidence that BNP and NT-proBNP are useful triage tools to aid in the diagnosis of the dyspneic patient. In this clinical setting, they have acceptable sensitivity and negative predictive value ("rules out" ventricular dysfunction), both in the range of 85% to 90%. In association with the other elements of clinical assessment, a low BNP helps to exclude ventricular dysfunction as the cause of dyspnea.
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Monitoring therapeutic response
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Because BNP levels correlate with atrial and ventricular filling pressures, it is reasonable to ask whether changes in BNP are able to mirror the effectiveness of therapies designed to reduce filling pressures. In patients being treated for acutely decompensated heart failure, BNP concentration decreases in parallel with the fall in pulmonary capillary wedge pressure during a period of 24 h (13). However, few data have yet been published on the effectiveness of BNP "guided" therapy.
A study of 69 hospitalized heart failure patients reported that BNP-guided management reduced the number of subsequent cardiovascular events by 65% during 9.5 months of follow-up (56). Although this is provocative and promising, confirmatory data are needed.
A single study of 152 patients with diastolic dysfunction due to amyloidosis indicated that plasma NT-proBNP was a sensitive indicator of the extent of cardiac amyloid involvement. The changes in NT-proBNP concentration correlated with changes in clinical symptoms (57).
The plasma natriuretic peptide concentration also may be of value in estimating the potential benefit of specific therapeutic interventions. In patients with ischemic cardiomyopathy, elevation of BNP without marked activation of norepinephrine identified a group who had the best response to beta-blockade with carvedilol (58). In a study of acute digitalis administration, patients with the highest plasma ANP concentration had the most impressive hemodynamic improvement from digitalis (14).
In summary, BNP assays are able to track therapeutic response in cohorts of patients where one is evaluating changes in group mean BNP concentrations. Therefore, BNP may be a useful end point in clinical trials. Early clinical experience applying these findings to individual patients, however, suggests that the intra-individual biologic variation of BNP may make interpretation of serial measurements difficult (22). The mean changes in BNP reported in groups of patients undergoing a therapeutic intervention mask the considerable biologic variance in BNP concentration observed within individuals. To be able to confidently interpret BNP changes within an individual, the magnitude of change must be large, and just how large has not been determined.
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Estimating prognosis
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Many factors have been shown to have prognostic value in heart failure. Demographic variables, symptom severity, physical signs, echocardiographic, roentgenographic and scintigraphic measurements, hemodynamic parameters, exercise capacity, neurohumoral perturbations, and genetic polymorphisms have been shown to be associated with poor outcome. Because these variables are all covariates of poor cardiac performance, it is not surprising that natriuretic peptides also have prognostic value.
An early effort to use a cardiac peptide in a cohort at high risk for developing new heart failure was the measurement of ANP in 310 elderly (mean age, 90 years) nursing-home residents (59). In this group, an elevated ANP was 85% sensitive and 66% specific for the development of a subsequent heart failure episode during one year of follow-up. Again, the positive predictive value was low at 30%, whereas the negative predictive value was high at 96%. A Framingham community study has further shown that after adjustment for cardiovascular risk factors, increased BNP is strongly associated with increased risk of heart failure, atrial fibrillation, and death (Fig. 3) (60).
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Figure 3 Cumulative incidence of heart failure according to plasma B-type natriuretic peptide level at baseline in Framingham participants. (Adapted, with permission from 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;350:655–63.)
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Elevated ANP and BNP have been shown to be predictive of poor long-term survival in outpatients with established heart failure (61–64). Also of interest is the observation that BNP was the only predictor of sudden cardiac death in a cohort of 452 heart failure patients followed for an average of 1.6 years (65). A further refinement of this observation is that of combining plasma BNP and prolonged rate-corrected QT-interval in heart failure patients; in those with elevated BNP, rate-corrected QT-interval was a strong and independent predictor of total mortality, as well as sudden death mortality (66).
Among patients with unstable angina and myocardial infarction, BNP has been shown to have prognostic value, incremental to troponin concentration, for subsequent cardiac events or death (67–72). When a panel of neurohormones (including BNP and catecholamines) was measured one to four days after acute infarction, BNP was the only independent predictor of late EF <40% and was the most powerful predictor of death within four months after infarction (71). In 2,525 acute myocardial infarction patients, the magnitude of BNP elevation correlated with mortality, heart failure, and recurrent infarction at both 30 days and 10 months (68). Studies using NT-proBNP have shown it to have similar independent predictive value for adverse postinfarction clinical outcomes (69,72). A strategy of combining EF and BNP (or NT-proBNP) improved risk stratification beyond using either alone (72).
A further refinement of the use of BNP to estimate prognosis is the evaluation of a change in BNP to predict clinical outcomes. In acutely decompensated hospitalized heart failure patients, a decrease in BNP during treatment was associated with fewer adverse events after discharge (73). Conversely, in 4,300 outpatients with chronic heart failure, those with the greatest increase in BNP despite therapy had the greatest morbidity and mortality (74).
Natriuretic peptides also have been used to estimate prognosis in other cardiovascular conditions. Two studies of acute pulmonary embolism show that patients with low plasma BNP or NT-proBNP concentrations had an uncomplicated clinical course when compared with those with high NT-proBNP (75,76). These findings are physiologically consistent with our understanding of the effect on abrupt and dramatic increase in right ventricular afterload would have on the stimuli for BNP release. In the setting of valve disease plasma, BNP increases with the severity of aortic stenosis and mitral regurgitation (77,78). Again, these conditions, as they advance, result in increased atrial pressure and distention.
In summary, plasma BNP concentration is a carrier of significant prognostic information. How much it adds to other routinely collected clinical information needs to be the focus of further study.
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Future research
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From the discussion outlined above, several fertile fields for future investigation are evident. To use BNP to screen populations for asymptomatic ventricular dysfunction, it will be important to demonstrate that BNP can be used to provide a cost-effective strategy for selecting persons in whom more definitive (and expensive) evaluation with echocardiography is warranted. This will require estimation of the cost per case identified and the savings in quality and duration of life that can be gained by early diagnosis and treatment of ventricular dysfunction. It may be that other plasma markers or combinations of markers, or plasma markers combined with other clinical variables, will be more discriminatory.
Because natriuretic peptide concentrations are affected by factors that impact cardiac filling pressure, their concentration in an individual patient may fluctuate over minutes to hours depending on posture, the timing of medication doses, recent sodium and water intake, and changes in ventricular afterload. The data on biological variability of BNP and NT-proBNP discussed above suggest that these tests may be helpful in studying the impact of therapy in large cohorts of patients (e.g., in clinical trials) but that it will be more difficult to apply them to the management of individual patients. For a plasma marker to be more useful in the management of individual patients, it would be desirable to have assays that reflect integrated "average" peptide concentrations over time. The analogy is that of measuring spot serum glucose versus hemoglobin A1c to monitor glycemic control in an individual diabetic patient. Although NT-proBNP appears to have a slight advantage in this regard, the search for better peptide markers should continue.
Long-term studies of the efficacy of peptide measurement will need to include direct comparison of different assay methods. Further studies also will be needed to isolate confounding variables that could affect BNP concentration, such as renal dysfunction, obesity, cor pulmonale, atrial fibrillation, or concomitant medications. Factors that change either secretion or clearance of the BNP peptide may change the plasma concentration and complicate its interpretation.
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Conclusions
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The introduction of the natriuretic peptides as diagnostic tools in ventricular dysfunction has given rise to high expectations as to their accuracy and clinical value. It should be noted, however, that the diagnostic utility of BNP is still a work in progress. At this time, it is reasonable to adopt plasma BNP as an aid in the diagnosis of dyspneic patients in whom the cause is uncertain. It also is appropriate to use BNP as a prognostic marker for unstable angina or in patients after myocardial infarction. At this time, the relative merits of the available assays for BNP and NT-proBNP, the value of BNP in the screening of asymptomatic patients, and value of BNP in monitoring therapy are important areas for continuing investigation.
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Acknowledgments
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The author thanks Tammy Burns for her meticulous manuscript preparation and Allan S. Jaffe, MD, for his manuscript review.
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Footnotes
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This study was funded by the Public Health Service (NIH HL 55502: to Dr. Rodeheffer), the Miami Heart Research Institute, and the Mayo Foundation. Dr. Jagat Narula acted as Guest Editor for this manuscript.
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Abstract
Physiology
