INTRODUCTION — The natriuretic peptide system impacts salt and water handling and pressure regulation and may influence myocardial structure and function.
B-type natriuretic peptide (BNP) is a natriuretic hormone initially identified in the brain but released primarily from the heart, particularly the ventricles. Cleavage of the prohormone proBNP produces biologically active 32 amino acid BNP as well as biologically inert 76 amino acid N-terminal pro-BNP (NT-proBNP).
Atrial natriuretic peptide (ANP) is a hormone that is released from myocardial cells in the atria and in some cases the ventricles in response to volume expansion and possibly increased wall stress . ANP circulates primarily as a 28 amino acid polypeptide, consisting of amino acids 99-126 from the C-terminal end of its prohormone, pro-ANP.
The release of both ANP and BNP is increased in heart failure (HF), as ventricular cells are recruited to secrete both ANP and BNP in response to the high ventricular filling pressures . The plasma concentrations of both hormones are increased in patients with asymptomatic and symptomatic left ventricular (LV) dysfunction, permitting their use in diagnosis (figure 1).
The diagnostic and prognostic value of measuring plasma BNP, NT-proBNP and mid-regional pro-ANP (MR-proANP) in patients with HF will be presented here.
Natriuretic levels in non-HF settings are discussed separately. (See "Natriuretic peptide measurement in non-heart failure settings".)
PHYSIOLOGIC ROLE IN HF — Both atrial natriuretic peptide (ANP) and BNP have diuretic, natriuretic, and hypotensive effects. They also inhibit the renin-angiotensin system, endothelin secretion, and systemic and renal sympathetic activity (figure 2) . Among patients with HF, increased secretion of ANP and BNP may partially counteract the effects of norepinephrine, endothelin, and angiotensin II, limiting the degree of vasoconstriction and sodium retention [4,5]. In one study of patients with moderately severe HF, for example, administration of an orally active inhibitor of the endopeptidase that degrades ANP led to reductions in plasma aldosterone concentrations and right ventricular (RV) and LV filling pressures, as well as a decrease in body weight presumed to be due to diuresis, natriuresis, or both . These effects were presumably mediated by enhanced natriuretic peptide activity.
An unexpected finding is that BNP may protect against collagen accumulation and the pathologic remodeling that contributes to progressive HF. Studies in BNP knockout mice reveal increased cardiac fibrosis in response to ventricular pressure overload . (See "Pathophysiology of heart failure with reduced ejection fraction: Hemodynamic alterations and remodeling", section on 'Remodeling'.)
Plasma BNP — A variety of clinical immunoassays are clinically available for plasma BNP . These include a rapid point-of-care assay [8-11] as well as central lab assays that offer improved precision compared to the point-of-care test. These assays are harmonized at a value of 100 ng/L, but above or below this level the correlations are not strong.
Plasma BNP concentrations have been variously reported in units of pmol/L, ng/L, or pg/mL. The currently available rapid assay reports results in pg/mL; the assay range is 5 to 1300 pg/mL  or 1.4 to 376 pmol/L .
Genetic factors may account for roughly 40 percent of the total variation in plasma BNP in normal subjects . Similar variability has been noted with N-terminal pro-BNP (NT-proBNP) . (See 'N-terminal pro-BNP' below.)
A potential source of error is that plasma BNP concentrations can vary with the assay used (due to various antibody configurations), age, sex, and body mass index . The normal values tend to increase with age and to be higher in women than men.
Plasma N-terminal pro-BNP — In normal subjects, the plasma concentrations of BNP and NT-proBNP are similar (approximately 10 pmol/L). However, in patients with LV dysfunction, plasma NT-proBNP rises more than BNP. Scaling varies among BNP assays while NT-proBNP assays are standardized, so there is no simple conversion factor to compare BNP and NT-proBNP levels. As discussed below, an NT-proBNP level >900 pg/mL provides roughly equivalent accuracy as a BNP level of >100 pg/mL for diagnosis of HF.
Plasma concentrations of NT-proBNP are higher in older individuals and in women than men . On the other hand, plasma BNP and NT-proBNP are lower in obese individuals , indicating that optimal reference intervals should account for age, sex, and perhaps body mass index (or other measure of body composition). In addition, NT-proBNP increases with renal failure and optimal cut-off values for diagnosis in such patients have not been clearly established . (See 'Renal failure' below.)
Assay purity — Available commercial assays for plasma BNP or NT-proBNP actually measure mixtures of peptides. Plasma BNP assays appear to detect various degradation products of BNP as well as proBNP. Assays for NT-proBNP likely also detect proBNP. The relative contribution of individual natriuretic peptides has not yet been elucidated.
Variability — Variability in peptide measurements must be considered when interpreting serial BNP or NT-proBNP results. Intraindividual biologic variation as well as analytic assay variation contribute to total variation . Manual and point-of-care assays have greater analytic variation than central laboratory analyzers . Total variability determines the percentage change (the relative change value or RCV) needed to demonstrate a significant difference in results over time. In a review of studies of BNP and NT-proBNP variability, a mean 25 percent decrease in BNP was required for a significant within day change and a mean 72 percent decline in BNP was required for a significant week to week change . Variability for NT-proBNP testing was less, so RCVs were lower: an 11 percent decrease was required for a significant within day change and a 47 percent decrease was required for a significant week to week change.
Impact of conditions and medications
Renal failure — Plasma BNP and NT-proBNP concentrations are elevated in patients with renal failure. In patients with chronic kidney disease, decreased estimated GFR is associated with increased plasma BNP and even greater elevation in NT-proBNP concentrations.
Plasma BNP concentrations are often elevated in patients with renal insufficiency, whether or not they have clinically diagnosed HF [19-22]. BNP is cleared by the receptor-mediated binding and removal, neutral endopeptidase [19,20], as well as by passive excretion so GFR is inversely related to BNP concentrations [16,23]. As a result, the cut-off values for plasma BNP in patients with renal insufficiency are different from those in patients with normal renal function. Elevations in BNP levels in renal failure may also result from volume expansion or from LV hypertrophy  and monitoring plasma BNP does not appear to facilitate the management of these patients .
We do not use plasma BNP or NT-proBNP for the diagnosis or management of HF in patients with renal failure, with or without dialysis. The main value would be a low plasma BNP, which would exclude LV dysfunction.
Measuring plasma NT-proBNP has an added problem since NT-proBNP is cleared by the kidney and its plasma concentration is elevated by renal failure alone. There are insufficient data to establish clear cut-off values for NT-proBNP in this setting. In a review of 599 patients with a serum creatinine ≤2.5 mg/dL (221 micromol/L) who presented to the Emergency Department with a complaint of dyspnea, cut-off values for patients with an estimated glomerular filtration rate (GFR) of ≥60 mL/min per 1.73 m2 were >450 pg/mL in those less than 50 years of age and >900 pg/mL in older patients; the cutoff was 1200 pg/mL for patients with a GFR <60 mL/min per 1.73 m2 . Using these values, the sensitivity and specificity for diagnosing HF were 85 and 88 percent for those with a GFR ≥60 mL/min per 1.73 m2 and 89 and 72 percent in those with a GFR <60 mL/min per 1.73 m2.
Age, sex, and body mass — Patients with obesity tend to have lower plasma BNP and NT-proBNP concentrations than nonobese patients [15,24-27]. There are conflicting data as to whether the lower values in patients with obesity reflect a direct association  or are a function of other variables including age, sex, and HF severity . Despite the lower values in patients with obesity, higher plasma BNP values within any body mass index category are associated with worse outcomes .
Drug effects — During treatment with the angiotensin receptor-neprilysin inhibitor sacubitril-valsartan, plasma NT-proBNP levels but not plasma BNP levels can be used to guide therapy. BNP is degraded by neprilysin so ARNI causes elevation of BNP levels. Since NT-proBNP is not degraded by neprilysin, its levels are not increased by neprilysin inhibition. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Monitoring'.)
Other conditions — Natriuretic peptide levels are elevated in some patients with non-HF conditions such as coronary heart disease, valvular heart disease, pulmonary hypertension, and sepsis. The diagnostic and prognostic value of measuring plasma BNP and NT-proBNP in asymptomatic individuals and patients with non-HF conditions is discussed separately (table 1). (See "Natriuretic peptide measurement in non-heart failure settings".)
PLASMA BNP IN HEART FAILURE — The circulating concentration of BNP is less than 20 percent of that of atrial natriuretic peptide (ANP) in normal subjects, but can equal or exceed that of ANP in patients with HF; this wider range of concentrations makes measurement of BNP more useful than ANP in evaluation of patients with HF. For this reason, the clinical experience with plasma BNP is much greater than with plasma ANP [28,29]. The plasma half-life of BNP is estimated to be about 20 minutes . However, as noted above, assays for BNP likely measure a mixture of BNP and proBNP.
Our approach — The utility of BNP in differentiating cardiac and noncardiac causes of dyspnea in difficult to assess patients remains uncertain. Plasma BNP concentration may be useful in the following clinical settings:
●As a part of the clinical evaluation of patients presenting with dyspnea of uncertain etiology, including patients with a history of cardiomyopathy and HF who may have a noncardiac cause of dyspnea. (See "Heart failure: Clinical manifestations and diagnosis in adults".)
Most dyspneic patients with HF have values above 400 pg/mL, while values below 100 pg/mL have a very high negative predictive value for HF as a cause of dyspnea . In the range between 100 and 400 pg/mL, plasma BNP concentrations are not very sensitive or specific for detecting or excluding HF. Other diagnoses, such as pulmonary embolism, LV dysfunction without exacerbation, and cor pulmonale should also be considered in patients with plasma BNP concentrations in this range.
Normal plasma BNP values increase with age and are higher in women than men . Thus, somewhat higher cutoff values may be needed in these settings, although the optimal discriminatory values that should be used have not been determined.
●Possibly, to monitor patients with an established diagnosis of HF, especially those with moderate to severe HF. Such measurements can be made as an adjunct to outpatient follow-up office visits. A rise in plasma BNP above the patient's own baseline value should trigger closer assessment for a possible exacerbation of HF.
BNP and the diagnosis of HF in the patient with dyspnea — Establishing HF as a cause of dyspnea in patients presenting to the emergency department is extremely important, but symptoms and physical findings may not be sufficiently sensitive to make an accurate diagnosis. The assay for plasma BNP is a useful test in the evaluation of patients with dyspnea, and is especially useful as a component of the evaluation of suspected HF when the diagnosis is uncertain [31-37].
Breathing Not Properly study — The value of rapid bedside measurement of plasma BNP for distinguishing between HF and a pulmonary cause of dyspnea was best evaluated in the Breathing Not Properly (BNP) study of 1586 patients presenting to the emergency department or urgent care setting with a major complaint of acute dyspnea . The final diagnosis was HF in 47 percent (confirmed by chest radiograph and/or echocardiography and other clinical tests by two independent cardiologists), no HF in 49 percent, and noncardiac dyspnea in patients with a past history of LV dysfunction in 5 percent. The following findings were noted:
●Plasma BNP was markedly higher in patients with clinically diagnosed HF (including patients with right HF due to cor pulmonale) compared to those without HF (mean 675 versus 110 pg/mL). Intermediate values were found in patients with baseline LV dysfunction without an acute exacerbation (346 pg/mL) (figure 3).
●A plasma BNP >100 pg/mL diagnosed HF with a sensitivity, specificity, and predictive accuracy of 90, 76, and 83 percent, respectively. Choosing values >125 or >150 pg/mL decreased sensitivity, increased specificity, and did not change overall predictive accuracy. The predictive accuracy of plasma BNP for HF was equivalent to or better than other parameters such as cardiomegaly on chest x-ray, a history of HF, or rales on physical examination, and was better than the widely used NHANES and Framingham criteria for the diagnosis of HF (83 versus 67 and 73 percent, respectively). (See "Approach to diagnosis and evaluation of acute decompensated heart failure in adults".)
A subsequent analysis showed that atrial fibrillation (AF), which was present in 292 patients, was associated with higher BNP levels in the patients who did not have a final diagnosis of HF (119 versus 25 pg/mL in patients without AF) . As a result, a BNP cutoff of ≥100 pg/mL was associated with a specificity of only 40 percent compared to 79 percent in patients without AF. Using a cutoff of ≥200 pg/mL in patients with AF increased specificity from 40 to 73 percent with a smaller reduction in sensitivity from 95 to 85 percent.
●The plasma concentration of BNP correlated with NYHA functional class, ranging from 244 to 817 pg/mL for class I to IV.
Another report from the BNP study compared plasma BNP to initial clinical judgment . Among patients judged clinically to have a ≥80 percent probability of HF, a plasma BNP >100 pg/mL was more sensitive (90 versus 49 percent) but less specific (73 versus 96 percent) than clinical judgment . Adding BNP to clinical judgment increased diagnostic accuracy (HF versus no HF) from 74 to 81 percent. Among patients with a 21 to 79 percent clinical probability of HF, a plasma BNP >100 pg/mL had a diagnostic accuracy of 74 percent and only misclassified 7 percent of patients who had HF. Among patients originally thought to have less than a 21 percent clinical probability of HF, 17 percent had a final diagnosis of HF and plasma BNP correctly diagnosed 90 percent of these patients.
Heart failure with preserved ejection fraction — Elevations in plasma BNP can establish the presence of HF with preserved ejection fraction (HFpEF) with similar accuracy to HF with reduced ejection fraction (HFrEF), though values are generally higher with HFrEF [34,39,40]. However, the values do not adequately differentiate between HFrEF and HFpEF [34,39]. (See "Heart failure with preserved ejection fraction: Clinical manifestations and diagnosis".)
Impact on outcomes and costs — Studies evaluating the impact on health outcomes and health services utilization of BNP measurement for evaluation of dyspnea have reported conflicting results which may be due to differences in patient populations and/or health systems (eg, high clinical diagnostic accuracy without BNP testing may be associated with less benefit with BNP testing).
Prognosis of HF — Plasma BNP levels are predictors of outcome in both acute and chronic HF.
A systematic review analyzed 19 studies in which plasma BNP was used to estimate the relative risk of death or cardiovascular events in patients with HF . Every 100 pg/mL increase in plasma BNP was associated with a 35 percent increase in the relative risk of death. In multivariable models, plasma BNP was a strong indicator of risk and may be a better predictor of survival than traditional risk factors such as NYHA class and possibly LV ejection fraction.
In an analysis of more than 4000 patients from the Val-HeFT trial, those with a baseline plasma BNP concentration in the highest quartile (≥238 pg/mL) had a significantly greater mortality at two years than those with a plasma BNP in the lowest quartile (<41 pg/mL) (32.4 versus 9.7 percent) (figure 4) .
Similarly, persistent elevation of plasma BNP despite optimal medical therapy also has prognostic significance [45,46,48,51,52]. In one series of 85 chronic HF patients, a plasma BNP below 73 pg/mL was associated with markedly and significantly higher survival compared to those with higher values (figure 5) . In another series of 102 patients with class III and IV HF, a plasma BNP concentration persistently above 240 pg/mL after treatment had a sensitivity and specificity of 73 and 74 percent for mortality at follow-up of more than two years . In hospitalized patients, persistent elevation of plasma BNP prior to discharge from the hospital is predictive of death or readmission .
As mentioned above, plasma BNP and N-terminal pro-BNP concentrations tend to be lower in obese and overweight patients [15,24-27]. Despite the relatively lower values, plasma BNP retains its prognostic value in such patients with advanced HF .
Acute decompensated HF — The relationship between admission plasma BNP levels and the risk of in-hospital mortality for patients with acute decompensated HF was assessed in the ADHERE registry . Admission BNP levels were available in 19,544 patients with HF due to systolic dysfunction and in 18,164 HF patients with preserved LV function. The following findings were noted:
●BNP values were categorized according to quartiles. Quartiles 1 to 4: <430, 430 to 839, 840 to 1729, and ≥1739 pg/mL respectively.
●There was a nearly linear relationship between BNP quartiles and in-hospital mortality. Quartiles 1 to 4: 1.9, 2.8, 3.8, and 6 percent respectively.
Screening for LV dysfunction — Plasma BNP has been evaluated as a screening test for asymptomatic LV dysfunction, with the goal being early identification so that therapy can be given to slow the progression to overt HF. This issue is discussed separately. (See "Approach to diagnosis of asymptomatic left ventricular systolic dysfunction".)
Major society recommendations — We agree with the following recommendations from the 2017 American College of Cardiology/American Heart Association/Heart Failure Society of America (ACC/AHA/HFSA) focused guideline update:
●To measure natriuretic peptide biomarkers in patients presenting with dyspnea, to support a diagnosis of HF . These measurements are to be viewed as part of the total evaluation but should not be used in isolation to confirm or exclude the presence of HF.
●To measure natriuretic peptide biomarkers for establishing prognosis in patients with chronic HF, and on admission to the hospital to establish prognosis in acutely decompensated HF. The measurement of a natriuretic peptide biomarker predischarge to establish prognosis may also be of value.
Limitations — There are several important limitations to the use of plasma BNP for diagnosis and follow-up of HF :
●Patients may present with more than one cause of dyspnea (such as pneumonia and an exacerbation of HF). Thus, a high plasma BNP concentration does not exclude the presence of other diseases.
●In some patients with acute decompensated HF, plasma BNP levels are not diagnostic.
●Some patients with severe chronic HF may have persistently elevated plasma BNP concentrations regardless of treatment, and such levels may not be useful in guiding management.
●Right HF and pulmonary hypertension are associated with elevations in plasma BNP (see "Natriuretic peptide measurement in non-heart failure settings", section on 'Pulmonary hypertension'). However, when right HF is due solely to lung disease and not due to secondary pulmonary hypertension from left sided heart disease or as part of a global cardiomyopathy, elevated plasma BNP may be misinterpreted since dyspnea in these patients is due to lung disease not left HF.
●Plasma BNP measurements alone are not sufficient to guide therapeutic decision-making in patients with HF. They should be used as an adjunct to, and not a substitute for, clinical assessment. As an example, failure of plasma BNP to change significantly should not be interpreted as conclusive evidence that the new therapy was of no benefit.
Not all patients with symptomatic HF have high plasma BNP concentrations and not all asymptomatic patients have low values. This was demonstrated in a review of 558 consecutive ambulatory patients with treated stable HF in a specialized outpatient HF clinic . The following observations were noted:
●Among the 449 symptomatic patients, 106 (24 percent) had plasma BNP <100 pg/mL. These patients were more likely to be young and female and to have a nonischemic cardiomyopathy.
●On the other hand, elevated plasma BNP was seen in some of the 109 asymptomatic patients. Although the mean plasma BNP in this group was 87 pg/mL, values as high as 572 pg/mL were seen.
These findings illustrate the importance of the range of individual patient variation, as with any diagnostic test. The use of serial serum BNP concentrations to monitor the clinical course of a patient provides a more reliable guide to management than can be obtained from a single measurement.
N-TERMINAL PRO-BNP — Like atrial natriuretic peptide (ANP), BNP is cleaved from the C-terminal end of its prohormone, pro-BNP. The N-terminal fragment, N-terminal pro-BNP (NT-proBNP), is also released into the circulation. NT-proBNP has a longer plasma half-life than BNP (approximately 25 to 70 versus 20 minutes) . However, as noted above, assays for NT-proBNP likely measure a mixture of NT-proBNP and proBNP. Issues related to the NT-proBNP assay are discussed above. (See 'Assay interpretation' above.)
Measurement of NT-proBNP, like measurement of plasma BNP, has diagnostic and prognostic value in HF and other cardiovascular diseases.
Role in HF — The accuracy of diagnosis of HF in both primary care and emergency department settings can be improved with NT-proBNP measurement. The following observations illustrate the utility of NT-proBNP primarily in patients with systolic HF; preliminary data suggest it is also useful in HF due to diastolic dysfunction as is plasma BNP . (See 'Heart failure with preserved ejection fraction' above.)
Acute decompensated HF — Like BNP, NT-proBNP has been found to be useful in the evaluation of a patient presenting with dyspnea in the acute setting [31,32,57-61]. This is best illustrated by a retrospective cohort study that combined and analyzed data from three previous prospective studies . Differences in plasma NT-proBNP among 1256 patients with and without acute HF were compared, and the relationship between plasma NT-proBNP and symptoms was examined. The following findings were noted:
●The optimal value for distinguishing HF from other causes of dyspnea varied with patient age. For patients <50, 50 to 75, and >75 years of age, the optimal plasma NT-proBNP cutoffs for diagnosing HF were 450 pg/mL, 900 pg/mL, and 1800 pg/mL respectively. Overall, these cutoffs yielded a sensitivity and specificity of 90 and 84 percent, respectively.
●Across the entire population, NT-proBNP levels below 300 pg/mL were optimal for excluding a diagnosis of HF, with a negative predictive value of 98 percent.
The concentration of NT-proBNP is elevated in the pleural fluid in patients with HF and a pleural effusion and may therefore be of some value in the diagnosis of pleural effusion. This issue is discussed separately. (See "Pleural fluid analysis in adults with a pleural effusion", section on 'N-terminal pro-BNP'.)
Prognosis — Plasma NT-proBNP correlates with prognosis in patients with acute and chronic HF [47,61-65]. In a subgroup of 1011 patients in the COPERNICUS study, the median baseline NT-proBNP concentration was 1767 pg/mL . All-cause mortality at one year was significantly higher for patients with a plasma NT-proBNP above the median, compared to levels below the median (22 versus 7 percent, risk ratio 2.7). A similar increase was found in the combined end point of all-cause mortality or hospitalization for HF (38 versus 19 percent, risk ratio 2.4). Similar observations were made in the Australia/New Zealand Heart Failure trial [47,63].
Primary care setting — The value of NT-proBNP in the primary care setting was demonstrated in a study of 305 patients presenting to their general practitioner with symptoms of HF who were initially evaluated and then randomly assigned to a second diagnostic evaluation with or without knowledge of the result . Final diagnoses were made by an expert panel. Diagnostic accuracy (either correct identification or exclusion of HF) improved from 52 to 60 percent without NT-proBNP (8 percent change) but from 49 to 70 percent with NT-proBNP (21 percent change).
Role in cardiomyopathy — NT-proBNP predicts cardiac involvement and prognosis in patients with AL amyloidosis  and may be a useful screen for LV dysfunction due to late cardiotoxicity in children who have received anthracycline chemotherapy . (See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity".)
COMPARISON OF PLASMA BNP AND N-TERMINAL PRO-BNP — Limited data are available comparing the diagnostic and prognostic values of plasma BNP and N-terminal pro-BNP (NT-proBNP). As noted above, there is no universal conversion factor to compare BNP and NT-proBNP levels. An NT-proBNP level >900 pg/mL provides roughly equivalent accuracy as a BNP level of >100 pg/mL for diagnosis of HF.
A study of 164 patients hospitalized with decompensated HF found that admission and discharge NT-proBNP and BNP levels predicted cardiac mortality and all-cause mortality at 90 day follow-up . NT-proBNP had greater prognostic value than BNP levels for all-cause mortality.
As alluded to above, greater increases in NT-proBNP than BNP levels are observed in renal failure. (See 'Renal failure' above.) It has been postulated that the diagnostic value of NT-proBNP may be in part be due to its sensitivity to renal dysfunction.
BNP OR NT-proBNP AS GUIDE TO THERAPY OF HF — The plasma concentrations of BNP and N-terminal pro-BNP (NT-proBNP) fall after effective chronic treatment of HF, which suggests that measurement of plasma BNP may be helpful in titrating therapy [41,46,70-73]. The utility of serial BNP measurements to monitor the response to acute HF therapies is currently being investigated.
Acute HF — Natriuretic peptide levels have prognostic value in patients with acute HF but the available evidence does not support targeting lower levels as a means of improving outcomes in this setting. Since natriuretic peptides have relatively short half-lives, it has been postulated that serial measurements may help guide management of acute HF . A systematic review including one randomized trial, three quasi-experimental studies, and 40 observational studies found low-quality evidence supporting an association between achievement of natriuretic predischarge thresholds (eg, BNP ≤250 pg/mL or NT-proBNP decline of at least 30 percent) and reduced acute HF mortality and readmission . However, the BOT-AcuteHF randomized controlled trial (and the PRIMA II trial that has been presented but not yet published) studying the effect of treating to a target natriuretic peptide level found no improvement in outcomes with a natriuretic peptide-guided strategy, although patients who achieved the natriuretic peptide target had better outcomes than those who failed to achieve the target [76,77]. One possible explanation for the failure of a natriuretic peptide-guided strategy to improve outcomes is that natriuretic targets are not achievable in some patients given the limitations of current therapies .
A separate issue is that some patients with acute HF do not have elevated BNP or NT proBNP levels; natriuretic peptide levels may be mildly or not significantly elevated if the etiology of the HF is inflow tract obstruction (eg, mitral stenosis) [78,79], constrictive pericarditis [80,81], or if the HF is very acute (first hour or so) [82-84]. (See "Treatment of acute decompensated heart failure: General considerations".)
Chronic HF — Randomized trials studying the effect of BNP- or NT-proBNP guided therapy on clinical outcomes have shown mixed results, although the weight of the evidence suggests modest or no clinical benefit from use of natriuretic peptide levels to aid optimization of HF drug doses. Although earlier trials found improved outcomes, the largest randomized trial (in which medical therapy was intensified similarly with or without natriuretic peptide level guidance) found no benefit.
A meta-analysis included 11 randomized trials (nine which provided individual patient data and two studies which provided aggregate data) comparing natriuretic peptide-guided treatment with usual care . All-cause mortality was significantly reduced by natriuretic peptide-guided care (hazard ratio [HR] 0.62; 95% CI 0.45-0.86) based on individual patient data from 2000 patients. With the addition of aggregate data from two additional studies (with 431 patients), the reduction in mortality rate was borderline significant (HR 0.82; 95% CI 0.67-1.00, p = 0.045). Hospitalization due to HF (HR 0.80; 95% CI 0.67–0.94) was lower in natriuretic peptide-guided patients based on individual patient data from 2151 patients. Increasing doses of guideline directed medical therapy (angiotensin converting enzyme [ACE] inhibitor/angiotensin II receptor blocker [ARB], beta blocker, and mineralocorticoid receptor antagonist) were associated with reduced all-cause mortality. At study end, there was a higher percentage of patients receiving target ACE inhibitor/ARB doses in the natriuretic peptide guided group compared to the clinically guided group.
Despite the promising results of this meta-analysis, the subsequent GUIDE-IT trial (the largest randomized trial evaluating this strategy to date) found that NT-proBNP–guided therapy was not more effective than usual in improving outcomes in high-risk patients with HFrEF when managed by HF specialists at multiple high level medical centers . This study assigned 894 patients with HFrEF (ejection fraction ≤40 percent), elevated natriuretic peptide levels within the prior 30 days, and a history of a prior HF event (HF hospitalization or equivalent) to either an NT-proBNP-guided strategy or usual care. The trial was stopped for futility when 894 of the planned 1100 patients had been enrolled with follow-up for a median of 15 months. The primary end point, composite of time-to-first HF hospitalization or cardiovascular mortality occurred in 164 patients (37 percent) in the NT-proBNP guided group and 164 patients (37 percent) in the usual care group (adjusted HR 0.98; 95% CI 0.79-1.22). Cardiovascular mortality was 12 percent in the NT-proBNP guided group and 13 percent in the usual care group (HR 0.94; 95% CI 0.65-1.37). None of the secondary end points nor the decreases in the NT-proBNP levels achieved differed significantly between groups. There were modest increases in HF drug doses in both groups.
However, the plasma BNP concentration may predict the likelihood of response to therapeutic intervention. In the Australia-New Zealand Heart Failure study, carvedilol appeared to reduce mortality only in patients with supramedian baseline values of BNP .
Exercise training — Exercise training programs are recommended in patients with chronic HF. (See "Cardiac rehabilitation in patients with heart failure" and "Cardiac rehabilitation in patients with heart failure", section on 'Evidence on effects of exercise'.)
The effect of exercise training on natriuretic peptide levels was evaluated in a series of 95 patients randomly assigned to either exercise training or standard therapy for nine months . In addition to a number of clinical improvements, patients assigned to exercise training had a decline in both BNP and NT-proBNP of approximately 30 percent, compared to no change in patients assigned to standard therapy.
ATRIAL NATRIURETIC PEPTIDE — Atrial natriuretic peptide (ANP) is primarily released from the atria in response to volume expansion, apparently sensed as atrial stretch. ANP levels are increased in HF and correlate more closely with atrial volume than atrial pressure . The prohormone of ANP (proANP) is a polypeptide of 126 amino acids. The N-terminal portion of proANP, termed proANP1–98 or N-terminal pro-ANP (NT-proANP), has a much longer half-life than mature ANP and has therefore been proposed as a more reliable analyte for measurement than ANP. An investigational commercial assay detects mid-regional pro-atrial natriuretic peptide (MR-proANP).
The multicenter BACH (Biomarkers in Acute Congestive Heart Failure) trial evaluated the utility of monitoring MR-proANP as compared to BNP in 1641 patients presenting to the emergency department with shortness of breath . MR-proANP (≥120 pmol/l) was noninferior to BNP (≥100 pg/ml) for the diagnosis of AHF (sensitivity 97 versus 95.6 percent; specificity 59.9 versus 61.9 percent). MR-proANP provided additional discriminant value to BNP in patients with intermediate BNP (or NT-proBNP levels) or patients with obesity but not in those with renal insufficiency, age >70 y, or edema.
The GISSI-HF trial provided evidence that measurement of MR-proANP provided prognostic information independent of NT-proBNP . Natriuretic peptides and other vasoactive peptides were measured in 1237 patients with chronic stable HF at randomization and at three months. The addition of MR-proANP improved classification for mortality when added to models based on clinical risk factors alone (net reclassification improvement [NRI] = 0.12) or together with NT-proBNP (NRI =0.06). Increases in MRproANP levels were associated with mortality (HR 1.38, 95% CI 0.99–1.93 and HR 1.58, 95% CI 1.13–2.21 in the middle and highest versus lowest tertiles).
More data are needed to define the clinical utility of MR-proANP measurements.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Heart failure in adults" and "Society guideline links: Cardiac valve disease".)
SUMMARY AND RECOMMENDATIONS
●Comparing BNP and NT-pro-BNP values – In normal subjects, the plasma concentrations of B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) are similar (approximately 10 pmol/L). However, in patients with left ventricular (LV) dysfunction, plasma NT-proBNP rises more than BNP, with NT-proBNP concentrations approximately four-fold higher than BNP concentrations. (See 'Plasma N-terminal pro-BNP' above.)
●Factors that influence interpretation – Factors that influence the interpretation of natriuretic peptide levels include:
•Chronic kidney disease – In patients with chronic kidney disease, decreased glomerular filtration rate (GFR) is associated with increased plasma BNP and even greater elevation in NT-proBNP concentrations, since NT-proBNP is cleared by the kidney. (See 'Renal failure' above.)
•Age, sex, and body mass – The normal values tend to increase with age and to be higher in women than men and lower in obese individuals. (See 'Age, sex, and body mass' above.)
•Assay variability – Plasma BNP and NT-proBNP concentrations vary with the assay used. Variability in peptide measurements must be considered when interpreting serial BNP or NT-proBNP results. (See 'Variability' above.)
●Evaluation of dyspnea – Plasma BNP or NT-proBNP is useful as a component of the evaluation of suspected heart failure (HF) when the diagnosis is uncertain (figure 3). (See 'BNP and the diagnosis of HF in the patient with dyspnea' above.)
•Most dyspneic patients with HF have plasma BNP values above 400 pg/mL, while values below 100 pg/mL have a very high negative predictive value for HF as a cause of dyspnea. In the range between 100 and 400 pg/mL, plasma BNP concentrations are not very sensitive or specific for detecting or excluding HF. (See 'Our approach' above.)
•For patients <50, 50 to 75, and >75 years of age, the optimal plasma NT-proBNP cutoffs for diagnosing HF were 450 pg/mL, 900 pg/mL, and 1800 pg/mL respectively. (See 'Acute decompensated HF' above.)
●Elevation in patients with HFpEF – Elevations in plasma BNP can establish the presence of HF due to diastolic dysfunction with similar accuracy to systolic dysfunction. However, the values do not differentiate between systolic and diastolic dysfunction. (See 'Heart failure with preserved ejection fraction' above.)
●Management guided by routine use of BNP values – Randomized trials studying the effect of BNP- or NT-proBNP-guided therapy for patients with chronic HF on clinical outcomes have shown mixed results, although the weight of the evidence suggests there is modest or no clinical benefit when natriuretic peptide levels are used to guide optimization of HF drug therapy. (See 'Chronic HF' above and 'Acute HF' above.)
●Prognostic value – Plasma BNP and NT-proBNP provide prognostic information in patients with acute and chronic HF, and plasma BNP has prognostic value in those with asymptomatic or minimally symptomatic LV dysfunction (figure 4 and figure 5). (See 'Prognosis of HF' above and 'Prognosis' above.)
●Atrial natriuretic peptides – Mid-regional pro-atrial natriuretic peptide (MR-proANP) appears to be noninferior to BNP for diagnosis of acute HF and to have prognostic value in patients with chronic HF. (See 'Atrial natriuretic peptide' above.)
●Use in non-heart failure settings – Natriuretic peptide levels are elevated in some patients without clinical evidence of HF. The potential value of natriuretic peptide measurement in patients with coronary heart disease, valve disease, constrictive pericarditis, pulmonary hypertension, and sepsis is discussed separately. (See "Natriuretic peptide measurement in non-heart failure settings".)
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