Amino-terminal pro-B-type natriuretic peptide (NT-proBNP) is one of the natriuretic peptide family of hormones that play a vital role in the regulation of circulatory volume and pressure, reducing activity of the renin–angiotensin–aldosterone system and minimising myocardial fibrosis in the setting of heart muscle stretch. Therefore, natriuretic peptides exert favourable effects on the heart in the context of heart failure (HF), and recent data suggest that the measurement of natriuretic peptide concentrations in patients with both acute and chronic HF not only aids in the diagnosis and prognosis of HF in both symptomatic and asymptomatic patients, but may also be useful in their clinical management. In recognition of the importance of NT-proBNP as an adjunct to the diagnosis, prognosis and management of patients with heart disease, NT-proBNP has been added to numerous guideline statements,1–4 and an international consensus panel recently published recommendations for its optimal use.5,6 This article will discuss the up-to-date understanding of NT-proBNP as a tool for HF applications.
Natriuretic Peptide Biology
Recent changes in the understanding of BNP and NT-proBNP biology have led to the recognition that what is measured clinically by assays designed to detect these analytes is actually a mixture of degraded BNP, NT-proBNP and an un-cleaved precursor protein (which lacks the biological activity of BNP) called proBNP. That clinical assays cross-react with proBNP remains purely speculative; however, data argue that there is no clear advantage of direct measurement of un-cleaved proBNP over clinical assays for NT-proBNP.7
Role of NT-proBNP in the Diagnosis of Heart Failure
Abundant data indicate that NT-proBNP is valuable for the diagnostic evaluation of HF in asymptomatic patients and those presenting with acute dyspnoea. It is important to note that as a sensitive indicator of structural heart disease, NT-proBNP may be elevated in a variety of clinical conditions, including non-systolic heart muscle diseases, valvular heart disease, atrial arrhythmias, anaemia, septic shock and shock due to other causes, ischaemic stroke and pulmonary hypertension8–22 (see Table 1). In each of these cases, irrespective of diagnosis, NT-proBNP has been shown to be prognostically meaningful.
Factors with Effects on NT-proBNP Values
When considering the value of NT-proBNP testing in apparently healthy individuals, it is necessary to recognise that concentrations of this biomarker are considerably lower in those without structural heart disease and thus more likely to be affected by processes with subtle effects on NT-proBNP, such as age, sex, renal function and body mass index (BMI).23–46 As an example, among healthy patients aged 45–59 and ≥60 years, the mean values of NT-proBNP were identified to be 28 and 61ng/l, respectively, or 53 or 86ng/l for male and females, respectively.23 The age-associated increase in NT-proBNP levels may be due to age-associated diastolic dysfunction of the heart along with declining glomerular filtration rate (GFR),28 while the difference between the sexes is probably related to the effects of androgens on the concentration of natriuretic peptides, such that men have lower values for BNP and NT-proBNP.46 With respect to renal function, NT-proBNP is partially renally excreted, and hence with declining renal function increasing levels of NT-proBNP are observed. How much of the measurable NT-proBNP present in the circulation of patients with impaired renal function is related to structural heart disease in these patients remains speculative; however, prognostic studies argue that the majority of the NT-proBNP signal measured in patients with chronic kidney disease is in fact a ‘true positive’ value, as concentrations of NT-proBNP vary widely among patients with similar levels of renal dysfunction and are powerfully prognostic when elevated.30–44 Lower than expected natriuretic peptide values may be seen in normal patients who are overweight; there is an inverse relationship between BMI and NT-proBNP levels.25 This is probably due to reduced release of NT-proBNP, as similar BMI-associated reductions in BNP are observed (and NT-proBNP and BNP are cleared in a different manner).45,46 The participation of increased activity of natriuretic peptide clearance receptor located in the adipose tissue remains debatable.29
NT-proBNP Testing for Diagnostic Evaluation of Symptomatic Primary Care Patients
Studies have analysed the role of utilising NT-proBNP levels to exclude HF in the evaluation of primary care patients presenting with dyspnoea.47–51 In this context, NT-proBNP has very good negative predictive value, which makes it a good screening test in the primary care setting to rule out HF rather than diagnose it.48 For this indication, an NT-proBNP value of 125ng/l for ruling out HF among patients <75 years of age is useful47–52 (see Figure 1). As noted above, age has a significant effect on NT-proBNP levels, and values of 300–450ng/l have been proposed for those aged >75 years.52
Utility of NT-proBNP for Diagnosing Acute Heart Failure in Those with Dyspnoea in the Emergency Department
NT-proBNP levels are typically increased in those with acutely decompensated HF, with concentrations that are usually much higher than in those with early or asymptomatic HF. Thus, the cut-off values for NT-proBNP-based diagnostic evaluation are considerably higher. Nonetheless, NT-proBNP retains its excellent diagnostic value for acute symptom evaluation and management.
Several clinical trials have lent clarity as to the appropriate application of NT-proBNP for acute symptom evaluation. Among these are the landmark ProBNP Investigation of Dyspnea in the Emergency Departments (PRIDE)53 and the International Collaborative of NT-proBNP (ICON)54 studies. In the PRIDE study,53 patients who presented to the emergency department with acute dyspnoea were analysed using NT-proBNP levels, clinical examination and other diagnostic modalities to determine the diagnosis of HF. Patients with acute HF had NT-proBNP levels that were extremely elevated compared with patients who had dyspnoea without acute HF. In the PRIDE study,53 an NT-proBNP cut-off of 300ng/l had a high negative predictive value to rule out HF compared with a value of 900ng/l, which had a comparable positive predictive value to a BNP value of 100ng/l to ‘rule in’ HF. Further analyses suggested that an NT-proBNP level of 450ng/l was superior to diagnose younger patients with HF. This concept of age-adjusted HF cut-points for NT-proBNP were further evaluated in the ICON study,54 where age-adjusted cut-off values for NT-proBNP were found to yield higher positive predictive value for HF than a single cut-off. NT-proBNP levels of 450ng/l (for those aged <50 years), 900ng/l (for those aged 50–75 years) and 1,800ng/l (for those aged >75 years) were suggested to ‘rule in’ heart failure, while an age-independent cut-off of 300ng/l excluded HF.
While age stratification necessarily injects more complexity than using a single cut-point, it has already been shown that a single BNP cutpoint of 100ng/l (equal to an NT-proBNP of 900ng/l, analytically speaking) is mainly useful for the diagnosis of HF in middle-aged patients;55 however, this cut-off yields an 89% negative predictive value for excluding the diagnosis of HF at best, and is certainly less useful for evaluating the elderly or those with renal dysfunction. Given the advantages of age adjustment with respect to sharpening sensitivity for the diagnostic evaluation of the young while improving the specificity of HF diagnosis in the elderly, the International NT-proBNP consensus panel5,6 endorsed the triple cut-point for the diagnostic evaluation of heart failure in patients presenting with acute dyspnoea (see Table 2). While a BNP of 200ng/l has been suggested for those with impaired renal function, no guidance regarding optimal cut-points for BNP in the elderly exist.31
More insights regarding the value of NT-proBNP testing have been gained from the PRIDE study.42,45,58–62 NT-proBNP testing was superior to clinical judgement for correctly identifying HF in dyspnoeic patients, and was useful for this indication in the presence or absence of clinician indecision for the diagnosis.58 NT-proBNP testing was accurate across the range of renal function in PRIDE,42 and was unaffected by the presence of lung disease59 or obesity.45 Neither sex nor race affected cut-points for NT-proBNP,60 and NT-proBNP was equally useful for diagnosis and prognosis in patients with diabetes mellitus.61 Concentrations of NT-proBNP strongly correlated with various cardiac structure and functional abnormalities in PRIDE,62 yet remained strongly prognostic even in the presence of echo data; indeed, an NT-proBNP concentration <300ng/l effectively excluded a broad range of abnormalities on echo, suggesting this cut-point to be useful to reduce the need for unnecessary echocardiography in the evaluation of dyspnoea.
It is important to recognise patients with ‘intermediate’ or ‘grey’ zone NT-proBNP values (levels between cut-point of 300ng/l and the consensus recommended age-adjusted cut point for ‘rule in’ heart failure) and their clinical correlation. The most important differential diagnoses are in mild HF, such as New York Heart Association class II symptoms,54 non-systolic HF,63,64 HF with increased BMI45,65 and other diagnosis66 (see Table 3). Importantly, intermediate or grey zone NTproBNP values are not associated with benign prognosis regardless of the cause, hence they should be taken seriously.
A challenging situation is the evaluation of patients with prior HF, since NT-proBNP values will typically be elevated. A useful tip when evaluating these patients is to ascertain their ‘dry’ NT-proBNP level (the concentration of NT-proBNP when these patients are in their compensated HF state); NT-proBNP levels that are 25% different from a dry value strongly suggest acute on chronic HF.67
NT-proBNP as a Prognostic Marker in Heart Failure and Its Potential Value for Management
Acute Heart Failure
Several studies indicate that in those with HF, NT-proBNP is a powerful tool for prognostication by itself or considered with other variables such as creatinine, haemoglobin or other cardiac biomarkers such as troponin, galectin-3 (released by activated macrophages in the context of HF) or ST2 (an interleukin receptor family member also secreted by myocytes in response to stretch and a participant in myocardial remodelling in HF).40,42,44,68–75
In the ICON study,54 an NT-proBNP of 5,180ng/l was useful for shortterm (76-day) mortality prediction, with a negative predictive value of 96%. In the PRIDE study,70 examining a relatively longer-term (one-year) time horizon, an NT-proBNP cut-point of approximately 1,000ng/l was associated with increased mortality. In addition, the NT-proBNP levels were able to predict mortality risk not only in acute HF, but also in dyspnoea without the diagnosis of HF. As complex and dynamic physiological changes occur in renal function during the management of patients with HF (so-called ‘cardio–renal’ syndrome), the interpretation of NT-proBNP levels in the context of renal failure is of particular interest. Among patients admitted with acute HF, those whose NT-proBNP levels were >4,647ng/l in the setting of impaired renal function had the worst prognosis compared with patients with median levels <4,647ng/l or those with reasonable renal function.40 These important findings suggest that renal dysfunction does not impair the ability of NT-proBNP to prognosticate, and indicates the potential importance of NT-proBNP to define the cardiac portion of the cardio–renal syndrome.
Given the value of NT-proBNP for prognostication, it is only logical to expect a potential for this marker to assist in the management of patients with HF. Indeed, NT-proBNP concentrations are affected by variable physiological changes that happen during acute decompensated HF states, and tend to parallel the process of recompensation of HF. For example, Knebel et al.76 found poor correlation between single haemodynamic parameters and NT-proBNP levels; however, significant decreases in NT-proBNP were found to be associated with significant responses in pulmonary capillary wedge pressure during HF therapy. Similarly, Bayes-Genis et al.77 demonstrated smaller changes (<15%) in NT-proBNP levels over a seven-day period during acute hospital admission among those who suffered complications compared with those who survived (who showed a decrease of 50%). Di Somma and colleagues78 also found a 58% reduction in NT-proBNP levels over a successful seven-day hospital admission for acute decompensated HF.
More definitive data supporting the measurement of NT-proBNP levels to monitor those with acutely destabilised HF came from Bettencourt et al.,68 who demonstrated that an NT-proBNP increase of ≥30% during hospitalisation was associated with a re-admission hazard ratio (HR) of 5.96 and a death HR of 3.67. Those with a <30% decrease in NT-proBNP levels had intermediate outcomes, while those with a >30% drop from baseline to discharge in their NT-proBNP concentrations had the best outcomes. Thus, recommendations are to aim for an NT-proBNP fall of >30% from presentation; when a baseline NT-proBNP is not available, a ‘discharge’ NT-proBNP level of 4,137ng/l is a reasonable target, as an 8% increase in the likelihood of death or re-admission over six months per 1,000ng/l of NT-proBNP levels over this threshold have been described (p<0.0001).
Lending support to these retrospective, observational data, the Improved Management of Patients with Congestive Heart Failure (IMPROVECHF)79 study recently demonstrated the importance of NT-proBNP testing to optimise the evaluation and management of those with acutely destabilised HF. In the trial, a prospective, randomised study of dyspnoea evaluation with or without NT-proBNP values, the use of NT-proBNP levels for diagnosis and management was associated with a 21% reduction in time spent in the emergency department, and 60- day re-hospitalisation rates decreased by 35% (with concomitant reductions in costs). These data argue the value of NT-proBNP for the evaluation and management of the dyspnoeic patient with HF.
Chronic Heart Failure
In chronic HF, NT-proBNP levels are strongly prognostic. As demonstrated,80 this risk increments over time when concentrations rise, suggesting that serial NT-proBNP measurement could be used as an important prognostication tool for chronic HF patients, particularly as tools with favourable effects on HF – such as loop diuretics, angiotensin-converting enzyme (ACE) inhibitors, β-adrenergic blockers and spironolactone – also tend to lower NT-proBNP concentrations.81–84 Troughton et al.84 demonstrated that an NT-proBNP level below approximately 1,700ng/l was associated with fewer combined events of HF decompensation, hospitalisation and mortality (19 versus 54; p=0.02) during a median 9.5 months of follow-up of stable HF patients. Importantly, this study was small and the medical management was not optimal, particularly in relation to β- blockers. Although several studies85–87 that achieved natriuretic peptide concentrations below ‘target’ levels have only just been published or are ongoing, the use of natriuretic peptides to ‘tailor’ outpatient HF remains an exciting prospect.
Other Applications of NT-proBNP
Acute myocardial ischaemia stimulates release of NT-proBNP by a variety of mechanisms, including myocardial stretch and ventricular dysfunction, and NT-proBNP has prognostic value across the spectrum of acute coronary syndrome (ACS). Several studies88–91 demonstrate that NT-proBNP levels obtained during the acute or subacute phase of ACS are predictors, independent of other cardiac risk factors, including troponins, for mortality: higher levels are associated with increased mortality. In the Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) study,92 measurement of NT-proBNP levels at baseline, 48 hours and 72 hours (serial measurements) found that baseline NT-proBNP levels >250ng/l were associated with higher event rates (adjusted odds ratio [OR] 3.7, 95% confidence interval [CI] 2.3–5.7; p<0.001).
In patients with low NT-proBNP baseline levels, a rise in NT-proBNP levels over 72 hours to >250ng/l was also linked to an adverse 30-day prognosis (OR 24.0, 95% CI 8.4–68.5; p≤0.001). The potential role of NT-proBNP to guide therapeutic interventions for patients with acute coronary syndrome is of interest. As demonstrated in the Fast Revascularization during Instability in Coronary Artery Disease (FRISC) II93 and Global Use of Strategies To Open Occluded Coronary Arteries (GUSTO) IV94 trials, one-year mortality was significantly lower with revascularisation in patients with NT-proBNP above the 25th percentile of 237ng/l (relative risk [RR] 0.63, 95% CI 0.5–0.8). In contrast, a Conservative Treatment in Unstable Coronary Syndromes (ICTUS) substudy95 showed that an early invasive strategy for patients with high NT-proBNP levels was not associated with mortality reduction. Thus, the use of natriuretic peptides to guide therapeutic intervention for ACS remains speculative.
NT-proBNP is also a strong prognostic marker among patients with stable coronary artery disease (CAD). In one study,96 after adjustment for independent predictors of cardiac risk the median NT-pro-BNP level was significantly lower among patients who survived rather than died (120pg/ml [ng/l] [interquartile range 50–318] versus 386pg/ml [ng/l] [146–897]; p<0.001). In another study,97 an association between NT-proBNP levels and cardiovascular end-points including myocardial infarction, stroke, HF and death existed among patients with stable CAD, even after adjustment for all prognostic indicators. These findings indicate potential utility for NT-proBNP to identify those at highest risk of adverse outcomes from ischaemic heart disease, and the potential for the marker to assist in more aggressive therapeutic intervention accordingly.
Besides acute and stable CAD, NT-proBNP has prognostic value in acute pulmonary embolism, presumably due to release of natriuretic peptide in the context of dilation/strain of the right ventricle. Importantly, in addition to rising in the context of pulmonary embolism, Kutcher et al.98 demonstrated that NT-proBNP levels <500ng/l had a negative predictive value of 97% for adverse clinical outcome, and was an independent prognostic predictor (OR 14.6, 95% CI 1.5–139.0; p=0.02) after adjusting for severity of pulmonary embolism, age, troponin T levels and a prior history of HF. Lutz Binder et al.99 observed that an NT-proBNP cut-point of 1,000ng/l had a negative predictive value of 95% for death and in-hospital complications, and of 100% for in-hospital deaths.
The measurement of NT-proBNP has been shown to have prognostic significance among critically ill patients patients admitted to intensive care units (ICUs) with non-cardiac diagnosis such as severe sepsis or septic shock.19 In one study,18 NT-proBNP levels were measured among patients with shock of various types in the ICU, and while NT-proBNP levels did not correlate with either haemodynamic parameters or filling pressures, they independently predicted ICU mortality (OR 14.8, 95% CI 1.8–125.2; p=0.013), irrespective of the presence of HF. Similar findings were recently reported supporting NT-proBNP as a powerful predictor of death in acute respiratory distress syndrome.100
NT-proBNP is a versatile marker with a multitude of potential and proven applications. It is valuable across the wide spectrum of cardiovascular disease, including and especially among patients with HF. Future applications of NT-proBNP will no doubt include its use for the monitoring and titrating of therapy for HF, as well as potential use among patients with ischaemic heart disease, including both acute/unstable as well as more chronic/stable forms.