BNP in the diagnosis and risk stratification of heart failure

Heart failure (HF) is a common disorder that is associated with significant mortality and morbidity. However, the diagnosis of HF may at times be difficult when using conventional tools. The cardiac natriuretic peptides, particularly brain (B-type) natriuretic peptide (BNP), have evolved to be useful biomarkers of cardiac function and prognosis in HF and other cardiovascular disorders. Multiple observational studies have established the close association between plasma BNP as well as the N-terminal fragment of the BNP prohormone (NT-proBNP) with the diagnosis of HF and an independent prediction of mortality and HF events. Although there are confounding variables to consider, when used in the correct clinical settings, BNP or NT-proBNP testing can be extremely useful. Furthermore, preliminary data from randomized controlled trials suggest that knowledge of BNP and/or NT-proBNP level may optimize the management of patients with HF. Large-scale randomized controlled trials that evaluate BNP/NT-proBNP-guided therapy are ongoing.     

B-type natriuretic peptide in heart failure

PURPOSE OF REVIEW: This review focuses on recent literature pertaining to the role of B-type natriuretic peptide (BNP) in heart failure. RECENT FINDINGS: Heart failure is a common disorder that is associated with significant mortality and morbidity. The diagnosis of heart failure may at times be difficult when using conventional tools. The cardiac natriuretic peptides, particularly BNP, have evolved to be useful biomarkers in heart failure and other cardiovascular disorders. Recent studies have established a close association between plasma BNP and the amino-terminal fragment of the BNP prohormone (NT-proBNP) with the diagnosis of heart failure and independent prediction of mortality and heart failure events. Furthermore, preliminary data from randomized controlled trials suggest that knowledge of BNP and/or NT-proBNP level may optimize the management of patients with heart failure. Exogenous natriuretic peptide in the form of recombinant human BNP (nesiritide) has been shown to improve hemodynamics and dyspnea and is approved in the USA and several other countries for the management of patients with acute decompensated heart failure. The effect of nesiritide on clinical outcome, however, remains unclear. SUMMARY: When used in the appropriate clinical settings, BNP or NT-proBNP testing is extremely useful in establishing diagnosis and predicting prognosis in heart failure. Nesiritide holds promise in the management of patients with acute decompensated heart failure. Large-scale randomized controlled trials to evaluate BNP/NT-proBNP-guided therapy are currently in progress and studies of the impact of exogenous BNP on clinical outcomes in heart failure are likely to be forthcoming.     

Biomarkers in the Management of Heart Failure

Biomarkers, especially natriuretic peptides such as B-type natriuretic peptide (BNP) and N-terminal-proBNP (NT-proBNP), are a valuable addition to standard clinical assessment in the diagnosis and prognosis of heart failure (HF). Furthermore, there is an increasing amount of evidence suggesting that natriuretic peptide–guided HF management may improve mortality, morbidity, and cost effectiveness. This work focuses on the use of BNP or NT-proBNP for the outpatient management of patients with chronic HF.     

Usefulness of B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide as biomarkers for heart failure in young children with single ventricle congenital heart disease

Children with single ventricle (SV) physiology have increased ventricular work and are at risk of heart failure (HF). However, a HF diagnosis is especially difficult, because few objective measures of HF have been validated in this cohort. We have previously shown that plasma B-type natriuretic peptide (BNP) levels are sensitive and specific for detecting HF in a small, heterogeneous SV cohort. The aim of the present study was to define the effect of SV morphology and stage of palliation on the correlation between BNP and HF. We also examined the utility of N-terminal pro-BNP (NT-proBNP), a more stable product of pre-BNP processing, as a biomarker of HF in these patients. A cross-sectional observational study of SV children aged 1 month to 7 years was conducted. The presence of HF was defined as a Ross score > 2. The association of BNP or NT-proBNP with HF was assessed using logistic regression analysis and receiver operating characteristic curves. Of the 71 included children, 22 (31%) had clinical HF. A doubling of BNP was associated with an odds ratio for HF of 2.20 (95% confidence interval 1.36 to 3.55, p = 0.001) with a c-statistic > 75%, yielding a detection threshold of ≥ 45 pg/ml. This threshold was preserved when patients were stratified by the right ventricular morphology or stage of surgical palliation. Similarly, a doubling of NT-proBNP was associated with an odds ratio for HF of 1.92 (95% confidence interval 1.17 to 3.14, p = 0.009). In contrast to BNP, the threshold value of NT-proBNP for predicting HF decreased with the stage of palliation. In conclusion, plasma BNP and NT-proBNP are reliable tests for clinical HF in young children with SV physiology, specifically those with right ventricular morphology, regardless of the stage of palliation.     

The integration of BNP and NT-proBNP into clinical medicine

B-type natriuretic peptide (BNP) and NTproBNP have been shown to be extremely helpful in the diagnosis and management of patients with heart failure (HF). These neurohormones are predominately secreted from the left and the right cardiac ventricle in response to volume and pressure overload. BNP and NT-proBNP can be seen as quantitative markers of HF summarizing the extent of systolic and diastolic left ventricular dysfunction. Research data from clinical studies and six years of clinical experience with BNP allow us to provide clear recommendations regarding the integration of BNP/NT-proBNP into clinical medicine. With multiple additional indications in prospect, current evidence clearly supports the use of BNP and NT-proBNP in three clinical settings: patients with acute dyspnoea, prior to discharge in patients hospitalised with acute HF, and the longterm management of patients with HF.     

The prolonged lowering effect of levosimendan on brain natriuretic peptide levels in patients with decompansated heart failure: clinical implications

The release of brain natriuretic peptide (BNP) is increased in heart failure (HF). The plasma concentrations of BNP and N terminal pro-BNP (NT-proBNP) fall after effective pharmacologic treatment of HF, which suggests that measurements of plasma BNP may be helpful in evaluating therapy. Despite the initial reports that suggested a positive effect of levosimendan on short- and long-term survival in patients with severe HF, the results of the recently presented large-scale clinical trials provided rather controversial results. Further clinical studies are needed to end the confusion regarding the effects of levosimendan on prognosis in patients with decompansated HF.     

Response of Novel Biomarkers to BNP Infusion in Patients with Decompensated Heart Failure: A Multimarker Paradigm

Multibiomarker paradigms have been proposed to diagnose, define progression, and to monitor therapy of heart failure (HF) patients. The aim of this study was to evaluate the prognostic and therapy-monitoring potential of four novel biomarkers (copeptin, midregional proatrial natriuretic peptide (MR-proANP), neopterin, and procalcitonin) which have been shown to be elevated in the plasma of patients with HF and reported to have prognostic value. In a prospective study of 40 patients hospitalized for decompensated HF and who received nesiritide infusions as part of their care, blood was drawn before, during, and postinfusion and assayed for the novel biomarkers. B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) which were previously measured and reported in this cohort were also included in the analyses. All biomarkers were elevated at baseline prior to nesiritide infusion, but copeptin, MR-proANP, and NT-proBNP demonstrated significant acute reductions in plasma levels in response to therapy. Copeptin levels were higher in posthospital nonsurvivors and by proportional hazards model were associated with an increased mortality risk (p = 0.04). Procalcitonin and neopterin added no incremental information on response to therapy or risk stratification. In contrast, copeptin and MR-proANP appear to have potential for monitoring acute responses to therapy. Only copeptin and BNP contributed to risk stratification in this cohort of advanced HF patients, but the conjoint use of BNP or NT-proBNP does not appear to impact the prognostic value of copeptin alone. These results are hypothesis generating to stimulate additional investigation.     

Use of Novel and Conventional Biomarkers for Management of Patients With Heart Failure

Investigation of the complex biochemical pathways that underlie heart failure (HF) has led to the recognition of multiple molecular markers that may help to characterize patients with this disease. Although a myriad of novel biomarkers are being studied, most attention continues to be focused on the natriuretic peptides, brain natriuretic peptide (BNP) and N-Terminal-proBNP (NT-proBNP). Numerous studies have established a role for these hormones in HF diagnosis and prognostication. More contentious has been their role in helping to guide HF management on a routine basis. This article aims to update the body of evidence surrounding conventional HF biomarkers and to highlight some emerging evidence on the use of novel markers. We believe that in select patients there may be a role for monitoring and cautious interpretation of HF biomarker levels to facilitate diagnosis, prognostication, and optimization of tailored therapy. However, there are not yet convincing data to suggest that routine hormone monitoring should be applied broadly and algorithmically to all HF patients. Moreover, to the extent that they are measured, HF biomarkers should serve only as a complement to—never as a substitute for—sound clinical judgment, watchful follow-up, and reliance on expert consultation when necessary.     

The role of B-type natriuretic peptide testing in patients with acute coronary syndromes

B-type (brain) natriuretic peptide (BNP) is a cardiac hormone whose measurement can be helpful in a variety of clinical settings, but has been most extensively studied in patients with heart failure and acute coronary syndrome (ACS). The value of both BNP and its N-terminal fragment, NT-proBNP, as independent prognostic biomarkers in ACS is supported by data from a number of clinical trials. BNP/NT-proBNP levels can predict death and subsequent development of heart failure, but not recurrent ischemic events. BNP may also be helpful as an aid in establishing the diagnosis of ACS in patients presenting with chest pain. The role of BNP in determining treatment has not yet been defined, though patients with high levels may derive more benefit from invasive management and from treatment with ranolazine. The National Academy of Clinical Biochemists (NACB) guidelines state that measurement of BNP/NT-proBNP may be useful in prognosis for ACS patients, but do not yet recommend its routine use, naming a number of other issues that need to be resolved in the use of this marker. Age- and gender-related decision limits should be determined, and cutoff levels of BNP/NT-proBNP corresponding to low, intermediate, and high risk patients should be ascertained. Additional evidence regarding the impact of BNP/NT-proBNP levels on treatment strategy in ACS patients will be helpful in further defining the role of B-type natriuretic peptide testing in the acute coronary syndromes.     

Natriuretic Peptides: Role in the Diagnosis and Management of Heart Failure: A Scientific Statement From the Heart Failure Association of the European Society of Cardiology,Heart Failure Society of America and Japanese Heart Failure Society

Natriuretic peptides, brain (B-type) natriuretic peptide (BNP) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) are globally and most often used for the diagnosis of heart failure (HF). In addition, they can have an important complementary role in the risk stratification of its prognosis. Since the development of angiotensin receptor neprilysin inhibitors (ARNIs), the use of natriuretic peptides as therapeutic agents has grown in importance. The present document is the result of the Trilateral Cooperation Project among the Heart Failure Association of the European Society of Cardiology, the Heart Failure Society of America and the Japanese Heart Failure Society. It represents an expert consensus that aims to provide a comprehensive, up-to-date perspective on natriuretic peptides in the diagnosis and management of HF, with a focus on the following main issues: (1) history and basic research: discovery, production and cardiovascular protection; (2) diagnostic and prognostic biomarkers: acute HF, chronic HF, inclusion/endpoint in clinical trials, and natriuretic peptides-guided therapy; (3) therapeutic use: nesiritide (BNP), carperitide (ANP) and ARNIs; and (4) gaps in knowledge and future directions.     

B-type natriuretic peptide-guided therapy: a systematic review

BNP/NT-proBNP measurement has not gained widespread use for the management of patients with heart failure (HF) despite several randomized controlled trials. A systematic review addressing the question of whether patients with HF benefit from BNP-assisted therapy or intensified therapy compared with usual care was undertaken. Relevant randomized controlled trial (RCTs) were selected by searching Medline, Embase, AMED, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and CINAHL for English-language articles published from 1980 to 2012. Selected studies required patients to be treated for chronic HF with medical therapy based on BNP/NT-proBNP or usual care. There were no restrictions except that BNP/NT-proBNP measurement had to be done by an FDA approved method. Nine RCTs were identified with 2,104 patients with study duration that ranged from 3 to 18 months. Overall, there was a wide variation in study design and how parameters were reported including patient selection, baseline characteristics, therapy goals, BNP/NT-proBNP cutpoint, and outcome types. Meta-analysis was not appropriate given this study heterogeneity. The strength of evidence for the outcome of mortality, reported in seven studies, was found to be low due to inconsistency and imprecision. This systematic review showed that the evidence is of low quality and insufficient to support the use of BNP/NT-proBNP to guide HF therapy. Further trials with improved design are needed.     

Natriuretic peptide testing in clinical medicine

Since the discovery of atrial natriuretic factor in 1981 by de Bold et al, there has been tremendous progress in our understanding of natriuretic peptides (NPs). Recently, testing for brain-type NP (BNP) and its amino terminal cleavage equivalent (NT-proBNP) has been rapidly adopted in clinical medicine for numerous indications, including the diagnosis and exclusion of heart failure (HF). In this regard, logical application of BNP or NT-proBNP testing may not only reduce healthcare costs but also potentially reduce adverse clinical outcomes. With respect to this fact, the potential importance of the concentration of the NPs for prognosis and the response of BNP or NT-proBNP to therapeutic intervention in terms of clinical events has been demonstrated. On the basis of these observations it is reasonable to expect that concentrations of these peptides might be useful for the management of patients with HF, acting as a gauge of therapeutic accuracy and/or stability of disease. Besides HF, the prognostic utility of NPs has been explored in other settings, particularly in ischemic heart disease and those conditions that lead to right ventricular dysfunction.     

Effect of Beta-blockade and ACE Inhibition on B-type Natriuretic Peptides in Stable Patients with Systolic Heart Failure

INTRODUCTION: The long-term effect of beta-blockade on the plasma levels of natriuretic peptides BNP and its N-terminal counterpart, NT-proBNP, as risk markers in heart failure (HF) is obscure. METHODS: Stable systolic HF patients from the CARMEN study were divided in groups matching their randomised treatment allocation: Carvedilol, enalapril or carvedilol+enalapril. Changes in BNP and NT-proBNP from baseline to 6 months maintenance visit were evaluated in each treatment arm. Furthermore, the prognostic value of BNP and NT-proBNP during monotherapy with carvedilol was assessed with univariate Cox proportional hazards models using a combined endpoint of all cause mortality and cardiovascular hospitalisation. RESULTS: NT-proBNP and BNP were significantly reduced after six months treatment with enalapril (NT-proBNP 1,303 to 857 pg/ml (P < 0.001), BNP 119 to 85 pg/ml (P < 0.001)) or carvedilol+enalapril (NT-proBNP 1,223 to 953 pg/ml (P = 0.003), BNP 117 to 93 pg/ml (P = 0.01)). In contrast, no change was observed in the carvedilol group (NT-proBNP 907 to 1,082 pg/ml (P = 0.06), BNP 114 to 130 pg/ml (P = 0.15). The prognostic value of NT-proBNP and BNP was maintained in the carvedilol group (NT-proBNP HR 1.018 95% CI (1.005-1.032), BNP 1.171 (1.088-1.260)). CONCLUSION: Treatment of HF patients with carvedilol alone does not reduce levels of natriuretic peptides, but treatment with enalapril does. Both BNP and NT-proBNP predict death and hospitalisation in HF patients treated with carvedilol for six months. The clinical implication of our results is that NT-proBNP and BNP can be used as risk markers of death and cardiovascular hospitalisations in systolic HF patients receiving carvedilol without ACE inhibition.     

The role of B-type natriuretic peptide in the diagnosis and treatment of decompensated heart failure

Heart failure (HF) is a common disease associated with increasing age. B-type natriuretic peptide (BNP), is a cardiac neurohormone, and is released as prepro BNP and then enzyrnatically cleaved to the Ntenninal-proBNP (NT-proBNP) and BNP upon ventricular myocyte stretch. Blood measurements of BNP have been used to identify patients with I-IF. The BNP assay is currently used as a diagnostic and prognostic aid in HF. In general, a BNP level below 100 pg/mL excludes acutely decompensated HF and levels ＞ 500 pg/ml indicate decompensation. Recombinant human BNP (hBNP, nesiritide) is an approved intravenous treatment for acute,decompensated -HF. Nesiritide given in supraphysiologic doses causes vasodilation, natriuresis, diuresis, and improved symptoms over the course of a 48-hour infusion. This paper will sort out the literature concerning the use of this peptide both as a diagnostic test and as an intravenous therapy.     

Natriuretic Peptide Testing in Primary Care

The incidence, as well as the morbidity and mortality associated with heart failure (HF) continue to rise despite advances in diagnostics and therapeutics. A recent advance in the diagnostic and therapeutic approach to HF is the use of natriuretic peptide (NP) testing, including both B-type natriuretic peptide (BNP) and its amino terminal cleavage equivalent (NT-proBNP). NPs may be elevated at an early stage among those with symptoms as well among those without. The optimal approach for applying NP testing in general populations is to select the target population and optimal cut off values carefully. Superior diagnostic performance is observed among those with higher baseline risk (such as hypertensives or diabetics). As well, unlike for acute HF, the cut off value for outpatient testing for BNP is 20-40 pg/mL and for NTproBNP it is 100-150 ng/L. In symptomatic primary care patients, both BNP and NT-proBNP serve as excellent tools for excluding HF based on their excellent negative predictive values and their use may be cost effective. Among those with established HF, it is logical to assume that titration of treatment to achieve lower NPs levels may be advantageous. There are several ongoing trials looking at that prospect.     

B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide - Diagnostic role in stable coronary artery disease

B-type natriuretic peptide (BNP) and its N-terminal fragment (NT-proBNP) are released from ventricular cardiomyocytes in response to an increase in ventricular wall stress and to myocardial ischemia. Both BNP and NT-proBNP have proven to be reliable diagnostic and prognostic biomarkers in patients with heart failure. Recently, the diagnostic roles of BNP and NT-proBNP in patients with coronary artery disease (CAD) have been investigated. For patients with acute coronary syndromes, data have been derived from a great number of studies, whereas in patients with stable CAD, only a limited amount of recent data is available; although limited, these data show that elevations in BNP and NT-proBNP levels are associated with the extent of CAD, thus providing prognostic information for an unfavourable clinical outcome. However, clinical and therapeutic implications are indistinct and need to be elucidated in further studies.     

The biologic variability of B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide in stable heart failure patients

BackgroundThere are conflicting data on the usefulness of B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) in the optimization of therapy for heart failure (HF). Discordant results may be explained by the intra-individual variability of these peptides. This study evaluates the intraindividual variability of BNP and NT-proBNP and the impact of the covariates of age, sex, and renal function.Methods and ResultsStable HF patients attending our unit were included. Blood samples were drawn 1 hour apart on 2 occasions 1 week apart. Forty-five patients were enrolled (69.6 ± 12.1 years, 64% male, 84% systolic HF). Within-hour and within-week intraindividual variability were: 6.9% and 21.1% for NT-proBNP; 14.6% and 28.4% for BNP (P < .01 for within-hour comparison of BNP and NT-proBNP). Reference change values over 1 week for NT-proBNP and BNP were 49.2% and 66.2%, respectively. There were no significant relationships identified between variability and age, gender, or glomerular filtration rate.ConclusionThere is considerable intraindividual variability in these peptides in stable HF patients. Changes of approximately 50% and 66% for NT-proBNP and BNP from week to week are needed to indicate an altered clinical status and caution should be exercised in interpreting serial changes in these peptide levels when monitoring patient responses to treatment or clinical status.     

NT-proBNP and the diagnosis of heart failure: a pooled analysis of three European epidemiological studies

Many studies have shown that the B-type natriuretic peptides (BNP and NT-proBNP) are proven diagnostic markers for heart failure due to left ventricular systolic dysfunction. The manner in which they are to be used is still being unravelled; most single centre studies have chosen the best concentration of the peptide on ROC analysis as their cut-point resulting in numerous different values for both BNP and NT-proBNP appearing in the literature. We report a different approach of defining an age and sex corrected abnormal concentration for NT-proBNP, derived from normal individuals within a large sample of 3051 subjects pooled from three European epidemiology studies and applying that to the entire population to detect HF and LVD. Three thousand and fifty one subjects were studied. Of these 10% (305) had significant LVD and 3.1% (94) had HF. The median concentrations of NT-proBNP (IQR) in normals, those with LVD and in heart failure subjects were 20 pg/ml (10.30), 117.3 pg/ml (28.145) and 269.6 pg/ml (54.323), P<0.001, respectively. The area under the ROC curve for NT-proBNP for the detection of 'heart failure' was 0.85 and 0.69 for LVD. NT-proBNP was an independent predictor of the presence of HF on multivariate analysis. An abnormal NT-proBNP was defined as being >95th centile for normals, age and sex corrected, and diagnosed HF with a sensitivity of 75% and a negative predictive value of 99%. In an additional analysis in a breathless subgroup of our population, in 30% a raised NT-proBNP concentration could be explained by HF due to LVD, in another 64% the high BNP level was associated with some other structural of functional cardiac abnormality or renal impairment. We were unable to assign a possible cause to the high NT-proBNP values in 5.9% of this breathless subgroup of the population. An abnormal NT-proBNP concentration is an accurate diagnostic test both for the exclusion of HF in the population and in ruling out LVD in breathless subjects. An elevated NT-proBNP merely indicates the presence of 'cardio-renal distress' and should prompt referral for further investigation.     

脑钠肽和N-末端脑钠肽前体对舒张性心力衰竭的诊断价值

舒张功能不全是触发心肌细胞释放脑钠肽（BNP）和氨基末端脑钠肽前体（NT—proBNP）的重要因素。血浆BNP和NT-proBNP水平是舒张性心力衰竭患者诊断和预后判断重要的生化学指标,独立于传统的临床症状及超声心动图检查结果。现简要介绍血浆BNP和NT—proBNP检测在舒张性心力衰竭患者的应用价值。     

Anaemia and renal dysfunction are independently associated with BNP and NT-proBNP levels in patients with heart failure

BACKGROUND: Anaemia may affect B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) levels, but this has not been well described in heart failure (HF) patients without the exclusion of patients with renal dysfunction. AIMS: To study the influence of both anaemia and renal function on BNP and NT-proBNP levels in a large group of hospitalised HF patients. METHODS AND RESULTS: We studied 541 patients hospitalised for HF (mean age 71+/-11 years, 62% male, and left ventricular ejection fraction 0.33+/-0.14). Of these patients, 30% (n=159) were anaemic (women: Hb<7.5 mmol/l, men: Hb<8.1 mmol/l). Of the 159 anaemic patients, 73% had renal dysfunction (eGFR<60 ml/min/1.73 m2) and of the non-anaemic patients, 57% had renal dysfunction. BNP and NT-proBNP levels were measured in all patients before discharge. In multivariable analyses both plasma haemoglobin and eGFR were independently related to the levels of BNP and NT-proBNP (standardised beta's of -0.16, -0.14 [BNP] and -0.19, -0.26 [NT-proBNP] respectively, P-values<0.01). CONCLUSION: Anaemia and renal dysfunction are related to increased BNP and NT-proBNP levels, independent of the severity of HF. These results indicate that both anaemia and renal dysfunction should be taken into consideration during the interpretation of BNP and NT-proBNP levels in HF patients.