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Clinical Chemistry 53: 1289-1297, 2007. First published May 10, 2007; 10.1373/clinchem.2006.080234
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(Clinical Chemistry. 2007;53:1289-1297.)
© 2007 American Association for Clinical Chemistry, Inc.

Lipids, Lipoproteins, and Cardiovascular Risk Factors

Comparison of Brain Natriuretic Peptide (BNP) and Amino-Terminal ProBNP for Early Diagnosis of Heart Failure

Michele Emdin1,a, Claudio Passino1,2, Concetta Prontera1, Marianna Fontana1, Roberta Poletti1, Alessandra Gabutti1, Chiara Mammini1, Alberto Giannoni1, Luc Zyw1, Giancarlo Zucchelli1 and Aldo Clerico1,2

1 CNR Institute of Clinical Physiology, Cardiovascular Medicine Department and Cardiovascular Endocrinology Laboratory, Pisa, Italy.
2 Scuola Superiore S. Anna, Pisa, Italy.

aAddress correspondence to this author at: Cardiovascular Medicine Department, CNR Institute of Clinical Physiology, via Giuseppe Moruzzi 1, 56124 Pisa, Italy. Fax 39-050-3152109; e-mail emdin{at}ifc.cnr.it.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: We compared the diagnostic accuracy of brain natriuretic peptide (BNP) and amino-terminal proBNP (NT-proBNP) for diagnosis of preclinical and mild heart failure (HF).

Methods: We assayed plasma NT-proBNP and BNP in 182 healthy controls and in a prospective cohort of 820 HF patients divided according to the American Heart Association/American College of Cardiology classification. These included 86 patients in stage A [mean (SE) ejection fraction 61% (1%); mean (SE) age 47 (2) years], 255 in stage B [65% (2%); 62 (1) years], 420 patients in stage C [35% (1%); 68 (1) years] and 59 in stage D [25% (1%); 74 (1) years]. Diagnostic accuracies of BNP and NT-proBNP were evaluated by ROC analysis, and a multivariate linear regression model was applied to predict HF staging.

Results: Median BNP and NT-proBNP concentrations increased from stage A to D 57-fold and 107-fold, respectively. Both assays were accurate (P <0.001) in separating stage B from controls or stage A, and stage C from controls or stage A or B. NT-proBNP was more accurate (P <0.001) than BNP in differentiating stage C from stages A and B patients and controls and was a better predictor of HF classification in a model including age, sex, and renal function (P <0.001).

Conclusions: Monitoring BNP or NT-proBNP enabled identification of asymptomatic patients at risk for the development of HF. NT-proBNP showed better accuracy than BNP for identifying mild HF.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The role of natriuretic hormones in identification of asymptomatic ventricular dysfunction remains to be clarified (1)(2). Brain natriuretic peptide (BNP) 1 and amino-terminal pro–brain natriuretic peptide (NT-proBNP) assays have been confirmed to be useful (2) for screening of heart disease (3), stratification of patients with heart failure (HF) (4)(5), detection of left ventricular systolic and/or diastolic dysfunction (2), and differential diagnosis of dyspnea (6)(7). The use of BNP and NT-proBNP for ruling out noncardiac dyspnea in HF assessment was proposed by recent American and European guidelines (8)(9)(10)(11).

Because BNP and NT-proBNP show different biochemical and physiological characteristics, monitoring BNP and NT-proBNP may give different clinical results (1)(2)(12)(13). A few studies have shown conflicting results regarding the diagnostic accuracy of BNP and NT-proBNP in patients with chronic stable (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) and acute (26)(27)(28)(29)(30)(31)(32)(33)(34)(35) HF. These studies show wide heterogeneity of the BNP and NT-proBNP immunoassays used, clinical characteristics of patients, clinical end-points, and clinical standards used for HF diagnosis, but all of the studies used the New York Heart Association (NYHA) classification for the stages of HF.

The American Heart Association/American College of Cardiology (AHA/ACC) task force for the diagnosis and management of chronic HF has proposed a new classification, updated in 2005 (11), focusing on the preclinical evolution of the disease. In this classification, stage A includes asymptomatic patients at risk for developing HF with no structural cardiac involvement, stage B includes asymptomatic patients at risk for developing HF with structural cardiac involvement, stage C includes patients with past/current symptoms of HF associated with structural heart disease, and stage D includes symptomatic patients with end-stage disease requiring specialized treatment strategies such as mechanical circulatory support, continuous inotropic infusions, cardiac transplantation, or hospice care. This classification is intended to complement the NYHA classification, which primarily gauges the severity of symptoms in stage C or D patients.

Our aim was to compare the diagnostic accuracy of BNP and NT-proBNP assays across a wide variety of patient populations, from asymptomatic individuals with clinical conditions that put them at risk for HF (AHA/ACC stage A–B), to patients with no, mild, or severe symptoms associated with mild-to-severe systolic dysfunction (C–D).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
patients
From February 1998 to January 2006 we prospectively evaluated 820 consecutive patients referred to our cardiovascular medicine department for the evaluation of risk or presence of HF. The diagnosis of HF was determined in accordance with the ESC and AHA/ACC recommendations (9)(10)(11). Cardiac morphology and function were assessed by 2-dimensional echocardiography. All patients were stratified according to AHA/ACC classification. Stage C and D patients were stratified according to NYHA class and left ventricular ejection fraction (EF) (9)(10)(11). Diagnosis of HF and classification of AHA/ACC HF stages A through D, determined by history, symptoms, and physical and instrumental findings for the assessment of structural myocardial involvement, were established by expert cardiologists blind to BNP and NT-proBNP findings.

A control group, n = 182 healthy individuals, was free from disease and denied drug intake during the 4 weeks before the study. In controls ≥50 years old, an echocardiogram and an effort stress test were performed to exclude asymptomatic heart disease.

The investigation conformed to the principles outlined in the Declaration of Helsinki and was approved by our Institutional Ethics Committee. Informed consent was obtained from all participants enrolled in the study.

bnp and nt-probnp assays
Blood was collected between 8 AM and 9 AM from study participants after they had fasted overnight and rested in a supine position for 20 min. Immediately after collection, samples (8–10 mL) were placed in ice-chilled disposable polypropylene tubes containing aprotinin (500 000 IU/L of plasma) and EDTA (1 g/L of plasma). Plasma samples were obtained shortly after venipuncture by centrifugation at 1500g for 15 min at 4 °C and, if not assayed immediately, were frozen and stored at –20 °C in 0.5-mL aliquots in polypropylene tubes. Both assays were performed within 1 month of sample collection.

NT-proBNP was measured by the Elecsys® 2010 analyzer (Roche Diagnostics) (12)(13) and BNP was measured with the 2-site IRMA method (Shionoria BNP), as described previously (12)(13). The analytical performance of electrochemiluminescence immunoassay (ECLIA) and IRMA methods, as tested in our laboratory, was previously reported in detail (12)(13). Total imprecisions were 4.0% (103 ng/L) and 3.8% (601 ng/L), respectively. For BNP, total imprecision was 11.0% (5 ng/L) and 9.0% (58 ng/L), respectively. The person executing and reading the tests was blind to clinical diagnosis.

statistical analysis
Statistical analysis was carried out using the SPSS 12.0 software (SPSS). Because BNP and NT-proBNP values do not show gaussian distribution in healthy individuals or in patients with HF (1)(2)(12)(13), natural logarithmic transformation of data was used for statistical analysis. Both the original (using nonparametric tests) and the logarithmically transformed (using parametric tests) data were used for statistical analysis, but only the results obtained with parametric tests after log transformation were reported here, because the parametric approach showed the same trend but with greater statistical power than the respective nonparametric tests. Differences among independent groups were analyzed by ANOVA. Linear regression analysis was performed to assess the relationship among peptides and other variables. The diagnostic accuracy of BNP and NT-proBNP was quantified in terms of area under the ROC curves. A significant difference in the area under the curve (AUC) defined the increment in predictive power between different models. ROC curve analysis furnished optimum cutoff values of BNP and NT-proBNP concentrations (at the point of ROC corresponding to maximal sum of specificity and sensitivity), as well as corresponding sensitivity, specificity, and positive and negative predictive value (PPV and NPV, respectively).

The statistical significance of AUC differences between BNP and NT-proBNP findings for each comparison were also computed by comparing AUC values and the SE.

To tease out the influence of age, sex, and renal function (estimated creatinine clearance by the Cockroft–Gault formula) as confounders of the relationship with NT-proBNP and BNP vs HF classification, a multiple logistic regression model was also used. The overall c-statistic (c-s) of the model was computed to assess the respective influence of either NT-proBNP or BNP. P <0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
clinical and demographic characteristics of the study population
Characteristics of patients in various HF stages, as well as corresponding BNP and NT-proBNP concentrations, are summarized in Table 1 . The stage A group included 86 patients [mean (SE) age 47 (2) years, range 15–84 years] who had normal left ventricular systolic and diastolic function but were affected by risk factors and/or clinical conditions prone to HF, including arterial hypertension and diabetes mellitus, but had no evidence of cardiac structural involvement at echocardiographic evaluation. The stage B group included 255 patients [age 62 (1) years, range 25–90 years] with structural alterations (including left ventricular hypertrophy and/or diastolic dysfunction) but without HF symptoms or left ventricular systolic dysfunction. Associated clinical conditions were arterial hypertension, diabetes mellitus, ischemic heart disease, and cardiac valve abnormalities. The stage C and D group included 479 patients [age 68 (1) years, range 24–94 years; 77% males] with a history of symptoms of HF and an EF <50% [mean (SE) 32% (1%)]; 420 patients were in stage C with past or current symptoms of HF associated with underlying structural heart disease [age 67 (1) years, range 24–94 years], and 59 patients were in stage D with symptomatic end-stage disease requiring specialized treatment strategies [age 74 (1) years, range 41–91 years)]. Underlying cardiac diseases in the C and D patients were idiopathic dilated cardiomyopathy in 230 patients (48%), ischemic cardiomyopathy in 199 patients (42%), and cardiomyopathy secondary to other diseases in 50 patients (10%) [including systemic arterial hypertension (n = 15), cardiac valve abnormalities (n = 14), cardiotoxicity after chemotherapy (n = 5), myopathies (n = 4), diabetes mellitus (n = 3), alcohol consumption (n = 3), myocarditis (n = 3), congenital cardiac abnormalities (n = 1), amyloidosis (n = 1), and chronic constrictive pericarditis (n = 1)]. NYHA classification of the stage C and D patients was NYHA I, 54 patients, 12%; NYHA II, 224 patients, 47%; NYHA III, 137 patients, 29%; and NYHA IV, 59 patients, 12%. Patients were stratified according to the disease severity by NYHA classification with corresponding BNP and NT-proBNP concentrations (Table 2 ). EF values were 35%–50% for 190 patients and <35% for 289 patients. Therefore, stage C and D patients were further divided into 4 groups according to NYHA class and EF: (a) 139 with no/mild symptoms (NYHA I–II) and mild systolic dysfunction (EF 35%–50%), (b) 138 with no/mild symptoms (NYHA I–II) and severe systolic dysfunction (EF <35%), (c) 51 with severe symptoms and mild systolic dysfunction, and (d) 151 with severe symptoms and severe systolic dysfunction.


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  		Table 1. Demographic and clinical characteristics of patients classified according to the AHA/ACC heart failure classification scheme.1


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  		Table 2. Demographic and clinical characteristics of Stage C and D patients classified according to NYHA classification and left ventricular ejection fraction value [EF; mean ± (SE)].1

Patient medications included monotherapy or polytherapy with calcium blockers, ß-blockers, diuretics, or angiotensin-converting enzyme inhibitors; 58% of stage A patients and 10% of stage B patients were free of medications. All stage C and D patients were treated with restriction of water and sodium intake and multidrug treatment (furosemide, 72% of patients; angiotensin-converting enzyme inhibitor or angiotensin-receptor blockers, 90%; carvedilol/bisoprolol, 63%; spironolactone, 49%) not stopped at the time of the study, for obvious ethical reasons. In stage D patients, blood sampling for BNP and NT-proBNP assays was obtained at hospital admission, before the initiation of inotropic and vasodilatory intravenous support. The control group included 182 healthy individuals [mean (SE) age 60 (2) years, range 18–85 years; 56% males].

peptide concentrations in controls and patients stratified according to structural stages a–d and nyha classification
Log-transformed concentrations of plasma BNP and NT-proBNP were significantly correlated (logNT-proBNP = 1.67 + 1.05 logBNP, n = 992, R =0.945, P <0.0001). Both BNP and NT-proBNP concentrations increased progressively (P <0.001) from stage A to stage D (Fig. 1 , top panel), whereas no difference was found between controls and stage A concentrations. NT-proBNP showed a greater increase than BNP values (P <0.001). Compared with controls, median NT-proBNP concentrations increased by 28- and 107-fold in stages C and D, respectively, and BNP concentrations increased 20- and 57-fold, respectively. Similar progressive increases in plasma concentrations were observed when BNP and NT-proBNP were plotted according to NYHA classifications in C and D patients (Fig. 1 , bottom panel). For both assays the control group concentrations were significantly lower (P <0.001) than those in patients at all NYHA stages. Furthermore, for both assays significant differences (P <0.001) were found among all NYHA class values.


Figure 1
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  		Figure 1. Plasma BNP (left) and NT-proBNP (right) concentrations in (top panel) 182 controls and 820 patients with stages A–D of HF and controls; (bottom panel) 479 stage C–D patients grouped according to NYHA class.

The 10th, 25th, 50th (median), 75th, and 90th percentiles are indicated as boxes and lines. Note that the peptide concentrations are reported in log scale. Significant differences among different stages are also reported: top panels, * = P <0.001 vs B, C, D; {dagger} = P <0.001 vs C, D; § = P <0.001 vs D; bottom panels, * = P <0.001 vs NYHA I, II, III, IV; {dagger} = P <0.001 vs NYHA II, III, IV; § = P <0.001 vs NYHA III, IV.

evaluation and comparison of diagnostic accuracy of bnp and nt-probnp assays: diagnosis of early asymptomatic hf
Both BNP and NT-proBNP did not show significant diagnostic accuracy for differentiating stage A patients from controls [Table 3 and Fig. 2 , top left panel, BNP, mean (SE): ROC AUC 0.604 (0.038) vs NT-proBNP: AUC 0.531 (0.038)]. The diagnostic accuracies of both BNP and NT-proBNP were significant (P <0.001), and comparable, for separating stage B patients from controls [Fig. 2 , top center panel, BNP, AUC 0.768 (0.022) vs NT-proBNP: AUC 0.750 (0.023)] and stage A patients [Fig. 2 , top right panel, BNP, AUC 0.679 (0.031) vs NT-proBNP: AUC 0.696 (0.030)].


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  		Table 3. Comparison of the diagnostic accuracy between BNP and NT-proBNP assays.1


Figure 2
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  		Figure 2. ROC analysis of BNP and NT-proBNP in differentiating (top panel) stage A patients from controls (left), stage B from controls (center), stage A from stage B (right); (bottom panel), and stage C from controls (left), stage A (center), and stage B (right).

Both BNP and NT-proBNP showed significant (P <0.001) and comparable accuracy in diagnosing mild left ventricular diastolic dysfunction [153 patients (60%) with altered relaxation, early-to-late phase ratio <1, deceleration time >220 ms, isovolumetric relaxation >110 ms] in stage B patients [BNP: AUC 0.761 (0.026), cutoff 21 ng/L, sensitivity 49%, specificity 88%, PPV 55%, NPV 73% vs NT-proBNP:AUC 0.748 (0.027), cutoff 21 ng/L, sensitivity 60%, specificity 82%, PPV 53%, NPV 77%, not significant (NS)].

evaluation and comparison of diagnostic accuracies of bnp and nt-probnp assays: diagnosis of symptomatic hf
The diagnostic accuracies of both BNP and NT-proBNP were significant in patients with symptomatic HF (P <0.001). NT-proBNP showed greater diagnostic accuracy (P <0.001) than BNP for differentiating stage C patients from (a) controls [Table 3Up and Fig. 2Up , bottom left panel, BNP, AUC 0.941 (0.009) vs NT-proBNP, AUC 0.974 (0.006)], (b) stage A patients [bottom center panel, BNP: AUC 0.908 (0.013) vs NT-proBNP: AUC 0.956 (0.008)], (c) stage B patients [bottom right panel, BNP: AUC 0.840 (0.015) vs NT-proBNP: AUC 0.880 (0.013)].

For stratification of patients according to NYHA class and EF values, the diagnostic accuracies of both BNP and NT-proBNP were significant (P <0.001), with NT-proBNP accuracy significantly better when patients with no or only mild current symptoms (NYHA classes I and II) were compared with controls (Table 3Up and Fig. 3 ), irrespectively of EF [top left panel EF 35%–50%, BNP: AUC 0.870 (0.021) vs NT-proBNP: AUC 0.939 (0.015), P <0.001; top right panel EF <50%: BNP: AUC 0.960 (0.012) vs NT-proBNP: AUC 0.989 (0.006), P <0.05)].


Figure 3
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  		Figure 3. ROC analysis of BNP and NT-proBNP corresponding to comparison between healthy controls and (a) patients with no or mild symptoms of HF (NYHA class I–II) and mild/moderate systolic dysfunction (EF between 35% and 50%; top left panel), (b) NYHA class I–II patients and severe systolic dysfunction (EF <35%; top right panel), (c) NYHA class III–IV patients with EF between 35% and 50% (bottom left panel), and (d) NYHA class III–IV patients with severe systolic dysfunction (EF <35%; bottom right panel).

When the patients with severe HF (NYHA classes III and IV) were considered, the 2 assays showed significant (P <0.001) and comparable diagnostic accuracy, irrespectively of EF [Table 3Up and Fig. 3Up ; bottom left panel EF 35%–50%: BNP: AUC 0.997 (0.007) vs NT-proBNP: AUC 1.000 (0.002), NS; bottom right panel EF <50%: BNP: AUC 0.995 (0.004) vs NT-proBNP: AUC 0.999 (0.002), NS].

predictors of acc-aha classification of hf
Multivariate logistic regression showed a significant increase (P <0.01) in the c-s when BNP or NT-proBNP was separately added to the starting model including age, sex, and creatinine clearance, in predicting stage C vs control group, stage A, or stage B. The c-s values were always significantly higher for models including NT-proBNP than BNP: stage C vs healthy condition, starting model (age, sex, and creatinine clearance) c-s, 0.506, SE 0.037 (BNP c-s 0.713, SE 0.066 vs NT-proBNP c-s 0.877, SE 0.062; P <0.05); stage C vs stage A: starting model c-s 0.703, SE 0.037 (BNP c-s 0.798, SE 0.033 vs NT-proBNP c-s 0.876, SE 0.027; P <0.05); stage B vs stage C: starting model c-s 0.607, SE 0.031 (BNP c-s 0.702, SE 0.029 vs NT-proBNP c-s 0.804, SE 0.026; P <0.01).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study evaluated the diagnostic accuracy of B-type natriuretic peptides in a large spectrum of patients at risk for HF, either without or with structural myocardial involvement. Present findings confirm that BNP and NT-proBNP share a clinically relevant diagnostic accuracy in HF patients (2) and suggest a significant difference in diagnostic accuracy between BNP and NT-proBNP, depending on the type of population studied. Another main finding is that cutoff concentrations are dependent on the study population and/or on the reference group studied. Our results demonstrate that the measurement of BNP or NT-proBNP is useful in stratifying patients according to the HF stages as suggested by AHA/ACC guidelines (11). In particular, both BNP and NT-proBNP showed diagnostic accuracy in separating out either asymptomatic ventricular impairment (stage B) vs controls or stage A patients. Moreover, BNP and NT-proBNP assays enabled differentiation of those patients with no or mild symptoms of disease (stage C, NYHA class I–II) from controls or stage A–B patients. For these clinical conditions, our study suggests that NT-proBNP has a better diagnostic accuracy than BNP, including a model based on age, sex, and renal function.

We have chosen for the present study the ECLIA method for NT-proBNP and the IRMA method for BNP, although the latter is not commonly used. Indeed, a previous multiassay comparison from our laboratory, between ECLIA NT-proBNP assay and several BNP immunoassays, indicated that the ECLIA NT-proBNP assay had a better diagnostic accuracy in detecting patients in the early stage of HF (NYHA class I–II), and that the IRMA BNP method showed better performance compared with other commercial immunoassays for BNP (12)(13). Results of several recent studies suggest that the diagnostic accuracy of BNP depends not only on the peptide measured but also on the platform used (2)(12)(13)(36)(37)(38). Commercial BNP immunoassays use different standard materials and antibodies, specific for different epitopes (2)(12)(13)(36)(37)(38). Therefore, BNP results may significantly vary dependent on the assay used (2)(12)(13)(36)(38). On the other hand, all fully automated NT-proBNP assays, using standard materials and antibodies harmonized against the Roche system, should likely give more homogeneous results, although this has not yet been proven.

The findings of the present study confirm that cutoff concentrations depend on the method as well as on the population studied (2)(12)(13)(36)(37)(38). For this reason it is impossible to suggest a specific cutoff concentration as valid for all clinical settings. In particular, because of their high NPVs, low concentrations of BNP (<40 ng/L) and NT-proBNP (<160 ng/L) should be used as cutoffs to differentiate healthy individuals or asymptomatic patients (stage A–B or NYHA class I) from patients with symptoms of HF (i.e., for the rule-out; Fig. 2Up ). More precise methods might show better diagnostic accuracy than IRMA compared with the ECLIA method. For this reason and for the differences in diagnostic accuracy among commercial BNP methods (12)(13), the cutoff concentrations found in the present study cannot be applied in other clinical settings, and findings on the IRMA assay might not be directly applicable to other BNP assays.


   Acknowledgments
 
Grant/funding support: None declared.

Financial disclosures: None declared.


   Footnotes
 
1 Nonstandard abbreviations: BNP, brain natriuretic peptide; NT-proBNP, amino-terminal pro–BNP; HF, heart failure; NYHA, New York Heart Association; AHA/ACC, American Heart Association/American College of Cardiology; EF, ejection fraction; ECLIA, electrochemiluminescence immunoassay; AUC, area under the curve; PPV, positive predictive value; NPV, negative predictive value; c-s, c-statistic; NS, not significant.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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A. Lokuge, L. Lam, P. Cameron, H. Krum, de Villiers Smit, A. Bystrzycki, M. T. Naughton, D. Eccleston, G. Flannery, J. Federman, et al.
B-Type Natriuretic Peptide Testing and the Accuracy of Heart Failure Diagnosis in the Emergency Department
Circ Heart Fail, January 1, 2010; 3(1): 104 - 110.
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