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Proteomics and Protein Markers |
1 Department of Medical Chemistry and Biochemistry, Division of Clinical Biochemistry, and2 Clinical Department of Internal Medicine, Clinical Division of Cardiology, Innsbruck Medical University, Innsbruck, Austria.
aAddress correspondence to this author at: Department of Medical Chemistry and Biochemistry, Division of Clinical Biochemistry, Innsbruck Medical University, Fritz-Pregl-Strasse 3, A-6020 Innsbruck, Austria. Fax 43-512-507-2876; e-mail Angelika.Lercher{at}uibk.ac.at.
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Abstract |
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Methods: We measured BNP (Triage® BNP), NT-proBNP (Biomedica), and N-terminal pro-A-type natriuretic peptide (NT-proANP; Biomedica) in 130 consecutive patients (age range, 28–83 years) with clinically suspected mild LVD. In patients with sufficient sample volume, we measured BNP and NT-proBNP with additional assays (Shionoria and Roche, respectively).
Results: For identifying patients with mild systolic LVD, BNP and NT-proBNP were the best markers, with mean (95% confidence interval) areas under the curves (AUC) of 0.78 (0.63–0.89) and 0.75 (0.58–0.87), respectively. However, the diagnostic performance of NT-proANP [AUC, 0.64 (0.48–0.77)] was significantly worse than that of BNP (P = 0.014). Both BNP assays (Triage and Shionoria) and both NT-proBNP assays (Biomedica and Roche) performed equally well for the diagnosis of systolic LVD despite the poor agreement between NT-proBNP assays. In patients with isolated diastolic LVD, the diagnostic performance of the Triage BNP [AUC, 0.70 (0.56–0.81)] was significantly better (P = 0.006) than that of Biomedica NT-proBNP [0.49 (0.34–0.65)]. Furthermore, the performance of the Biomedica NT-proBNP assay was significantly worse (P = 0.03) than that of the Roche NT-proBNP assay for diagnosis of isolated diastolic LVD.
Conclusions: The performance of BNP for the diagnosis of systolic or diastolic LVD is not affected by the assay used, whereas the performance of NT-proBNP for the diagnosis of isolated diastolic LVD is assay dependent.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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50% (1). The prevalence of the disease in the elderly is high (2). Most patients with HF are diagnosed as New York Heart Association (NYHA) class I and II (asymptomatic or mildly symptomatic patients) (3). This is clinically relevant because the majority of these patients are currently underdiagnosed. However, it has been shown that treatment of these patients with angiotensin-converting enzyme inhibitors or beta-blockers substantially delays disease progression (4)(5). Therefore, screening for HF in high-risk populations would be of clear benefit. Among all investigated neurohormones and natriuretic peptides, B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) (6)(7)(8)(9)(10)(11)(12) are the best markers to rule out left ventricular dysfunction (LVD). Some studies have also proposed NT-pro-A-type natriuretic peptide (NT-proANP) as a useful marker for the diagnosis of LVD (13)(14)(15)(16). Yamamoto et al.(9) demonstrated that BNP is a more powerful marker of either left ventricular systolic dysfunction, left ventricular diastolic dysfunction, or left ventricular hypertrophy than is ANP or NT-proANP. A consistent finding of all reports is the excellent negative predictive value of BNP. Furthermore, BNP has a good negative likelihood ratio for diagnosis of LVD compared with standard clinical indices, such as clinical history, electrocardiogram, and chest x-ray (17). These clinical results led to the development of numerous commercially available assays to determine different natriuretic peptide hormones (18). However, different epitopes and fragments of the same analyte are detected by different assays, and cross-reactivities of antibodies with prohormone fragments may vary. Because natriuretic peptide assays are not standardized at present, clinical study results must be interpreted with caution when different assays are used.
The aims of this study were (a) to investigate which of the natriuretic peptides, BNP, NT-proBNP, or NT-proANP, performs best in the diagnosis of mild forms of LVD and (b) to investigate the impact of using different assays on the diagnostic performance of these natriuretic peptides.
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Materials and Methods |
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16 mmHg in the presence of a normal LVEF (>50% in two-dimensional echocardiography). This precluded misclassification based on higher age alone. All patients with diastolic dysfunction showed the pattern of impaired relaxation in echocardiography. Systolic dysfunction was graded by use of the echocardiographically determined LVEF. Patients were grouped into three classes based on the following criteria: mild systolic LVD was defined as a LVEF of 40–50% on two-dimensional echocardiography, moderate LVD was defined as a LVEF of 30–40% on echocardiography; and severe LVD was defined as a LVEF <30%. Forty-seven patients with neither systolic nor diastolic LVD served as age- and sex-matched controls.
For the clinical study on the diagnostic performance of markers in suspected mild LVD, 44 patients were excluded for the following reasons: 6 patients had moderate to severe LVD; 31 patients had a myocardial infarction within 2 weeks of blood withdrawal; 5 patients presented with renal diseases; and 2 patients underwent a high-dose corticosteroid pretreatment for contrast-agent allergy. The final study population for this clinical investigation comprised 86 individuals (Table 1
). All patients of this population had calculated systolic right ventricular pressures (by echocardiography) within the reference interval (<35 mmHg) and no evidence of right ventricular dysfunction on echocardiography. However, samples from all 130 patients were used for testing assay agreement of the different natriuretic peptides.
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Blood was drawn into EDTA-containing plastic tubes after a standardized period of rest (10 min) in a supine position. After blood withdrawal, samples were stored at 4 °C (up to 1 h) until measurement of BNP in whole blood (Triage® BNP); subsequently samples were centrifuged at 2000g for 10 min at 4 °C, and the plasma was stored below –20 °C for up to 1 month for later determination of BNP, NT-proBNP, and NT-proANP by the different assays. The study design was prospective with respect to measurement of BNP, NT-proBNP, and NT-proANP for the clinical evaluation of the diagnostic performances of these different natriuretic peptides and retrospective with respect to the measurement of these peptides with different assays for assay comparison. Because of limited sample volumes, not every sample could be tested with all assays (see the Results). All patient samples were analyzed with the Triage BNP, Biomedica NT-proBNP, and Biomedica NT-proANP assays; subsequently, if the sample volume was sufficient, samples were analyzed with the Roche NT-proBNP and finally with the Shionoria BNP assay.
assays
BNP was measured with the Triage BNP Test (Biosite Diagnostics) as described previously (22). This assay uses a murine Omniclonal® antibody bound to the fluorescent label and a murine monoclonal antibody against the mono-disulfide bond-mediated ring structure of BNP-32. This monoclonal antibody is bound to the solid phase (personal communication by the manufacturer).
In addition, BNP was measured by a commercially available IRMA (cat. no. IC-1049; Shionoria), which does not need plasma extraction procedures as described previously (23). The assay uses an antibody specific to the C-terminal structure (amino acids 27–32) immobilized on a bead and a 125I-labeled antibody specific to the intramolecular ring structure of human BNP-32 (amino acids 14–21), respectively (24).
NT-proBNP(8–29) was assayed by a competitive enzyme immunoassay (cat. no. BI-20852; Biomedica) that uses an antibody specific against NT-proBNP(8–29) as described previously (25).
Additionally, NT-proBNP(1–76) was measured by a sandwich electrochemiluminescence immunoassay (Elecsys 1010; Roche Diagnostics) that uses polyclonal antibodies specific against the epitopes NT-proBNP(1–21) and NT-proBNP(39–50) as described previously (26)(27).
NT-proANP(1–98) was measured by a sandwich enzyme immunoassay (cat. no BI-20892; Biomedica), which uses antibodies specific for distinct epitopes of proANP(1–98), as described previously (28).
coronary angiography and left ventriculography
Coronary angiography and left ventriculography were performed via femoral artery access using the Seldinger puncture technique. A 6-French pigtail catheter was used to measure left ventricular end-diastolic and end-systolic filling pressures, and the first derivative of left ventricular pressure (dP/dt). The ventriculogram was analyzed by use of a computer software package. Calculation of the end-diastolic and end-systolic left ventricular volumes and ejection fraction was performed by use of the right anterior oblique projection by the area-length method. The frame nearest to the R-wave peak in the electrocardiogram was used as the end-diastolic frame, and the frame with the smallest ventricular volume was taken to calculate the end-systolic volume. Left ventricular volumes were normalized to body surface area.
Coronary angiography was performed according to the Judgkin technique. The degree of stenosis of coronary vessels was assessed visually in several projections by an experienced invasive cardiologist. Stenosis >70% of the vessel diameter was classified as hemodynamically significant.
echocardiography
Each patient underwent a complete standardized echocardiographic examination using an Acuson ultrasound imaging system (Acuson Sequoia C256; Siemens) equipped with a 3.5-MHz transducer suitable for second harmonic imaging. Parasternal long- and short-axis views as well as four, two, and three long-axis chamber views were obtained. Left ventricular volumes and ejection fraction were measured from the two-dimensional apical four-chamber view by the area-length method (modified Simpson method). The end-diastolic thicknesses of the intraventricular septum and the left ventricular posterior wall were measured in a parasternal short-axis view using the M-mode technique, and the Penn formula was used to calculate left ventricular mass. Left ventricular mass and volumes were normalized to body surface area. Left ventricular diastolic filling was evaluated by pulsed-wave Doppler measurement of velocities of early and late ventricular diastolic filling (E- and A-wave), as well as the deceleration time of the E-wave. Right ventricular systolic pressure was estimated by measurement of the systolic retrograde blood flow velocity into the right atrium by the continuous wave Doppler technique.
statistics
ROC plot analysis (29) was carried out to illustrate and compare the diagnostic performance of the different natriuretic peptides and assays. Spearman rank correlation coefficients were calculated. The Mann–Whitney U-test was used for group comparisons. Data are given as the mean (SD), or as median and interquartile range (25th and 75th percentiles) if more appropriate, and natriuretic peptide concentrations are given in ng/L. Assays were compared by use of Bland–Altman plots (30) with Analyze-it of the software package Microsoft Excel (Ver. 1.63). A P value <0.05 was considered to indicate statistical significance.
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Results |
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). BNP as measured by the Triage BNP assay [median, 146 ng/L (interquartile range, 47–209 ng/L)] and NT-proBNP as measured by the Biomedica NT-proBNP assay [3602 (2023–4517) ng/L] were significantly increased in patients with mild systolic LVD compared with controls (BNP, P = 0.001; NT-proBNP, P = 0.002) and patients with isolated diastolic LVD (Triage BNP, P = 0.026; Biomedica NT-proBNP, P = 0.011; Fig. 1, A and B
). Additionally, in patients with isolated diastolic LVD Triage BNP concentrations [37 (22–81) ng/L; P = 0.018; Fig. 1A
] showed significant increases compared with controls. By contrast, NT-proANP concentrations were not significantly increased in either patients with mild LVD or patients with isolated diastolic LVD (Fig. 1C
).
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comparison of markers
Mild systolic LVD.
In patients with mild systolic LVD, the Triage BNP and Biomedica NT-proBNP showed comparable diagnostic performances (Fig. 2
) with mean [95% confidence interval (CI)] areas under the curves (AUC) of 0.78 (0.63–0.89) and 0.75 (0.58–0.87), respectively. However, NT-proANP gave a significantly (P = 0.014) smaller AUC [0.64 (0.48–0.77)] than Triage BNP; the AUC for NT-proANP was not significantly different from the AUC for NT-proBNP. The negative predictive values (95% CI) at optimal cutoff values (see Fig. 2
) were 90 (76–97)% for BNP, 83 (67–94)% for NT-proBNP, and 77 (61–88)% for NT-proANP, respectively.
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Isolated diastolic LVD.
In patients with isolated diastolic LVD, the mean (95% CI) AUC for the Triage BNP (Fig. 3
) of 0.70 (0.56–0.81) showed significantly better (P = 0.006) diagnostic performance than the AUC for the Biomedica NT-proBNP [0.49 (0.34–0.65)]. At the optimal cutoff value of 25 ng/L for Triage BNP, the sensitivity was 70 (46–88)%, the specificity was 57 (42–72)%, the positive predictive value was 41 (25–59)%, the negative predictive value was 82 (65–93)%, and the efficiency was 61 (49–73)%. NT-proANP had a smaller mean AUC of 0.63 (0.48–0.76), but was not significantly different from the Triage BNP.
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correlations of natriuretic peptides with each other and with hemodynamic data
We found close correlations between the Triage BNP and Roche NT-proBNP (r = 0.88; P <0.001), between the Shionoria BNP and Biomedica NT-proBNP (r = 0.82; P <0.001), and between the Shionoria BNP and Roche NT-proBNP (r = 0.88; P <0.001). The Triage BNP and Biomedica NT-proBNP correlated as well (r = 0.78; P <0.001). Correlations between NT-proANP and the other natriuretic peptides were weak (r = 0.34–0.51; P <0.001).
There were only weak correlations between natriuretic peptides and myocardial mass, atrial and ventricular dimensions, or hemodynamic data (r = –0.052 to 0.337; P <0.001–0.96). The closest correlations were between the natriuretic peptides and LVEF obtained from left ventriculography (Triage BNP, r = –0.459; Biomedica NT-proBNP, r = –0.376; P <0.001).
comparison of assays
BNP.
In 81 individuals, the Triage BNP and Shionoria BNP assays showed a close correlation (r = 0.96; P <0.01). Nevertheless, absolute BNP values measured with both assays differed markedly (P <0.001), with concentrations measured by the Triage BNP being, on average, 110 ng/L higher (mean value of difference). However, there was better agreement of test results below concentrations of 100 ng/L (mean value of difference, 9.2 ng/L; Fig. 4A
).
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NT-proBNP.
In 113 individuals, the NT-proBNP(8–29) assay (Biomedica) showed a moderate correlation with the NT-proBNP(1–76) assay (Roche; r = 0.73; P <0.01). These assays also showed a marked concentration difference (see Fig. 4B
) with a mean difference of 1803 ng/L (P <0.001).
influence of measuring with different assays on the diagnostic performance of bnp and NT-PROBNP
In a subgroup analysis, we compared the diagnostic performance of the Triage BNP and Shionoria BNP assays. There was equal diagnostic performance for both assays [mean (95% CI) AUC, 0.68 (0.49–0.84) for Triage BNP and 0.74 (0.56–0.88) for Shionoria; P = 0.09; Table 3
] for the diagnosis of mild systolic LVD. In a further subgroup analysis, the diagnostic performance of the Biomedica and Roche NT-proBNP was compared. There was no statistically significant impact of assays on the ability of NT-proBNP to differentiate between controls and patients with mild systolic LVD (Table 4
). However, in the comparison of the diagnostic performances of NT-proBNP in patients with isolated diastolic LVD, the diagnostic performance of the Biomedica NT-proBNP assay was significantly worse compared with the Roche NT-proBNP assay [P = 0.03; mean (95% CI) AUC, 0.44 (0.29–0.59) vs 0.58 (0.42–0.73); Table 4
].
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Using the European Society of Cardiology classification of isolated diastolic dysfunction based on echocardiographic and hemodynamic data, we confirmed the significant increase in BNP, as measured by the Triage BNP assay, reported previously by Lubien et al. (34), who used only echocardiographic criteria. However, we did not observe a similarly high diagnostic performance of Triage BNP, which may be explained by the fact that our cohort did not include patients with restrictive filling patterns. The high negative predictive value of BNP (82%) in the present study confirms the results of a previous report (35) and underlines the accuracy of BNP as a rule-out marker even for isolated diastolic LVD. Thus, BNP is a promising marker for the diagnosis of isolated diastolic LVD as well. We found no significant difference in the diagnostic performance of BNP and NT-proANP for the diagnosis of isolated diastolic LVD, which confirms a previous report of increased ANP and BNP concentrations in diastolic LVD (36).
We found significant correlations among all tested natriuretic peptides. In accordance with previous studies, we found only weak inverse correlations of LVEF and BNP (7)(8)(9)(12)(37). There are only two published studies (in which LVEF was determined by magnetic resonance imaging) showing a close correlation between BNP and LVEF (r = –0.78) (38) and between NT-proBNP (Roche) and LVEF (r = –0.75) (39) in patients in NYHA classes II–IV. The more severely reduced LVEF than in our study population and the more precise method for the calculation of LVEF likely account for the closer correlations.
There was a close correlation between BNP measured by Biosite Triage and by Shionoria assay. However, Bland–Altman plots showed an acceptable agreement between methods only at concentrations <100 ng/L. There was no influence of the BNP assay used on the diagnostic performance of the marker. By contrast, the correlation between NT-proBNP measured by the Biomedica and Roche methods was only moderate, and Bland–Altman plots revealed only poor test agreement over the whole measuring range. Nevertheless, NT-proBNP assays were not significantly different in identifying patients with mild systolic LVD. However, in patients with isolated diastolic LVD, the AUC were significantly different. The epitopes detected by the different assay antibodies in the NT-proBNP molecule are different, which may influence diagnostic endpoints in very mild forms of LVD.
There are very limited data on the influence of measuring natriuretic peptides with different assays on diagnostic performance. In accordance with our results, Tjeerdsma et al. (40) and Fischer et al. (22) found a close correlation between Triage BNP and Shionoria BNP results, with Triage BNP values being higher than Shionoria values. However, the AUC for the assays were higher in both studies compared with our AUC for BNP, which can be explained in part by either the more severely diseased patient cohort or by a younger control group not age-matched to the LVD patient group. Our data confirm the lack of influence of the assay used on the diagnostic performance of BNP in less severe LVD. Data regarding the recently Food and Drug Administration-cleared Centaur (Bayer) BNP assay showed a high correlation with the Shionoria as well as with the Triage BNP assays in a large multisite study (24). The close correlation with the Shionoria assay is not surprising because the antibodies are identical in both assays (24). However, the slope of 0.78 between the Centaur (Bayer) and the Triage (Biosite) BNP assays showed that these assays did not agree very well. Nevertheless, similar to our results, there was a high agreement at a cutoff value of 100 ng/L. For the Roche and Biomedica methods, a recent report demonstrated a similar lack of assay and analytical agreement with a large mean concentration difference between the NT-proBNP assays similar to that seen in our study (41).
Our results for differentiating patients with isolated diastolic LVD from controls showed better performance of the Roche assay compared with the Biomedica assay, similar to that seen in the previous study for differentiating patients with asymptomatic structural heart disease from individuals without. Both assays did not differ significantly in their diagnostic performances for the diagnosis of symptomatic LVD. The commercially available Triage BNP and NT-proBNP (Roche) assays were compared with different locally developed in-house RIAs for BNP and NT-proBNP (42). Close correlations between all assays were found, but data on analytical assay agreement were not published. We found higher diagnostic efficiency of BNP and NT-proBNP than did the authors of that study (42), although we included only patients with mild forms of LVD who consequently had lower BNP and NT-proBNP concentrations.
In conclusion, our study confirms the usefulness of BNP and NT-proBNP and extends previous findings by directly comparing commercially available BNP and NT-proBNP assays in the same study population. Furthermore, our results highlight the diversity of the natriuretic peptide assays on the market. Thus it is difficult to compare study results that are based on different assays. Published decision limits are valid only for the particular assay used. Our study population was too small for additional subgroup analysis to calculate age- and sex-dependent decision limits, but from our results a cutoff of 50 ng/L (14 pmol/L) for the Triage BNP assay could be a good screening value to exclude LVD in high-risk patients.
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Acknowledgments |
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Footnotes |
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), and NT-proANP (Biomedica; 
) for identifying patients with mild systolic LVD (n = 19 patients and 47 controls).
