Download Capability of B-Type Natriuretic Peptide (BNP) and Amino

Clinical Chemistry 51:12
2245–2251 (2005)
Proteomics and
Protein Markers
Capability of B-Type Natriuretic Peptide (BNP)
and Amino-Terminal proBNP as Indicators of
Cardiac Structural Disease in Asymptomatic
Patients with Systemic Arterial Hypertension
Thomas Mueller,1* Alfons Gegenhuber,2 Benjamin Dieplinger,1 Werner Poelz,3 and
Meinhard Haltmayer1
Background: The aim of the present study was to
prospectively evaluate the diagnostic utility of B-type
natriuretic peptide (BNP) and amino-terminal proBNP
(NT-proBNP) measurements for the detection of cardiac
structural disease in asymptomatic patients with systemic arterial hypertension and to test the hypothesis
that the 2 analytes are equally useful in this clinical
setting.
Methods: We studied a consecutive series of 149 asymptomatic patients referred for echocardiographic evaluation of the cardiac effects of systemic arterial hypertension. Diagnosis of cardiac structural disease was based
on the presence of systolic or diastolic dysfunction, left
atrial dilatation, left ventricular dilatation or hypertrophy, pulmonary hypertension, and wall motion or valvular abnormalities. Blood concentrations of BNP and
NT-proBNP were measured by 2 commercially available
assays (Abbott AxSYM and Roche Elecsys, respectively).
Diagnostic accuracies of BNP and NT-proBNP were
assessed by ROC curve analysis. Areas under the curves
were compared by analysis of equivalency.
Results: In distinguishing between hypertensive patients with cardiac structural disease (n ⴝ 118) and
hypertensive patients without (n ⴝ 31), areas under the
curves were 0.740 (95% confidence interval, 0.662– 0.808)
for BNP and 0.762 (0.685– 0.828) for NT-proBNP and
Departments of 1 Laboratory Medicine and 2 Internal Medicine, Konventhospital Barmherzige Brueder, Linz, Austria.
3
Institute for Applied System Sciences and Statistics, University of Linz,
Linz, Austria.
* Address correspondence to this author at: Department of Laboratory
Medicine, Konventhospital Barmherzige Brueder, Seilerstaette 2, A-4021 Linz,
Austria. Fax 43-732-7897-3799; e-mail [email protected].
Received June 23, 2005; accepted September 23, 2005.
Previously published online at DOI: 10.1373/clinchem.2005.056648
were significantly equivalent (P ⴝ 0.015). Cutoff values
with a 90% sensitivity for cardiac structural disease were
17 ng/L for BNP and 39 ng/L for NT-proBNP, with 29%
and 32% specificity, respectively.
Conclusions: BNP and NT-proBNP have similar capabilities for detecting cardiac structural disease in asymptomatic patients with systemic arterial hypertension.
However, in the setting evaluated, a screening strategy
relying on measurement of BNP or NT-proBNP may be
of limited value because of the low specificity at the
selected cutoff values.
© 2005 American Association for Clinical Chemistry
It is now generally accepted that cardiac natriuretic peptide concentrations in the peripheral blood are augmented
by factors that increase cardiac pressure and volume
overload (1–3 ). An intracellular prohormone containing
108 amino acids (proBNP) is split into B-type natriuretic
peptide (BNP;4 amino acids 77–108), which is considered
the biologically active hormone, and an inactive aminoterminal fragment (NT-proBNP; amino acids 1–76) (2, 3 ).
Although BNP and NT-proBNP are secreted on an
equimolar basis, their molar ratio in plasma is not 1:1
because BNP has a shorter plasma half-life than does
NT-proBNP (2, 3 ).
The measurement of BNP and NT-proBNP concentrations in plasma may aid decision making in a variety of
clinical settings. The diagnostic value of circulating BNP
and NT-proBNP is well established in symptomatic patients with suspected heart failure, but their utility as a
screening tool for cardiac structural disease in the general
population appears to be limited (1–3 ). However, in
4
Nonstandard abbreviations: BNP, B-type natriuretic peptide; NTproBNP, amino-terminal fragment of proBNP; and AUC, area under the curve.
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Mueller et al.: BNP and NT-proBNP in Arterial Hypertension
populations at high risk for the development of symptomatic heart failure, the role of the 2 analytes for the
detection of asymptomatic cardiac dysfunction remains to
be clarified.
In the American College of Cardiology/American
Heart Association guidelines for the evaluation and management of chronic heart failure in the adult, it has been
suggested that 4 stages be considered in the evolution of
heart failure (heart failure stages A through D) (4 ).
Typically, in asymptomatic patients at high risk for developing heart failure (e.g., patients with systemic arterial
hypertension, diabetes mellitus, or coronary artery disease), echocardiography is used to detect patients progressing from stage A to stage B along the heart failure
pathway, which is important because these patients require more intensive therapy (4 ). Thus, a screening test
(such as plasma BNP or NT-proBNP) to be performed
before echocardiography would be clinically useful for
ruling out cardiac structural disease in this high-risk
population and thereby reducing the frequency of echocardiography. Consequently, if plasma BNP and/or NTproBNP cutoff concentrations, set at a high sensitivity,
were associated with a clinically useful specificity, both
markers could be used as a screening test to select patients
for further assessment by echocardiography. Given the
relatively high incidence of structural heart disease (e.g.,
diastolic dysfunction and left ventricular dilatation or
hypertrophy) in patients with systemic arterial hypertension, the proposed application of BNP and NT-proBNP as
a screening test could be clinically useful. The aims of the
present study, therefore, were to prospectively evaluate
the diagnostic utility of plasma BNP and NT-proBNP
measurements for the detection of cardiac structural disease in asymptomatic patients with systemic arterial hypertension and to test the hypothesis that the 2 analytes
are equally useful in this clinical setting.
Materials and Methods
patient recruitment
The present single-center trial, performed during a study
period of 12 weeks between February 7, 2005, and April
29, 2005, at the St. John of God Hospital, Linz, Austria,
was approved by the local ethics committee in accordance
with the Declaration of Helsinki, and informed consent
was obtained from the study participants. All patients
referred for echocardiographic evaluation of the cardiac
effects of systemic arterial hypertension were eligible for
the present prospective clinical evaluation.
Hypertensive patients without known cardiac structural disease were included if echocardiography was
performed satisfactorily, as detailed below, and if blood
samples for the measurement of plasma BNP and NTproBNP concentrations and serum creatinine were collected on the same day. The estimated glomerular filtration rate was calculated as recommended recently (5 ).
Patients with acute coronary syndromes (cardiac troponin
positive or negative), patients with actual or previous
symptomatic heart failure, and critically ill patients were
excluded from the study. Other exclusion criteria included indications other than arterial hypertension for
echocardiography, such as chest pain, palpitations, any
symptoms related to heart failure (i.e., dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, nocturnal cough, jugular venous distension, pulmonary rales,
third heart sound, and peripheral edema), prosthetic
valves, pericardial disease, pulmonary embolism, acute
stroke or actual transient or temporary stroke, and congenital heart disease.
Before echocardiography, each patient enrolled in the
study was thoroughly evaluated by use of a history,
physical examination, 12-lead electrocardiogram, and
chest x-ray. The participants’ height and weight were
routinely measured. The body mass index was obtained
from the ratio of weight to height squared. Resting
systolic and diastolic blood pressure and the patients’
actual medications were recorded on the same day the
echocardiography was performed. Heart rate was determined during echocardiography. Echocardiography was
performed without knowledge of the BNP and NTproBNP plasma concentrations.
echocardiography
M-Mode and 2-dimensional images and spectral and
color-flow Doppler recordings were obtained with a single commercially available instrument operating at 2.0 –
3.5 MHz. Two-dimensional imaging examinations were
performed in the standard fashion in parasternal longand short-axis views and apical 4- and 2-chamber views.
All measurements were performed as recommended (6 ).
Two-dimensional echocardiograms were subjected to
careful visual analyses to detect regional contractile abnormalities. Left ventricular systolic and diastolic volumes and ejection fraction were derived from biplane
apical (2- and 4-chamber) views with the modified Simpson’s rule algorithm. Left ventricular dimensions were
measured from M-mode images by the leading-edge
technique, which included interventricular septal thickness at end diastole, posterior wall thickness at end
diastole, and left ventricular internal dimension at end
diastole. The greatest thickness measured at any site in the
left ventricular wall was considered to represent maximal
left ventricular wall thickness. Diastolic dysfunction was
determined according to a previous report (7 ). For measurement of right ventricular systolic pressure, we used
continuous-wave Doppler recording of tricuspid regurgitation according to the modified Bernoulli equation (four
times the square peak velocity of the tricuspid jet plus
adding to the right atrial pressure 5, 10, or 15 mmHg in
relation to the clinical aspect, jugular venous pulse, and
x-ray of the chest).
For the assessment of aortic stenosis, the pressure
gradient across the aortic valve was estimated by the
simplified Bernoulli equation from flow velocity detection
by continuous-wave Doppler integrated throughout sys-
Clinical Chemistry 51, No. 12, 2005
tole. For the evaluation of mitral stenosis, the transmitral
gradient at rest during diastole was assessed by the
pressure half-time using continuous-wave Doppler. Color-flow Doppler of the aortic valve from the parasternal
long- and short-axis views was used to detect and assess
the severity of aortic regurgitation based on the ratio of
the width of regurgitant jet to the width of the regurgitant
jet in the outflow tract. Color-flow Doppler was also
applied for the detection of mitral regurgitation, and
severity was estimated by the regurgitant jet area expressed as percentage of the left atrial area.
definitions
Arterial hypertension was defined as the use of any
antihypertensive medication, resting systolic blood pressure ⱖ140 mmHg, or resting diastolic blood pressure ⱖ90
mmHg. Diabetes mellitus was defined as the use of any
glucose-lowering medication or as fasting blood glucose
concentration ⱖ7 mmol/L (126 mg/dL). Renal dysfunction was defined as an estimated glomerular filtration rate
⬍60 mL 䡠 min⫺1 䡠 (1.73 m2)⫺1. Coronary artery disease was
defined as remote myocardial infarction by history, occult
myocardial infarction by electrocardiography, and previous coronary bypass surgery or percutaneous transluminal coronary angioplasty. The diagnosis of atrial fibrillation was defined as first episode, paroxysmal, persistent,
or permanent.
Systolic dysfunction was defined as a left ventricular
ejection fraction ⬍50%. Diastolic dysfunction was defined
as impaired relaxation or a restrictive or pseudonormal
pattern. Left atrial dilatation was defined as left atrial
diameter ⬎40 mm. Left ventricular dilatation was defined
as left ventricular end diastolic diameter ⬎56 mm. Left
ventricular hypertrophy was defined as septal thickness
at end diastole or posterior wall thickness at end diastole
⬎11 mm. Pulmonary hypertension was defined as right
ventricular systolic pressure ⱖ35 mmHg. Valvular abnormality was defined as stenosis or regurgitation grade 2 or
higher for the mitral or aortic valve.
A study participant was considered to have cardiac
structural disease if at least one of the following echocardiographic findings was present: systolic or diastolic
dysfunction, left atrial dilatation, left ventricular dilatation, left ventricular hypertrophy, pulmonary hypertension, wall motion abnormalities, or valvular abnormalities.
BNP and NT-proBNP measurements
Blood for measurement of natriuretic peptide concentrations was collected by venipuncture in Vacuette polyethylene terephthalate glycol EDTA tubes (Greiner Bio-One)
on the day of the echocardiographic evaluation. Blood
samples were centrifuged at 3500g for 10 min at 4 °C
immediately after collection. Both BNP and NT-proBNP
were assayed within 4 h after blood withdrawal by
commercially available assays. Plasma BNP was assayed
on an AxSYM analyzer using the AxSYM BNP assay
2247
(Abbott Laboratories), and plasma NT-proBNP was measured by the Elecsys proBNP assay on an Elecsys 2010
instrument (Roche Diagnostics).
The precision of the 2 methods was evaluated according to the Clinical and Laboratory Standards Institute
(CLSI, formerly NCCLS) guideline EP5-A (8 ). Three
pooled patient plasma samples were aliquoted into 40
tubes (1.5 mL) for each concentration and frozen at
⫺70 °C. We analyzed these samples in duplicate in 2 runs
every day for 20 days on the 2 analyzers. Total imprecision was calculated by the CLSI double-run precision
evaluation test (8 ). The precision data for the 2 methods
were as follows: the AxSYM BNP assay had a total CV of
8.1% at a mean concentration of 108 ng/L (pool 1), a total
CV of 7.5% at a mean concentration of 524 ng/L (pool 2),
and a total CV of 10% at a mean concentration of 2117
ng/L (pool 3). The Elecsys NT-proBNP assay had a total
CV of 3.8% at a mean concentration of 246 ng/L (pool 1),
a total CV of 4.7% at a mean concentration of 891 ng/L
(pool 2), and a total CV of 2.2% at a mean concentration of
10666 ng/L (pool 3).
statistical analysis
Data were analyzed statistically with SPSS 13.0 software
(SPSS Inc.), the MedCalc 8.0.0.0 package (MedCalc Software), and the software N package (IDV). All probabilities
were 2-tailed, and P values ⬍0.05 were regarded as
significant. Sample size calculation was based on the
following assumptions: AUC for BNP ⬃0.750 with an
estimated SE of 0.045 and a correlation coefficient of 0.800
for BNP and NT-proBNP plasma concentrations. Thus,
testing for equivalency, our calculation showed that a
sample size of 120 patients had to be enrolled into this
study if the limit of equivalency was set at ⫾15% difference of the areas under the curves (AUCs) for the 2
analytes (␣ ⫽ 0.050, 2-sided; ␤ ⫽ 0.100).
Using the nonparametric Mann–Whitney U-test or
Fisher exact test, as appropriate, we compared the univariate data for the demographic and clinical features between the patients with cardiac structural disease caused
by arterial hypertension and hypertensive patients without cardiac structural disease; the P values were not
adjusted for multiple comparisons and are therefore only
descriptive. We used the Spearman coefficient of rank
correlation to assess the relationship between BNP and
NT-proBNP concentrations in the study population. To
determine the diagnostic accuracy of plasma BNP and
NT-proBNP for cardiac structural disease, we analyzed
the ROC curves and calculated AUCs for both analytes.
According to our study hypothesis, AUCs were compared
by analysis of equivalency. Cutoff concentrations for BNP
and NT-proBNP were determined at the 90% sensitivity
criterion derived directly from the ROC curves.
To determine whether BNP and NT-proBNP plasma
concentrations were independent predictors for cardiac
structural disease and to calculate multivariate odds ratios, we performed 2 logistic regression analyses without
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Mueller et al.: BNP and NT-proBNP in Arterial Hypertension
variable selection (all relevant variables were included
simultaneously into the models). Dichotomous risk factors were coded with an indicator variable of 1 for having
the condition and 0 for its absence; an incremental approach was used for continuous variables (i.e., the calculated odds ratios are related to the increase of a certain
continuous variable by the given amount).
Results
A total of 881 echocardiographies were performed in our
hospital during the 12-week study period. Of these, 160
were done with the indication to evaluate whether cardiac
structural disease was present in asymptomatic patients
with essential arterial hypertension but without known
cardiac structural disease. Echocardiography was unsatisfactory in 3 patients. Thus, 157 patients with complete
clinical evaluation were allocated a cardiac structural
disease classification. BNP and NT-proBNP results were
available for all of them. In 8 patients with a left ventricular ejection fraction ⱖ50%, concomitant atrial fibrillation
during echocardiography prohibited exact classification
of diastolic dysfunction; therefore, the final number studied was 149. Classification of the study participants
showed that 118 of the hypertensive patients had cardiac
structural disease and 31 did not (disease prevalence,
79%). The demographic and clinical characteristics of the
study participants according to this classification are
listed in Table 1. The median BNP and NT-proBNP
concentrations for the patients with cardiac structural
disease were ⬃2-fold and 3-fold higher, respectively, than
for the patients without cardiac structural disease.
In distinguishing between hypertensive patients with
cardiac structural disease (n ⫽ 118) and hypertensive
patients without cardiac structural disease (n ⫽ 31), the
AUCs were 0.740 (SE ⫽ 0.045; 95% confidence interval,
0.662– 0.808) for BNP and 0.762 (SE ⫽ 0.043; 95% confidence interval, 0.685– 0.828) for NT-proBNP (Fig. 1). The
Spearman coefficient of rank correlation for BNP and
NT-proBNP plasma concentrations was 0.841 (95% confidence interval, 0.787– 0.883; P ⬍0.001). Equivalence testing was based on a ⫾15% range as detailed in the
Materials and Methods. Accordingly, given the standard
AUC of 0.740, the confidence limits were 0.629 and 0.851.
Because the 97% confidence interval for the AUC of
NT-proBNP was 0.671– 0.851, both AUCs were significantly equivalent (P ⫽ 0.015).
The cutoff values with a 90% sensitivity (95% confidence interval for both BNP and NT-proBNP, 83%–95%)
for cardiac structural disease were 17 ng/L for BNP
[specificity, 29% (14%– 48%)] and 39 ng/L for NT-proBNP
[specificity, 32% (17%–51%)]. On the basis of a disease
prevalence of 79%, the positive and negative predictive
values at these cutoff concentrations were 83% and 43%
for BNP and 83% and 45% for NT-proBNP, respectively,
and the diagnostic accuracy was 77% for BNP and 78% for
NT-proBNP. When we used the respective cutoff concentrations, classification by both BNP and NT-proBNP was
correct in 106 and incorrect in 24 patients, whereas we
obtained discordant false classifications for 10 cases by the
BNP assay and 9 cases by the NT-proBNP assay.
As shown in Table 2, BNP and NT-proBNP plasma
concentrations were predictors of cardiac structural disease independent of possible confounding variables. In
the first multivariate model, BNP was an independent
and significant predictor (P ⫽ 0.005) of cardiac structural
disease with an odds ratio of 2.91 (95% confidence interval, 1.37– 6.14) for an increment of 50 ng/L. The second
statistical model revealed that NT-proBNP was also independently related to cardiac structural disease (P ⫽ 0.004),
displaying an odds ratio of 2.57 (95% confidence interval,
1.35– 4.89) for an increment of 100 ng/L. All other variables included failed to reach statistical significance.
Discussion
The present study revealed that circulating BNP and
NT-proBNP have similar diagnostic accuracies for the
detection of cardiac structural disease in asymptomatic
patients with systemic arterial hypertension. This was
demonstrated by significantly equal AUCs for the 2
analytes and by equal specificities for selected cutoff
concentrations at the 90% sensitivity criterion (17 ng/L for
BNP and 39 ng/L for NT-proBNP). These cutoff concentrations were in a low/normal range for BNP and NTproBNP (1 ), and accordingly, the specificities of BNP and
NT-proBNP for the detection of asymptomatic cardiac
structural disease were only 29% and 32%, respectively, at
these cutoff values. Although the median concentrations
of BNP and NT-proBNP for the patients with cardiac
structural disease were ⬃2-fold and 3-fold, respectively,
higher than for the patients without cardiac structural
disease and despite the fact that BNP and NT-proBNP
were the only significant predictors of cardiac structural
disease in multivariate analysis, a screening strategy
relying on measurement of plasma BNP or NT-proBNP to
select patients with arterial hypertension for further echocardiography is of limited value, in our opinion, in the
investigated setting because of the low specificity of this
proposed strategy.
In general, many studies have shown a correlation of
BNP and/or NT-proBNP with several indicators of left
ventricular and right ventricular function as assessed by
echocardiography (2, 3, 9 ). This, of course, should also
hold true for hypertensive patients. Indeed, published
data indicate that increased plasma BNP (10 –17 ) and
NT-proBNP (10, 18 ) concentrations are associated with
left ventricular systolic and diastolic dysfunction, left
ventricular dilatation, left ventricular hypertrophy, pulmonary hypertension, and significant valve disease in
asymptomatic or mildly symptomatic patients with arterial hypertension. However, most of these studies focused
on either 1 or 2 of the above-mentioned indicators of
cardiac impairment. Of them, only the study by Bhalla et
al. (10 ), retrospective in design, used a more complex
approach measuring both plasma BNP and NT-proBNP
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Clinical Chemistry 51, No. 12, 2005
Table 1. Patient characteristics according to disease classification (n ⴝ 149).
Cardiac structural disease present
No (n ⴝ 31)
Demographic and clinical features
Male sex, n (%)
Median (IQR)a age, years
Median (IQR) body mass index, kg/m2
Systemic arterial hypertension, n (%)
Median (IQR) blood pressure, mmHg
Systolic
Diastolic
Median (IQR) heart rate, beats/min
Atrial fibrillation, diagnosis, n (%)
Diabetes mellitus, n (%)
Renal dysfunction, n (%)
Coronary artery disease, n (%)
Medication, n (%)
Angiotensin-converting enzyme inhibitors
Angiotensin-receptor blockers
Calcium antagonists
Beta-blockers
Digitalis
Diuretics
Echocardiographic data
Atrial fibrillation during echocardiography, n (%)
Median (IQR) LV ejection fraction, %
Systolic dysfunction, n (%)
Diastolic dysfunction, n (%)
Median (IQR) LA diameter, mm
LA dilatation, n (%)
Median (IQR) LV end diastolic diameter, mm
LV dilatation, n (%)
Median (IQR) maximal LV wall thickness, mm
LV hypertrophy, n (%)
Median (IQR) RV systolic pressure, mmHg
Pulmonary hypertension, n (%)
Wall motion abnormalities, n (%)
Valvular abnormalities, n (%)
Biochemical markers
Median (IQR) serum creatinine, mg/L
Median (IQR) eGFR, mL 䡠 min⫺1 䡠 (1.73 m2)⫺1
Median (IQR) plasma BNP, ng/L
Median (IQR) plasma NT-proBNP, ng/L
24 (77)
60 (51–74)
27 (25–30)
31 (100)
150 (135–160)
80 (75–90)
64 (58–68)
0 (0)
6 (19)
2 (7)
2 (7)
Yes (n ⴝ 118)
P
79 (67)
69 (60–76)
28 (26–31)
118 (100)
0.285
0.016
0.439
NA
145 (140–160)
80 (75–90)
62 (58–68)
10 (9)
29 (25)
21 (18)
24 (20)
0.738
0.555
0.569
0.122
0.639
0.164
0.108
14 (45)
4 (13)
6 (19)
10 (32)
0 (0)
11 (36)
62 (53)
26 (22)
22 (19)
44 (37)
5 (4)
63 (53)
0 (0)
63 (60–65)
0 (0)
0 (0)
37 (35–39)
0 (0)
52 (50–55)
0 (0)
9 (9–10)
0 (0)
15 (15–20)
0 (0)
0 (0)
0 (0)
2 (2)
60 (56–64)
6 (5)
94 (80)
39 (38–42)
35 (30)
55 (52–57)
35 (30)
12 (10–13)
61 (52)
22 (20–25)
12 (10)
21 (18)
1 (1)
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
9 (7–11)
81 (65–103)
63 (32–158)
185 (78–486)
0.668
0.158
⬍0.001
⬍0.001
9 (8–10)
87 (77–100)
31 (16–55)
66 (31–139)
0.546
0.322
0.999
0.678
0.584
0.106
a
IQR, interquartile range (25th to 75th percentiles); NA, not applicable; LV, left ventricular; LA, left atrial; RV, right ventricular; eGFR, estimated glomerular filtration
rate.
concentrations and demonstrating that these markers
might be useful to identify the presence of left ventricular
dysfunction (determined by the presence of systolic or
diastolic dysfunction, valvular or wall motion abnormalities, or left ventricular hypertrophy). In fact, such an
approach is convincing because BNP and NT-proBNP are
considered indicators of increased intracardiac pressure,
irrespective of whether the increased intracardiac pressure is caused by left ventricular hypertrophy, left ventricular systolic dysfunction, valve disease, or even fast
atrial fibrillation (19 ). In our study, we used an approach
for classifying the study participants as having cardiac
structural disease if at least one of the following echocardiographic findings was present: systolic or diastolic
dysfunction, left atrial dilatation, left ventricular dilatation, left ventricular hypertrophy, pulmonary hypertension, wall motion abnormalities, or valvular abnormalities
(see Materials and Methods), and, as detailed, we found
equal diagnostic accuracies for BNP and NT-proBNP for
differentiating between patients with and without asymptomatic cardiac structural disease.
Because most patients in our study were on oral
antihypertensive medications, it is important to emphasize that drugs, including diuretics, angiotensin-convert-
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Mueller et al.: BNP and NT-proBNP in Arterial Hypertension
Fig. 1. ROC curves for the detection of cardiac structural disease by
BNP and NT-proBNP in asymptomatic patients with arterial hypertension.
Solid line, ROC curve for BNP; dashed line, ROC curve for NT-proBNP. The arrows
indicate selected cutoff concentrations for BNP and NT-proBNP on the ROC
curves.
ing enzyme inhibitors, and adrenergic agonists, can modify circulating concentrations of natriuretic peptides (1–3 ).
A recent study demonstrated that BNP concentrations for
treated hypertensive patients were not statistically significantly different from those for an age-matched control
population (20 ). Our study design, however, with inclusion of asymptomatic patients referred for echocardiographic evaluation of the cardiac effects of systemic
arterial hypertension, represents a real-world scenario;
thus, it is conceivable that this population is often on
therapy before the evaluation of structural heart disease
by echocardiography.
Our study has several potential limitations. It is a
single-center study performed in a relatively small sample
of hypertensive patients and may not accurately represent
the general demographics of patients referred for echocardiographic evaluation of the cardiac effects of systemic
arterial hypertension. Because the diagnostic accuracies of
BNP and NT-proBNP assays are considered to depend on
the disease prevalence in the population studied and on
the reference standard used for classification of study
participants (21 ), the relatively high prevalence of structural heart disease in our population (79%) compared
with other populations might be an important issue.
Although we believe that the high disease prevalence is
related to both the tertiary care setting and the consider-
Table 2. Results of logistic regression analyzing the capability of BNP and NT-proBNP to predict cardiac structural disease
independently of possible confounding variables.
Independent variables
Multivariate logistic regression model including BNP
Male sex (vs female sex)
Age (⫹10 years)
Body mass index (⫹5 kg/m2)
Heart rate (⫹10 beats/min)
Coronary artery disease (vs not)
Angiotensin-converting enzyme inhibitors (vs not)
Angiotensin-receptor blockers (vs not)
Calcium antagonists (vs not)
Beta-blockers (vs not)
Diuretics (vs not)
eGFR 关⫹10 mL 䡠 min⫺1 䡠 (1.73 m2)⫺1兴
Plasma BNP concentration (⫹50 ng/L)
Multivariate logistic regression model including NT-proBNP
Male sex (vs female sex)
Age (⫹10 years)
Body mass index (⫹5 kg/m2)
Heart rate (⫹10 beats/min)
Coronary artery disease (vs not)
Angiotensin-converting-enzyme inhibitors (vs not)
Angiotensin-receptor blockers (vs not)
Calcium antagonists (vs not)
Beta-blockers (vs not)
Diuretics (vs not)
eGFR 关⫹10 mL 䡠 min⫺1 䡠 (1.73 m2)⫺1兴
Plasma NT-proBNP concentration (⫹100 ng/L)
a
CI, confidence interval; eGFR, estimated glomerular filtration rate.
Odds ratio (95% CI)a
P
1.20 (0.39–3.67)
1.13 (0.70–1.83)
1.35 (0.76–2.40)
0.78 (0.48–1.27)
2.84 (0.49–16.5)
0.89 (0.28–2.79)
1.86 (0.45–7.66)
0.62 (0.18–2.20)
0.48 (0.16–1.50)
1.69 (0.56–5.08)
1.01 (0.85–1.19)
2.91 (1.37–6.14)
0.748
0.612
0.300
0.314
0.244
0.843
0.391
0.460
0.207
0.352
0.912
0.005
1.51 (0.46–4.97)
1.09 (0.67–1.79)
1.45 (0.81–2.61)
0.68 (0.40–1.14)
2.85 (0.49–16.6)
0.90 (0.28–2.90)
1.98 (0.46–8.41)
0.79 (0.23–2.73)
0.45 (0.14–1.43)
1.46 (0.48–4.43)
1.09 (0.90–1.32)
2.57 (1.35–4.89)
0.502
0.723
0.216
0.138
0.246
0.853
0.357
0.705
0.177
0.504
0.364
0.004
Clinical Chemistry 51, No. 12, 2005
ation of diastolic dysfunction for the reference standard,
the reproduction of our results in other centers or by
multicenter studies would argue for their validity. Furthermore, we must acknowledge that the optimal cutoff
BNP and NT-proBNP concentrations assessed in our
study, and probably the diagnostic accuracies as well,
may have been influenced by the assay choice, because
authors of some recent reports have suggested that the
diagnostic information provided by BNP and NT-proBNP
measurements might be method-dependent (21–23 ). This
may specifically hold true for the comparison of older
generation assays (e.g., IRMAs and enzyme immunoassays) with fully automated newer generation assays.
However, in the present evaluation, plasma BNP and
NT-proBNP concentrations were determined by newer
generation assays that have been proposed for widespread use in clinical practice.
9.
10.
11.
12.
13.
14.
This work was supported in part by a grant for scientific
research from the Upper Austrian Government. We thank
Abbott Diagnostics (Vienna, Austria) and Roche Diagnostics (Vienna, Austria) for providing reagents free of
charge. Neither of these companies played a role in the
design of the study; data collection, analysis, and interpretation; or preparation of the manuscript.
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