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Original article

B-type natriuretic peptide predicts disease severity in

children with hypertrophic cardiomyopathy
J P Kaski, M T Tome Esteban, S Mead-Regan, A Pantazis, J Marek, J E Deanfield,
W J McKenna, P M Elliott
Inherited Cardiovascular
Diseases Unit, Department of
Cardiology, Great Ormond Street
Hospital for Children, London, UK
Correspondence to:
Dr J P Kaski, Department of
Cardiology, Great Ormond Street
Hospital, Great Ormond Street,
London WC1N 3JH, UK;
j.kaski@ucl.ac.uk
Accepted 6 November 2007
Published Online First
10 December 2007

ABSTRACT
Background: In adults with hypertrophic cardiomyopathy
(HCM), plasma B-type natriuretic peptide (BNP) levels
correlate with dyspnoea class and other markers of
disease severity. In children with HCM, symptoms are a
poor guide to disease severity and no studies have
evaluated the clinical utility of BNP testing.
Objective: To assess the relation of BNP levels to
symptoms and markers of disease severity in children
with HCM.
Methods: Forty-four consecutive patients with HCM (27
male, age (17 years (median 13.6) underwent
assessment of plasma BNP. Clinical evaluation of patients
was carried out, including ECG, echocardiography and
tissue Doppler imaging.
Results: BNP levels correlated with maximal left
ventricular (LV) wall thickness (rs = 0.631, p,0.001),
resting LV outflow tract gradient (rs = 0.611, p,0.001),
transmitral E/septal Ea (E/Eas) ratio (rs = 0.770, p,0.001)
and percentage predicted maximum VO2 (rs = 20.390,
p = 0.025); there was no relation between BNP and heart
failure symptoms. BNP levels were higher in patients who
had undergone implantation of an internal cardioverterdefibrillator than in those who had not (309 (interquartile
range (IQR) 181391) vs 50 (IQR 18188) pg/ml,
p = 0.001). BNP was independently associated with E/Eas
(rs = 0.632, p,0.001) and maximal LV wall thickness
(rs = 0.412, p = 0.008) on multivariate analysis. At a cutoff point of 50 pg/ml, BNP had a positive predictive value
of 93% and a negative predictive value of 80% for
predicting E/Eas .10 (area under the receiver operator
characteristic curve = 0.875 (p,0.001)).
Conclusions: BNP levels correlate with non-invasive
parameters of disease severity in children with HCM,
including measures of raised LV filling pressures. For
patients in whom evaluation of symptoms is difficult, BNP
may be a useful additional tool in the assessment of
disease severity.

Hypertrophic cardiomyopathy (HCM) is a genetic

cardiac disease that, in addition to causing sudden
cardiac death, also results in progressive heart
failure in people of all ages.17 In children with
HCM, assessment of symptoms and the severity of
exercise limitation present a major challenge as
most clinical scoring systems are designed for
adults8 and functional tests such as cardiopulmonary exercise testing can be difficult to perform in
the very young.
B-type natriuretic peptide (BNP) is synthesised
and released by ventricular myocardial cells in
response to myocyte stretch.9 Serum BNP (and
amino-terminal fragment NT-proBNP) levels are a
useful diagnostic tool in patients with systolic and
Heart 2008;94:13071311. doi:10.1136/hrt.2007.126748

diastolic heart failure10 11 and correlate well with

haemodynamic variables such as left ventricular
end-diastolic pressure.12 In patients with chronic
heart failure, high serum BNP levels are associated
with increased cardiovascular mortality9 1316 and
sudden death.17
In adults with HCM, BNP levels correlate with
heart failure symptoms, maximal wall thickness,
systolic and diastolic dysfunction1820 and exercise
capacity.21 Data on BNP levels in the paediatric
population are more limited2230 and there have
been no studies specifically evaluating the clinical
utility of BNP testing in children with HCM. The
aim of this study was to determine BNP levels in a
cohort of children with HCM and to assess their
relation to symptoms and a number of predetermined markers of disease severity.

PATIENTS AND METHODS

Patients
Forty-four consecutive patients aged (17 years
(median 13.6; range 3.317; interquartile range
10.815.1) evaluated in the hypertrophic cardiomyopathy clinic at Great Ormond Street Hospital,
London, UK, underwent blood sampling for the
measurement of plasma BNP levels. All patients
fulfilled conventional diagnostic criteria for HCM
(unexplained left ventricular hypertrophy more
than 2 SDs corrected for body surface area31).
Patients with metabolic or syndromic HCM,
including Noonan syndrome, were excluded.
Patients underwent non-invasive assessment
including clinical history, physical examination,
12-lead ECG and echocardiography. Thirty-three
patients also underwent symptom-limited ergometric cardiopulmonary exercise testing; the
remaining 11 patients were either too young to
perform the test (n = 6), underwent exercise
testing without metabolic gas analysis (n = 2),
had submaximal tests (n = 1) or had exercise tests
more than 1 year before BNP levels were assayed
(n = 2). Table 1 shows the clinical characteristics of
the study group.

Echocardiography
Standard two-dimensional and M-mode views
were obtained using GE Vivid 7 machines (GE
Healthcare, Waukesha, Wisconsin, USA). Left
atrial and ventricular internal dimensions were
determined by conventional techniques and
expressed as a deviation from the mean (z-score)
based on our previously published normal values.32
End-diastolic left ventricular (LV) wall thickness was
measured by two-dimensional echocardiography at
1307

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Original article
Table 1 Clinical and echocardiographic characteristics
of 44 patients with HCM
Characteristics
Demographics
Age (years), median (IQR)
Male/female, n (%)
NYHA class, n (%)
I
II
III/IV
Chest pain, n (%)
Syncope
Palpitation
Medication, n (%)
b Blocker
Calcium antagonist
Disopyramide
Amiodarone
ICD
Echocardiography
MLVWT (mm), median (IQR)
MLVWT z-score, mean (SD)
LVEDD z-score, mean (SD)
LVESD z-score, mean (SD)
FS (%), mean (SD)
LA z-score, mean (SD)
LVOT gradient (mm Hg), median (IQR)
MR
Trivial, n (%)
Mild, n (%)
Moderate/severe, n (%)
E/A, median (IQR)
E/Eas, median (IQR)
E/Eal, median (IQR)
RVH, n (%)

velocities, and systolic velocities (Sa) at the lateral mitral, septal

and lateral tricuspid walls, as previously reported.34

Value

BNP analysis
13.6 (10.815.1)
27/17 (61/39)
39 (89)
3 (7)
2 (4)
9 (20)
1 (2)
4 (9)
25 (57)
22 (50)
4 (9)
8 (18)
3 (7)
13 (30)

19 (1326)
+15.54 (9.46)
21.99 (2.41)
22.90 (2.50)
44 (10)
2.26 (2.39)
10 (623)

Blood samples were collected by venepuncture at rest and

placed in tubes containing EDTA. BNP levels were measured
using the Triage BNP assay (Biosite Diagnostics, San Diego,
California, USA), a two-site fluorescence immunoassay for BNP
in whole-blood specimens. The precision and sensitivity of this
assay have been previously reported.11 A BNP concentration of
32.7 pg/ml was used as the upper limit of normal, based on
published values.24

Statistical analysis
SPSS (version 11.0) statistical package was used for all analyses.
Data are expressed as mean (SD) for normally distributed
variables or median (interquartile range (IQR)) for nonparametric variables. Categorical data are expressed as percentages. The Student t test or one-way analysis of variance was
used to compare means of continuous variables, and the x2
test was used for comparison of categorical data. Nonparametric data were assessed using the MannWhitney U or

19 (43)
16 (36)
1 (2)
1.6 (1.22)
15 (820)
8.5 (611)
19 (43)

E/A, ratio of left ventricular inflow early diastolic/atrial peak filling

velocities; E/Eas, E/septal Ea ratio; E/Eal, E/lateral Ea ratio; FS,
fractional shortening; ICD, implantable cardioverter-defibrillator; LA,
left atrium; LVEDD, left ventricular end-diastolic dimension; LVESD,
left ventricular end-systolic dimension; LVOT, left ventricular outflow
tract; MLVWT, maximum left ventricular wall thickness; MR, mitral
regurgitation; NYHA, New York Heart Association functional class;
RVH, right ventricular hypertrophy.

the level of the mitral valve and papillary muscles in the anterior
and posterior septum and the lateral and posterior wall, and at
apical level in the anterior and posterior septum using parasternal
short-axis views. Maximum LV wall thickness was defined as the
greatest thickness in any single segment. z-Scores were calculated
for septal and posterior LV wall thickness measured using Mmode in the parasternal long-axis view. The presence of right
ventricular hypertrophy (RVH) was determined using standard
views, as previously described.33 The peak LV outflow tract
gradient was determined at rest from continuous wave Doppler
imaging using the modified Bernoulli equation. LV outflow tract
obstruction was defined as a peak gradient >30 mm Hg. Pulsedwave Doppler imaging was used to record mitral inflow peak Eand A-wave velocities, E-wave deceleration time, A-wave duration
and isovolumic relaxation times at the tips of the valve leaflets in
the apical four-chamber view. Pulmonary vein inflow Doppler
patterns were analysed to determine peak systolic, diastolic and
atrial reversal velocities. Tissue Doppler imaging (TDI) was
obtained from the apical four-chamber view, using the lowest
wall filter settings and minimum optimal gain.31 The following
variables were measured: early (Ea) and late (Aa) diastolic
1308

Figure 1 Correlation of serum B-type natriuretic peptide (BNP) levels

(pg/ml) with (A) transmitral E/septal Ea (E/Eas) ratio; and (B) maximum
left ventricular wall thickness (mm) (MLVWT).
Heart 2008;94:13071311. doi:10.1136/hrt.2007.126748

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Original article
Table 2 Accuracy of B-type natriuretic peptide (BNP) in predicting an
E/Eas ratio .10
BNP level
(pg/ml)

Sensitivity

Specificity

PPV

NPV

>32.7
>50
>100
>150
>200
>300

89
89
79
64
46
36

71
86
93
93
93
100

86
93
96
95
93
100

77
80
68
57
46
44

Values are given as percentages.

NPV, negative predictive value; PPV, positive predictive value.

KruskalWallis tests. Correlations were assessed using Pearsons

correlation coefficient for normally distributed variables and
Spearmans correlation coefficient for non-parametric data. The
relationship between significant variables was investigated
using a multivariate linear regression analysis, in which clinical
variables were selected stepwise to reduce the model to only
statistically significant parameters.
Sensitivity, specificity and positive and negative predictive
values were calculated for selected BNP cut-off points, in
relation to E/Ea ratios .10 (as a measure of raised LV filling
pressures extrapolated from normal values in adults34). Receiver
operator characteristic (ROC) curves were constructed by
plotting sensitivity against 12specificity. A p value ,0.05 was
considered significant for all analyses.

RESULTS
Plasma BNP levels ranged from 4 pg/ml to 791 pg/ml (mean
(SD) 187 (192) pg/ml; median 135, IQR 26306 pg/ml).
Seventy-one per cent of patients had BNP levels that exceeded
the upper limit of normal (32.7 pg/ml).

Correlation between BNP and clinical features

Plasma BNP level correlated with age (rs = 0.453, p = 0.002),
maximal left ventricular wall thickness (rs = 0.631, p,0.001),
resting LV outflow tract gradient (rs = 0.611, p,0.001) and left
atrial z-score (rs = 0.343, p = 0.023) (fig 1). BNP also correlated
with LV wall thickness expressed as z-score (r = 0.658,

p,0.001). Serum BNP levels were higher in patients receiving

medication (163 (IQR 60367) vs 35 (IQR 17205) pg/ml,
p = 0.012), in patients with RVH (205 (IQR 130382) vs 35
(IQR 19209) pg/ml, p = 0.035) and with increasing grades of
mitral regurgitation (none: 23 (IQR 11132); trivial: 122 (IQR
17254); mild: 238 (IQR 82375); moderate: 458 (n = 1) pg/ml;
p = 0.022). There was a negative correlation between serum
BNP levels and peak VO2 levels expressed as a percentage of
predicted values corrected for age, gender and body surface area
(rs = 20.390, p = 0.025). Serum BNP levels were significantly
higher in patients who had undergone implantation of a
cardioverter-defibrillator than in those who had not (309 (IQR
181391) vs 50 (IQR 18188) pg/ml, p = 0.001). There was a
trend towards higher BNP levels in symptomatic patients (New
York Heart Association (NYHA) class II/III) than in asymptomatic patients (279 (IQR 205545) vs 122 (IQR 21309) pg/ml),
but this was not significant (p = 0.062). No significant relation
was found between serum BNP and left ventricular cavity
dimension z-scores or fractional shortening.

BNP and LV diastolic function

Complete echocardiographic and TDI data were available in 42/
44 patients (table 1). Serum BNP levels correlated with the
transmitral E/septal Ea (E/Eas) ratio (rs = 0.770, p,0.001; fig 1),
the transmitral E/lateral Ea (E/Eal) ratio (rs = 0.665, p,0.001)
and negatively with the transmitral E/A ratio (rs = 20.397,
p = 0.008). There was no significant correlation between BNP
levels and pulmonary vein Doppler parameters.
Table 2 shows the accuracy of different cut-off points of
plasma BNP levels for predicting an E/Eas ratio .10. BNP levels
above the upper limit of normal predicted E/Eas .10 with a
sensitivity of 89%, specificity 71%, positive predictive value 86%
and negative predictive value 77%. A BNP value >300 pg/ml
was the most predictive of an E/Eas .10, although a cut-off
point of 50 pg/ml was most accurate overall at predicting E/Eas
.10. The sensitivity and negative predictive values for predicting an E/Eal ratio .10 were higher for all BNP cut-off levels than
for predicting E/Eas .10, but the specificity and positive
predictive values were lower (data not shown).
The ability of BNP to predict LV diastolic impairment was
assessed using ROC curve analysis (fig 2). At the normal cut-off
point of 32.7 pg/ml, BNP levels were moderately accurate at
discriminating between patients with E/Eas .10 vs E/Eas (10
(area under the ROC curve (AUC) = 0.804, p = 0.001).
However, using a cut-off point of 50 pg/ml, the power of BNP
levels to predict an E/Eas ratio .10 increased substantially
(AUC = 0.875, p,0.001), with a similar sensitivity (89%). The
accuracy of BNP at predicting an E/Eal ratio .10 was lower than
for predicting E/Eas .10 (AUC = 0.717, p = 0.025 for BNP
>32.7 pg/ml; AUC = 0.750, p = 0.01 for BNP >50 pg/ml;
AUC = 0.817, p = 0.001 for BNP >100 pg/ml).

Multivariate analysis

Figure 2 Receiver operator characteristic (ROC) curve of B-type

natriuretic peptide (BNP) levels at cut-off points of 32.7 pg/ml and
50 pg/ml for predicting an E/Eas .10 in patients with hypertrophic
cardiomyopathy.
Heart 2008;94:13071311. doi:10.1136/hrt.2007.126748

Plasma BNP levels correlated with E/Eas and maximal LV wall

thickness after adjusting for all other factors that correlated
with BNP in the multivariate analysis (table 3). Together, these
two variables accounted for about 56% of the variability in BNP
levels (R2 = 0.558), with maximal LV wall thickness contributing 9% (DR2 = 0.09; p = 0.008). The same result was obtained
when maximal LV wall thickness z-scores were used in the
multivariate analysis instead of absolute maximal LV wall
thickness values (R2 = 0.558; DR2 = 0.09, p = 0.008). When E/Eal
was used as the TDI measure of LV filling pressures in the
1309

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Original article
Table 3 Univariate and multivariate regression analysis in 44 patients
with hypertrophic cardiomyopathy

Variable

Univariate
p value

Multivariate
standardised
coefficient

Multivariate
partial
correlation

p Value

Age
E/A
E/Eas
LA z-score
LVOT gradient
Medication
MLVWT
MR
RVH

0.002
0.008
,0.001
0.023
,0.001
0.012
,0.001
0.022
0.005

0.576

0.319

0.632

0.412

,0.001

0.008

E/A, left ventricular inflow early diastolic/atrial filling ratio; E/Eas, E/septal Ea ratio; LA,
left atrium; LVOT, left ventricular outflow tract; MLVWT, maximal left ventricular wall
thickness; MR, mitral regurgitation; RVH, right ventricular hypertrophy.

multivariate model, maximal LV wall thickness and E/Eal were

independently associated with BNP, but were less predictive
(R2 = 0.377). When the percentage predicted maximal VO2 was
entered into the multivariate analysis (therefore reducing the
number of patients in the analysis to 33), E/Eas and age were
independently associated with BNP (R2 = 0.589), with age
contributing 14.7% (DR2 = 0.147; p = 0.004).

DISCUSSION
This study shows that serum BNP levels are increased in
children with HCM compared with published normal values24 29
and correlate with other markers of disease severity, including
maximal LV wall thickness, LV outflow tract obstruction, left
atrial size and echocardiographic measures of LV filling
pressures. BNP levels did not correlate with subjectively assessed
symptoms. We therefore speculate that BNP levels may provide
an additional tool for assessing disease severity and haemodynamic impairment.

Assessment of symptoms in paediatric HCM

In children with HCM, symptoms are a poor guide to disease
severity, particularly in the very young, and are not a useful
prognostic determinant.35 The application of cardiac symptom
scores such as NYHA functional class can be problematic in the
young8 and alternative scoring systems have not been fully
validated in children. Objective measures of functional capacity
such as peak VO2 on cardiopulmonary exercise testing have
been shown to predict heart failure symptoms in children with
HCM,36 but this technique cannot be performed easily in the
very young. The finding in this study that BNP levels correlate
with echocardiographic measures of LV filling pressures, despite
the lack of a significant relation with NYHA functional class,
supports the observation that diastolic dysfunction in paediatric
HCM is often not associated with typical heart failure
symptoms,36 and suggests that BNP levels may represent a
more objective measure of haemodynamic status in the young
than subjective symptom scores.

BNP and TDI measures of LV filling pressure in children did not

demonstrate any relation between these two measures.28 This
difference may be explained by the fact that the patients
included in that study had several different causes of LV systolic
impairment and most had E/Ea ratios within the normal range
(median E/Eal = 6.7 (IQR 5.611]).28 Furthermore, the majority
of patients were receiving heart failure drug treatment, which
can reduce BNP levels and left ventricular filling pressures.37

Mechanisms of raised BNP in HCM

The data in this study showing a correlation between BNP and a
number of echocardiographic disease markers are consistent
with findings in adults with HCM.18 21 38 BNP is synthesised in
bursts and released constitutively from ventricular myocytes in
response to myocyte stretch.9 A number of mechanisms may
have a role in increasing myocyte stretch in HCM, including
local myocardial factors such as myocyte disarray and myocardial hypertrophy, and ventricular and haemodynamic alterations such as LV outflow tract obstruction, raised LV filling
pressures and myocardial ischaemia. It is, therefore, not
surprising that BNP levels correlated with maximal LV wall
thickness and RVH, LV outflow tract obstruction and noninvasive markers of raised LV filling pressures, including left
atrial size, transmitral E/A ratio and TDI parameters in this
study. However, the univariate relations between BNP and each
individual marker are modest at best, implying that the
mechanisms triggering BNP release are multifactorial.

Clinical implications
The results of this study suggest that BNP levels may have a
useful role in the assessment of disease severity in children with
HCM. The finding that BNP levels predict abnormal E/Eas ratios
is important, as this measure has previously been shown to
predict adverse outcomes (death, cardiac arrest or ventricular
tachycardia) in children.36 This study was not designed to
examine the relation between BNP levels and prognosis, but it is
noteworthy that BNP levels were significantly higher in patients
with an implantable cardioverter-defibrillator (and therefore
presumed to be at a higher risk of sudden death). Longitudinal
studies are needed to examine this relation further.

Limitations
This study is limited by its cross-sectional design and by the fact
that normal values for E/Ea ratios have been extrapolated from
adult data, in the absence of similar values in the paediatric
population. However, comparison with published age-related
normal values for transmitral E wave and septal and lateral Ea
wave velocities36 3941 suggests that this extrapolation is valid. In
addition, given the absence of subjective measures of heart
failure in children with HCM, studies to further characterise the
relationship between BNP and more objective measures of
functional capacity such as maximal VO2 on cardiopulmonary
exercise testing are warranted. Finally, it is possible that some of
the variability in BNP levels may be overcome by measuring
NT-proBNP, which is inherently more stable.

Previous studies of BNP in children

Previous reports of BNP levels in children have focused on the
differentiation between cardiac and non-cardiac dyspnoea23 26 or
have examined children with left ventricular systolic dysfunction28 30 and congenital heart disease.22 25 27 30 The BNP levels in
this study are similar to those reported for children with chronic
LV systolic impairment.28 The only previous report evaluating
1310

CONCLUSIONS
The data in this study show that serum BNP levels correlate
with non-invasive parameters of disease severity in children
with HCM, including TDI measures of raised LV filling
pressures. In a group of patients in whom the evaluation and
significance of symptoms is difficult to establish, BNP may
Heart 2008;94:13071311. doi:10.1136/hrt.2007.126748

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Original article
represent a useful additional tool in the assessment of disease
severity.

19.
20.

Acknowledgements: We are grateful to the staff at the biochemistry laboratory at

Great Ormond Street Hospital/Institute of Child Health, London, UK.
Funding: JPK is supported by a British Heart Foundation Junior Research Fellowship
(FS/05/036); JED is supported by the British Heart Foundation.
Competing interests: None.

21.
22.
23.

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B-type natriuretic peptide predicts disease

severity in children with hypertrophic
cardiomyopathy
J P Kaski, M T Tom-Esteban, S Mead-Regan, A Pantazis, J Marek, J E
Deanfield, W J McKenna and P M Elliott
Heart 2008 94: 1307-1311 originally published online December 10, 2007

doi: 10.1136/hrt.2007.126748
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