Download The role of NT-proBNP in the diagnostics of isolated diastolic

Clinical research
European Heart Journal (2005) 26, 2277–2284
doi:10.1093/eurheartj/ehi406
The role of NT-proBNP in the diagnostics of
isolated diastolic dysfunction: correlation with
echocardiographic and invasive measurements
Carsten Tschöpe*{, Mario Kašner{, Dirk Westermann, Regina Gaub, Wolfgang C. Poller,
and Heinz-Peter Schultheiss
Department of Cardiology and Pneumology, Charité—University Medicine Berlin, Campus Benjamin Franklin,
Hindenburgdamm 30, 12200 Berlin, Germany
Received 11 February 2005; revised 14 June 2005; accepted 16 June 2005; online publish-ahead-of-print 13 July 2005
KEYWORDS
Left ventricular diastolic
dysfunction;
N-terminal pro-B type
natriuretic peptide;
Heart failure;
Biomarker
Aims Diastolic heart failure is a frequent entity but difficult to diagnose. N-terminal pro-B type natriuretic peptide (NT-proBNP) was therefore investigated as a possible non-invasive parameter to diagnose
isolated diastolic dysfunction.
Methods and results Sixty-eight symptomatic patients with isolated diastolic dysfunction and preserved
left ventricular ejection fraction (LVEF) (50%) and 50 patients with regular left ventricular (LV) function were examined by conventional echocardiography, tissue Doppler imaging (TDI), and left and right
heart catheterization. Plasma NT-proBNP levels were determined simultaneously. Median NT-proBNP
plasma levels were elevated [189.54 pg/mL (86.16–308.27) vs. 51.89 pg/mL (29.94–69.71);
P , 0.001] and increased with greater severity of the diastolic dysfunction (R ¼ 0.67, P , 0.001).
According to the recevier operating characteristic analysis, LV end-diastolic pressure [area under the
curve (AUC) 0.84] was the most specific parameter, which had a low sensitivity (61%), however. The
reliability of NT-proBNP was similar to TDI indices (AUC 0.83 vs. 0.81) and improved when compared
with conventional echocardiography (AUC 0.59–0.70). NT-proBNP levels had the best negative predictive value of all methods (94%) and correlated strongly with indices of LV filling pressure, as determined
by invasive measurements. Multivariable linear regression analysis confirmed NT-proBNP as an independent predictor of diastolic dysfunction with an Odds ratio of 1.2 (1.1–1.4, CI 95%) for every unit increase
of NT-proBNP.
Conclusion NT-proBNP can reliably detect the presence of isolated diastolic dysfunction in symptomatic
patients and is an useful tool to rule out patients with reduced exercise tolerance of non-cardiac origin.
Introduction
Heart failure with normal or minimally impaired systolic
function is attributed to diastolic dysfunction. More than
one-third of patients presenting with symptoms and signs
of congestive heart failure (CHF) have isolated diastolic dysfunction, which is associated with a poor prognosis.1,2
Clinical examination cannot distinguish between systolic
and diastolic heart failure.3 The diagnosis of diastolic
heart failure is rather based on exclusion. Doppler echocardiography is used for a quick bedside assessment of diastolic
function, but its sensitivity and specificity in detecting diastolic abnormalities are unsatisfactory due to many factors
including heart rate, age, left ventricular (LV) loading
conditions, and operators skills. Similar problems may be
expected for tissue Doppler imaging (TDI), AV-plane displacement, and magnetic resonance techniques. Invasive
* Corresponding author. Tel: þ49 30 8445 4802; fax: þ49 30 7871 7823.
{
E-mail address: [email protected]
The first two authors contributed equally.
investigations via left and right heart catheterization to
measure LV filling pressures are more reliable, but also
load-dependent and not useful for wide spread clinical
implementation. For these reasons, simple and reliable
diagnostic criteria for diastolic heart failure are lacking
and a rapid non-invasive diagnostic test would be of high
clinical value.
Abnormal diastolic filling pressure, the key functional
abnormality in diastolic heart failure, leads to a release of
cardiac neurohormones including natriuretic peptides.4
Previous studies have reported that B type natriuretic
peptide (BNP) and its biologically inactive fragment
N-terminal proBNP (NT-proBNP), both of which are released
predominantly by the ventricles in response to stretch, may
be used for the diagnosis of systolic heart failure.5 However,
the role of these peptides in patients with diastolic heart
failure is still under investigation.6–11 Although it has been
found that BNP and NT-proBNP correlate with diastolic
abnormalities in patients with reduced systolic function9
and in patients with advanced forms of isolated diastolic
& The European Society of Cardiology 2005. All rights reserved. For Permissions, please e-mail: [email protected]
2278
heart failure,6,12,13 several Doppler echocardiographic
studies found them not to be useful for the detection of
mild diastolic failure.11–17 The latter is associated with
increased filling pressures at exertion only and will be
missed by conventional Doppler echocardiography, which is
performed at rest. Because NT-proBNP circulates at higher
plasma concentrations and has a longer half-life when
compared with BNP,18 NT-proBNP could be useful for the
detection of all degrees of diastolic dysfunction. To study
this hypothesis, we have investigated the potential of NTproBNP to detect isolated diastolic dysfunction, according
to the guidelines of the European Study Group On Diastolic
Heart Failure,19 and its accuracy in comparison to established invasive and non-invasive methods including left and
right heart catheterization, transmitral Doppler echocardiography, pulmonary venous Doppler, and TDI in a series of
patients with clinically suspected CHF despite preserved LV
systolic contractility and dimensions.
Methods
Patient population
We investigated prospectively 118 patients admitted to our unit who
had preserved LV function and normal LV dimensions as determined
by echocardiography and ventriculography. Sixty-eight patients with
exertional dyspnoea (NYHA class I–III) who met the criteria for isolated diastolic dysfunction were compared with 50 patients with
normal diastolic function. Patients with atrial fibrillation, lung
diseases, renal dysfunction, significant heart valve disease, or
other severe concomitant diseases were excluded. Medications
that can influence haemodynamics (diuretics, beta-blockers,
calcium-blockers, and ACE- and AT1-receptor inhibitors) were all
paused for 48 h before examinations were performed.
All investigated patients gave informed written consent for invasive diagnostic procedures, including echocardiography and right
and left cardiac catheterization, which were performed by using
standard techniques. Our study complies with the Declaration of
Helsinki. The locally appointed Ethics Committee has approved
the research protocol.
Definition and assessment of diastolic dysfunction
Following the guidelines from the European Study Group on Diastolic
Heart Failure,19 the diagnosis of diastolic dysfunction was defined
after the evidence of abnormal LV relaxation, filling, and/or diastolic distensibility in the presence of clinical signs of CHF, with
demonstrable normal or only mildly impaired systolic function
(EF 50%). During LV angiography, slow isovolumic LV relaxation
was indicated by an increase in dP/dtmin ( 2 1100 mmHg/s) and/
or a prolongation of the time constant of LV pressure decay (Tau
48 ms) as derived and calculated from digitalized LV pressure
recordings using a modified commercially available software
program (MacLab, Wisstech, Germany), and/or during echocardiography (VINGMED System Five operating at 2.5–3.5 MHz) by a prolongation of isovolumic relaxation time (IVRT 94–100 ms) as
derived from LV outflow tract Doppler signals. Slow early LV filling
was indicated by a reduction of the ratio of E-wave (early filling)
to A-wave (atrial filling) peak velocities (E/A 1) and/or of the
E-wave deceleration time (DT 220–260 ms) as derived from LV
Doppler signals. Because the specificity and sensitivity of any one of
these three echocardiographic parameters per se are low, diastolic
dysfunction was considered when at least two of these parameters
were abnormal after age and heart rate relaxation.20 Confirmation
included also pulmonary vein flow analysis in the right upper paraseptal pulmonary vein where systolic (S) and diastolic (D) velocities
were measured, as well as the velocity (Ar) and duration of the
C. Tschöpe et al.
atrial reversal wave. Using TDI, the ratio of early-to-late annular
velocity of lateral mitral leaflets origin (E0 /A0 ) was determined in
the apical four-chamber view. All echocardiography data were
copied to VHS videotape for subsequent playback, analysis, and
measurement. Reduced LV diastolic distensibility was indicated by
an increase in LV end-diastolic pressure (LVEDP 16 mmHg) as
derived from LV pressure recordings and/or by pulmonary capillary
wedge pressure (PCWP) measured by right heart catheterization
(Swan–Ganz catheter) at rest (12 mmHg) or during exercise
(20 mmHg) (bicycle ergometry). Exercise was performed by
bicycle ergometry in a recumbent position with the use of a continuous protocol, which began with a workload of 25 W that was
increased by 25 W every 2 min. Patients were asked to cycle at a
rate of 50 r.p.m. at each stage, and exercise was terminated when
the patient reached 75% of the calculated maximum heart rate or
because of dyspnoea or of the occurrence of leg/general fatigue.
NT-proBNP plasma levels were determined at rest using the commercially available Elecsysw proBNP sandwich immunoassay on an
Elecsys 2010 (Roche Diagnostics, Germany). All measurements
were obtained without knowledge of NT-proBNP data.
Overall diastolic stage, determined from the pattern of mitral and
pulmonary venous flow, was defined as impaired relaxation (stage I:
E/A ratio ,1, DT . 220 ms; S/D ratio .1, Ar , 35 cm/s), pseudonormal (stage II: E/A ratio 1–2, DT . 150–220 ms; S/D ratio ,1,
Ar . 35 cm/s), or restrictive (stage III: E/A ratio .2, DT , 150 ms;
S/D ratio ,1, Ar . 35 cm/s).21,22 Reduction of the E0 /A0 ratio (,1)
in TDI confirmed diastolic dysfunction, including stages I and II. E0
and A0 amplitude ,8 cm/s indicated a restrictive flow pattern.
LV mass index was calculated according to Devereuxs formula23
divided by body surface area. We calculate left atrial volume
index (LAVI) according to the already described formula: LAV ¼ p/6
(diameter in parasternal long-axis view) (short-axis in the
apical four-chamber) (long-axis in the apical four-chamber)24 at
ventricular end-systole divided by body surface area.
Statistical analysis
SPSS Inc. for Windows Standard version 11.0.1 was used for statistical
analysis. Continuous variables are expressed as mean + SD (range).
Quantitative normally distributed data were compared using the
Student’apos; t-test. Non-normally distributed variables were
analysed with non-parametric Mann–Whitney U test. To compare
qualitative data, x2 test was performed. Receiver operating characteristic (ROC) curves were constructed to determine the ability of
NT-proBNP throughout the range of concentrations (cut-off points)
to identify diastolic dysfunction. The diagnostic utility of NT-proBNP
alone was compared with the echocardiographic probability of LV
dysfunction through the estimation of the area under the curve
(AUC) for each parameter separately. Linear regression analysis was
used to determine correlations between continuous variables and
the log-transformed NT-proBNP levels were used, as the values
were not normally distributed. Spearman correlation was used for
correlation assessment of NT-proBNP with the groups of LVDD.
Multivariable logistic regression (backward likelihood ratio model)
was performed to evaluate the ability of NT-proBNP to identify diastolic dysfunction over and above the information provided by other
indicators from Table 1 [age, sex, hypertension, diabetes mellitus,
CAD, LV-hypertrophy, and body mass index (BMI)]. A value of
P , 0.05 was considered statistically significant and a-level adjustment (Bonferroni correction) with factor 3 (P , 0.017) is used to
avoid the experiment-wise Type I error due to multiple testing
between the LV diastolic dysfunction groups.
Results
Study participants
From 180 patients initially planned to enter the study, 11 of
them were excluded because of the low quality of data
Diagnostics of isolated diastolic dysfunction
2279
Table 1 Patients characteristics [variable expressed as mean + SD (range)]
Demographic variables
Women/men [n (%)]
Age (years)
BMI (kg/m2)
Vital signs
MAP (mmHg)
NYHA II–III [n (%)]
Heart rate (min21)
Left heart dimensions
LVEDD (mm)
LVMI (g/m2)
LAVI (mL/m2)
LVEF (%)
Concomitant diseases [n (%)]
Hyperlipoproteinemia
Smoker
Arterial Hypertension
Diabetes mellitus
Coronary artery disease
Viral/inflammatory
myocardiopathy
a
Population
(n ¼ 118)
Diastolic dysfunction
(n ¼ 68)
Regular diastolic function
(n ¼ 50)
P-valuea
53 (45)/59 (55)
49 + 13 (70–26)
26.1 + 4.1 (32.7–16.3)
31 (46)/37 (54)
51 + 9 (69–26)
26.8 + 4.0 (31.9–16.5)
22 (44)/28 (56)
49 + 10 (70–28)
25.3 + 4.0 (32.7–17.9)
0.708
0.091
0.120
91.9 + 12 (123–61)
66 (56)
71 + 11 (58–90)
93.6 + 11 (117–73)
58 (85)
70 + 12 (60–82)
90.1 + 12 (123–61)
8 (16)
71 + 11 (58–90)
0.172
0.001
0.865
50 + 6 (38–59)
107 + 31 (65–198)
18.8 + 5.9 (11.3–34.2)
67 + 10 (84–51)
51 + 6 (40–59)
114 + 28 (65–198)
21.0 + 6.8 (10.4–34.2)
68 + 9 (78–51)
50 + 4 (38–58)
103 + 26 (72–154)
18.1 + 4.5 (11.3–27.9)
65 + 10 (84–52)
0.473
0.371
0.303
0.093
49 (41)
33 (28)
44 (37)
11 (9)
43 (34)
28 (24)
30 (44)
21 (31)
29 (43)
9 (13)
28 (41)
22 (32)
19 (37)
12 (24)
15 (30)
2 (0.4)
15 (30)
6 (12)
0.687
0.433
0.060
0.011
0.086
0.023
Diastolic dysfunction vs. regular diastolic function.
recorded from echocardiography or heart catheterization
measurements. Four patients refused to be examined. In
addition, 47 patients were excluded by which the right
heart catheterization could not perform and, therefore, no
PCWP at rest or exercise was determined. Finally, the
study group consisted of 118 patients. From these 118
patients, 68 patients with diastolic dysfunction (mean age
51 + 9; 31 women and 37 men) were studied prospectively
and compared with 50 control subjects with normal diastolic
function (mean age 49 + 10; 22 women and 28 men)
(Table 1 ). All 118 patients had normal LV systolic function
(EF . 55%) and normal LVEDD in the parasternal long axis
(,60 mm). There were no significant differences between
both groups with respect to LVEF (68 + 9 vs. 65 + 10%,
P ¼ 0.093), LVEDD [51 + 6 (40–59) vs. 50 + 4 (38–58) mm,
P ¼ 0.473], sex, BMI, LVMI, or LAVI. As expected, the prevalence of committed disease was increased in patients with
diastolic dysfunction,1,25 indicated by a trend for a higher
prevalence of arterial hypertension and coronary heart
disease (CAD) and a higher frequency of diabetes mellitus
and suspected myocarditis with abnormal diastolic function
(Table 1 ).
In 68 patients, diastolic dysfunction was confirmed by
abnormal values of LVEDP, Tau, IVRT, DT, and/or by the E/A
ratio. Pseudonormal and restrictive flow pattern were diagnosed using pulmonary vein flow and TDI. Among 118 patients
who underwent right heart catheterization, 61 had an
increased PCWP at rest and/or at exercise (Table 2 ).
dP/dtmin, which probably reflects systolic relaxation rather
than early diastolic filling, did not differ between both
groups. Diastolic dysfunction was diagnosed with a high rate
of objective measured abnormal diastolic indices. Fifty-one
per cent of patients with diastolic dysfunction had three or
four abnormal diastolic echocardiographic and/or invasive
parameters, 22% had more than five and 15% had more than
seven positive indices.
NT-proBNP levels in patients with isolated
diastolic dysfunction
NT-proBNP levels were four-fold elevated in patients with
diastolic abnormalities when compared with control
patients [189.54 pg/mL (86.16–308.27) vs. 51.89 pg/mL
(29.9–69.7); P , 0.001). There was no significant difference
between men and women with diastolic abnormalities
[164.3 pg/mL (72.6–260.5) vs. 204.0 pg/mL (108.9–318.9);
P ¼ 0.112]. NT-proBNP levels increased significantly according to the severity of overall diastolic dysfunction, ranging
from impaired relaxation [151.6 pg/mL (90.6–278.1)
vs. controls 51.89 pg/mL (29.9–69.7), P , 0.001] to pseudonormal filling [308.1 pg/mL (261.7–568.2) vs. 151.6 pg/mL
(90.6–278.1), P ¼ 0.003] and restrictive filling [2307.1 pg/mL
(1592.0–6440.1) vs. 308.1 pg/mL (261.7–568.2), P , 0.001]
and correlated with the Spearman coefficient R ¼ 0.67,
P , 0.001 (Figure 1 ). Even after a-level adjustment, the
differences between LVDD groups remained significant
(P , 0.017). The proportion of patients with abnormal sexand age-adjusted NT-proBNP levels among the control,
impaired relaxation, pseudonormal, and restrictive subgroup amounted to 8, 74, 94, and 100%, respectively
(Figure 2 ).
Similarly, NT-proBNP levels increased significantly
according to the NYHA-classification, ranging from NYHA
class I [97.5 pg/mL (77.2–120.6) vs. controls 55.7 pg/mL
(32.7–86.3), P , 0.040] to NYHA class II [177.3 pg/mL
(74.1–293.3) vs. 97.5 pg/mL (77.2–120.6), P ¼ 0.008] and
NYHA class III [334.7 pg/mL (180.2–976.8) vs. 177.3 pg/mL
2280
C. Tschöpe et al.
Table 2 Echocardiographic and invasive parameters in patients with diastolic dysfunction vs. regular diastolic function
LV/RV catheter
LVEDP (mmHg)
Tau (ms)
dP/dtmin (mmHg/s)
PCWP rest (mmHg)
PCWP exercise (mmHg)
Echocardiography
IVRT (ms)
DT (ms)
E/A ratio
S/D (PV)
E0 /A0 ratio (TDI)
All
Diastolic dysfunction
Regular diastolic function
P-valuea
12.3 + 5.7 (27–4)
41.5 + 9.1 (72–23)
21613 + 378 (22738–(2864))
8.6 + 5.1 (29–2)
19.1 + 8.8 (47–5)
15.5 + 5.3 (27–5)
43.7 + 9.9 (72–28)
21574 + 376 (22487–(2864))
11.0 + 6.0 (29–3)
21.7 + 10.3 (47–7)
9.1 + 4.5 (15–4)
38.9 + 7.3 (46–23)
21659 + 380 (22738–(21115))
6.4 + 3.2 (11–2)
13.8 + 5.5 (20–5)
,0.001
0.009
0.271
,0.001
0.002
105 + 27 (160–65)
193 + 44 (265–131)
1.2 + 0.42 (0.42–3.56)
1.1 + 0.34 (0.49–2.0)
1.20 + 0.54 (2.14–0.29)
113 + 30 (160–65)
198 + 48 (265–134)
0.9 + 0.39 (0.42–3.56)
1.3 + 0.38 (0.49–2.00)
0.87 + 0.26 (1.36–0.49)
97 + 19 (119–65)
187 + 36 (251–131)
1.3 + 0.29 (0.54–1.84)
0.9 + 0.24 (0.64–1.64)
1.51 + 0.56 (2.14–0.63)
0.002
0.250
,0.001
0.008
,0.001
Variable expressed as mean + SD (range).
a
Diastolic dysfunction vs. regular diastolic function.
Figure 2 Proportion of patients with abnormal NT-proBNP levels. Controls,
impaired relaxation, pseudonormal, and restrictive filling pattern amount
to 8, 74, 94, and 100%, respectively.
Figure 1 NT-proBNP levels in the patients with LV diastolic dysfunction are
significantly elevated and correlate with the severity of disease: controls
51.89 pg/mL (29.9–69.7) vs. impaired relaxation 151.6 pg/mL (90.6–278.1)
(P , 0.001) vs. pseudonormalization 308.1 pg/mL (261.7–568.2) (P ¼ 0.003)
vs. restriction 2307.1 pg/mL (1592.0–6440.1) (P , 0.001).
(74.1–293.3), P , 0.015], and correlated with the Spearman
coefficient R ¼ 0.48, P . 0.001.
Diagnostic accuracy of NT-proBNP to diagnose
isolated diastolic dysfunction
ROC curve analyses revealed an AUC for NT-proBNP of 0.83,
between the AUCs of LVEDP (0.84) and TDI (0.81) (Table 3 ).
All others were less reliable with the following AUC value:
PCWP at exercise 0.76, PCWP at rest 0.74, E/A ratio 0.70,
Tau 0.64, IVRT 0.63, DT 0.59, and dP/dtmin 0.58. Thus,
NT-proBNP was almost as good as the LVEDP and TDI and
better than the E/A ratio of Doppler echocardiography.
At a cut-off value of 110 pg/mL (Table 3 ), NT-proBNP
showed a high sensitivity of 72%, a specificity of 97%, a
positive predictive value of 84%, and the highest negative
predictive value of all investigated techniques (94%)
(Table 4 and Figure 3 ). After performing the multivariable
logistic regression analysis, NT-proBNP was an independent
predictor of isolated diastolic dysfunction with an Odds
ratio of 1.2 (1.1–1.4, CI 95%), for every unit increase in
the NT-proBNP level (Table 5 ).
Correlation of the NT-proBNP plasma levels with
Doppler echocardiographic indices, TDI, and
invasive measured diastolic indices
Linear regression analysis revealed significant correlations
between NT-proBNP and various echocardiographic parameters (Table 6 ). Thereby, a moderate relation to early
diastolic velocity (E0 ) (R ¼ 20.41, P , 0.001), early-to-late
diastolic velocity ratio (E0 /A0 ) (R ¼ 20.36, P , 0.001) of
mitral lateral annular movement, and a weak relation to
A–Ar duration (R ¼ 20.31, P ¼ 0.037) were found. NTproBNP and E0 /A0 analysis by TDI correlated significantly
with all invasive LV diastolic parameters as measured
directly by left and right heart catheterization. The best
correlation was found with LVEDP, PCWP at rest, and at
maximal exercise with R-values of 0.45, 0.42, 0.49
(P , 0.001), respectively. NT-proBNP did not correlate significantly with LVEDD, LVMI, DT, early and late mitral flow,
Diagnostics of isolated diastolic dysfunction
2281
Table 3 Sensitivity/specificity/positive and negative predictive
values by different cut-off values
NT-proBNP
cut-off (pg/mL)
Sensitivity
(%)
Specificity
(%)
PPV
(%)
NPV
(%)
90
100
110
120
130
140
304
75
74
72
69
56
53
19
86
88
90
91
92
92
100
54
58
61
63
61
59
100
94
94
94
93
91
90
85
Table 4 AUC, sensitivity, specificity, and positive and negative
predictive values by NT-proBNP at a cut off-value of 120 pg/mL
Parameter AUC
(95% CI)
Sensitivity Specificity PPV NPV
(%)
(%)
(%) (%)
LVEDP
NT-proBNP
E0 /A0 (TDI)
PCWP
exercise
PCWP rest
E/A
Tau
IVRT
DT
dP/dtmin
0.84 (0.73–0.91)
0.83 (0.78–0.89)
0.81 (0.75–0.90)
0.76 (0.65–0.84)
61
69
71
39
94
91
87
94
69
63
55
59
92
93
93
88
0.74 (0.59–0.85)
0.70 (0.62–0.77)
0.64 (0.52–0.74)
0.63 (0.58–0.77)
0.59 (0.46–0.68)
0.58 (0.47–0.67)
42
53
33
69
33
11
87
79
91
60
79
95
41
36
45
27
26
33
87
88
86
90
84
83
mitral E/A ratio, PV systolic and diastolic, PV systolic to
diastolic ratio (S/D ), and reversal atrial flow.
Discussion
To investigate the role of NT-proBNP in the detection of
isolated diastolic dysfunction, we formed a comparative
study of NT-proBNP, invasive haemodynamics, and comprehensive echocardiography. Our study showed that NTproBNP plasma levels were increased in patients with
diastolic dysfunction and preserved systolic function and
correlated with the severity of the disease. NT-proBNP had
the best negative predictive value of all methods investigated. The best correlation was found between the
NT-proBNP levels and the invasive parameters of LV filling
pressure. NT-proBNP levels had similar diagnostic accuracy
for diastolic heart failure as TDI and were superior to conventional echocardiography.
The role of NT-proBNP in the detection
of diastolic dysfunction
Instant measurement of plasma natriuretic peptides that are
normally increased as part of the neurohormonal activation
in both diastolic and systolic heart failure is a powerful biochemical test. There are several reports on the efficacy of
BNP 26,27 or NT-proBNP25,28–32 in diagnosing chronic heart
failure due to LV systolic dysfunction. A particular advantage
of that test is its high negative predictive value, allowing to
rule out systolic heart failure. The usefulness of BNPs in
Figure 3 ROC analysis revealed the reliability of NT-proBNP to diagnose an
isolated diastolic dysfunction with 82.7%.
Table 5 Multivariable logistic regression for evaluating the ability of NT-proBNP to identify diastolic dysfunction when compared
with other indicators
Indicator
OR
P-value
95% CI
Sex
Age
Dyspnoea
Diabetes mellitus
Hypertension
LV mass index
CAD
NT-proBNP
BMI
1.902
1.102
0.840
1.042
1.644
1.028
1.382
1.240
1.167
0.467
0.067
0.848
0.914
0.533
0.143
0.355
0.001
0.206
0.336–10.765
0.997–1.194
0.141–5.000
0.340–4.710
0.337–8.026
0.991–1.067
0.611–3.050
1.086–1.416
0.918–1.484
After backward likelihood ratio, analysis reminds NT-proBNP as an independent predictor with OR 1.2 (1.1–1.4). OR, Odds ratio; CI, confidence
interval; CAD, coronary artery disease; BMI, body mass index.
detecting diastolic heart failure is still under investigation.
Few studies have examined the value of BNPs in diagnosing
diastolic dysfunction in comparison with conventional echocardiography. Significantly higher BNP and NT-proBNP levels
were found in patients with advanced diastolic dysfunction
(restrictive and pseudonormal)6,12,13 and our study supports
these findings. Although these peptides were found to correlate with severe diastolic dysfunction, however, their role in
the detection of mild diastolic heart failure is uncertain.14
Lubien et al. 6 found that BNP levels were increased in
patients with exertional dyspnoea and impaired LV relaxation (202 pg/mL). Although Mottram et al. 12 also found
BNP levels increased in patients with hypertension-caused
impaired LV relaxation compared with controls, however,
in up to 75%, BNP levels were in the normal range (89 pg/mL)
in patients with impaired relaxation in this study. Wei
et al. 15 also reported low but significantly increased BNPlevels in hypertension-caused diastolic dysfunction, which
showed a moderate sensitivity but an excellent specificity
in detecting ventricular diastolic dysfunction in hypertensive
2282
C. Tschöpe et al.
Table 6 Correlation of NT-proBNP levels with invasive and noninvasive diastolic indices according to univariate linear regression
analysis
R-value
Age
Systolic RR
Diastolic RR
MAP
Heart rate
LVEDD
LVMI
Mitral flow
E
A
E/A
IVRT
DT
PV flow
S
D
S/D
Ar
A–Ar duration
Tissue Doppler
E0
A0
E0 /A0
Catheterization
LVEDP
dP/dtmin
Tau
PCWP, rest
PCWP, exercise
P-value
0.33
0.28
0.06
0.19
0.27
20.07
0.08
0.001
0.014
0.593
0.063
0.011
0.949
0.514
20.08
0.02
20.07
0.30
0.01
0.426
0.829
0.417
0.006
0.969
20.15
20.18
0.04
20.20
20.31
0.404
0.319
0.844
0.075
0.037
20.41
0.11
20.36
,0.001
0.438
,0.001
0.45
0.21
0.22
0.42
0.49
,0.001
0.049
0.024
,0.001
,0.001
patients. Similarly, Dahlström17 found only a trend for both
BNP and NT-proBNP to be increased into the upper normal
reference range of patients with little changes of Doppler
echocardiography indices. These conflicting reports may
reflect the heterogeneity of the diastolic heart failure populations investigated, the impact of a variety of clinical features, and differences in study design and emphasize the
need for a particularly careful characterization of study
patients in this field of research. Most previous studies
used conventional echocardiographic parameters as the
sole diagnostic criteria to identify isolated diastolic dysfunction. Obviously, the accuracy of transmitral flow analysis is
limited as also observed in our study. To overcome this key
problem, we have defined abnormal diastolic performance
by a combination of invasive and comprehensive echocardiographic measurements. We found that increased NT-proBNP
levels correlate with the severity of diastolic disease. This
even includes the subgroup of clinically stable patients
with near normal LVEDP at rest, impaired relaxation, and
exertional dyspnoea. It appears that the prolonged halflife of NT-proBNP when compared BNP is advantageous
under these circumstances and enables NT-proBNP to identify mild isolated diastolic dysfunction already. HammererLercher et al. 10 recently reported that the performance of
NT-proBNP and BNP for the diagnosis of diastolic dysfunction
was assay-dependent with a clear benefit for the Elecsys
NT-proBNP and Triagew BNP assays, but further comparative
evaluations are warranted.
Impaired LV relaxation was detected with a specificity of
90% and a negative predictive value of 94% by a NT-proBNP
of 120 pg/mL in 75% of symptomatic patients. This value is
similar to the recently recommended official NT-proBNP
cut-off value of 120 pg/mL. However, this cut-off value is
an average value from several community studies focusing
more on LV systolic function and not based on the complicated diagnostic, which is necessary to analyse also sufficient isolated diastolic dysfunction. Our study shows that
even lower NT-proBNP levels (90–110 pg/mL) reached the
negative predictive value of 94% accompanied with only a
slight reduction in specifity (Table 3 ). Therefore, NTproBNP is an useful tool to rule out patients with reduced
exercise tolerance of non-cardiac origin. From the clinical
point of view, the negative predictive value of 94%
appears most useful, because in patients with exerciseinduced dyspnoea at NT-proBNP ,90 pg/mL, a cardiac
origin of symptoms is highly unlikely, whereas at NTproBNP .110 pg/mL, diastolic dysfunction is the prominent
differential diagnosis. But as advanced forms of diastolic
dysfunction may reach NT-proBNP levels similar to those in
patients with severe systolic heart failure, NT-proBNP
cannot differentiate between diastolic and systolic heart
failure and is not a surrogate for echocardiography.
Although the sensitivity of NT-proBNP to detect isolated
diastolic dysfunction was moderate (69%) and therefore
not accurate for a screening test as already also shown by
Redfield et al.,16 NT-proBNP had one of the best sensitivity
of the tested methods in our study.
In conclusion, NT-proBNP reliably detects diastolic dysfunction in patients with filling abnormalities and preserved
LV systolic function, however, in line with the recent
European guidelines incorporating BNPs in to the algorithm
for the diagnosis of heart failure.33
NT-proBNP vs. invasive and echocardiographic
measurements
This study is the first to compare NT-proBNP for the diagnosis
of isolated diastolic dysfunction in symptomatic patients with
a broad panel of established methods including left and right
heart catheterization, transmitral, PV Doppler, and TDI. Gold
standard for the assessment of diastolic function is invasive
measurement with a conductance catheter providing
pressure–volume relationships. In the clinical practice, the
more easily available measurement of LV pressures during
routine left and right heart catheterization also enables
direct analysis of the early (dP/dtmin, Tau) and late period
(LVEDP and PCWP) of diastole. However, these values are
volume- and heart rate-dependent, which is reflected by
our finding of a high specificity (89–95%) but low sensitivity
(,61%) of LVEDP and PCWP, respectively, to detect diastolic
dysfunction (Table 4 ). The differences between PCWP at
rest and exercise were not as high as expected, because
several patients with diastolic dysfunction did not really
reach high exercise levels (mean maximal outcome: 83 W;
mean exercise duration time 7.3 min) due to dyspnoea,
fatigue, or leg pain, which shows the limitation of this
method in the clinical routine. Nevertheless, LVEDP and
PCWP, both reflecting LV filling pressure, correlated stronger
with NT-proBNP levels. PCWP at exercise, used to investigate
symptomatic patients with near normal filling pressures at
rest, correlated best with NT-proBNP, as we had also shown
Diagnostics of isolated diastolic dysfunction
recently,34 and is consistent with the fact that the release of
BNPs being triggered by ventricular volume expansion and
pressure overload.35 In addition, dP/dtmin and tau, reflecting
systolic relaxation or early diastolic relaxation rather than
myocardial filling pressure, correlated weaker with NTproBNP levels.
As the aforementioned reliable invasive measurements
are not routinely available in the diagnostic workup of suspected diastolic heart failure, appropriate non-invasive
tests are needed for the pre-invasive screening. Doppler
echocardiography is currently the non-invasive method of
choice for the assessment of diastolic function, but its
implementation in clinical routine is suboptimal due to operator dependency and limited availability in primary health
care. Furthermore, E/A, IVRT, and DT do not directly
measure diastolic function but diastolic flow over the
mitral valve only and this may explain its rather low accuracy.6,12,36 It is also in agreement with our finding that
none of the conventional echocardiographic parameters
reached sufficient sensitivity and specificity (33–79%) for
reliable detection of isolated diastolic function and may
explain why the NT-proBNP levels of our study population
did not correlate with DT and most of the indices determined
by PV Doppler. Although IVRT correlated significantly the
diastolic function in patients with concomitant systolic
heart failure, Mottram et al. 12 could not verify IVRT as an
important diagnostic marker in patients with isolated diastolic dysfunction. Similarly, although a short DT indicates
an increase in LA mean pressure in patients with systolic32
or restrictive diastolic heart failure,6 our data do not
support a diagnostic relevance of DT, reflecting early
diastolic filling, as 24% of our patients with diastolic
failure had prolonged DTs. This confirms Dahlström and
co-workers11,17 who also found no significant relationship
between DT and BNP or NT-proBNP in a study population
with mild diastolic abnormalities. In summary, owing to
many limitations, Doppler echocardiography cannot provide
unequivocal evidence of diastolic dysfunction.37
TDI is a more recent technique that measures myocardial
velocities directly. The early diastolic mitral annular velocity
(E0 /A0 ) has been shown to be a relatively load-independent
measure of myocardial relaxation. It correlated significantly
better with the NT-proBNP levels in our study population
than the E/A ratio determined by conventional echocardiography, consistent with studies of diastolic function comparing TDI or the ratio of mitral velocity to early diastolic velocity
of the mitral annulus (E/E0 ) derived from TDI and BNP levels in
intensive care patients38 or patients with systolic or diastolic
heart failure.9,34,39 Thus, NT-proBNP levels have similar diagnostic accuracy for diastolic heart failure as TDI and are
superior to conventional echocardiography.
In conclusion, according to its ROC, NT-proBNP stands in
the line with invasive parameters of LV filling pressure and
is characterized by a high negative predictive value.
Therefore, NT-proBNP can reliably detect the presence of
isolated diastolic dysfunction in symptomatic patients and
is a useful tool to rule out patients with reduced exercise
tolerance of non-cardiac origin.
Acknowledgement
The study was supported by the Deutsche Forschungsgesellschaft
(DFG: SFB/TR 19).
2283
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