Hindawi

Computational and Mathematical Methods in Medicine

Volume 2023, Article ID 1896026, 5 pages
https://doi.org/10.1155/2023/1896026

Research Article
Doppler Echocardiography Combined with NTproBNP/BNP in
the Diagnosis of Pulmonary Artery Hypertension Associated with
Congenital Heart Disease

Xi Zhang,1,2,3 Zhinan Zhai,1,2,3 Xu Geng,3 Yanbo Zhu,4 Shijuan Yang,5 Tongyun Chen,5
Xue Wu,6 Jingkun Zhang,7 Zhi-Gang Guo ,5 and Min Hou 1,2,3
1
Department of Clinical Laboratory, Clinical School of Thoracic, Tianjin Medical University, Tianjin 300222, China
2
Department of Clinical Laboratory, Tianjin Chest Hospital, Nankai University, Tianjin 300222, China
3
Department of Clinical Laboratory, Chest Hospital, Tianjin University, Tianjin 300222, China
4
Department of Ultrasonography, Tianjin Chest Hospital, Tianjin 300222, China
5
Department of Cardiovascular Surgery, Tianjin Chest Hospital, Tianjin 300222, China
6
Institute for Global Health Sciences, University of California, San Francisco, CA, USA
7
Cardiovascular Research Institute, University of California, San Francisco, CA, USA

Correspondence should be addressed to Zhi-Gang Guo; zhigangguo@yahoo.com and Min Hou; hmxkyy@163.com

Received 17 August 2022; Revised 14 December 2022; Accepted 28 January 2023; Published 13 February 2023

Academic Editor: Mario Sansone

Copyright © 2023 Xi Zhang et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background. Pulmonary artery hypertension (PAH) is a common complication of congenital heart disease (CHD) and is
associated with worse outcomes and increased mortality. The Doppler echocardiography (DE) is a commonly used imaging
tool for both diagnosis and follow-up examination of PAH. Here is to evaluate the diagnostic performance of DE combined
with NTproBNP/BNP as screening strategy in PAH patients with CHD. Methods. A retrospective study in 64 patients with
CHD has been carried out to compare estimate pulmonary artery systolic pressure (PASP) measured with DE to that measured
with right heart catheterization (RHC). The Pearson correlation analyses were used to calculate the correlation coefficients
between RHC and DE. The Bland-Altman analyses were carried out to assess the agreement between the two methods. ROC
analyses were used to evaluate the diagnostic performance of DE, NTproBNP/BNP, and DE combined with NTproBNP/BNP.
Results. Our data have demonstrated that a mild correlation (r = 0:4401, P < 0:01) was observed between PASP (78:1 ± 29:0
mmHg) measured during RHC and PASP (74:9 ± 19:7 mmHg) as estimated using DE. The Bland-Altman analysis
demonstrated that the bias for DE PASP estimates was 3.2 mmHg with 95% limits of agreement ranging from -49.53 to
55.90 mmHg. The results of DE showed an AUC of 0.848 (95% CI = 0:666-1; P < 0:001), the sensitivity of which was 98.3%
and the specificity was 77.8%. The AUC of NTproBNP/BNP for the identification of PAH was 0.804 (95% CI = 0:651-0.956; P
< 0:001), the sensitivity of which was 81.4% and the specificity was 87.5%. The AUC of DE combined with NTproBNP/BNP
was 0.857 (95% CI = 0:676-1; P < 0:001), of which sensitivity was 100% and specificity was 77.8%. The positive predictive value
(PPV) and negative predictive value (NPV) were 96.6% and 100%, respectively. Conclusions. Our study shows that the Doppler
echocardiography combined with NTproBNP/BNP has better diagnostic performance in pulmonary artery hypertension
associated with congenital heart disease, especially when DE negative screening in PAH patients.

1. Introduction vessels, with an incidence of about 7‰ to 10‰ in live births,

and is the primary birth defect disease in humans. In adults,
Congenital heart disease, referred to as CHD, is an abnormal- approximately 6.5%-10% of CHD patients will develop into
ity of cardiovascular morphology, structure, and function pulmonary artery hypertension (PAH) [1]. The assessment
caused by developmental disorders of the heart and blood of PAH directly affected the timing of CHD surgery, surgical
2 Computational and Mathematical Methods in Medicine
methods, and prognosis. However, right heart catheter
(RHC) is an invasive examination with high risk, requiring
professional equipment as well as experienced physicians,
especially low birth weight newborns have poor tolerance to
RHC, while the Doppler echocardiography (DE) is widely
used for its simplicity, cheapness, and ease. Pulmonary arte-
rial systolic pressure (PASP) is considered close to right ven-
tricular systolic pressure (RVSP) in the exclusion of right
ventricular outflow tract obstruction [2].
NTproBNP or BNP are secreted by cardiomyocytes due
to excessive stretching of the ventricles, which remain the
most promising blood biomarkers for risk prediction of
patients with PAH [3].
Here, we investigate the accuracy of DE and, further, DE
combined with NTproBNP/BNP in estimating the pulmo-
nary arterial pressure of patients with CHD by comparing
with RHC.
2. Methods
2.1. Study Population. A total of 64 patients diagnosed as
CHD or PAH associated with congenital heart disease
(PAH-CHD) by the Doppler echocardiography (DE) and
RHC who were hospitalized in the Department of Cardio-
vascular Surgery, Tianjin Chest Hospital, between March
2017 and March 2022 were collected. All patients had no
right ventricular outflow tract obstruction and tricuspid
valve prolapse and no family history of pulmonary hyper-
tension. The RHC examination was performed within 72 h
after the DE examination, and the relevant parameters were
recorded. This study was approved by the Ethics Committee
of Tianjin Chest Hospital, and all patients and their families
signed informed consent.
2.2. Evaluation Criteria for PAH. The 2015 European Society
of Cardiology/European Respiratory Society (ESC/ERS)
guidelines for the diagnosis and treatment of pulmonary
hypertension was used: mean pulmonary arterial pressure
≥ 25 mmHg by right heart catheterization at sea level and
at rest [4]. Furthermore, according to the 2015 Chinese
Expert Consensus on Diagnosis and Treatment of Pulmo-
nary Arterial Hypertension Associated with Congenital
Heart Disease, according to the degree of PASP, the patients
were divided into as follows: normal PAH: 15-30 mmHg,
mild PAH: 31-45 mmHg, moderate PAH: 46-70 mmHg,
and severe PAH: > 70 mmHg.
2.3. Doppler Echocardiography. Philips IE 33 Doppler ultra-
sonic diagnostic apparatus was applied with a probe frequency
of 1 ~ 5 MHz. Supine position was placed before testing; the tri-
cuspid valve area, tricuspid pressure gradient, left-to-right shunt
pressure gradient, right atrial and right ventricular diameters,
main pulmonary artery, tricuspid annular systolic excursion,
and ejection fraction were measured under two-dimensional
ultrasound at the end of expiration. Under the condition of
excluding right ventricular outflow tract obstruction, according
to the simplified Bernoulli equation, pulmonary artery systolic
pressure (PASP = 4V max2 + right atrial pressure (RAP), where
V is the maximum velocity of tricuspid valve) was estimated
with the tricuspid valve method (hereinafter referred to as the
three-back method), and for PDA and VSD cases, PASP
(PASP = sBP − 4V max2, where V is the maximum velocity of
left-to-right shunt and sBP is the systolic pressure of brachial
artery) was also estimated with the left-to-right shunt differen-
tial pressure method (hereinafter referred to as the differential
pressure method).
2.4. Right Heart Catheterization. Standardized right heart
catheterization was performed in patients under basic anes-
thesia, and their pressures were continuously measured:
vena cava pressure, right atrial pressure (RAP), pulmonary
arterial pressure (PAP), pulmonary arteriolar wedge pres-
sure (PCWP), and aortic pressure; the saturation of each
cardiac chamber and great vessels was measured. Hemody-
namic parameters such as pulmonary blood flow (Qp), sys-
temic blood flow (Qs), pulmonary circulation resistance
(RP), systemic vascular resistance (Rs), and pulmonary vas-
cular resistance (PVR) were calculated by the Fick method.
2.5. NTproBNP and BNP Plasma Levels. Blood was collected
after admission and transferred immediately to the Depart-
ment of Laboratory. The samples were processed and ana-
lyzed using CLIA assay for plasma BNP (CL-6000i,
Mindray, China) and ECLIA assay for serum NTproBNP
concentrations (Cobas® e602, Roche, Switzerland). The nor-
mal reference range of NTproBNP was 0-300 pg/ml and also
0-100 pg/ml for BNP in our laboratory.
2.6. Statistical Analysis. SPSS 22.0 was used for statistical
analysis, and P < 0:05 was defined as statistically significant
difference. Mean ± SD was calculated to present continuous
data, while the percent and frequency were used to present
categorical data. Chi-square test and Student’s t-test were
used to analyze data when appropriate. Statistical signifi-
cance was defined as a two-side value of P < 0:05. The Pear-
son correlation analyses were used to calculate the
correlation coefficients between RHC and DE.
3. Results
3.1. Patients’ Baseline Characteristics and Hemodynamics. A
total of 64 CHD patients were prospectively enrolled in this
study. All of the patients estimated PASP using both DE and
RHC. Patients’ baseline characteristics are presented in
Table 1. Sixty-four patients were aged 43:8 ± 18:3 years,
and 28.1% were males. The clinical diagnoses of these
patients are presented in Table 1: atrial septal defect
(57.8%), ventricular septal defect (2.2%), and patent ductus
arteriosus (1.8%).
A wide range of PASP (33-160 mmHg by RHC and 25-
110 mmHg by DE) was measured. A mild correlation was
observed between PASP (78:1 ± 29:0 mmHg) by RHC and
PASP (74:9 ± 19:7 mmHg) by DE (r = 0:4401, P < 0:01)
(Figure 1). Using the Bland-Altman analysis, a bias for PASP
DE estimates was determined to be 3.2 mmHg with 95% limits
of agreement ranging from -49.53 to 55.90 mmHg (Figure 2).
3.2. The Diagnostic Performance of DE and DE Combined
with NTproBNP/BNP for PAH-CHD. Here, PAH was
Computational and Mathematical Methods in Medicine
Table 1: Baseline characteristics and hemodynamics measured by
RHC and estimated by DE of the patients.
Male, n (%)
Age (mean ± SD, years)
ASD, n (%)
VSD, n (%)
PDA, n (%)
PASP measured by RHC (mmHg)
PASP estimated by DE (mmHg)
ASD: atrial septal defects; VSD: ventricular septal defects; PDA: patent
ductus arteriosus; DE: Doppler echocardiography; RHC: right heart
catheterization; PASP: pulmonary artery systolic pressure.
150
PASP estimated by DE (mmHg)
100
50
0 rather than for diagnosis [5]. Many humoral regulators are
0 50
PASP measured by RHC (mmHg)
Figure 1: Relationship between PASP estimated by DE and
measured by RHC (r = 0:4401, P < 0:01). DE: Doppler
echocardiographic; RHC: right heart catheterization; r: correlation
coefficient (Pearson); PASP: pulmonary artery systolic pressure.
Difference between DE and RHC measurement
150
100
50
0 ing pulmonary hypertension and has a sample size of 64
50
–50
Average of DE and RHC measurement
Figure 2: The Bland-Altman plot of PASP estimated by DE and
RHC. The bias was 3.2 mmHg, and the 95% limits of agreement
were -49.53–55.90 mmHg. PASP: pulmonary artery systolic
pressure; DE: Doppler echocardiography; RHC: right heart
catheterization.
defined as a PASP ≥ 30 mmHg, pulmonary artery wedge
pressure ≤ 15 mmHg, and PVR index > 3 wood units·m2 by
RHC. And also, PAH was identified when PASP > 40
mmHg or mean PAP ≥ 25 mmHg at rest either by DE.
ROC curve analyses were constructed to evaluate the predic-
tive values of DE with/or NTproBNP/BNP levels for the
3
identification of PAH (Figure 3). The results of DE showed
an AUC of 0.848 (95% CI = 0:666-1; P < 0:001), the sensitiv-
ity of which was 98.3% and the specificity was 77.8%. The
18 (28.1%) AUC of NTproBNP/BNP for the identification of PAH was
43:8 ± 18:3 0.804 (95% CI = 0:651-0.956; P < 0:001), the sensitivity of
37 (57.8%) which was 81.4% and the specificity was 87.5%. The AUC
19 (29.7%) of DE combined with NTproBNP/BNP was 0.857 (95% CI
8 (12.5%) = 0:676-1; P < 0:001), of which sensitivity was 100% and
specificity was 77.8%. The positive predictive value (PPV)
78:1 ± 29:0
and negative predictive value (NPV) are listed in Table 2.
74:9 ± 19:7
4. Discussion
The blood flow of left-to-right shunt in CHD continuously
impacts the pulmonary artery, causing vascular remodeling,
which in turn leads to the progressive increase of pulmonary
arterial pressure and resistance, and finally reverses the
blood flow direction to right-to-left and develops into Eisen-
menger’s syndrome (ES). Therefore, accurate diagnosis, fol-
low-up, and timely intervention of PAH are of great clinical
significance. Although the Doppler echocardiography is an
excellent noninvasive screening tool for PAH, it has limited
accuracy in estimating the right ventricular systolic pressure
in PAH and is typically used for assessing the risk of PAH
100 150 200 involved in the regulation of the cardiovascular system dur-
ing the development of PAH. Circulating BNP and
NTproBNP levels have been demonstrated related to PAH:
NTproBNP levels correlate with mPAP, PVR, RAP, and car-
diac index [6, 7]. An increase of NTproBNP level may reflect
right ventricular remodeling leading to impaired right ven-
tricular systolic function [8]. Overall, a correlation was
reported that ranged from r = 0:31 to r = 0:99 [9].
According to Tsujimoto et al.’s review [10], a fixed spec-
ificity of 86%, the estimated sensitivity derived from the
median value of specificity using HSROC model was 87%
in assessing the diagnostic accuracy of the Doppler transtho-
racic echocardiography for the diagnosis of PAH, which is
higher than the specificity (77.8%) in our study (Table 2).
Our study is a retrospective study assessing the value of
DE in estimating pulmonary arterial pressure and diagnos-
100 150 subjects. We controlled for the time interval between the
two examination methods within 72 hours, as well as the
parameters measured and the examination conditions.
These control measures will greatly reduce the limitations
of the study and improve the credibility of the research. In
our study, PASP estimated by DE showed a relatively mild
correlation in linear regression analysis with PASP by RHC
measurements in patients with CHD, and these results were
consistent with previous studies [11–13].
Since pathological changes in the pulmonary arteries
occur prior to cardiac affection in PAH, pulmonary derived
biomarkers would be optimal to detect early PAH. However,
although such biomarkers are promising results that have
recently been reported as TGF-β1 and VEGF165b [14, 15],
they are not yet established in clinical use. BNP is a hormone
precursor synthesized and released from the atria and ven-
tricles and becomes active BNP and NTproBNP after
4 Computational and Mathematical Methods in Medicine

Sensitivity
1.00
NTproBNP/BNP
DE+NTproBNP/BNP
DE
Specificity 0.75
NTproBNP/BNP
DE+NTproBNP/BNP

Sensitivity
Predictor

DE
PPV 0.50 DE = 0.848 (0.666 – 1)
NTproBNP/BNP
NTproBNP/BNP = 0.804 (0.651 – 0.956)
DE+NTproBNP/BNP
DE DE+NTproBNP/BNP = 0.857 (0.676 – 1)
0.25
NPV

NTproBNP/BNP
DE+NTproBNP/BNP
DE 0.00
0 25 50 75 100
0.00 0.25 0.50 0.75 1.00
Mean (95% CI)
1 – specificity
(a) Performance (b) ROC using gold standard

Figure 3: Receiving operator curves using DE and NTproBNP/BNP plasma levels for diagnosis of PAH. (a) The diagnostic performance of
DE, NTproBNP/BNP, and DE combined with NTproBNP/BNP for PAH-CHD. (b) The area under the curve (AUC) for the DE was 0.848,
for NTproBNP/BNP levels was 0.804, and for the combination of DE and NTproBNP/BNP was 0.857.

while PAH is suspected by clinicians, BNP or NT-proBNP

Table 2: The diagnostic performance of DE and DE combined with
NTproBNP/BNP for PAH.
Ss Sp
DE 98.3% 77.8%
NTproBNP/BNP 81.4% 87.5%
DE+ NTproBNP/BNP 100% 77.8%
DE: Doppler echocardiographic; Ss: sensitivity; Sp: specificity; PPV: positive
predictive value; NPV: negative predictive value.
digestion [16]. BNP reduces blood volume by increasing sys-
temic vascular permeability and natriuretic effects and
relaxes vascular smooth muscle cells by increasing intracel-
lular cGMP synthesis, both of which reduce blood pressure
and ventricular preload. BNP has a plasma half-life of 22
minutes and NTproBNP is 2 hours. NTproBNP/BNP have
been widely used as noninvasive markers and prognostic
markers of cardiac dysfunction and are currently the only
biomarkers recommended by PAH risk stratification guide-
lines [17]. Analysis of NTproBNP is available in several lab-
oratories, and the diagnostic cut-off is 300 pg/ml at our
laboratory. Here, ROC was used for the diagnosis of PAH
by DE and NTproBNP/BNP plasma levels. The AUC of
DE combined with NTproBNP/BNP was 0.857, of which
sensitivity was 100% and specificity was 77.8%. The positive
predictive value (PPV) and negative predictive value (NPV)
were 96.6% and 100%, respectively.
The NPV is higher than the single detection, suggesting
that, when the Doppler echocardiography fails to detect
are useful as subsequent screening tests.
In summary, our study also showed that the accuracy,
PPV NPV sensitivity, specificity, positive predictive value, and negative
predictive value of NTproBNP/BNP combined with the
96.6% 87.5%
Doppler echocardiography for the prognosis prediction of
98.3% 35% pulmonary hypertension in CHD-PAH patients were higher
96.6% 100% than those of single detection. The results are consistent with
the research of Yin et al. [18], and the combined detection of
NTproBNP/BNP and DE can improve the diagnostic value
and help clinical decision.
Nevertheless, there are several limitations regarding this
study. First of all, there is noticeable heterogeneity across
studies both in terms of the spectrum of the underlying con-
genital heart disease and the age of the patients. Secondly,
two essays used for NTproBNP/BNP measurement and we
used cut-off values for PAH diagnosis respectively here.
Finally, both invasive and noninvasive measurements were
carried out within 72 h in our study; however, PASP can
fluctuate widely within a single day due to the variability of
pulmonary vascular resistance.
5. Conclusion
Our study shows that the Doppler echocardiography com-
bined with NTproBNP/BNP has better diagnostic perfor-
mance in pulmonary artery hypertension associated with
congenital heart disease, especially when DE negative
screening in PAH patients.
Computational and Mathematical Methods in Medicine 5

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The authors declare that they have no conflicts of interest.
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