Nghiên cứu biến đổi hình thái tim, áp lực động mạch phổi và NT proBNP huyết tương ở bệnh nhân tim bẩm sinh có luồng thông trái phải trước và sau can thiệp TT TIENG ANH

MINISTRY OF EDUCATION

MINISTRY OF DEFENSE

AND TRAINING
MILITARY MEDICAL ACADEMY

TRAN VAN PHU

STUDY ON CHANGES OF HEART MORPHOLOGY,
PULMONARY ARTERY PRESSURE AND
PLASMA NT-proBNP IN CONGENITAL HEART
DISEASES PATIENTS WITH LEFT TO RIGHT SHUNT
BEFORE AND AFTER TRANSCATHETER CLOSURE

Speciality: Internal medicine
Code:

9720107

SUMMARY OF PHD DISSERTATION

HA NOI - 2021


THIS THESIS WAS COMPLETED AT
MILITARY MEDICAL ACADEMY

Scientific supervisor:
1. Associate Professor. PhD. Nguyen Lan Hieu
2. Associate Professor. PhD. Pham Van Tran

Reviewer 1: Do Doan Loi
Prof. MD., PhD.
Reviewer 2: Pham Thien Ngoc
Assoc. Prof. MD., PhD.
Reviewer 3: Nguyen Oanh Oanh
Assoc. Prof. MD., PhD.
The thesis will be examined and assessed by termination
Council at:
hour
date month year

It can be found at:

1.
2.

National Library
The Library of Military Medical Academy


3

INTRODUCTION
Congenital heart diseases with an incidence of about 1% in infants is
the leading cause of infant and child mortality and a growing burden of
disease for their family, health system and society.
Among congenital heart diseases, the group of congenital heart
diseases with left to right shunt is the most common pathology. This is also
a group of heart diseases that can be completely cured by interventional

cardiac catheterization or surgical closure of the catheter if diagnosed early.
Despite the advancement of science and technology and investment
in equipment, the diagnosis of congenital heart diseases, as well as the
monitoring of treatment, is not always perfectly determined by
echocardiography and cardiac catheterization always possible, especially in
lower level medical facilities.
NT-proBNP is an endogenous biomarker produced by pressure
overload and cardiac chamber volume and is a sensitive and specific
indicator of cardiac function. Measurement of NT-proBNP levels is
increasingly used to aid in the diagnosis, assessment of prognosis, and
appropriate treatment in people with congestive heart failure. NT-proBNP
may also be useful in other conditions such as hypertrophic
cardiomyopathy, myocardial infarction, or congenital heart diseases.
Studies around the world have proven that plasma NT-proBNP
concentrations increase higher than in people with congenital heart diseases
and are related to pulmonary artery pressure and the ratio of Qp/Qs. In
Vietnam, this biomarker has been studied and applied in clinical practice,
including some types of congenital heart diseases, but there has been no
study on NT-proBNP concentration and its relationship with cardiac
morphological characteristics and pulmonary artery pressure.
Therefore, we conducted the study: "Study on changes in heart
morphology, pulmonary artery pressure and plasma NT-proBNP in
congenital heart patients with left to right shunt before and after
intervention" with two objectives of the study:
1. Study on changes in heart morphology, pulmonary artery pressure
and plasma NT-proBNP in congenital heart diseases patients with left to
right shunt before and after treatment 24 hours and three months.


4

2. The relationship of NT-proBNP with cardiac morphological
characteristics, pulmonary artery pressure and Qp/Qs.
The thesis consists of 121 pages with including main chapters:
- Introduction:
2 pages
- Chapter 1 Literature overview:
32 pages
- Chapter 2 Subjects and methods:
22 pages
- Chapter 3 Results:
24 pages
- Chapter 4 Discussion:
35 pages
- Conclusions and recommendations:
3 pages
- There were 40 tables, 10 illustrations and 7 charts.
- Two articles related to the thesis have been published.
- There were 151 references with 7 in Vietnamese documents and
the rest were English documents.
Chapter 1
LITERATURE OVERVIEW
1.1. Classification of congenital heart diseases
The congenital heart diseases can occur in the heart chambers, heart
valves or blood vessels, and the patient may have only one or more
congenital heart defects. The morphology of congenital heart diseases
lesions ranges from simple to complex.
There are many different classifications of congenital heart diseases:
Purple and non-violet congenital heart diseases; congenital heart diseases in
children and adults; congenital heart diseases disease has left to right

shunting, right to left shunt, and obstructive congenital heart diseases and
valvular regurgitation injury.
1.1.1. Congenital heart diseases disease with left to right shunt
In this group, it is common to see atrial septal defect, ventricular
septal defect and patent ductus arteriosus. Less common are the
aortopulmonary windows, partial atrioventricular canals and right atrial
septal defects. Clinically common atrial septal defect, ventricular septal
defect and patent ductus arteriosus account for about 85% of all congenital
heart diseases seen in children and almost all in adults.


5

Atrial septal defect is a congenital heart disease caused by a defect in
the septum of the two atria. This is a common congenital pathology,
accounting for about 25% of congenital heart disease cases in children.
Ventricular septal defect alone is the most common congenital heart
disease, accounting for about 37% of all congenital hearts in children.
The rate of patent ductus arteriosus reported in full term newborn is 1
in 2,000 births, accounting for 5% - 10% of all congenital heart diseases.
1.1.2. Congenital heart diseases with right to left shunt
Characteristic of this group of diseases is often purple.
1.1.3. Obstructive congenital heart diseases and valvular regurgitation
injury.
Also called congenital heart diseases group without shunt. These
patients have underdeveloped heart chambers or blocked large blood
vessels, preventing blood flow to meet the needs of body tissues.
1.2. Congenital heart diseases with left to right shunt
1.2.1. Morphological and hemodynamic changes
Congenital heart diseases with left to right shunt is described when

blood flows from the left atrium, left ventricle or aorta to the right atrium,
right ventricle or pulmonary artery or its branches.
The importance of left to right shunt can be expressed by the ratio
Qp/Qs. The patients with congenital heart diseases with left to right which
of them are Qp/Qs will be > 1.
1.2.1.1. Atrial septal defect
Because there are defect in the atrial septum so blood flows from the
left atrium to the right atrium. Chronic mass overload in the atrial septal
defect also causes dilation of the entire pulmonary vascular. Hypertrophy of
the muscular layer between the pulmonary arteries and veins, although its
extent is often masked by vascular dilation.
The magnitude of the left to right shunt in the atrial septal defect
depends on the size of the shunt, the pressure between the two ventricles,
and the relative pulmonary and systemic vascular.
The left to right shunt is the cause of volume overload and
morphological changes of right ventricle, right atrium, left atrium and
pulmonary circulation. However pulmonary arterial pressure was only
slightly increased and in most patients, pulmonary vascular resistance
remained within the normal range in patients aged 3 months.


6

1.2.1.2. Ventricular septal defect
With ventricular septal defect, the blood flows from the left ventricle
through the right ventricle into the pulmonary artery. The right and left
ventricles contract simultaneously, the right ventricle does not recognize the
overloaded volume in this situation. The right atrium also failed to
recognize a mass overload. However the pulmonary artery receives
increased blood volume.

Lesions in the ventricular septal defect allow blood from the systemic
circulation to pass through the pulmonary circulation, shifting the flow from
an area of high pressure to an area of low pressure (from left to right
ventricle).
In general, the ventricular septal defect leaves two main
consequences on the heart: (i) Gradual change in the pulmonary arteriole
system by increasing pulmonary artery flow. (ii) Overloading the left heart.
Morphological changes of left ventricle and left atrium.
If the ventricular septal defect is small, the right ventricular pressure
and pulmonary artery pressure increase insignificantly. Conversely, if the
ventricular septal defect is wide then the high right ventricular pressure can
equal the left ventricular pressure.
The consequences in the lungs depend on the response of the
pulmonary vasculature to increased blood flow, affecting the capacity and
elasticity of the pulmonary circulation.
The resistance of the pulmonary vasculature is also an important
factor determining the shunt.
1.2.1.3. Patent ductus arteriosus
When in the patent ductus arteriosus then the blood flows from the
aorta to the pulmonary artery so the pulmonary artery, the left atrium, and
the left ventricle are overloaded, but the right atrium and right ventricle are
not. Consequences causing changes in left heart morphology.
Due to the presence of coronary artery and more blood flows through
the pulmonary artery cause increasing the pressure in the pulmonary
circulation.
1.2.2. Natural progression
1.2.2.1. Natural progression of atrial septal defect
Spontaneous progression of atrial septal defect is relatively benign
except for large fistulas and the patient with other associated cardiac

7

defects. Typically, the patient with atrial septal defect remain physically
active and non symptom in the childhood, and many patients whom have
survived and even average sized atrial septal defect by age 40 before the
symptoms develop.
Secondary atrial septal defect may close spontaneously or remain
open. Sometimes it is enlarge.
1.2.2.2. Natural progression of ventricular septal defect
The natural progression of ventricular septal defect ranges from
spontaneous closure of the shunt to congestive heart failure and death in the
childhood.
Spontaneous closure of the fistula usually occurs in children younger
than 2 years of age. However it is uncommon after the age of 4 years.
1.2.2.3. Natural progression of patent ductus arteriosus
Risks associated with long term of patent ductus arteriosus include
endocarditis, patent ductal arteriosus calcification, patent ductal arteriosus
aneurysm or enlargement, heart failure and pulmonary hypertension.
1.3. NT-proBNP
NT-proBNP is a cardiac biomarker secreted primarily from cardiac
ventricular myocytes in response to increased volume and chamber
pressure. Elongated cardiomyocytes are the main stimulator for the
secretion of NT-proBNP into the blood. Clinically, the value of NT-proBNP
is used in the diagnosis of left ventricular systolic and diastolic dysfunction
and prognosis which are including heart failure, acute coronary syndromes,
stable coronary artery disease and stable angina. NT-proBNP may also be
useful in other settings such as hypertrophic cardiomyopathy, right
ventricular dysplasia, or congenital heart diseases.
BNP was approved for use by the FDA in 2001 and NT-proBNP in

2002 as a marker for cardiac dysfunction. NT-proBNP does not indicate
specific heart disease, but elevated test results indicate the presence of
underlying cardiac dysfunction. Normal plasma NT-proBNP levels are
unlikely to include cardiac dysfunction. The high plasma NT-proBNP
levels, even in the clinical setting of undiagnosed cardiovascular disease,
are predictive of future cardiovascular events.


8

Chapter 2
SUBJECTS AND METHODS
2.1. Subjects
The patients with a definitive diagnosis of congenital heart diseases
with left to right shunt such as: Atrial septal defect, ventricular septal defect
and patent ductus arteriosus. There are indications to close the shunt by
intervention.
The study was conducted at Bach Mai hospital from March 2015 to
September 2017. Including 190 congenital heart diseases with left to right
shunt such as: Atrial septal defect, ventricular septal defect and patent
ductus arteriosus. 107 healthy people.
2.2. Methods
2.2.1. Design
Described cross sectional study with before and after comparison.
Using a group of healthy people to compare indicators related to the
concentration of NT-proBNP levels.
Selected random and convenient sample.
2.2.3. Steps and variables
- The study patients were collected data, before and after cardiac
catheterization 24 hours and reexamination after 3 months.

- Clinical and paraclinical:
+ Age and gender (<16 years old, 16-40 years old, 41-60 years old, > 60
years old).
+ Described clinical characteristics: chest pain, dyspnea, palpitations,
hemoptysis, edema, hepatomegaly...
+ Described electrocardiographic characteristics: electrocardiographic axis
and heart rhythm.
- Described cardiac morphology and echocardiography:
+ Atrial septal defect, ventricular septal defect and patent ductus arteriosus,
congenital heart diseases others.
+ Right ventricular diameter, aortic diameter, Dd, Ds, FS, EF,
interventricular septum thickness, left ventricular posterior wall thickness,
size of shunt, size and pressure of pulmonary artery.
+ Pulmonary pressure is divided into three levels: normal pulmonary
pressure: < 30 mmHg; mild to moderate increase 30-59 mmHg and severe
increase ≥ 60 mmHg.


9

- Cardiac chamber and vascular variables measured by cardiac
catheterization: size of shunt, pulmonary artery pressure, Qp/Qs.
+ Based on the influence of catheter flow on pulmonary artery
hemodynamics, the size of the catheter is divided into two types: large and
small: for patients with atrial septal defect, the size < 20 mm is small, the
rest is large; for patients with ventricular septal defect, the size < 10 mm is
small and for patient with patent ductus arteriosus, the size is 7 mm.
+ Qp/Qs is divided into 3 levels: < 1.5 was small shunt; between 1.5-2 was
medium shunt and >2 was high shunt.
- Test variables of plasma NT-proBNP: NT-proBNP is calculated in units of

pg/ml.
2.2.5. Methods of information collection
The patient is allowed to make a study record, the PhD student
directly asked the patient, clinical examinated and entered data.
Facilities: testing machine, echocardiogram machine and cardiac
catheterization system.
2.2.6. Data processing and analysis
- Data processing in the study used SPSS software version 22.0.
- Used logistic regression to analyze the correlation between dependent
variable and influencing factors that are independent variables (qualitative
or quantitative). To eliminate confounding factors, we consider univariate
logistic correlation between each factor with treatment outcome and which
factors are not significant (p > 0.05). Then consider the multivariable
logistic correlation and remove the non-significant factors (p > 0.05).
2.2.7. Ethical issues in study
- Approved by the board of the Military Medical Academy.
- The study was approved by Bach Mai Hospital.
- Patient's family agrees to participate.
- The treatment regimens and treatment results were not changed.

Chapter 3
RESULTS
3.1. General characteristics of the study subjects
3.1.1. Age and sex characteristics
A total of 190 patients and 107 normal people were recruited into the
study. The age of study group was < 16 (45; 23.7%); 16-40 (86; 45.30%);


10

41-60 (47; 24.70%) and > 60 (12; 6.3%). There were not different from the
control group. The mean age of patients with atrial septal defect, ventricular
septal defect and patent ductus arteriosus were: 41.31 ± 15.82, respectively;
21.58 ± 13.52; 21.74 ± 17.84 years old.
Male 62 (32.6%), female 128 (67.4%).
3.1.2. Characteristics of the distribution of patients
Atrial septal defect 88 (46.3%), ventricular septal defect 60 (31.6%),
and patent ductus arteriosus 42 (22.1%).
Patients with symptoms such as exertional dyspnea, palpitations, etc.,
should been stable treatment before cardiac catheterization 2-3 days.
3.2. Cardiac morphology, pulmonary artery pressure, plasma NTproBNP concentration and Qp/Qs ratio
3.2.1. Cardiac morphology and left ventricular systolic function
Table 3.1. Echocardiographic parameters
before and after closing of shunt with atrial septal defect
Before 24
After 24
After 3
hours
hours
months
p
Parameters
Mean±SD(n=88
)

Mean±SD(n=8
8)

Mean±SD(n=3
5)

RV (mm)

31.06 ± 5.89

26.32 ± 4.46

25.93 ± 3.63

PA (mm)

28.18 ± 5.80

25.38 ± 5.21

24.69 ± 3.19

Dd (mm)

3.75 ± 4.28

37.49 ± 4.56

37.57 ± 4.19

Ds (mm)

24.49 ± 3.48

22.10 ± 3.59

23.64 ± 3.06

FS (%)

37.89 ± 5.62

40.61 ± 5.75

37.91 ± 6.05

EF (%)

68.56 ± 6.73

70,74 ± 8.14

69.16 ± 4.79

<0.01;
<0.01*
>0.05;
<0.05*
>0.05;
<0.05*
>0.05;
<0.05*
>0.05;
>0.05*
>0.05;

>0.05*

*Comparison before closing the shunt after 24 hours and follow-up 3
months
After closing atrial septal defect 24 hours, right ventricular diameter
was smaller than before closing (p < 0.01); The pulmonary artery origin and
the left ventricular dimensions smaller than before closure but with p >
0.05). At 3 months after closing th shunt, the right ventricular and


11

pulmonary artery origin and left ventricular diameters decreased
comparation with before closing of the shunt (p < 0.05). The fraction
shortening and ejection fraction had not changed (p > 0.05).
Table 3.2. Echocardiographic parameters
before and after closing of shunt with ventricular septal defect
Before 24
After 24
After 3
Parameter
hours
hours
months
p
s
Mean±SD(n=8 Mean±SD(n=8 Mean±SD(n=3
RV (mm)
PA (mm)
Dd (mm)

Ds (mm)
FS (%)
EF (%)

8)
18.94 ± 3.95

8)
17.25 ± 3.84

25.26 ± 6.15

22.75 ± 5.50

45.36 ± 8.50

41.95 ± 8.39

28.87 ± 5.95

26.28 ± 5.89

37.15 ± 7.06

41.10 ± 8.13

65.95 ± 5.44

66.46 ± 9.28

5)
17.99 ± 3.14
22.71 ± 4.01
44.00 ± 4.76
27.29 ± 4.30
45.50 ± 12.02
68.71 ± 7.02

<0.05;
<0.01*
<0.01;
<0.01*
<0.05;
<0.05*
<0.05;
<0.05*
>0.05;
>0.05*
>0.05;
>0.05*

*Comparison before closing the shunt after 24 hours and follow-up 3
months
After 24 hours and 3 months the closing of the shunt, the right
ventricular diameter, pulmonary artery origin and the left ventricular
dimensions reduced comparation with to before closing of the shunt (p < 0.05).
The fraction shortening and ejection fraction had not changed (p > 0.05).
Table 3.3. Echocardiographic parameters
before and after closing of shunt with patent ductus arteriosus
Before 24

After 24
After 3
Paramete
hours
hours
months
p
rs
Mean±SD(n=8 Mean±SD(n=8 Mean±SD(n=3
8)

8)

5)

RV (mm)

17.63 ± 3.71

16.21 ± 3.39

17.59 ± 2.21

PA (mm)

26.08 ± 6.83

23.52 ± 6.11

22.94 ± 3.79

Dd (mm)

45.50 ± 10.73

40.57 ± 8.12

43.06 ± 3.07

<0.01;
<0.01*
<0.01;
<0.01*
<0.01;


12
Ds (mm)

28.89 ± 8.03

25.67 ± 7.10

27.53 ± 4.49

FS (%)

37.33 ± 6.57

41.40 ± 7.67

44.12 ± 8.99

EF (%)

66.33 ± 6.48

64.26 ± 10.59

64.12 ± 9.26

<0.01*
<0.01;
<0.01*
>0.05;
>0.05*
>0.05;
>0.05*

*Comparison before closing the shunt after 24 hours and follow-up 3
months
After 24 hours and 3 months the closing of the shunt, the right
ventricular diameter, pulmonary artery origin and the left ventricular
dimensions reduced comparation with to before closing of the shunt (p <
0.05). The fraction shortening and ejection fraction had not changed (p >
0.05).
3.2.2. Characteristics of the shunt
Average size of the shunt with atrial septal defect: 27.22 ± 7.04 mm;
ventricular septal defect 5.94 ± 4.10 mm; and patent ductus arteriosus: 5.24
± 3.22 mm.

The majority of patients with atrial septal defect had large shunt of
86.4%, in contrast to ventricular septal defect and patent ductus arteriosus
had small shunt of 85% and 80.9%.
3.2.3. Characteristics of pulmonary artery systolic pressure on
echocardiography
The systolic pulmonary arterial pressure on echocardiography and
cardiac catheterization were: 37.20 ± 19.34 and 40.02 ± 16.25, respectively
(p > 0.05).
Most of the patients in the study did not have severe pulmonary
hypertension when the shunt was closed. The proportion of patients with
severe pulmonary hypertension (≥ 60 mmHg) ranges from 7%.
The systolic pulmonary artery pressure tended to increase with age
group (p < 0.05).
The Pulmonary artery pressure tended to increase with the size of the
shunt (p < 0.05).
Table 3.4. Systolic pulmonary artery pressure
before and after closing of shunt


13
SPAP
(mmHg)

Before 24
hours (n=190)

After 24
hours (n=190)

Mean ± SD

40.02 ± 16.25

31.99 ± 10.39

After 3
months

p

(n=74)
26.13 ± 4.52

<0.01;
<0.01*

*Comparison before closing the shunt after 24 hours and follow-up 3
months
The systolic pulmonary artery pressure after closing the shunt 24
hours and follow-up 3 months (p < 0.01).
3.2.4. Characteristics of Qp/Qs ratio
Average Qp/Qs ratio of the atrial septal defect: 2.54 ± 0.78; ventricular
septal defect: 1.70 ± 0.62 and patent ductus arteriosus: 1.52 ± 0.34.
The majority of patients with atrial septal defect had Qp/Qs > 2
(65.9%); ventricular septal defect and patent ductus arteriosus Qp/Qs > 2
(9.5-16.7%).
3.2.5. Characteristics of plasma NT-proBNP concentration
Table 3.5. Plasma NT-proBNP concentration before intervention
NT-proBNP (pg/ml) - Median (Q1 - Q3)

p

Study group
Study group (n=190)
ASD (n=88)

70.79 (43.51 - 214.94)

VSD (n=60)

50.53 (21.78 – 108.38)

PDA (n=42)

50.99 (28.67 – 144.02)

Total

60.51 (31.80 – 151.13)

Control group (n=107)
<0.01
<0.01
20.69 (10.45 – 37.34)

<0.01
<0.01

The plasma NT-proBNP concentration of patients with congenital
heart diseases with left to right shunt was higher than that of control group

(p < 0.01). The plasma NT-proBNP concentration of each patient group was
higher than NT-proBNP of control group (p < 0.01).
Table 3.6. Plasma NT-proBNP concentration
before and after closing of shunt
Study
group

NT-proBNP (pg/ml)

Before 24
hours (n=190)

After 24 hours
(n=190)

p

After 3
months


14
Median (Q1Q3)

Median (Q1Q3)

ASD
(n=88)

70.79

(43.51 – 214.94)

87.15
(57.51 – 242.46)

VSD
(n=60)
PDA
(n=42)

50.53
(21.78 – 108.38)
50.99
(28.67 – 144.02)
60.51
(31.80 – 151.13)

57.43
(32.83 – 79.69)
53.70
(24.48 – 82.38)
63.31
(43.32 – 180.51)

Total

(n=74)
Median (Q1Q3)
61.07
(29.46 –

102.97)
30.96
(19.55 – 37.77)
29.67
(15.92 – 40.64)
36.57
(23.10 - 74.99)

>0.05
<0.01*
>0.05
<0.01*
>0.05
<0.01*
>0.05
<0.01*

There was no difference between plasma NT-proBNP
concentration before closing of shunt and after closing of shunt 24 hours
but after 3 months, the plasma NT-proBNP concentration decreased
comparation with closing of shunt (p < 0.01).


15

3.3. Relationship of plasma NT-proBNP concentration with cardiac
morphology, pulmonary artery pressure and Qp/Qs ratio
3.3.1. Relationship of plasma NT-proBNP concentration with cardiac
morphology
Table 3.7. Correlation of plasma NT-proBNP concentration

with echocardiography parameters
Ratio\ NTproBNP
RV (mm)
PA (mm)
Dd (mm)
Ds (mm)

ASD
r
0. 27
0.34
0.10
0.17

p
<0.05
<0.01
0.34
0.12

VSD
r
0.60
0.57
0.55
0.56

p
<0.01
<0.01

<0.01
<0.01

PDA
r
0.36
0.26
0.42
0.37

p
<0.05
<0.05
<0.01
<0.05

The plasma NT-proBNP concentration correlated moderately with
the right ventricular and pulmonary artery origin diameter in patients with
atrial septal defect. The patients with ventricular septal defect and patent
ductus arteriosus, the plasma NT-proBNP concentration correlated
moderately with the right ventricular and pulmonary artery origin diameter.
3.3.2. Relationship of plasma NT-proBNP concentration with the sizi of shunt
The plasma NT-proBNP concentration increased in patients with
large shunt, the difference was statistically significant (p < 0.01).
The plasma NT-proBNP concentration positive correlated with sizi of
shunt in patients with atrial septal defect (r=0.43; p<0.05); ventricular septal
defect (r = 0.31; p < 0.05), and patent ductus arteriosus (r = 0.36, p < 0.05).
3.3.3. Relationship of plasma NT-proBNP and pulmonary artery pressure
and Qp/Qs ratio
The plasma NT-proBNP concentration increased with the increasing

of pulmonary artery pressure in patients with normal pulmonary pressure.
The median of plasma NT-proBNP concentration was 42.62 pg/l. When the
pulmonary artery pressure increased mildly to moderate: 82.63 and when it
severity increased was 298.11 pg/l. The difference was statistically
significant with p < 0.01.
The plasma NT-proBNP concentration positive correlated with
systolic pulmonary artery pressure ( r = 0.46, p < 0.01).
The area under the ROC curve of the plasma NT-proBNP
concentration with the cut-off at 60 mmHg was 0.75. It showed that
relatively good prognosis.


16

Table 3.8. Prognostic value of plasma NT-proBNP concentration
with pulmonary artery pressure ≥ 60
Study group
(n=190)
ASD (n=88)
VSD (n=60)
PDA (n=42)
Total

Point cut-off NT-proBNP (pg/ml)

Sensitivity (%)

Specificity (%)

Values without and (after) adjusted for age and sex

285.4 (189.4)
76.1 (87.9)
72.4 (129.4)
52.9 (126.4)

77.1 (77.1)
100 (100)
100 (100)
100 (94.6)

85.2 (88.9)
86.1 (71.9)
82.5 (80)
78 (72)

Prognosis value of plasma NT-proBNP concentration when
pulmonary arterial pressure ≥ 60 after adjustment for age and sex. The cutoff of plasma NT-proBNPoncentration was 126.4 pg/ml with sensitivity of
94.6% and specificity of 2%, in all patients. The cutoff of plasma NTproBNP concentration was 189.4 pg/ml with sensitivity of 77.1% and a
specificity of 88.9% in the patients with atrial septal defect. The cut-off of
plasma NT-proBNP concentration was 87.9 pg/ml with sensitivity of 100%
and specificity of 71.9% in the patients with ventricular septal defect. The
cut-off of plasma NT-proBNP concentration was 129.4 pg/ml with
sensitivity of 94.6% and specificity of 94.6% and 72% in the patients with
patent ductus arteriosus.
The plasma NT-proBNP concentration positive correlated with the
ratio Qp/Qs ratio (r = 0.38, p < 0.05).
The area under the ROC curve of plasma NT-proBNP concentration
with Qp/Qs > 2 was 0.67. It was showed that ability prognostic.
Table 3.9. Prognostic value of plasma NT-proBNP concentration
with Qp/Qs ratio (>2)

Study group
(n=190)
ASD (n=88)
VSD (n=60)
PDA (n=42)
Total

Point cut-off NT-proBNP (pg/ml)

Sensitivity (%)

Specificity (%)

Values without and (after) adjusted for age and sex
232.2 (154.2)
203.2 (138.1)
203.7 (126.7)
204.7 (127.4)

52.8 (68.3)
60 (70)
75 (100)
57.5 (82.2)

96.7 (76.7)
98 (84)
89.5 (60.5)
92.4 (74.4)

Prognosis value of of plasma NT-proBNP concentration with Qp/Qs ratio

> 2 was 127.4 pg/ml with sensitivity and specificity of 82.2% and 74.4%.
Chapter 4


17

DISCUSSIONS
4.1. General characteristics of the study subjects
4.1.1. Age and sex
- The study was conducted for 190 cases of congenital heart diseases
with left to right at the Vietnam Heart Institute, 88 patients with atrial septal
defect, 60 patients with ventricular septal defect, 42 patients with patent
ductus arteriosus and 107 healthy people. These patients were enrolled in
the study from March 2015 to September 2017.
- The mean age of patients in the study was 30.75 ± 18.38 years old,
not different from the healthy group (p > 0.05). The gender distribution of
the study group which there was female twice as often as male.
4.2. Cardiac morphology, pulmonary artery pressure and NT-proBNP
4.2.1. Cardiac morphology and function
When investigated some cardiac morphological features, we
conducted echocardiography to collected some parameters, 190 patients
were performed before and after 24h closed of the shunt, after 3 months
only collected 74 patients.
4.2.1.1. Atrial septal defect
The septal defect creates a left right shunt, so blood flows from the
left atrium to the right atrium, then to the right ventricle and pulmonary
vascular system. There were overloaded and dilated the left atrium, right
atrium, right ventricle and pulmonary artery.
The results in our study showed that the right ventricular diameter
after closing the shunt decreased at 24 hours, and continued to decrease

after 3 months, the difference was statistically significant (p < 0.01).
The diameter of the pulmonary artery 24h after closing the shunt
decreased compared to before closing, but it was not significant (p > 0.05).
However at 3 months, the diameter of the pulmonary artery decreased
compared to before closing shunt (p < 0.05).
When the shunt is closed, the right ventricular and pulmonary arteries
which reduced too much circulation were causing the smaller size. Other
studies had also similar results.
Left ventricular diastolic and systolic diameters of patients with atrial
septal defect at the time of survey before and after 24 hours of atrial septal


18

defect closing had no statistically significant difference. Though at 3
months after atrial septal defect closing, both left ventricular diastolic and
systolic diameters decreased statistically with p < 0.05.
Some studies with a smaller age of patients with atrial septal defect
resulted in a larger left ventricular size compared to before closed the shunt.
Studies with the same patient age showed similar results to our study. The
patients with atrial septal defect in our study had an average age of 41.31 ±
15.82, belonging to the group of elderly patients, the left ventricular
diastolic filling phase slowed down with age, leading to a difference in
blood pressure diastolic filling rate in the passive phase. Left ventricular
filling moves into end-diastole and the left atrium dilates. Such a
mechanism leads to left ventricular preload elevation and abrupt volume
expansion due to increased left ventricular end-diastolic pressure, left
ventricular dilatation, and increased left atrial pressure. When closing the
atrial septal defect in these elderly patients, the left ventricular filling
pressure decreases so the left ventricular size decreases. The fraction

shortening and ejection fraction after closing of the shunt did not change.
4.2.1.2. Ventricular septal defect and patent ductus arteriosus
Cardiac morphology of patients with ventricular septal defect was
investigated with some echocardiographic parameters. Survey at the time
before closing with ventricular septal defect and after 24 hours on all 60
patients and at 3 months survey on 22 patients.
In patients with ventricular septal defect with left to right shunt,
blood flows from the left ventricle through the right ventricle into the
pulmonary artery. Blood passes through the right ventricle but the right and
left ventricles contract simultaneously so the right ventricle does not
recognize the overloaded volume in this situation. The right atrium also
failed to recognize a mass overload. However, the pulmonary artery
receives increased blood volume so cardiac morphology changes with left
atrium and left ventricular dilatation, increased pulmonary artery diameter
and eventually increased right ventricular pressure and right ventricular
dilatation.
The size of the right ventricle before closing the shunt was 18.94 ±
3.95 mm which reduced at 24 hours after closing to 17.25 ± 3.84 mm (60
patients); 20.14 ± 3.23 mm before closing the shunt decreased to 17.99 ±


19

3.14 mm (22 patients) at 3 months after ventricular septal defect closing,
the difference was statistically significant at the time points before and after
closed the shunt of ventricular septal defect (p < 0.01). The size of the
pulmonary artery also decreased at 24 hours and 3 months after the closing
of the shunt. Reduced from 25.26 ± 6.15 mm (60 patients) and 25.53 ± 4.96
mm (22 patients) to 22.75 ± 5.50 mm and 22.71 ± 4.01 mm with time
corresponding time (p < 0.01).

The left ventricular size of patients with ventricular septal defect
before and after closing the shunt also had a statistically significant
decrease (p < 0.01). The left ventricular diastolic diameter before closing
45.36 ± 8.50 mm (60 patients) and 48.71 ± 6.23 mm (22 patients) to 41.95
± 8.39 mm and 44.00 ± 4.76 mm. The left ventricular systolic diameter
before closing 28.87 ± 5.95 mm (60 patients) and 30.79 ± 4.44 mm (22
patients) to 26.28 ± 5.89 mm and 27.29 ± 4.30 mm.
The value of fraction shortening and left ventricular ejection fraction
had not changed.
In 42 patients with patent ductus arteriosus, the results were similar
to those of patients with ventricular septal defect. The blood flow from the
aorta to the pulmonary artery so the pulmonary artery, the left atrium and
the left ventricle are overloaded with circulating volume but the right atrium
and right ventricle are not. The right ventricular size before closing of the
shunt was 17.63 ± 3.71 mm, decreased at 24 hours after closing of the shunt
to 16.21 ± 3.39 mm (42 patients); 19.94 ± 2.46 mm before closing
decreased to 17.59 ± 2.21 mm (17 patients) at 3 months later, the difference
was statistically significant at the time points before and after closing of the
shunt (p < 0.01).
The pulmonary artery size also decreased at 24 hours and 3 months
after closing of the shunt from 26.08 ± 6.83 mm (42 patients) and 27.01 ±
4.75 mm (17 patients) to 22.75 ± 5.50 mm and 22.71 ± 4.01 mm; the
difference was statistically significant with p < 0.01). The size of the left
ventricle of the patients with patent ductus arteriosus before and after
closing of th shunt also decreasing had a statistically significant with p<
0.01. The diameter of the left ventricular diastolic before closing was 45.50
± 10.73 mm (42 patients) and 52.31 ± 6.98 mm (17 patients) which
reducted 40.57 ± 8.12 mm and 43.06 ± 3.07 mm. The diameter of the left

20

ventricular systolic before closing was 28.89 ± 8.03 mm (42 patients) and
33.15 ± 5.40 mm (17 patients) which reducted 25.67 ± 7.10 mm and 27.53
± 4, respectively 4.49 mm.
The changes in cardiac morphology for ventricular septal defect and
patent ductus arteriosus of the studies also gave similar results.
4.2.2. Characteristics of pulmonary artery systolic pressure on
echocardiography
The chronic left to right shunt of the atrial septal defect of cause
increases pulmonary blood flow and right ventricular load. In general, atrial
septal defect has increased pulmonary blood flow which is usually well
tolerated in the early stages by dilating the chambers of the heart and the
pulmonary artery. However, the pulmonary pressure is only slightly
increased. In all most of patients, the pulmonary vascular resistance
remained within the normal range in younger patients. According to the age,
the chronic left to right shunt of the atrial septal defect can increase
pulmonary artery pressure.
If the shunt of atrial septal defect is small then the right ventricular
pressure and pulmonary artery pressure increase insignificantly because the
left to right shunt is still limited, the pressure difference between the left
and right ventricle is much. Conversely, if the shunt of atrial septal defect is
wide (if the ratio of shunt diameter to aortic valve diameter is ≥ ½) then
right ventricular pressure can increase equal with left ventricular pressure.
The left to right shunt of the patent ductus arteriosus leads to an increase in
left ventricular end-diastolic volume and dilation of the left ventricular
chamber, increased systolic ejection flow, and increased left atrial and
pulmonary vascular pressures.
The mean value of systolic pulmonary artery pressure in patients with
congenital heart diseases with left to right shunt was 40.02 ± 16.25 mmHg

(echocardiography) and 37.20 ± 19.34 mmHg (cardiac catheterization). The
difference between the two measurement methods was not statistically
significant with p > 0.05.
The ratio of patients with severe pulmonary artery pressure (≥ 60
mmHg) ranged from 6-7%. The value of systolic pulmonary artery pressure
tended to increase with age. The difference was statistically significant with
p < 0.05.


21

Pulmonary artery pressure tended to increase according to the size of
the shunt. The difference had statistical significance in all three groups of
atrial septal defect, ventricular septal defect and patent ductus arteriosus
with p < 0.05.
Surveying the systolic pulmonary artery pressure before and after
closing of the shunt, we found that the systolic pulmonary pressure after
closing of the shunt 24 hours and after 3 months was lower than before
closing, the difference was statistically significant with p < 0.01. The
closing of the left to right septal defect in congenital heart diseases
immediately blocked left to right blood flow so reducing the increase in
right cardiac volume and at the same time stopping the direct transmission
of the right heart and reduced of pulmonary artery pressure.
4.2.3. Characteristics of Qp/Qs ratio on cardiac catheterization
When assessing the value of Qp/Qs according to each disease group,
the ratio of Qp/Qs of the group with the highest ventricular septal defect
which was 2.54 ± 0.78. The group with the atrial septal defect was 1.70 ±
0.62 and the group with the patent ductus arteriosus was 1.52 ± 0. 0.34. The
results of the atrial septal defect group were different from the two groups
of ventricular septal defect and the patent ductus arteriosus group was

statistically significant (p < 0.01). In ventricular septal defect group, we
recorded that 51.7% of patients who had Qp/Qs>1.5. Meanwhile, only
33.3% of patients with patent ductus arteriosus group had Qp/Qs > 1.5.
4.2.4. Characteristics of plasma NT-proBNP concentration
In this study, the median plasma NT-proBNP of study group was
higher than that of healthy people with statistically significantly (p < 0.01).
Even in the study group of the patients without pulmonary artery pressure
increased, the median of plasma NT-proBNP was about 2 times higher than
that of the control group. Moreover, the plasma NT-proBNP concentration
in the study group was higher than in the control group, the difference was
statistically significant with p < 0.01.
The plasma NT-proBNP concentration of patients with congenital
heart diseases with left to right shunt in the study group was higher than
that of healthy people, regardless of whether pulmonary artery pressure is
increased or not The plasma NT-proBNP concentration had reflected
cardiac chamber overload caused by the left to right shunt as well as the


22

increased higher pulmonary circulation than the systemic circulation. The
results consistented with the description of increased levels of NT-proBNP
in patients with congenital heart diseases with left to right shunt.
The plasma NT-proBNP concentration also increased gradually with
the increase of pulmonary pressure, indicating that when the pulmonary
pressure increased, the right ventricular chamber dilates more in response to
the pressure over time, ventricular myocardial fibers elongated due to
increased left ventricular filling pressure.
When comparing the plasma NT-proBNP concentration before and
after closing of the shunt in patients with congenital heart diseases with left

to right shunt. The median of plasma NT-proBNP concentration after 24
hours closing of the shunt was higher than before closing with not
statistically significant (p > 0.05). But after 3 months, the plasma NTproBNP concentration decreased before closing the shunt statistically
significant with p < 0.01. When analyzed the data in each group of patients
with atrial septal defect, ventricular septal defect and patent ductus
arteriosus also gives similar results. The increased of the plasma NTproBNP concentration after 24 hours closing of the shunt despite the
reduced size of the left heart chamber, may be due to the direct impact of
the device when closing the shunt to the myocardium, causing the
myocardium to be stimulated and temporarily contracted abnormal
secretion of NT-proBNP.
Our data were consistent with the research results when at the same
time quantification of plasma NT-proBNP concentrations with some other
authors. The plasma NT-proBNP concentration increased at 24 hours after
the closing of the shunt, about the mechanism why we had not found
another reason to explain.


23

4.3. Relationship of plasma NT-proBNP with cardiac morphology,
pulmonary artery pressure and Qp/Qs
4.3.1. Relationship of plasma NT-proBNP concentration with cardiac
morphology
4.3.1.1. Relationship of plasma NT-proBNP concentration with some
echocardiographic parameters
Results of assessing the relationship of plasma NT-proBNP
concentration in patients with atrial septal defect. The plasma NT-proBNP
concentration positive correlated with right ventricular diameter (r = 0.29;
p < 0.05), the pulmonary artery origin diameter (r = 0.31; p < 0.05), the left
ventricular systolic diameter (r = 0.36; p < 0.05) and the left ventricular

diastolic diameter (r = 0.40; p < 0.05). In patients with ventricular septal
defect and patent ductus arteriosus, the plasma NT-proBNP concentration
positive correlated with right ventricular diameter, pulmonary artery
diameter, and left ventricular diameters (r ranged from 0.31 to 0. 44; p <
0.05).
In our study, the plasma NT-proBNP concentration was correlated
with right ventricular diameter, pulmonary artery diameter and left
ventricular diameter so it may be reflected the volume overload and
pressure. This volume and pressure overload may be one of the factors
leading to increased the plasma NT-proBNP concentration.
Our results were consistent with the results of other studies.
4.3.1.2. Relationship of the plasma NT-proBNP concentration with the size
of shunt
The plasma NT-proBNP concentration was higher in patients with
large shunt compared with small shunt. However, when compared
separately in patients with atrial septal defect, ventricular septal defect and
patent ductus arteriosus with large and small shunts, the difference in
plasma NT-proBNP concentration was not statistically significant even
though the NT-proBNP concentration of the patients with large shunts were
higher (p > 0.05).
The size and location of the shunt in patients with congenital heart
diseases with left to right shunt together with pulmonary vascular resistance
can determine the level of increased blood flow to the pulmonary artery,
pulmonary vein, and left atrium. The diastolic filling phase slows down


24

with age, leading to differences in diastolic filling rates during the passive
phase. The diastolic filling phase was transitions to end-diastolic and atria

dilation, because the atria play an important role in increasing left
ventricular diastolic volume. Such a mechanism leaded to increased left
ventricular preload elevation and left ventricular end-diastolic pressure, left
ventricular dilatation and increased left atrial pressure. The increasing left
ventricular filling pressure with age increased NT-proBNP secretion, and
plasma NT-proBNP concentration positive correlated with the size of shunt
and pulmonary artery pressure.
When the size of shunt was larger, the blood flow through the shunt
can be larger, the pulmonary artery pressure increases higher so the plasma
NT-proBNP concentration is released by the cells of the ventricles in
response to the volume overload of biventricular pressure are produced by
the significant left to right shunt.
4.3.2. Relationship of plasma NT-proBNP concentration with pulmonary
artery pressure and Qp/Qs
The plasma NT-proBNP concentration increased with the increase of
pulmonary artery pressure, the difference was statistically significant with p
< 0.01. The significant increasing was present even when the pulmonary
pressure of the patients had not increased. This probably explains the
immediate compensatory phase of pulmonary vasodilatation and the
absence of pulmonary pressure. This results increased right ventricular
circulation flow and right ventricular dilatation with the atrial septal defect.
There were increased the volume of left ventricular and left ventricular
dilatation with ventricular septal defect and patent ductus arteriosus. The
consequence were enough to increase the secretion of NT-proBNP into the
blood.
When analyzing the correlation between the plasma NT-proBNP
concentration with pulmonary artery pressure and the ratio of Qp/Qs. The
results showed that plasma NT-proBNP concentration moderate positive
correlated with systolic pulmonary artery pressure (r = 0.46, p< 0.01). The
area under the ROC curve of plasma NT-proBNP concentration with

pulmonary artery pressure with cutoff at 60 mmHg shows a relatively good
prognosis with NT-proBNP cutoff of 126.4 pg/ml; sensitivity and specificity
were 96.4% and 72.0%.


25

The pulmonary artery pressure created pressure overload on the right
ventricle leading to right ventricular dilatation and tricuspid regurgitation.
These pressures and volume overloads on the right ventricle can lead to
increased plasma NT-proBNP concentration. The results, we believed that
plasma NT-proBNP concentration can be used to the prognosis of
pulmonary artery pressure in patients with congenital heart diseases with
left to right shunt.
When investigating the correlation between plasma NT-proBNP
concentration with Qp/Qs ratio. We found that plasma NT-proBNP
concentration positive correlated with the ratio Qp/Qs (r = 0.38, p < 0.05).
The area under the ROC curve of the plasma NT-proBNP concentration
with Qp/Qs > 2 was only 0.67.
A series of studies as presented on the correlation of plasma NTproBNP concentration with pulmonary artery pressure and Qp/Qs ratio also
have the same results with our study. There were showing that the plasma
NT-proBNP concentration positive correlated with pulmonary artery
pressure and the ratio of Qp/Qs in patients with congenital heart diseases
with left to right shunt.
CONSLUSIONS
Through the study of 190 patients with congenital heart diseases with
left to right shunt, we draw the following conclusions:
1. Cardiac morphological characteristics, pulmonary artery pressure
and plasma NT-proBNP concentration.
- Increased pulmonary vascular flow caused by left to right shunt in

congenital heart diseases has changed the morphology of the heart and
pulmonary artery, so the size of the right ventricle, the size of the
pulmonary artery and the size of the left ventricular chamber decrease
immediately after the closure of the shunt 24h and at the time after 3
months (p < 0.05).
- The majority of patients with atrial septal defect had large sized
shunt while the majority of patients with ventricular septal defect and patent
dutus arteriosus had smal sized shunt.