THE CORRELATION BETWEEN MEAN PULMONARY

ARTERIAL PRESSURE AND HEMOGLOBIN LEVEL IN

PATIENTS WITH ATRIAL SEPTAL DEFECT

RESEARCH PROPOSAL

Submitted to the Board of Examiners as
Partial Fulfilment of the Requirement of
Sarjana Degree in Faculty of Medicine
Universitas Gadjah Mada














By:
MUHAMMAD YUSUF ZAWIR ABD RAHIM
10/304766/KU/14169


FACULTY OF MEDICINE
UNIVERSITAS GADJAH MADA
YOGYAKARTA

2013
RESEARCH PROPOSAL

THE CORRELATION BETWEEN MEAN PULMONARY
ARTERIAL PRESSURE AND HEMOGLOBIN LEVEL IN
PATIENTS WITH ATRIAL SEPTAL DEFECT


Submitted by



MUHAMMAD YUSUF ZAWIR ABD RAHIM
10/304766/KU/14169



Approved by




Material advisor Date:



Dr. Lucia Krisdinarti, SpPD, SpJP (K)
NIP. 196103021987012001



Methodology advisor Date:



Dr. Dyah Wulan Anggrahini, PhD
NIU.1120110088


CHAPTER I. INTRODUCTION
a. Background
Atrial Septal Defect (ASD) is a congenital
malformation which results in left to right shunting
between the atria of the heart. As a consequence, there
is volume overload of the right heart chambers and
pulmonary circulation. (Sommer et al., 2008)
ASD constitutes 10% of all cases of congenital
heart disease and 46% of congenital heart disease in
adults. ASD is often asymptomatic in childhood. Hence,
some of the cases remain undetected until adulthood.
Undetected ASD can lead to various complications such
as right ventricular failure, atrial arrhythmias,
paradoxical embolization leading to cerebrovascular
accident or transient ischemic attacks, cerebral
abscess and irreversible pulmonary hypertension that
leads to right to left shunting known as Eisenmengers
Syndrome. (Zaidi et al., 2013)
The prevalence of pulmonary hypertension in ASD
patients has been reported to be between 6 and 27%.
(Humenberger et al., 2010) Pulmonary hypertension is a
haemodynamic and pathophysiological condition defined
as an increase in mean pulmonary arterial pressure
(PAP) of >25 mmHg at rest as assessed by right heart
catheterization. Pulmonary hypertension can be found in
multiple clinical conditions including atrial septal
defect under congenital heart disease associated
pulmonary arterial hypertension (APAH). (Simonneau et
al., 2009).
Elevated pulmonary blood flow causes damages to
the intimal layer which mainly composed of endothelial
cells. This triggers the release of various cytokines
and chemokines to mediate vascular repair and
neointimal remodelling processes. As the disease
progresses, the systemic oxygen saturation decreases.
(Humbert et al., 2004)
The resulting decrease in oxygen saturation
initiates a compensatory increase of renal
erythropoietin (Epo) production. Binding of Epo to its
receptor on the erythrocyte progenitor cells present in
the bone marrow maintains the viability of the cells,
promotes cell division, and results in secondary
erythrocytosis which increases the haemoglobin
synthesis followed by increased haematocrit levels.
(Jelkmann, 2005)
Hemoglobin (Hb) is an iron-containing
metalloprotein which binds oxygen in the red blood cell
(RBC). The hemoglobin level serves as an indicator of
the effectiveness of oxygen transport to the cells.
(Vajpayee et al., 2011)
The compensatory secondary erythrocytosis results
in the variations in haemoglobin level in ASD patients.
However the variation of haemoglobin level is yet to be
studied.

b. Problem formulation
In Atrial Septal Defect patients, there is an
increased incidence of cardiovascular complications.
Left-to-right shunt between the atria increases the
pulmonary blood flow which causes the increase in mean
pulmonary arterial pressure. As the mean pulmonary
arterial pressure increases, pulmonary artery
hypertension (PAH) may develop. This will result in
decreasing systemic oxygen saturation, activating a
compensatory mechanism known as secondary
erythrocytosis which is the increase in erythrocyte
production by the bone marrow. This results in the
variations in haemoglobin level in ASD patients.
However the variation of haemoglobin level is still
unknown.
c. Research authenticity
The correlation between mean pulmonary arterial
pressure and hemoglobin (Hb) level in ASD patient has
not been studied yet. However there are one study of
similar variables done on a different group of
patients.
Nakamura et al., (2000) studied about the effects
of hemoglobin on pulmonary arterial pressure and
pulmonary vascular resistance in patients with chronic
emphysema. Multiple-regression analysis and F test were
performed to investigate both direct effects of Hb and
PaO
2
as independent variables on mPAP and PVR as
dependent variables. Significant correlations were
found between PaO
2
and mPAP (or PVR), or Hb and mPAP
(or PVR), indicating that both Hb and PaO
2
are
contributory to mPAP and PVR. They demonstrated that Hb
and PaO
2
could directly affect the level of either mPAP
or PVR. It was concluded that Hb had a direct effect on
mPAP and PVR, independently of hypoxia in patients with
chronic emphysema.
The difference between our study and the study
mentioned above is mainly on the research subjects. In
this study, we mainly focuses on atrial septal defect
(ASD) patient compared to the latter which was done on
patients with chronic obstructive pulmonary disease
(COPD).
d. Research benefits
The benefit of this research is mainly to find out
the correlation between mean pulmonary arterial
pressure and hemoglobin level in ASD patient. Besides
that, some additional knowledge on cardiology would be
obtained from this study.
e. Objective
This research is carried out to find out the
correlation between mean pulmonary arterial pressure
and hemoglobin level in ASD patients.








CHAPTER II. LITERATURE REVIEW
a. Literature review
a.i. Atrial Septal Defect
Atrial Septal Defect (ASD) is a congenital
malformation which results in left to right shunting
between the atria of the heart. As a consequence, there
is volume overload of the right heart chambers and
pulmonary circulation. (Sommer et al., 2008)
The common cause of Atrial Septal Defect is
currently unknown. ASDs are more common in females with
a ratio of 2:1 with higher incidence in patients with
Down syndrome. ASD constitutes 10% of all cases of
congenital heart disease and 46% of congenital heart
disease in adults. ASD is often asymptomatic in
childhood. Hence, some of the cases remain undetected
until adulthood. Undetected ASD can lead to various
complications such as right ventricular failure, atrial
arrhythmias, paradoxical embolization leading to
cerebrovascular accident or transient ischemic attacks,
cerebral abscess and irreversible pulmonary
hypertension that leads to right to left shunting known
as Eisenmengers Syndrome. (Zaidi et al., 2013)
Generally, this interatrial defect is classified
anatomically according to the defect location in the
interatrial septum. They are classified into ASD
secundum, ASD primum and sinus venosus ASD. Secundum
defects occurs in the region of fossa ovalis are the
most common type contributing to 60% of overall cases.
Whereas, primum defect accounts for 20% and superior
sinus venosus defects located near the orifice of the
superior vena cava make up to 15% of cases (Radojevic
and Rigby, 2011).
Patients frequently remain asymptomatic until
adulthood. However, the majority develop symptoms
beyond the fourth decade including reduced functional
capacity, exertional shortness of breath, and
supraventricular tachyarrhythmias leading to
palpitations, and less frequently pulmonary infections
and right heart failure
(Humenberger et al., 2010).
Life expectancy is reduced overall, but survival
is much better than previously assumed. Pulmonary
artery pressure can be normal, but on average increases
with age. Severe pulmonary vascular disease is
nevertheless rare constituting less than 5 percent of
ASD cases and its development presumably requires
additional factors, including genetic predisposition.
Systemic embolism is caused by atrial fibrillation or
rarely by paradoxical embolism (Humenberger et al.,
2010).
With increasing age and with increasing pulmonary
artery pressure, tachyarrhythmias become more common
leading to atrial flutter or atrial fibrillation
(Gatzoulis et al., 1999).
In early stages, the flow between the atria almost
exclusively left-to-right, causing volume overload of
the right heart chambers and pulmonary circulation. In
the third to fourth decade of life with uncorrected
ASD, the patient may experience fatigue, dyspnea, and
arrhythmias occur as pulmonary hypertension causes an
increase in right heart pressures. This shunt may
reverse causing blood to flow from right to left. In
the fourth decade of life onwards, there is increasing
right-to-left shunt which leads to cyanosis,
ventricular dysfunction, and worsening pulmonary
hypertension. (Zaidi et al., 2013)



a.ii. Mean Pulmonary Arterial Pressure (mPAP)and
Pulmonary Hypertension
Mean pulmonary arterial pressure (mPAP)is the mean
blood pressure exerted on the pulmonary artery after
being pumped by the heart. It can be measured
invasively by right heart catheterization or non-
invasively using transthoracal echocardiography (TTE).
The normal range of mPAP is 9- 18 mmHg at sea level.
(Blanco Vich et al., 2007).
Pulmonary hypertension is a haemodynamic and
pathophysiological condition defined as an increase in
mean pulmonary arterial pressure (PAP) of >25 mmHg at
rest as assessed by right heart catheterization.
Pulmonary hypertension can be found in multiple
clinical conditions including atrial septal defect
under congenital heart disease associated pulmonary
arterial hypertension (APAH). (Simonneau et al., 2009).
Pulmonary arterial hypertension (PAH) has a
multifactorial pathobiology. Vasoconstriction,
remodeling of the pulmonary vessel wall, and thrombosis
contribute to increased pulmonary vascular resistance
in PAH. The process of pulmonary vascular remodeling
involves all layers of the vessel wall and is
complicated by cellular heterogeneity within each
compartment of the pulmonary arterial wall. Indeed,
endothelial cells, smooth muscle cells, and fibroblast,
as well as inflammatory cells and platelets, may play a
significant role in PAH. Pulmonary vasoconstriction is
believed to be an early component of the pulmonary
hypertensive process. Excessive vasoconstriction has
been related to abnormal function or expression of
potassium channels and to endothelial dysfunction. PAH
represents the type of pulmonary hypertension in which
the most important advances in the understanding and
treatment have been achieved in the past decade. It is
also the group in which pulmonary hypertension is the
core of the clinical problems and may be treated by
specific drug therapy (Gali et al., 2009).
Any increase in blood flow through the pulmonary
arteries increases shear stress on the arterial wall.
This leads to changes in the pulmonary vasculature that
result in increased pulmonary vascular resistance and
eventually development of pulmonary arterial
hypertension (Phillips, 2009).
PAH comprises of heterogeneous conditions that
share comparable clinical and haemodynamic pictures and
virtually identical pathological changes of the lung
microcirculation. Even if many pathobiological
mechanisms have been identified in the cells and
tissues of patients with PAH, the exact interactions
between them in the initiation and progression of the
pathological processes are not well understood. The
consequent increase in pulmonary vascular resistance
leads to right ventricular overload, hypertrophy, and
dilatation, and eventually to right ventricular failure
and death (Gali et al., 2009).
Based on a study on 225 ASD patients, pulmonary
hypertension noted in 16% of the cases and only 6% had
reversed atrial shunt (Besterman, 1961). Whereas,
according to European Society of Cardiology guidelines,
PAH is apparently higher in sinus venosus defect (16%)
compared with ostium secundum defect (4%). It was also
noted that the development of PAH in ASD is related to
the size of defect where larger defect had more severe
PH.





a.iii. Secondary Erythrocytosis as an outcome of
increasing mPAP
In a study on patients with chronic emphysema
demonstrates that the mean pulmonary arterial pressure
(mPAP) increases as hemoglobin concentration increases.
This demonstrates that the increased hemoglobin
concentration increases the blood viscosity leading to
increased pulmonary vascular resistance. The mPAP also
increases as oxygen saturation decreases. (Nakamura et
al., 2000).
Prolonged decrease in oxygen saturation leads to
chronic hypoxia which activates a compensatory increase
of erythropoietin (Epo) production. A compensatory
erythrocytosis results (Hg et al., 1987).

Binding of Epo to its receptor on the erythrocyte
progenitor cells present in the bone marrow maintains
the viability of the cells, promotes cell division, and
results in secondary erythrocytosis which increases the
hemoglobin synthesis followed by increased hematocrit
levels. (Jelkmann, 2005)
Erythrocytosis is defined as an increase in the
quantity of red cells or red cell mass. An elevated
hemoglobin or hematocrit raises the possibility of an
erythrocytosis. The hematocrit reflects whole blood
viscosity most accurately. Any process where there is
reduced oxygen supply and thus hypoxia will lead to
stimulation of EPO production and ultimately
erythrocytosis (McMullin MF, 2008).
b. Theoretical Framework


Atrial Septal Defect
Increased blood flow and pressure in the
pulmonary arteries
Increased mean pulmonary arterial
pressure (mPAP)
Decreased systemic
oxygen saturation
Increased renal
erythropoietin secretion
(Epo)
Increased erythropoiesis
(compensatory)
Increased hemoglobin (Hb) level
c. Conceptual Framework















d. Hypothesis
The increase in the mean pulmonary arterial pressure
(mPAP) is followed by the increase in hemoglobin level
in patients with Atrial Septal Defect (ASD).



Atrial Septal
Defect
Mean Pulmonary
Arterial Pressure
(mPAP)
Hemoglobin level
(g/dL)
Confounding variables

Type of ASD, size of
defect, comorbidity
including other
primary lung disease
and
hemoglobinopathies,
onset of diagnosis,
onset of treatment,
drugs (exogenous
erythropoietin), age,
sex, and diet.
External
variables

Socio
economic
status
and
educatio-
nal
status
CHAPTER III. METHOD

a. Design

The study done is an observational cross-sectional
study. The data will be obtained retrospectively from
the Registry of adult ASD patients diagnosed in
Poliklinik Jantung Rumah Sakit Umum Pusat (RSUP) Dr.
Sardjito, Yogyakarta.

b. Subject
This research will be carried out in Department of
Cardiology and Vascular Medicine, Faculty of Medicine,
Universitas Gadjah Mada, Yogyakarta. The time range for
this research is from July 2012 to October 2013.
The research populations are patients which are
treated in Poliklinik Jantung Rumah Sakit dr. Sardjito,
Yogyakarta which are diagnosed as ASD patients
according to European Society of Cardiology Guidelines.
Subjects are recruited using time based consecutive
sampling from July 2012 to October 2013.
Inclusion criteria for this research includes (1)
adult patients aged >18 years old who is diagnosed as
atrial septal defect patient and included in the atrial
septal defect registry. (2) ASD patients stated in (1)
whether or not being closed surgically or transcatheter
closure. Patients stated in (1) and (2) are willing to
participate in the study by signing an informed consent
form.
Whereas, the exclusion criteria involved are (1)
those who are suffering from (1) other congenital heart
defect, heart valve disease (2) any primary pulmonary
disorders determined during anamnesis (3) hematologic
disorders especially hemoglobinopathies, anemia and
myeloproliferative disorders (4) pulmonary veno-
occlusive disease, (5) collagen-vascular disease, (6)
portopulmonary hypertension (7) HIV-associated
pulmonary hypertension (8) schistosomiasis (9) systemic
disorders, including sarcoidosis, pulmonary Langerhans
cell histiocytosis, lymphangioleiomyomatosis,
neurofibromatosis, and vasculitis, (10) thyroid
disorders, (11) kidney disease and (12) miscellaneous
conditions, including tumor obstruction, mediastinal
fibrosis, and chronic renal failure on dialysis.




c. Tool and Material
Since this is a cross sectional study, all data
are derived from the registry of adult ASD patients
diagnosed in Department of Cardiology and Vascular
Medicine, Faculty of Medicine, Gadjah Mada University,
Rumah Sakit Umum Pusat (RSUP) Dr. Sardjito.

d. Data collection method
Patients aged >18 years old defined to have
interatrial gap defect with left to right shunting or
right to left shunting and diagnosed as ASD patients
are treated and included into the ASD registry.
Echocardiography results includes mean pulmonary
arterial pressure (mPAP). Both mPAP and hemoglobin
level are later derived from the ASD registry to be
analysed.








e. Research framework

f. Variable
Independent variable: Mean pulmonary arterial
pressure (mPAP)
Dependent variable: Hemoglobin level (g/dL)
Confounding variable: Type of ASD, size of defect,
comorbidity, onset of
diagnosis, onset of treatment,
drugs, age, sex, lifestyle.



Patient diagnosed with ASD according
to ESC Guidelines for the management
of grown-up congenital heart disease
Data collection from ASD registry.
Fits research criteria
Data input
Data analysis
g. Operational Definition
Atrial Septal Defect (ASD) is a congenital
malformation which results in left to right shunting
between the atria of the heart. (Sommer et al.,
2008. As recommended in the 2010 American College of
Cardiology/American Heart Association (ACC/AHA)
adult congenital heart disease (ACHD) guidelines,
diagnosis of ASD by imaging techniques should show
the presence of interatrial gap defect with left to
right shunting or right to left shunting is
indicative of ASD. (Warnes et al., 2008)
Haemoglobin (Hb) is an iron containing
metalloprotein which binds oxygen in the red blood
cell (RBC). The Hb level serves as an indicator of
the effectiveness of oxygen transport to the cells.
The normal serum hemoglobin level in male is 14.0 to
17.5 g/dL, while in female it ranges from 12.3-15.3
g/dL. (Vajpayee et al., 2011)
Patients defined to have iron deficiency anemia or
hemoglobinopathies such as hemoglobin C disease,
hemoglobin S-C disease, sickle cell anemia, and
thalassemia are excluded from this research as they
will produce lower hemoglobin levels. (Steinberg,
2011)
Mean pulmonary arterial pressure (mPAP)is the mean
blood pressure exerted on the pulmonary artery after
being pumped by the heart measured by transthoracal
echocardiography (TTE). The normal range of mPAP is
9- 18 mmHg at sea level. (Blanco Vich et al., 2007).
Pulmonary hypertension has been defined as an
increase in mean pulmonary arterial pressure (PAP)
25 mmHg at rest as assessed by right heart
catheterization (Gali et al., 2009).
Patients defined to have pulmonary veno-occlusive
disease, collagen-vascular disease, portopulmonary
hypertension, HIV-associated pulmonary hypertension,
schistosomiasis, hematologic disorders, including
myeloproliferative disorders, systemic disorders,
including sarcoidosis, pulmonary Langerhans cell
histiocytosis, lymphangioleiomyomatosis,
neurofibromatosis, and vasculitis, metabolic
disorders, including glycogen storage disease,
Gaucher disease, and thyroid disorders, and
Miscellaneous conditions, including tumor
obstruction, mediastinal fibrosis, and chronic renal
failure on dialysis are excluded from the study as
they serve as a confounding etiological factors
which contributes to the development of pulmonary
hypertension and will interfere with the results of
the study. (Simonneau et al., 2009). These data is
obtained through assessment of medical records.


















h. Result analysis
The data acquired from the ASD registry will be
analysed using SPSS for Windows Version 20.0.
Correlation coefficient (r) is used to analyse the data
statistically. It measures the strength of linear
association between the two variables. When it is
squared (r
2
), the correlation coefficient represents
the proportion of the spread (variance) in an outcome
variable that results from its linear association.
(Hulley et al., 2007)










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