research proposal atrial septal defect

8/12/2019 Research Proposal Atrial Septal Defect

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THE CORRELATION BETWEEN MEAN PULMONARY

ARTERIAL PRESSURE AND HEMOGLOBIN LEVEL INPATIENTS WITH ATRIAL SEPTAL DEFECT

RESEARCH PROPOSAL

Submitted to the Board of Examiners asPartial Fulfilment of the Requirement of

Sarjana Degree in Faculty of MedicineUniversitas Gadjah Mada

By:

MUHAMMAD YUSUF ZAWIR ABD RAHIM10/304766/KU/14169

FACULTY OF MEDICINEUNIVERSITAS GADJAH MADA

YOGYAKARTA

2013


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RESEARCH PROPOSAL

THE CORRELATION BETWEEN MEAN PULMONARY ARTERIAL PRESSURE AND HEMOGLOBIN LEVEL IN

PATIENTS WITH ATRIAL SEPTAL DEFECT

Submitted by

MUHAMMAD YUSUF ZAWIR ABD RAHIM10/304766/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


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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


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(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


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(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.


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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


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(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.


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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


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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


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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 t reated 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


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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


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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 thepulmonary arteries

Increased mean pulmonary arterialpressure (mPAP)

Decreased systemicoxygen saturation

Increased renal

erythropoietin secretion(Epo)

Increased erythropoiesis(compensatory)

Increased hemoglobin (Hb) level


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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


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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.


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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.


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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 accordingto ESC Guidelines for the managementof grown-up congenital heart disease

Data collection from ASD registry.

Fits research criteria

Data input

Data analysis


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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
http://www.nlm.nih.gov/medlineplus/ency/article/000572.htmhttp://www.nlm.nih.gov/medlineplus/ency/article/000527.htmhttp://www.nlm.nih.gov/medlineplus/ency/article/000587.htmhttp://www.nlm.nih.gov/medlineplus/ency/article/000587.htmhttp://www.nlm.nih.gov/medlineplus/ency/article/000527.htmhttp://www.nlm.nih.gov/medlineplus/ency/article/000572.htm


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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, h ematologic 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


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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.


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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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