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Congenital heart disease


Congenital heart diseases (CHD) are serious and common conditions that
have significant impact on morbidity, mortality, and health-care costs in children
and adults , these are abnormalities of the heart's structure and function caused
by abnormal or disordered heart development before birth (Go et al.,2013).

Congenital cardiovascular defects, also known as congenital heart defects

(CHD), That the wellknown birth deformity in the U.S (Parker et al., 2010). It
represent almost 33% of infants with major congenital anomalies detected
prenatally or early infancy in Europe (Zimbeck et al., 2009). A decrease in infant
loss and an increase in children and grownups with CHD is due to awesome
advances in treatment in late decades (Khoshnood et al., 2005).

More patients with CHD reach adulthood, creating what is called patients
with grownup congenital heart disease (GUCH), Those patients need long-term
expert medical care and healthcare related costs are high. Therefore, the global
health burden as a result of CHD increases quickly (Van der Linde et al., 2011).
There is additionally expanding acknowledgement of neuro-developmental
issues in adolescent among CHD survivors (Massaro et al., 2008).

Definition :

CHD, Inborn heart defects is defined as the structural malformation(s) of

one or more heart chambers and/or deformities of the major intra- thoracic blood
vessels and the ensuing malady that occurs during embryonic development
(Lioyd-Jones et al., 2009).

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This term usually excludes congenital arrhythmias and cardiomyopathies

even though these may be based on genetic or other abnormalities that are present
at birth (Hoffman and Kaplan., 2002).

Developmental anatomy :- As in figure (A)

The precursors of the cardiovascular system are angio-genic cell groups. At

first, these bunches shape twin tubular structures, which then by 22 days of
development append in the mid-line on the ventral side of the fetus to take shape
of a solitary, marginally twisted cardiac tube. Segments of the heart can be
recognized, including the sinus venosus, furthermore the chamber {left (LA) and
right atria(RA)}, the primitive ventricle {left ventricle (LV)}, the bulbus cordis
{right ventricle (RV)}, and the truncus arteriosus (aorta and pneumonic supply
routes) before cardiovascular circling. By the twenty two day, the cardiac tube
starts to overlap ventrally and move in the direction of the right side, though the
caudal atrial part starts to twist in the postero superior course (Sadeghpour et
al., 2014).

When circling occurs, so the future LV left ward and the future RV right
ward. With a specific end goal to make the systemic and respiratory flows
independentally, the first single chamber heart starts to be apportioned. The
improvement of endo cardial pads at both atrioventricular and conotruncal
intersections begins at 26 days and prompts the septation of the heart
(Sadeghpour et al., 2014).

By the fifth week, the superior and inferior cushions fused with one another,
forming a right (tricuspid) and left (mitral) atrioventricular orifice. At 30 days the
atria start septation with the slipping development of the of the septum primum,
The ostium primum is therefore closed because of the combination of the septum
primum along side the endocardial pads. In the mean time, the ostium secundum,

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shape up of the septum primum. Toward the end of the procedure, the septum
secundum becomes descending and lies at the right half of the septum primum,
however an interatrial hole stays until birth (i.e., the foramen ovale) (Bird et al.,
2008). The dilation of right and left conus swellings resulted in the
interventricular septum formation (two primitive ventricles) with the opposition
of the medial walls. The bulbus cordis divides into subaortic and subpulmonary
muscular conuses at the distal portion of the cardiac tube, So the subpulmonary
conus stretches and the subaortic conus resorbs, permitting the aorta to exchange
posteriorly and attach to the other side (Bird et al., 2008).

The aortopulmonary septum is made by the edges isolating the fourth (up
and coming aortic arch) and the sixth (forth coming pulmonary supply routes)
aortic curves. At that point, the truncus edges are designed in the zone where the
semilunar valves are proposed to be molded, in this manner producing the septum
at the middle of the ascending aortic trunk and the main pulmonary artery
(Abdulla et al., 2004).

Atria :

More than one source share formation of the atria, trabeculated portions are
shape up by the primitive atria, while the smooth posterior parts of the RA and
LA are created by the union of the venous vessels. The back side of the left atrial
chamber is made by a mix of the pulmonary veins; On the other hand, the sinus
venosus give rise to posterior smooth part of the right atrium. At that point the
embryonic sinuatrium is separated into the LA and RA by developing downward
from the roof of the septum primum toward the atrioventricular (AV) canal,
fusing with the cushions (Abdulla et al., 2004). The endocardial cushions (EC)
anteriorly and posteriorly fuse together splitting the AV canal into tricuspid and
mitral inlets. The inferior part of the atrial septum and superior part of the
ventricular septum and portions of the septal leaflet of the tricuspid valve and

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also, the anterior leaflet of the mitral valve are formed by EC. The posterior
leaflet of the mitral valve pre-dominantly develops from a piece of the AV
myocardium that protrudes into the lumen of the ventricle (Bonow et al., 2011).

Ventricles :

The division of the ventricles happens as the cephalic development, of the

fundamental ventricular septum results in it’s union with the EC, and the
infundibular or conus septum will develop (Bonow et al., 2011).

Pulmonary Veins :

The pulmonary veins are recorded as channels entering the atrial part
neighboring the atrioventricular intersection. After the conclusion of the
interventricular correspondence, it exchange to the top of the left chamber
(Ariane et al., 2012).

Great Arteries:

At various times along embryogenesis, a few sections of aortic arches

system disappear. The first, second, and fifth groups of the paired arches regress
completely. The proximal parts of the 6th arch adds to the right and left
pulmonary arteries, and the distal left 6th arch adds the ductus arteriosus. The
third aortic arch made the connection between the internal and external carotid
routes, The part between the left carotid and subclavian arteries is made by the

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left fourth one. At that point, the proximal part of the right subclavian artery is
framed by the right fourth arch (Sadeghpour et al., 2014).

Fig: (A): Early steps in heart development (Bruneau., 2008).

At the earliest stages of heart formation (cardiac crescent), two pools of cardiac
precursors exist. The first heart field (FHF) contributes to the left ventricle (LV), and the
second heart field (SHF) contributes to the right ventricle (RV) and later to the outflow tract
(OT), sinus venosus (SV), and left and right atria (LA and RA, respectively).V,
ventricle. b, Maturation of the heart. The cardiac cushions (CC) will give rise to the
atrioventricular valves. The ventricular septum (VS) arises from myocardium from the left and
right ventricles. Atrial septation (AS) occurs by the growth of two septa: the primary septum
(green) and the secondary septum (pink). Outflow tract septation separates the common
outflow tract (OT) into the aorta (AO, connected to the left ventricle) and the pulmonary artery
(PA, connected to the right ventricle)

Incidence of CHD :

The incidence of CHD is about 4–6/1000 live births and the true prevalence
could be 40/1000 if bicuspid aortic valve is included(Wren et al., 2012). Nearly
33% to 50% of these defects are critical, requiring intervention in the first year
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of life itself (Hoffman and Kaplan., 2002). Tragically 20% of spontaneous

abortions and 10% of stillbirths are attributed to CHD (Botto., 2001).

Although antenatal detection of CHD has improved over the past decade,
though recent studies suggest that greater than 60% remain undiagnosed (Chew
et al., 2006)

Etiology of congenital heart disease :

Multifactorial congenital heart disease :

At present, around 20% of cases with CHD can be referred to known causes
for example, hereditary disorders and teratogens, however almost no is thought
about the etiology of most cases (about 80%). It is for the most part of CHD
lesions with obscure etiology follows a multi-factorial inheritance model, which
involves both genetic and environmental factors in disease development (Blue et
al., 2012).

Chromosome defect :

Chromosomal peculiarities range from 8% to 10% of presenting cases of

CHD (Roos Hesselink et al., 2005).

Defects in chromosomes associated with CHD are diverse; some examples

are aneuploidy or polyploidy, improper re-arrangement during mitosis and
meiosis, translocation, inversion or deletions. Importantly, certain chromosomes
were reported to have a greater degree of significance and of percentages to heart
development . About 0.30-2.0% of all live births have chromosomal defects .
Among all CHDs detected during infant period, the chromosomal defects account
for approximately 6 - 10% (Zhang et al., 2010). As shown in table (A)

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Table (A): Chromosomal anomalies associated with CHD (Pierpont et al.,


Syndrome Chromosomal Associated cardiac lesions Proportion of

anomalies patients With
Down Triosomy 21 AVSD, ASD, VSD, TOF 40 -50
Edwards Triosomy 18 VSD, ASD, DORV, TOF, 90 -100

Patau Triosomy 13 ASD,VSD, DORV,L–TGA. 50

Turner Monosomy X CoA, AS, HLHS, PAPVR 25 -35
Klienfelter 47,XXY ASD, PDA, MVP 50
Cat eye Tetrasomy 22p TAPVR, PAPVR 50
Pallister-Killian Tetrasomy 12p VSD, CoA, PDA, ASD, AS 25
Velocardiofacial (Del 22q11.2) IAA(B), TA, TOF, aortic 75 -85
Williams (Del7q11.23) SAVS, +_PVS, PS, PPS 50 -80
ASD= atrial septal defect. AS=aortic stenosis. AVSD=atrioventricular septal defect. CoA=coarctation of
the aorta.DORV=double outlet right ventricle. HLHS=hypoplastic left heart syndrome. IAA (B)= interrupted
aortic arch (type B). L-TGA=congenitally corrected transposition of the great arteries. MVP=mitral valve
prolapse. PAPVR=partial anomalous pulmonary venous return. PDA=patent ductus arteriosus.PPS=peripheral
pulmonary stenosis. PS=pulmonary stenosis. PVS=pulmonary valve stenosis. SVAS= supravalvular aortic
stenosis. TA=truncus arteriosus TOF= teratology of fallot TAPVR= total anomalous pulmonary venous

Mendelian syndromes :

CHD can be associated with extra-cardiac defects and can be diagnosed as

a part of a syndrome in some cases. Around 3%–5% of CHD can be referred to
Mendelian- syndromes where a single mutation in the DNA results in
pathological consequences, following a Mendelian inheritance mode (Van der
Bom et al., 2011). As shown in (table B)

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Table (B): Microdeletions and single gene disorders associated with CHD (Pierpont
et al., 2007)

Syndrome Gene(region) Associated cardiac Proportion

lesions of patients
with CHD
Alagile JAGI,NOTCHI(del20q12) PPS, TOF, ASD, 85 -95
Noonan PTPN11,SOS1, KRAS, PVS, ASD, Coa, 80 -90
Holt –Oram TBX5 ASD, VSD, AVSD, 80
Char TFAP2B PDA 60
Ellis –Van – EVC,EVC2 Primum ASD, 60
Creveld Common atrium,
Smith –Lemli DHCR7 AVSD, Primum 45
–Opitz ASD, VSD,
Kabuki MLL2 in some cases CoA, ASD, VSD 40
Heterotaxy ZIC3 Dextrocardia, L- 90 -100

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Table (C): Selected genes associated with non-syndromal CHD (Jongbloed et

al., 2011)

Gene Function Associated Cardiac Lesion

NKX2-5 Transcription factor ASD–AV block, TOF, HLHS, TGA,
DORV, Ebstein anomaly, VSD
NKX2-6 Transcription factor TA
GATA4 Transcription factor ASD ± PS, TOF, VSD, DORV
GATA6 Transcription factor TA, TOF, AVSD
TBX1 Transcription factor IAA, aortic arch anomalies, VSD
TBX5 Transcription factor ASD, VSD, AVSD, conduction
TBX20 Transcription factor ASD, VSD, valve defects, LVOTO
CITED2 Transcription factor ASD, VSD, TOF, TGA
ZIC3 Transcription factor Heterotaxy, ASD, AVSD, TGA, VSD,
ZFPM2 Transcription factor TOF
FOXH1 Transcription factor TOF ,VSD
HAND1 Transcription factor HLHS(somatic mutation)
TFAP2B Transcription factor PDA
NOTCH1 Membrane ligand– AS ,BAV
NODAL Membrane ligand– Heterotaxy, ASD, AVSD, TGA, VSD,
receptor TAPVR, PS
JAG1 Membrane ligand– PS TOF
CFC1 Membrane ligand– Heterotaxy, TGA, DORV, TOF
MYH6 Sarcomeric protein ASD
MYH7 Sarcomeric protein ASD, Ebstein anomaly
MYH11 Sarcomeric protein PDA
ACTC1 Sarcomeric protein ASD ,VSD
GJA1 Gap junction protein HLHS (somatic mutation)
GJA5 Gap junction protein TOF
CRELD1 Matricellular protein AVSD, dextrocardia AVSD, dextrocardia

ELN Structural protein SVAS


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Environmental factors and teratogens:-

The best recorded maternal risk element is maternal diabetes, with a reported
fivefold extended risk of CHD from pregestational diabetes (Wren et al., 2003).
Other environmental factors have been associated with an increased risk of CHD
in table (D)

Table (D): Environmental risk factors associated with CHD (Jenkins et al.,

Teratogenic influence Associated cardiac lesionsProportion at risk

of CHD
Maternal diabetes VSD, ASD, L-TGA, AVSD, 5%
Maternal rubella PDA, VSD, ASD,PS ,TOF 30%–60%
Maternal TOF ,VSD ,PDA ,Left sided 15%–50%
phenylketonuria lesions
Systemic lupus Complete heart block Uncertain
Febrile illness PS, right- and left-sided Uncertain
obstructive defects, tricuspid
atresia, VSD
Thalidomide TOF, ASD, VSD, TA Up to 30%
Retinoic acid TA ,TOF ,IAA ,DORV 25%
Anticonvulsants Any defect Uncertain
Lithium Ebstein anomaly, tricuspid Lower than
atresia initially reported
Selective serotonin VSD, ASD, TOF Uncertain
reuptake inhibitors
Alcohol VSD, ASD, TOF Uncertain
Marijuana VSD, Ebstein anomaly Uncertain

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Recurrence- risks in CHD:-

It is accounted that up to 20% of asymptomatic first-degree relatives of

patients with obstructive left heart might have undiagnosed CHD, particularly
bicuspid aortic valve (Kerstjens-Frederikes et al., 2011).

Classification of CHD:

Congenital heart disease could be categorized into:-

I- According to clinical perspective: (Yun., 2011)

1. Life debilitating CHD: Structural cardiac distortions in which

cardiovascular collapse is commonly and traded off if not treated early.They
incorporate TGA, COA / IAA, AS, and HLHS / mitral atresia, PA and
obstructed TAPVR.

2. Clinically significant CHD: Is the cardiovascular distortions that have

consequences on cardiac work, where the break-down is unrealistic to be need
early mediation. This include VSD, complete AVSD, ASD and TOF with
great pulmonary course life structures.

3. Clinically non critical CHD: Anatomically characterized cardio-vascular

without affection of function or clinical aspects. They incorporate little VSD,
ASD, PS, they just noticeable with echocardiography and requiring no

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II. According to presence of cyanosis (Figure B)

Fig: (B): CHD subtypes according to presence of cyanosis (Piers et al., 2012).

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III- According to Pathophysiological point of view:-as in (table E)

Table (E)-Pathophysiological classification of CHD (Wu and Child., 2004).

Cardiac defect Example

Left-to-right shunt ● Atrial septal defect
● Ventricular septal defect
● Patent ductus arteriosus
● Partial anomalous pulmonary
venous connection
● Endocardial cushion defect
● Sinus of Valsalva aneurysm
● Coronary artery fistula

Outflow obstruction lesions ● Bicuspid aortic valve

● Coarctation of aorta
● Pulmonary stenosis

Cyanosis and decreased ● Tetralogy of Fallot

pulmonary blood flow ●Tricuspid atresia
● Pulmonary atresia
● Hypoplasia of right ventricle
● Ebstein’s anomaly

Cyanosis and increased ●Transposition of great arteries

pulmonary blood flow ● Double-outlet ventricle
● Double-inlet ventricle
● Truncus arteriosus
● Total anomalous pulmonary
venous connection

Cyanosis and increased ● VSD with Eisenmenger syndrome

pulmonary vascular resistance ● PDA with Eisenmenger syndrome
● ASD with Eisenmenger syndrome

Anomalies of major blood ● Congenitally corrected

vessels transposition of great arteries
● Coronary artery anomalies

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Clinical manifestations:

Clinical presentation may vary from the incidental finding of a heart murmur
in an otherwise healthy neonate to cyanosis or life threatening arrhythmias or
cardiovascular collapse, including congestive heart failure or shock (Silberbach
and Hannon., 2007).

The clinical marker for the debilitating heart defects in the newborn might
be obscure. Ordinary heart murmur is not useful in this circumstance. It is
imperative for pediatricians to recognize the infant that " not doing well " and
having a high index of suspicion, and distinguishing the requirement for fast heart
assessment and guideline inherent cardiovascular issue which needs early
intercession. They incorporate cyanosis, un-explained acidosis, tachypnea
without lung issues, and so forth. Beginning assessment would incorporate
evaluation of oxygen saturation, blood gas investigation and blood pressure in all
extremities (Keane et al., 2006).

Some neonate with critical CHD might exhibit clinical symptoms first few
hours to days of life when PDA is closed. At this time, the babies would show
serious acidosis / cyanosis / shock even sudden death might occur (Krishnan.,

Radiological findings:

1. Chest- x- ray (CXR):-

When the newborn is suspected to have CHD, roentgenogram is performed

to exclude chest problems and in addition to assess pulmonary vascular checking
and cardiomegaly. Some CHD have specific high lights for instance:

 Boat shaped heart; which could be found in the TOF / PA and it’s variations
(Yee., 2007).

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 Another specific element called the "egg on string" appearance can be seen in
TGA (Keane et al., 2006).
 Rather than these established elements, the majority of critical CHD that
need early mediation have no specific discoveries beside cardiomegaly,
change of pulmonary vascular checking and un-pretentious finding of venous
congestion (Fleisher et al., 2006).

2. Electrocardiography (ECG) :-

ECG has been a helpful instrument in the assessment of CHD, particularly

if echocardiogram is not accessible. In acyanotic newborn superior axis deviation
would refer to AVSD, while, left axis deviation with left ventricular hyper trophy
would indicate tricuspid atresia. The majority of TOF and its variants show as
right axis deviation with right ventricular hypertrophy (Fleisher et al., 2006).

3. Echocardiography:-

Echocardiogram (ECHO) is the most productive technique in the conclusion

of CHD which outlines the whole itemized structures in the different areas (Yun.,

Evaluation of systolic ventricular capacity, estimation of wall thickness and

chamber dimensions can be made by M-mode ECHO . Doppler wave strategies
can be utilized to survey the pressure gradients slopes over the stenotic or
regurgitation flow through the valves. Different doppler wave structures can
evaluate abnormal heart physiology; diminished flow in the descending aorta as
seen in the COA; and estimation of pulmonary arterial pressure by estimation of
the tricuspid regurgitation gradient. Color flow is an extraordinary technique in
detecting the course of flow when valve regurgitation and shunt exist, the
increased flow across defects or narrowed valves, and it likewise distinguishes

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unusual turbulent flow, for example, coronary arteriovenous fistulas (Fleisher et

al., 2006).

4. Cardiac catheterization:-

Cardiovascular catheterization was viewed as best quality for assessment

and analysis of different issues in CHD and still holds a vital spot in pediatric
patients (Kumar et al., 2014).

5- Cardiac computed tomography (CT):-

CT provides excellent evaluation of the pulmonary vasculature, mediastinal

structure, and lung parenchyma. High resolution CT is useful to assess pulmonary
arterial thrombi, intra pulmonary hemorrhage or infarction in patients with PAH.
Main pulmonary artery diameter has a good predictive value regarding the
severity of PAH (Grubstein et al., 2008).

Pulmonary neo-vascularity finding (small, tortuous intra-pulmonary

vessels), lobular ground glass opacity, and hilar and intercostal systemic
collaterals were more prevalent in Eisenmenger syndrome, with greater severity
in post tricuspid communication (Sheehan et al., 2005).

6-Cardiac magnitic resonant imaging (CMR):-

 Provides a powerful tool, giving anatomical and physiological information

that echocardiography and catheterization alone cannot provide.
 Assessment of systemic and pulmonary veins (abnormal connection or
 Calculation of RV volumes and EF, for instance after repair of TOF.
 Assessment of the right ventricular outflow tract (RVOT), RV pulmonary
atresia courses (site of stenosis or aneurysm) and the branch stenosis.
 Calculation of pulmonary regurgitation.

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 Assessment of shunts by estimation of flow in the ascending aorta and

pulmonary trunk, Evaluation of the whole aorta (aneurysm, dissection
 Aortopulmonary collaterals and arterio venous abnormalities (while CT
gives better spatial resolution).
 Coronary abnormalities and coronary artery disease, including possible
evaluation of viability and perfusion (Kilner et al., 2010).

Differential Diagnosis:- shown in (table F)

Table (F): Non-Cardiogenic Etiologies in the Differential Diagnosis of CHD.

(Christopher et al., 2011).

Respiratory Bronchiolitis, Pneumonia, Spontaneous

pneumothorax, Laryngomalacia, Pulmonary
hemangioma, Cystic denomatoid malformation ,
Reactive airways disease
Hemodynamic Sepsis Anaphylaxis
Gastrointestinal Gastroesophageal reflux, Tracheoesophageal

Toxic/Metabolic Methemoglobinemia, Toxic ingestion, Congenital

adrenal hyperplasia
Other Non-accidental trauma

Sequalae:- (Porth et al., 2011)

Particular complications of CHD according to the type and severity of the

particular condition. The following conditions could be developed:

 Endocarditis can occur at any time when microbes enter circulation system.

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 Delayed development, learning inabilities, growth delay

 Cyanosis, blacking out, seizures

 Mental hindrance because of absence of oxygen to the cerebrum during child


 Structural harm to the heart chambers and vessels.

 Pulmonary hypertension

 CHF in which the patient develop easy fatigability

 Arrhythmia

 Stroke


Essential anticipation measures presently incorporate rubella vaccination,

good diabetic control, and avoidance of teratogenic medications, for example,
some antiepileptic drugs and isotretinoin. Recent suggestions incorporate staying
away from contact with flu and febrile sicknesses and avoidance of exposure to
natural solvents and restricted connection with maternal smoking and
introduction to air contamination. There is in like manner expanding proof that
folic acid might be protective (Van Beynum et al., 2010).


Which treatment is used, and how well the baby responds to it, depends on
the condition. Many defects need to be followed carefully. Some will heal over
time, while others will need to be treated. Some congenital heart diseases can be

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treated with medication alone. Others need to be treated with one or more heart
surgeries (Leonar and Lilly., 2011).

Prognosis for CHD:

Children with CHD are about 50% more likely to receive special education
services compared to children without birth defects (Riehle-Colarusso et al.,

Survival of infants with CHDs relies on how severe the defect is, the time
when it is diagnosed, and how it is treated. About 97% of babies born with a
non-critical CHD are expected to survive to one year of age. About 95% of babies
born with a noncritical CHD are expected to survive to 18 years of age. About
75% of babies born with a critical CHD are expected to survive to one year of
age, when about 69% of these are expected to survive to 18 years of age (Oster
et al., 2013).

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Pulmonary arterial hypertension

Pulmonary arterial hypertension is a life-threatening disease characterized
by vasoconstriction and progressive remodelling of the pulmonary arterial wall
leading to right ventricular failure and death (D’Alto and Mahadevan, 2012)

Many children presenting with PH have heterogeneous disease consisting of

varying predisposing factors, including prematurity, a chromosomal or genetic
anomaly, congenital heart disease, and sleep disordered breathing ( Ivy, 2012).

Definition of PAH:
Pulmonary arterial hypertension is defined as an elevated mean pulmonary
arterial pressure (mPAP) of 25 mmHg or higher and a pulmonary wedge pressure
of 15 mmHg or lower (Simonneau et al., 2009 and Sanli et al., 2012).

Causes of Pulmonary hypertension:

Pulmonary hypertension is a group of conditions with multiple causes rather
than a single one. Pathogenesis and management differ among entities (park,

Table G lists, according to pathogenesis, conditions that cause pulmonary

hypertension of a temporary or permanent, acute or chronic nature.

PAH associated with congenital systemic to pulmonary shunts occurs

frequently in CHD patients (CHD with shunt- associated PAH), including
approximately 50% of patients with ventricular septal defects (VSDs) and 10%
of patients with atrial septal defects (ASDs) (Fine et al., 2009).

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Table (G) Causes of pulmonary hypertension (park, 2008c)

1. Large left-to-right shunt lesions (hyperkinetic pulmonary hypertension): ventricular septal

defect, patent ductus arteriosus, endocardial cushion defect

2. Alveolar hypoxia

a. Pulmonary parenchymal disease

1). Extensive pneumonia

2). Hypoplasia of lungs (primary or secondary, such as that seen in

diaphragmatic hernia)

3). Bronchopulmonary dysplasia

4). Interstitial lung disease (Hamman-Rich syndrome)

5). Wilson-Mikity syndrome

b. Airway obstruction

1). Upper airway obstruction (large tonsils, macroglossia, micrognathia,

laryngotracheomalacia, sleep-disordered breathing)

2). Lower airway obstruction (bronchial asthma, cystic fibrosis)

c. Inadequate ventilatory drive (central nervous system diseases, obesity

hypoventilation syndrome)

d. Disorders of chest wall or respiratory muscles

1). Kyphoscoliosis

2). Weakening or paralysis of skeletal muscle

e. High altitude (in certain hyperreactors)

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3. Pulmonary venous hypertension: mitral stenosis, cor triatriatum, total anomalous pulmonary
venous return with obstruction, chronic left heart failure, left-sided obstructive lesions
(aortic stenosis, coarctation of the aorta). Rarely, congenital pulmonary vein stenosis causes
incurable pulmonary hypertension.

4. Primary pulmonary vascular disease

a. Persistent pulmonary hypertension of the newborn

b. Primary pulmonary hypertension—rare, fatal form of pulmonary hypertension with

obscure cause

5. Other diseases that involve pulmonary parenchyma or pulmonary vasculature

a. Thromboembolism: ventriculoatrial shunt for hydrocephalus, sickle cell anemia,


b. Connective tissue disease: scleroderma, systemic lupus erythematosus, mixed

connective tissue disease, dermatomyositis, rheumatoid arthritis

c. Disorders directly affecting the pulmonary vasculature: schistosomiasis, sarcoidosis,

histiocytosis X

d. Portal hypertension, human immunodeficiency virus infection

Pathology and pathophysiology of PAH

The histopathologic lesions in patients with pulmonary hypertension are the
result of long-standing hypertension rather than a consequence of different
causes. The plexiform lesion is observed in patients with all types of PAH
(Simonneau et al., 2009).

Cardiac defects resulting in left-to-right shunting cause PAH because the

increased pulmonary blood flow induces increases in shear stress and
circumferential stretch. These haemodynamic forces within the pulmonary
vessels induce endothelial dysfunction. This loss of endothelial barrier function

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may be associated with degradation of the extracellular matrix and the release of
growth factors which, in turn, induce smooth muscle hypertrophy and
proliferation, with migration into the pulmonary vasculature ( Diller and
Gatzoulis, 2007).

The vascular remodelling seen in PAH-CHD results in a progressive

increase in pulmonary vascular resistance. The early lesions display medial
hypertrophy (grade 1), progressing to intimal proliferation (grade 2), lumen
occlusion (grade 3), progressive arterial dilatation and plexiform lesions (grade
4), thinning and fibrosis of the media (grade 5) and, finally, necrosis (grade 6)
Fig. (C) (Gatzoulis, 2009).

Figure (C): Histopathological features of PAH (Gatzoulis, 2009).

Once the increasing pulmonary vascular resistance equals systemic resistance,

the left-to-right shunt becomes bi-directional, and once pulmonary vascular
resistance exceeds systemic resistance, shunt reversal and the development of
Eisenmenger syndrome occurs. Eisenmenger syndrome is the most advanced
form of PAH-CHD and is characterised by bi-directional or right-to-left shunting
and chronic cyanosis (Beghetti and Galiè, 2009).

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Cells playing role in pulmonary hypertension

Smooth muscle cells and fibroblasts:

Each cell type (endothelial, smooth muscle, and fibroblast) in the pulmonary
vascular wall plays a specific role in the response to injury (Jeffery and Morrell,
2002). A feature common to all forms of PAH remodeling is the distal extension
of smooth muscle into small peripheral, normally nonmuscular, pulmonary
arteries within the respiratory acinus. The cellular processes underlying
muscularization of this distal part of the pulmonary arterial tree are incompletely
understood. In addition, a hallmark of severe pulmonary hypertension is the
formation of a layer of myofibroblasts and extracellular matrix between the
endothelium and the internal elastic lamina, termed the neointima (Humbert et
al., 2004).

In some model systems, particularly in hypoxia models, the adventitial

fibroblast appears to be the first cell activated to proliferate and to synthesize
matrix proteins in response to the pulmonary hypertensive stimulus (Stenmark
et al., 2002). The mechanisms that enable the adventitial fibroblast to migrate
into the media (and ultimately the intima) are currently unclear, but there is good
evidence to suggest that upregulation of matrix metalloproteinases (MMP2 and
MMP9) occurs and that these molecules are involved in migration (Humbert et
al., 2004).

In many forms of pulmonary hypertension, as the vessel wall thickens, a

concomitant increase occurs in neovascularization of the vasa vasorum. This
neovascularization occurs primarily in the adventitia, although it extends into the
outer parts of the media. This adventitial vessel formation could provide a conduit
for circulating progenitor cells to access the vessel wall from the adventitial side
(Nunes et al., 2017).

Review of literature

Endothelial cells:

Disorganized endothelial cell proliferation leading to formation of

plexiform lesions is described in many cases of PAH. The initiating stimulus or
injury that results in abnormal endothelial proliferation is unknown, but may
include hypoxia, shear stress, inflammation, or response to drugs or toxins on a
background of genetic susceptibility (Humbert et al., 2004).

Endothelial cells may respond to injury in various ways affecting the

process of vascular remodeling. Injury can alter not only cell proliferation and
apoptosis but also homeostatic functions of the endothelium (including
coagulation pathways, and production of growth factors and vasoactive agents).
The cells comprising plexiform lesions are endothelial channels supported by a
stroma containing matrix proteins and myofibroblasts. Endothelial cells express
markers of angiogenesis, such as vascular endothelial growth factor (VEGF) and
its receptors (Humbert et al., 2004).

Inflammatory cells:

Inflammatory mechanisms appear to play a significant role in some types of

pulmonary hypertension of various origins in humans including connective tissue
diseases and human immunodeficiency virus infection (Dorfmuller et al., 2003).

Lung histology revealed inflammatory infiltrates (macrophages and

lymphocytes) in the range of plexiform lesions in severe PAH as well as an
increased expression of chemokines RANTES and fractalkine (Guignabert and
Dorfmüller, 2017). Further analysis of the role of inflammatory mechanisms is
necessary to understand whether this component of the disease is relevant to its
pathophysiology (Humbert et al., 2004).

Review of literature

Platelets and thrombosis:

Thrombotic lesions and platelet dysfunction are potentially important

processes in PAH (Simonneau et al., 2017). In situ pulmonary artery thrombosis
may be initiated or aggravated by abnormalities in the clotting cascade, the
endothelial cells, or the platelets. Intravascular coagulation is a continuous
process in PAH patients, characterized by elevated plasma levels of
fibrinopeptide A- and D-dimers. In addition, procoagulant activity and
fibrinolytic function of the pulmonary endothelium are altered in PAH. This
dysfunction is reflected by the demonstration of elevated plasma levels of von
Willebrand factor and plasminogen activator inhibitor type-1 (Humbert et al.,

Indeed, in addition to its role in coagulation, the platelet stores and releases
important contributors to pulmonary vasoconstriction and remodeling such as
thromboxane A2, platelet activating factor, serotonin (5-hydroxytryptamine [5-
HT]), platelet-derived growth factor (PDGF), TGF-ß, and VEGF. In most cases,
however, it remains unclear whether thrombosis and platelet dysfunction are
causes or consequences of the disease (Herve et al., 2001).

Molecular mechanisms
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, as well as to endothelial
dysfunction. Endothelial dysfunction leads to chronically impaired production of
vasodilators such as nitric oxide (NO) and prostacyclin along with prolonged
overexpression of vasoconstrictors such as endothelin (ET)-1, which not only
affect vascular tone, but also promote vascular remodeling and, therefore,
represent logical pharmacological targets figure (D) It appears that most stimuli
that acutely enhance vasoconstriction ultimately also cause cell proliferation

Review of literature

(e.g., K+ channel inhibition, ET-1) (Humbert et al., 2004).

Figure (D). Consequences of pulmonary artery endothelial cell dysfunction

on pulmonary artery smooth muscle cell tone and proliferation. Dysfunctional
pulmonary artery endothelial cells (blue) have a decreased production of prostacyclin and nitric oxide, with an
increased production of endothelin-1- promoting vasoconstriction and proliferation of pulmonary artery smooth
muscle cells (red). cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine monophosphate; ET =
endothelin; ETA = endothelin receptor A; ETB =endothelin receptor B; PDE5 = phosphodiesterase type 5.
(Humbert et al., 2004).

Prostacyclin, vasoactive intestinal peptide, and NO:

Prostacyclin (prostaglandin I2) is an important endogenous pulmonary

vasodilator acting through activation of the cyclic adenosine monophosphate
(cAMP)-dependent pathways. Prostacyclin also inhibits the proliferation of
vascular smooth muscle cells and decreases platelet aggregation. Prostacyclin
synthesis is decreased in endothelial cells from PAH patients. Analysis of urinary
metabolites of prostacyclin showed a decrease in the amount of excreted 6-
ketoprostaglandin F1α, a stable metabolite of prostacyclin, in patients with
idiopathic PAH . Moreover, pulmonary endothelial cells of PAH patients are
characterized by reduced expression of prostacyclin synthase , and prostacyclin
therapy has been shown to improve hemodynamics, clinical status, and survival

Review of literature

of patients displaying severe PAH (Humbert et al., 2004).

Vasoactive intestinal peptide (VIP), a neuropeptide primarily functioning as

a neurotransmitter, acts as a potent systemic and pulmonary vasodilator. It also
inhibits the proliferation of vascular smooth muscle cells and decreases platelet
aggregation; VIP acts through two receptor subtypes (VPAC-1 and -2), which are
coupled to adenylate cyclase and expressed in the lung vasculature. Stimulation
of VPAC receptors leads to the activation of the cAMP and cyclic guanosine
monophosphate (cGMP) systems ( Petkov et al., 2003).

NO is a potent endothelium-derived vasorelaxant substance and an inhibitor

of smooth muscle cell growth . NO is produced in various cell types by the action
of NO synthase (NOS). Additionally, studies of endogenous NOS inhibitors, such
as asymmetrical dimethylarginine (ADMA), support the hypothesis that eNOS is
important in maintenance of normal pulmonary vascular tone (Barst et al.,

Endothelin-1 and thromboxane:

Important vaso-constrictive and proliferative mediators implicated to date

in paediatric include thromboxane (TX)A2 and endothelin-1 (ET-1), opposing
vasodilator and antiproliferative vasoactive mediators, such as prostacyclin and
nitric oxide (NO) ( Gupta and Ahsan, 2010).

Because TXA2 is a potent pulmonary vasoconstrictor and a stimulus for

platelet aggregation, whereas prostacyclin produces the opposite effects an
imbalance between these two vasoactive mediators in favour of TXA2 could
contribute to both pulmonary vasoconstriction and local thrombosis in situ (Barst
et al., 2011).

Barst and Stalcup (1985) reported increased TX levels in 16 PAH patients

aged 1.5–23 yrs. An imbalance favouring TXA2 production has also been

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observed in children with PAH-CHD . This imbalance is usually restored to

normal after corrective open-heart surgery

ET-1 is a potent vasoconstrictor and a mitogen for smooth-muscle cells and

fibroblasts . Elevated plasma ET-1 levels have been reported in adult PAH
patients with increased pre-proET-1 gene expression in pulmonary vascular
endothelial cells. Similar alterations of ET-1 signalling have been reported in
infants and children with PAH . Children with PAH-CHD also have increased
ET-1 immunoreactivity and endothelin receptor type A (ETA) density in the
pulmonary arterial wall (Barst et al., 2011).

Potassium channels :

Hypoxic pulmonary vasoconstriction is elicited when hypoxia inhibits one

or more voltage-gated potassium channels (Kv) in the pulmonary artery smooth
muscle cells of resistance pulmonary arteries. The resulting membrane
depolarization increases the opening of voltage-gated calcium channels, raising
cytosolic calcium and initiating constriction and cell proliferation. The Kv1.5 is
downregulated in pulmonary artery smooth muscle cells in humans with PAH
(Humbert et al., 2004).

Von Willebrand factor (vWF):

In addition to regulating vasoreactivity and cellular mitogenesis, the

endothelium also modulates local haemostasis. Von Willebrand factor (vWF), a
large multimeric plasma glycoprotein produced by endothelial cells , is involved
in platelet adhesion. vWF has been proposed as both a marker of endothelial
dysfunction and a prognostic parameter in PAH. Plasma vWF is increased but
dysfunctional because of a loss of its high molecular weight multimers, resulting
in reduced platelet binding (Barst et al., 2011).

Review of literature


In PAH, circulating serotonin levels are elevated, where as the level in

platelets, the major repository of serotonin (5-hydroxytryptamine [5-HT]), is low.
A role for 5-HT has been suggested in PAH (Shao et al., 2018).

The mechanism by which 5-HT affects the pulmonary vasculature is still a

matter of debate. The 5-HTT expression, activity, or both in pulmonary artery
smooth muscle cells contribute to the pulmonary vascular remodeling occurring
in both clinical and experimental PAH (MacLean et al., 2000).

TGF-ß superfamily:

The TGF-ß superfamily is composed of multifunctional mediators,

including the TGF-ß isoforms (TGF-ß 1–3), the bone morphogenetic proteins
(BMPs), activins, and growth and differentiation factors. The TGF-ß superfamily
has diverse roles in a wide variety of physiological processes (Figure E).
Germline mutations in the gene coding for BMP type-II receptor (BMPR2) have
been identified in 60% of familial PAH and 10% to 30% of idiopathic PAH
(Humbert et al., 2004).

Figure (E) Potential roles of transforming growth factor-beta (TGF-β)

superfamily in vascular remodeling. The TGF-β superfamily has diverse roles in a wide variety of
physiological processes, including cell proliferation, differentiation, immunity, and inflammation. BMP = bone
morphogenetic protein; GDF = growth and differentiation factor (Humbert et al., 2004).

Review of literature


Vascular endothelial growth factor is an endothelial-cell-specific-angiogenic

mitogen acting via two high-affinity tyrosine kinase receptors (VEGFR-1 and
VEGFR-2). Although the physiological role of the abundantly expressed VEGF
in the lung is unknown, it has been proposed that VEGF supports pulmonary
endothelial cell maintenance and survival. In PAH, the VEGF expression is
increased within the pulmonary vasculature, including the plexiform lesions
(Humbert et al., 2004).

Although the isoform VEGF-A has been most extensively studied in the
context of pulmonary hypertension and has been proposed to play a protective
role, a study identified a pathogenic role for VEGF-B. Animal studies have
emphasized the positive effects of VEGF in models of pulmonary hypertension.
Indeed, cell-based VEGF gene transfer has proved an effective method of
preventing the development and progression of pulmonary hypertension.
Vascular endothelial growth factor would minimize progression of the disease by
preventing loss of existing vessels or by inducing the development of new blood
vessels within the lung (Campbell et al., 2001).

Various other growth factors including PDGF, basic fibroblast growth factor,
insulin-like growth factor-1, and epidermal growth factor have also been
implicated in the development of remodeling and all have been reported to be
increased in the pulmonary hypertensive lung. The mechanism that leads to
induction of these growth factors in the pulmonary vasculature is unclear, though
reactive oxygen species have been implicated because hydrogen peroxide

Review of literature

induces PDGF expression in human pulmonary endothelial cells, as does hypoxia

and mechanical stretch and shear stress (Humbert et al., 2004).


Evidence that proteolysis of the extracellular matrix may be important in the

pathobiology of pulmonary vascular disease came from observations of
degradation of elastin in pulmonary arteries from patients with a congenital heart
defect and pulmonary vascular disease. These studies were supported by work in
a variety of rat models of pulmonary hypertension (hypoxia, monocrotaline) in
which heightened activity of elastase in the pulmonary arteries was documented
as a very early feature after the injurious stimulus ( Lang et al., 2004).

Elastase activity:

Ultrastructural studies of PAs from children with congenital heart defects

and associated PAH suggested that elastolytic activity may be an early feature of
this complication. Elevated serine elastase activity was subsequently documented
in rodent and murine models of PAH, which led to the successful experimental
use of elastase inhibitors to prevent pulmonary vascular pathology (Kang et al.,

The mechanism relating elastase activity to PAH is based on studies in

cultured PA SMCs showing that serum and EC factors can mediate the cells’
production of serine elastase. This enzyme can release growth factors from the
extracellular matrix and induce production of matrix metalloproteinases and
tenascin-C, a glycoprotein associated with activation of SMC growth factor
receptors and survival pathways (Rabinovitch, 2012).

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Clinical Manifestations
Natural history:

 Pulmonary hypertension with large left-to-right shunt lesions

(hyperkinetic type) or associated with pulmonary venous hypertension
improves or disappears after surgical repair of the cause, if treatment of
the condition is possible and performed early.

 Pulmonary hypertension associated with Eisenmenger's syndrome is

usually irreversible and has a poor prognosis but may be stable for two to
three decades.

 Right-sided heart failure is common in the late stage.

 Chest pain, hemoptysis, and syncope are ominous signs.

 Atrial and ventricular arrhythmias also occur late.

 The two most frequent causes of death are progressive RV failure and
sudden death (probably secondary to arrhythmias).

 Cerebrovascular accident from paradoxical embolization is a rare

complication (Park, 2008c).

Physical examination:

Physical examination of a patient with PAH may reveal a right parasternal

lift, accentuated pulmonary second heart sound, pansystolic murmur (tricuspid
regurgitation), third heart sound, and a diastolic murmur (pulmonary valve
insufficiency). Edema may present as jugular vein distension, hepatomegaly,
peripheral edema, or ascites. In the European guidelines, PAH-CHD patients
have been classified into four main clinical groups (table H) (Galie et al., 2009a)

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Table (H) Clinical classification of congenital, systemic-to-pulmonary shunts

associated with pulmonary arterial hypertension (Galie et al., 2009a)

Group A. Eisenmenger’s syndrome

Eisenmenger’s syndrome includes all systemic-to-pulmonary shunts due to large defects leading to a
severe increase in PVR and resulting in a reversed (pulmonary-tosystemic) or bidirectional shunt.
Cyanosis, erythrocytosis and multiple organ involvement are present.

Group B. PAH associated with systemic-to-pulmonary shunts

In these patients with moderate-to-large defects, the increase in PVR is mild-to-moderate, systemic-to-
pulmonary shunt is still largely present and no cyanosis is present at rest.

Group C. PAH with small defects

In cases with small defects (usually VSD ,1 cm and ASD ,2 cm of effective diameter assessed by
echocardiography), the clinical picture is very similar to idiopathic PAH.

Group D. PAH after corrective cardiac surgery

In these cases, CHD has been corrected but PAH is either still present immediately after surgery or has
recurred several months or years after surgery in the absence of significant post-operative residual
congenital lesions or defects that originate as a sequelae to previous surgery.

PVR: pulmonary vascular resistance; VSD: ventricular septal defect; ASD: atrial septal defect; CHD: congenital
heart disease.

Functional status in patients with pulmonary hypertension table (I):

Table (I): Modified New York Heart Association classification of functional
status in patients with pulmonary hypertension (PHT) (Strange et al., 2009)
Class I Patients with PHT but without resulting limitation of physical activity. Ordinary
physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope.

Class II Patients with PHT resulting in slight limitation of physical activity. They are
comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain, or
near syncope.

Class III Patients with PHT resulting in marked limitation of physical activity. They are
comfortable at rest. Less-than-ordinary physical activity causes undue dyspnea or fatigue, chest
pain, or near syncope.

Class IV Patients with PHT with inability to carry out any physical activity without symptoms.
These patients manifest signs of right heart failure. Dyspnea and/or fatigue may even be present
at rest. Discomfort is increased by any physical activity.

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Comorbidities associated with PAH-CHD:

Patients with PAH-CHD suffer from a range of comorbidities associated
with their underlying cardiac disorder, most commonly arrhythmias, heart
failure, renal failure, hepatic dysfunction and diabetes mellitus. Arrhythmias,
ranging from bradycardiac arrhythmias to ventricular tachycardia and atrial
fibrillation, are common late complications of CHD (D’Alto and Mahadevan,

The development of atrial arrhythmia is associated with an increased risk of

mortality due to heart failure-related death, sudden cardiac death and
perioperative death in patients with CHD, and PAH is an independent risk factor
for mortality in these patients ( Yap et al, 2011).

Eisenmenger’s syndrome is a multisystem disorder and its development is

associated with particularly high morbidity. Cyanosis leads to exercise
intolerance and a range of potential problems including erythrocytosis,
hyperviscosity, abnormalities of haemostasis, cerebral abscesses, stroke and
endocarditis (DeFilippis et al., 2007) .

Diagnosis of PAH
Laboratory studies:

Include pulmonary function tests; blood tests to exclude HIV, autoimmune

diseases, and liver disease; arterial blood gas measurements. Blood BNP level is
also being used now to follow progress of patients with pulmonary hypertension
(Rubin and Badesch, 2005).

Chest radiography

The radiographic findings are variable, and the chest radiograph may be
remarkably normal for some patients. Right atrial and right ventricular

Review of literature

enlargement with dilatation, aneurysm or calcification of the central pulmonary

arteries may also be present. Enlarged central pulmonary arteries with“pruning”
of the peripheral pulmonary vessels are usually late findings (Jung, 2007).


An electrocardiogram typically demonstrates right axis deviation and right

ventricular hypertrophy. A right ventricular strain pattern may be present with
associated ST-T segment changes (Jung, 2007).


Two-dimensional echocardiography may demonstrate any of the following:

a dilated right heart, tricuspid regurgitation, pulmonary insufficiency, flattening
or posterior bowing of the interventricular septum, right ventricular hypertrophy,
diminished right ventricular function, and bidirectional or right-to-left shunting
across the cardiac defect (Chung et al., 2006).

Cardiac catheterization

Although pulmonary arterial pressure can be estimated on the basis of

echocardiography, pressure measurements with a Swan-Ganz catheter provides
the most definite assessment. PAP and PVR cannot be measured directly with
echocardiography. Therefore, diagnosis of PAH requires right-sided cardiac
catheterization. A Swan-Ganz catheter can also measure the cardiac output,
which is far more important in measuring disease severity than the pulmonary
arterial pressure (Rubin and Badesch, 2005).

A mean PAP(mPAP) greater than 25 mmHg at rest or greater than 30 mmHg

with exercise, with a pulmonary capillary wedge pressure or left ventricular end
diastolic pressure of 15 mmHg or less and the pulmonary vascular resistance is
greater than 3 units (Jung, 2007).

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Lung biopsy

Biopsy of the lung is usually not indicated unless the pulmonary

hypertension is thought to be due to an underlying interstitial lung disease;
further, lung biopsies are fraught with risks of bleeding due to the high
intrapulmonary blood pressure (Rubin and Badesch, 2005).

Assessment of exercise capacity

Clinical improvement is often measured by a "six-minute walk test" i.e. the

distance a patient can walk in six minutes. Stability and improvement in this
measurement correlate with better survival (Rubin and Badesch, 2005).

Treatment of PAH
Early diagnosis and treatment for a large systemicto- pulmonary shunt is
critical for preventing Eisenmenger syndrome. The treatment options for patients
with PAH associated with congenital heart disease are limited to palliative
measures and heart-lung transplantation for highly selected patients with
Eisenmenger syndrome. The treatment may include the use of supplemental
oxygen, digitalis, diuretics, vasodilators and anticoagulants, or lung
transplantation and repair of the congenital heart defect(s), or heart-lung
transplantation (Jung, 2007).

General Management :

Patients with Eisenmenger syndrome must avoid circumstances that may

exacerbate their pulmonary vascular disease. Exercise should be guided by the
patients’ symptoms with strict limits adhered to (Jung, 2007).

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Conventional treatment:

The aim of therapy in patients with PAH is to improve survival, disease-related

symptoms and quality of life (QoL) (Strange et al., 2009).

Measures to remove or treat the underlying cause include the following:

1. Timely corrective surgery for congenital defects, such as large-shunt VSD,

endocardial cushion defect, or PDA, before obstructive anatomic changes
occur in the pulmonary vessels

2. Tonsillectomy and adenoidectomy when the cause of pulmonary

hypertension is the upper airway obstruction

3. Treatment of underlying diseases, such as cystic fibrosis, asthma,

pneumonia, or bronchopulmonary dysplasia (park, 2008c).

Anticoagulation with warfarin (Coumadin) is widely recommended in
patients with thromboembolic disease and may be beneficial in those with
pulmonary hypertension from other causes, with significant improvement in
survival. An International Normalized Ratio (INR) of 2.0 to 2.5 is the goal of
therapy. Unlike the approach for patients with a prosthetic mechanical heart
valve, concomitant use of aspirin is not recommended because it may increase
effects of warfarin. Some recommend antiplatelet drugs (aspirin) instead of
warfarin to prevent microembolism in the pulmonary circulation (Park, 2008c).

Therapy of PAH:

Similarities in the pathobiology of PAH have led to similar treatment

algorithms, in children (figure F) (Abman and Ivy, 2011).

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Figure (F): Treatment algorithm in children with severe pulmonary arterial

hypertension (Abman and Ivy, 2011).

If during right heart catheterization (RHC), the pulmonary vasoreactive tests

are positive, the treatment of choice is high-dose calcium channel blockers
(CCBs), as improved survival with long-term use has been demonstrated in this
cohort of patients (Strange et al., 2009).

Vasoreactivity is considered to be present when the mPAP has decreased by at

least 10 mmHg to 40 mmHg or less with normal or high cardiac output after
intervention with pulmonary vasodilators, such as 100% oxygen, nitric oxide
inhalation or intravenous prostacyclin (Barst et al, 2004).

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Figure (G) Therapeutic approaches to pulmonary hypertension. A model of the

pulmonary arteriolar system and alveolus is illustrated, with the sites of action of
each of the six major classes of agents (Farber and Loscalzo , 2004)

Based on understanding of abnormalities of the vascular endothelium, three

classes of drugs have been studied for the treatment of PAH: prostanoids
(epoprostenol, treprostinil, iloprost), endothelin receptor antagonists (bosentan,
ambrisentan), and phosphodiesterase inhibitors (sildenafil, tadalafil) (Figure G)
(Ivy, 2012).

Calcium channel blockers:

Treatment of PAH with calcium channel blockers is decreasing with the

approval of more targeted therapy, and is limited to select patients with a positive
acute vasodilator challenge (Ivy, 2012).

There are no data to support the use of calcium channel blockers in patients
with PAH-CHD and their use must be avoided. In particular, their use is

Review of literature

contraindicated in Eisenmenger’s syndrome patients as this treatment class can

result in an acute decrease in systemic arterial pressure and increase of the right-
to-left shunt, which may lead to syncope and sudden death. Patients who present
with significant haemoptysis should be considered for embolisation of relevant
collateral vessels if appropriate (Ivy, 2012).

Prostanoids (Prostacyclins):

Therapy with prostacyclin and its analogues has been extrapolated for use in
children. Long-term IV epoprostenol has improved survival for children with
PAH with a 4-year survival rate of 94% in IPAH, and a 10-year treatment success
rate (freedom from death, transplantation, or atrial septostomy) of 37% (Ivy,

Epoprostenol has a short half-life rendering a continuous intravenous infusion

with a permanent central venous catheter necessary. Complications such as line
sepsis, local infection and catheter dislodgement are not unusual and can be
responsible for life-threatening rebound PH (Doran et al., 2008).

Recently, the use of specific closed hub systems has been shown to decrease
the infection rate. Although uncommon, children with a dramatic sustained
response to epoprostenol may be weaned to oral or inhaled therapy if
hemodynamics return to near normal values (Ivy, 2012).

Iloprost is an inhaled prostacyclin analogue with a longer half-life. In

children treated with iloprost, WHO functional class has been shown to be
improved in 35%, remained unchanged in 50% and decreased in 15%. Lower-
airway reactivity is a problem in some children, as well as poor compliance with
the need for frequent aerosol administrations (6-8 times daily). Iloprost has been
used in postoperative congenital heart disease associated with PH and has been

Review of literature

shown to be as efficacious in lowering mean PVR and improve systemic oxygen

saturation compared to NO (Ivy, 2012).

Nevertheless, clinical deterioration, side effects, and poor compliance limit

its chronic administration in children. Treprostinil, a prostacyclin analogue, is
approved by the FDA for subcutaneous use (2002), intravenous administration
(2004) and inhalation (2009) (Ivy, 2012). Treprostinil in an inhaled form is
increasing in usage. (Rosenzweig et al., 2011).

a recent study of subcutaneous treprostinil in young children showed

promise with tolerabl side effects. Similar to epoprostenol, intravenous
treprostinil requires central line access and continuous infusion, but is easier for
families to mix, has a longer half-life, and may allow use of a smaller pump.
Intravenous treprostinil has fewer side effects than intravenous epoprostenol, but
there are no studies comparing efficacy (Ivy, 2012).

Endothelin recptor antagonist:

Blockade of the receptors of ET-1,a potent vasoconstrictor peptide, with

bosentan lower pulmonary artery pressure and resistance, and improves exercise
tolerance in adults with PAH (Lakshminrusimha et al., 2016).

Although bosentan is not approved for use in children with PAH in the US,
several studies have suggested safety and a delay in disease progression (Hislop
et al., 2011). A specific pediatric formulation has been recently approved in
Europe (Ivy et al., 2010).

Bosentan was well tolerated and improved exercise capacity and

hemodynamics without compromising peripheral oxygen saturation (Galie et al.,

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Studies in children suggest that some patients treated with bosentan may
show additional improvement on transition to ambrisentan (Ivy et al., 2010).

Phosphodiesterase-5 inhibitors

Sildenafil and tadalafil, are specific phosphodiesterase-5 inhibitors,which

promote an increase in cGMP levels and thus promote pulmonary vasodilation.
Sildenafil may also be useful in the setting of inhaled nitric oxide therapy
withdrawal in postoperative PH, or in the presence of PH related to chronic lung
disease. Sildenafil is approved for use in children with PAH in Europe: 10 mg
t.i.d. in patients up to 20 kg, and 20 mg t.i.d. in heavier patients (0.25-1 mg/kg.
starting with lower dose), but sildenafil is not approved for children with PAH in
the U.S. Intravenous sildenafil has been shown to potentiate the increase in cGMP
in response to NO in children with increased PVR related to CHD or in the post-
operative state. Nevertheless, sildenafil infusion may be associated with
increased intrapulmonary shunting and augmentation of hypoxemia related to
V/Q mismatch in the postoperative CHD patient (Ivy, 2012).

However, a study of intravenous sildenafil has shown improvement in

oxygenation index in persistent pulmonary hypertension of the newborn in
patients treated with or without inhaled nitric oxide (Steinhorn et al., 2009).

Other PDE-5 inhibitors, such as tadalalfil, have been studied leading to US

FDA approval in 2009 (Galie et al.,2009b).

Novel Therapies:

Therapies targeting remodeling of the pulmonary vasculature are under

study. Imatinib, an antagonist of the platelet-derived growth factor (PDGF)
receptor, is approved for the treatment of chronic myeloid leukemia. PDGF
contributes to vascular remodeling and participates in mytogenic signaling and

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smooth muscle cell recruitment. Bone-derived endothelial progenitor cells

(EPCs) normally function to repair and regenerate blood vessels (Ivy, 2012).

Other targets in the future may include blockade of stem cell populations
contributing to the fibroproliferative process, such as fibrocytes (Yeager et al.,

Novel agents leading to pulmonary vasodilation are being developed.

Riociguat, a direct oral soluble guanylate cyclase (sGC) stimulator, increases
cGMP directly in a non-NO dependent manner but also increases the sensitivity
of sGC to NO (Ivy et al., 2010).

Selexipag is an orally available prostacyclin receptor (IP receptor) agonist

that is chemically distinct from PGI2. Where prostacyclin and its analogs can
activate prostanoid receptors other than the IP receptor, direct stimulation of these
receptors may help minimize gastric side effects such as nausea and vomiting.
Novel endothelin receptor antagonists are currently under study in Phase III trials
as well. (Ivy, 2012). Macitentan is a highly potent, tissue-targeting dual ETA,
ETB receptor antagonist (Sidharta et al., 2011).

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Speckle tracking echocardiography (STE)


Speckle-tracking echocardiography )STE) is a new noninvasive

ultrasound imaging technique that allows for an objective and quantitative
evaluation of global and regional myocardial function independently from the
angle of insonation and from cardiac translational movements.(Perk et al., 2007
, Dandel et al., 2009)

Although tagged MRI may be considered the reference standard in this

area of study, its routine use is limited by its high costs, poor availability, relative
complexity of acquisitions, and time-consuming image analysis. (Buchalter et
al., 1990, Shaw et al., 2008)

By tracking the displacement of speckles during the cardiac cycle, STE

allows semi-automated elaboration of myocardial deformation in 3 spatial
directions: longitudinal, radial, and circumferential. In addition STE offers an
evaluation of the occurrence, direction, and velocity of left ventricle (LV)
rotation (Teske et al., 2007). The semi-automated nature of STE guarantees good
intraobserver and interobserver reproducibility. (van Dalen et al., 2009)

Nonetheless, although this new technique was introduced for the

exclusive analysis of LV function, several studies have recently extended its
applicability to other cardiac chambers, such as the left atrium (Okamatsu et al.,

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Figure (H): Assessment of different LV movements (Okamatsu et al., 2009).


Strain (S)

Strain represents a measure that evaluates the degree of deformation of

the analyzed segment in relation to its initial dimensions. By convention,
depending on the direction, a lengthening or thickening deformation is given a
positive value, whereas a shortening or thinning deformation is given a negative
one. (Perk et al., 2007)

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Strain Rate (SR)

The strain rate represents the myocardial deformation rate. It is expressed

as seconds−1; in other words, if the same strain value is reached in half the time,
the strain rate value will be doubled. Experimental studies have shown that the
strain rate is less dependent on LV load variations than strain. However, because
the strain rate signal is noisier and less reproducible, most clinical studies still
use strain measurements (Dandel et al., 2009)

Longitudinal Strain (LS)

Longitudinal strain represents myocardial deformation directed from the

base to the apex. During systole, ventricular myocardial fibers shorten with a
translational movement from the base to the apex; the consequent reduction of
the distance between single kernels is represented by negative curves as in figure
(H) (Heimdal et al., 1998). Through LS analyses in 4-chamber, 2-chamber, and
apical long-axis views, both segmental and global strain values can be obtained.
Global LS recently has been validated as a quantitative index for global LV
function (Brown et al., 2009). The same measurement can be applied to the
speckle tracking echocardiographic analysis of longitudinal myocardial
deformation of the left atrium and right ventricle , obtaining the peak atrial LS
(Cameli et al., 2009) and the right ventricle longitudinal strain (Horton et al.,
2009) respectively.

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Figure (I): measurement of LV longitudinal strain through analysis

of the LV segments in apical 4-chamber(a), 2- chamber(b) and
apical long axis views(c) Average segmental values are used to
generate a ‘‘bull’s-eye’’ display of myocardial
deformation(D).(Dandel et al,2009)
Table (J): Mean left ventricular longitudinal systolic segmental strain values
(Sebastiaan et al., 2014)

All levels Basal Mid Apical P-value (levels)

All walls −15.9 ± 6.0 −16.9 ± 6.6 −14.9 ± 5.2 −16.0 ± 6.1 <0.001

Anterior −15.2 ± 6.7 −19.9 ± 6.6 −15.0 ± 5.9 −11.6 ± 4.7 <0.001

Anteroseptal −16.0 ± 5.5 −14.6 ± 6.0 −15.8 ± 4.9 −17.6 ± 5.3 0.01

Inferoseptal −15.8 ± 5.4 −14.1 ± 5.6 −15.4 ± 4.7 −17.6 ± 5.3 0.004

Inferior −16.6 ± 5.8 −16.2 ± 5.8 −14.5 ± 4.8 −19.3 ± 5.6 <0.001

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Inferolateral −15.5 ± 6.0 −17.2 ± 6.5 −13.7 ± 5.2 −15.6 ± 5.7 <0.001

Anterolateral −16.9 ± 6.3 −20.3 ± 6.3 −15.2 ± 5.6 −15.6 ± 5.7 <0.001

P-value <0.001 <0.001 <0.001 <0.001 –


Radial Strain (RS)

Radial strain (RS) represents radially directed myocardial deformation,

i.e., toward the center of the LV cavity, and thus indicates the LV thickening and
thinning motion during the cardiac cycle. Consequently, during systole, given the
progressive radial propulsion of single kernels, RS values are represented by
positive curves (Figure 8).Radial strain values are obtained by speckle-tracking
echocardiographic analysis of both basal and apical LV short-axis views (Saito
et al., 2009).

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Figure (J) speckle tracking echocardiography, measurement of radial strain of

left ventricle in parasternal short axis view. (Dandel et al, 2009)

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Table (K): Mean left ventricular radial segmental strain values. (Sebastiaan et
al., 2014)

All levels Basal Mid Apical P-value


All walls 35.4 ± 17.5 34.8 ± 17.8 38.5 ± 18.2 31.5 ± 15.2 <0.001

Anterior 40.4 ± 18.2 40.2 ± 18.1 46.1 ± 18.6 34.8 ± 14.2 0.001

Anteroseptal 38.1 ± 17.0 39.8 ± 18.1 42.4 ± 16.8 32.4 ± 14.4 0.09

Inferoseptal 33.0 ± 15.3 32.3 ± 16.0 34.2 ± 15.4 32.4 ± 14.4 0.16

Inferior 27.4 ± 15.9 27.9 ± 16.6 28.8 ± 16.1 25.4 ± 14.9 0.54

Inferolateral 33.8 ± 16.6 32.1 ± 15.5 36.1 ± 18.2 33.0 ± 15.7 0.008

Anterolateral 38.1 ± 17.6 37.5 ± 17.3 43.7 ± 18.0 33.0 ± 15.7 <0.001

P-value <0.001 <0.001 <0.001 <0.001 –


Circumferential Strain (CS)

Circumferential strain (CS) represents LV myocardial fiber shortening

along the circular perimeter observed on a short-axis view (Figure J) (Saito et

Review of literature

al., 2009). Consequently, during systole, for circumferential speckle-to-speckle

distance reduction, CS measurements are represented by negative curves. As for
LS, it is possible to obtain a global CS value.

Table (L) : Mean left ventricular circumferential strain values. (Sebastiaan et

al., 2014)

All levels Basal Mid Apical P-value


All walls −30.5 ± 6.0 −29.6 ± 6.3 −31.4 ± 5.7 −30.5 ± 5.9 <0.001

Anterior −29.2 ± 5.8 −28.7 ± 5.9 −30.7 ± 5.5 −28.0 ± 5.5 <0.001

Anteroseptal −31.2 ± 6.0 −29.7 ± 6.2 −32.4 ± 6.0 −31.4 ± 5.7 <0.001

Inferoseptal −31.0 ± 6.2 −29.6 ± 6.7 −31.8 ± 6.0 −31.4 ± 5.7 <0.001

Inferior −31.4 ± 5.7 −30.5 ± 6.1 −31.5 ± 5.5 −32.1 ± 5.4 0.054

Inferolateral −30.3 ± 6.0 −29.6 ± 6.3 −31.0 ± 5.5 −30.4 ± 6.1 0.01

Anterolateral −30.2 ± 6.1 −29.2 ± 6.5 030.9 ± 5.6 −30.4 ± 6.1 0.001

P-value 0.004 0.055 0.007 <0.001 –


Review of literature

Figure (K) speckle tracking echocardiography, measurement of circumferential

strain of left ventricle in parasternal short axis view. (Dandel et al, 2009)

Clinical applications:

In general, STE may allow an in-depth evaluation of myocardial systolic

and diastolic dynamics across a broad range of physiologic and pathologic
conditions beyond traditional echocardiographic techniques. For example, not
only has a good correlation between longitudinal strain (LS) and the left
ventricular ejection fraction (LVEF) been shown in several studies, but in

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addition LS provides a quantitative myocardial deformation analysis of each LV

segment, also allowing for early systolic dysfunction detection in patients with a
preserved LVEF (Brown et al., 2009).

STE in Coronary Artery Disease

Detection of Coronary artery disease:

Because strains and SRs are homogenously distributed across the
myocardium, the detection of even subtle changes in either measure suggests
myocardial dysfunction. Although strain imaging has a potential role in the
diagnosis and management of virtually any disease that affects the myocardium,
arguably its greatest potential is in the detection of ischemic heart disease.
Because longitudinal mechanics predominate in the ischemia-vulnerable sub
endocardium, either Doppler- or 2D-derived strain can be used because both
analyze the longitudinal component of deformation. In the appropriate patient at
rest, subclinical LV systolic dysfunction has been shown to correlate with the
presence of obstructive coronary disease. Thus, Doppler longitudinal systolic
strain and SRs were significantly abnormal in visually normokinetic segments
supplied by stenotic (70%) arteries (Jamal et al., 2002).

Choi et al (2009) reported that a lower LS value in asymptomatic patients

without wall motion abnormalities is a strong predictor of stable ischemic
cardiomyopathy )ICM). Studies in patients with AMI found that LS is related to
peak levels of cardiac troponin T and the left ventricle infarct size (Sjøli et al.,

Moreover, when measured immediately after reperfusion therapy LS is an

excellent predictor of LV remodeling and adverse events, such as congestive
heart failure (CHF) and death (Park et al., 2008). In addition, it has been shown

Review of literature

that LS correlates with the global and regional extent (transmurality) of scar
tissue as evaluated by contrast-enhanced MRI (Becker et al., 2008, Roes et al.,

Voigt et al (2004) had used STE to validate an analysis of post-systolic

motion, identified as LV regional myocardial motion after aortic valve closure,
and showed that the post-systolic index represents an important quantitative
marker for analysis of the ischemic myocardium. However, data from studies on
large populations are still lacking.

In a prospective, observational study, tissue Doppler systolic and early

diastolic strains in the basal anterior segment of patients with left anterior
descending (LAD) coronary artery disease remained depressed for 1 hour after
exercise (whereas velocity and SR quickly normalized), suggesting that strain
identified regional post ischemic dysfunction (i.e., myocardial stunning) may be
diagnostic in patients with chest pain in whom the ECG has normalized
(Williams et al., 2005).

In another study of 108 patients undergoing coronary angiography, a 2D

longitudinal strain of _17.9% discriminated severe 3-vessel or left main disease
from lesser coronary artery disease with a sensitivity and specificity of 79%
and 79%, respectively. (Choi et al., 2009).

Taken together, these studies support the use of STE to identify and risk-
stratify atherosclerotic coronary disease with good accuracy and reproducibility.

Myocardial Infarction

Longitudinal strains are reduced in patients with myocardial infarctions

(Jurcut et al., 2008). And correlate with infarct size and ejection fraction
(Gjesdal et al., 2007. Delgado et al., 2008).and predict LV remodeling and

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clinical events (Park et al., 2008) and response to reperfusion strategies.

(Korosoglou et al., 2008).

In a study of patients with recent first myocardial infarctions and matched

control subjects, S and SR -but not tissue Doppler velocities- could differentiate
normal from abnormally contracting segments. (Jamal et al., 2001). In a
subpopulation of the same study who also underwent both Doppler stress
imaging (DSI) and coronary angiography, longitudinal Doppler strain data
displayed 85% sensitivity and specificity for the detection of infarct involved

segments using strain and SR cutoffs of -13% and -0.8 s-1, respectively. DSI
and regional myocardial blood flow (contrast echo) predicted LV remodeling
(20% increase in end-diastolic diameter) in 10 patients 4 to 6 months after
reperfused ST-elevation myocardial infarction and correlated with an LV
functional improvement (ejection fraction increases 10%) in an additional 19
patients. (Korosoglou et al., 2008).

In 20 patients with severe angina ineligible for revascularization, an

improvement in New York Heart Association angina class was associated with
improvement in DSI (peak systolic strain), and systolic and diastolic myocardial
and diastolic transmitral velocities with enhanced external counterpulsation.
(Esmaeilzadeh et al., 2009).

Extent of Myocardial Infarction

A related issue, differentiating nontransmural from transmural

infarction has important implications for management, in sofar as transmural
segments worsen prognosis are unlikely to improve after revascularization.
(Zhang et al., 2005).

Radial S and SR responses to dobutamine infusion were compared in a

study of closed-chest pigs with chronic non transmural and transmural

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infarctions. Before infarction, dobutamine produced a linear increase in SR and

a biphasic (increase with low dose, decrease w i t h h i g h d o s e ) S response. In
n o n t r a n s mu r a l infarcts, baseline SR and S were reduced compared with
control; during dobutamine infusion, S did not change and the SR response
became biphasic. In transmural infarctions, both SR and S were considerably
reduced and failed to respond to dobutamine. Post systolic deformation occurred
in both non- transmural and transmural infarctions (although markedly so in the
latter). (Weidemann et al., 2003).

The ability of STE to differentiate the transmural extent of infarction

measured with ceMRI and dobutamine stress echo was tested in 80 patients with
chronic LV ischemic dysfunction. Segments with transmural scar had lower
circumferential strain and SRs than subendocardial (1% to 50% wall thickness)
infarcts and normal myocardium. However, neither radial nor longitudinal
deformation indices discriminated transmural from subendo- cardial scar,
although longitudinal strain and SR (unlike dobutamine stress wall motion
analysis) distinguished subendocardial infarct from normal segments. (Chan et
al., 2006). In contrast, a regional longitudinal strain cutoff value of -4.5%
distinguished nontransmural from transmural infarction with high sensitivity and
specificity (81.2% and 81.6%, respectively), (Roes et al., 2009 ).and a segmental
radial strain cutoff value of 16.5% distinguished nontransmural from transmural
infarctions with reasonable sensitivity and specificity (70.0% and 71.2%,
respectively), as did a circumferential strain cutoff value of -11.1%
(Becker et al.,2006).

In a study of 61 patients with non–ST-elevation myocardial infarction,

LV global longitudinal strain before revascularization (28% surgical, 69%
percutaneous coronary intervention) predicted infarct size (as did wall motion
score index) 9 months after infarction. (Eek et al., 2010).

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Detection of myocardial viability

The assessment of myocardial viability based on wall motion scoring

during low-dose dobutamine infusion is subjective and often difficult. DSI
measures may be useful to identify viable myocardium. Stunned myocardium
displays reduced systolic SRs that improve with dobutamine infusion or recovery.
(Jamal et al., 2001)

The incremental value of strain rate imaging (SRI) parameters over low-
dose dobutamine wall motion scoring for predicting functional recovery 9 months
after revascularization was studied in 55 patients with a previous myocardial
infarction. Abnormal segments that recovered function (146 of 369 segments)
had lower wall motion score and strain and SRs (and SRI increments), with
similar sensitivity and specificity for predicting functional recovery; however, the
combination of wall motion score and SRI parameters increased the sensitivity
for prediction of functional recovery over wall motion scoring alone without a
change in specificity. (Hanekom et al., 2005)

In contrast, post systolic shortening may better represent scarring than

viability. The prevalence of color Doppler SRI postsystolic shortening was
increased in transmural versus nontransmural infarcted segments as determined
from late-enhancement gadolinium MRI (96% versus 50%) and occurred equally
in nontransmurally infarcted segments with or without contractile reserve. (Lim
et al., 2008)

Global LV strain (averaged peak systolic strain using semi-automated

software) in 147 patients with an acute myocardial infarction was correlated with
a viability index derived from single-photon emission-computed tomography (r
= 0.79) and predicted an improvement in ejection fraction 1 year after the index
infarction (sensitivity and specificity for improved ejection fraction ≥ 5% of 86%

Review of literature

and 74%, respectively) using a global LV strain cutoff of -13.7%.( Mollema et

al., 2010)


All speckle-tracking measurements require more capability in image

acquisition and, to obtain correct endocardial border delineation, are contingent
on the presence of adequate echocardiographic views. Furthermore, considering
the close dependence of speckle-tracking echocardiography and single-cardiac-
cycle myocardial deformation analysis, it is not possible to even conduct strain
measurements in patients with non-sinus rhythms. An additional limitation of the
technique is that results depend critically on the machine with which the analyses
are performed (Hurlburt et al., 2007).