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Review Article

Pathophysiology, Etiology, and Recent Advancement in the

Treatment of Congenital Heart Disease
Jyoti Upadhyay, Nidhi Tiwari, Mahendra Rana, Amita Rana, Sumit Durgapal, Satpal Singh Bisht1
Department of Pharmaceutical Sciences, Campus Bhimtal, Kumaun University, 1Department of Zoology, D.S.B. Campus, Kumaun University,
Nainital, Uttarakhand, India

Abstract
The most common birth anomaly occurring in infants is the congenital heart disease (CHD). It is the important cause of mortality and morbidity
among children. The aim of this review is to conduct searches for peer‑reviewed research papers published since 1980, with keywords “congenital
heart defects,” “incidences,” “pathophysiology,” and “congenital anomalies.” Recent advances in the treatment of CHD have allowed many
children to survive, causing a growing population of adults with the congenital heart defect. Lesser information exists regarding survival,
prevalence, comorbidities, and late outcomes in this emerging group and several barriers hampers research in congenital heart defect. Some
investigating research of congenital heart defect offers good opportunity in understanding and identifying high‑risk population. This review
provides an overview of the etiology, prevalence, pathophysiology, and advances in the treatment of congenital heart defect. Future research
is needed to understand congenital heart defects, by the health‑care providers and families, who are taking care of these patients. Experimental
and epidemiological studies will provide us important information related to the physiology of congenital heart defects and identifying the
etiological hypothesis behind it.

Keywords: Atrial septal defect, congenital heart defects, patent ductus arteriosus, pulmonary stenosis, tetralogy of Fallot, ventricular septal
defect

Introduction the diagnosis and treatment, the incidences of congenital

heart defects from various studies differ from about 4/1000
Congenital anomalies occur in developing fetus. Congenital
to 50/1000 live births.[4‑6] The congenital heart defects can
heart disease  (CHD) is major congenital anomalies, which
be life‑threatening during early childhood, and infants born
consists of heart defects present from the birth.[1] CHD among
with this disorder are at much higher risk (∼12) of mortality
all birth defects is the main cause of death in infancy. It is the
especially in the 1st year of life.[11] Newborns with congenital
structural abnormality of heart or great vessels, detected either
heart disorders are symptomatic and soon identified after
at the time of birth or later in life.[2] Globally, CHD constitutes
birth and some cases of CHD remains undiagnosed until or
the major cause of mortality among children, especially in
unless the disease progresses to a severe stage. The severity
developing countries.[3,4] It also accounts for more than 20%
and type of diseases depend on the signs and symptoms. High
of infant’s death prenatally.[5,6] The prevalence rate of CHD is
morbidity and mortality rate is associated with critical cardiac
estimated to be 8/1000 live births.[7] The classification of CHD
lesions in infants and the risk increases as diagnosis and
is of great complexity, generally classified as moderate, severe,
treatment gets delayed. Therefore, the screening process is very
and simple CHD.[8] The estimated prevalence of moderate and
severe CHD is more consistently assessed on 1.5/1000 live
births in each group.[9] The detection of cardiac defects by Address for correspondence: Dr. Jyoti Upadhyay,
prenatal ultrasound and subsequent termination of pregnancy Department of Pharmaceutical Sciences, Kumaun University,
Campus Bhimtal, Nainital, Uttarakhand, India.
further affects the prevalence rate of CHD. Previous studies E‑mail: jyotsna_pharma07@yahoo.co.in
showed approximately 57-85% of severe lesions are detected
before the end of pregnancy.[10] Despite recent advances in
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DOI: How to cite this article: Upadhyay J, Tiwari N, Rana M, Rana A,

10.4103/JICC.JICC_11_19 Durgapal S, Bisht SS. Pathophysiology, etiology, and recent advancement in
the treatment of congenital heart disease. J Indian coll cardiol 2019;9:67-77.

© 2019 Journal of Indian College of Cardiology | Published by Wolters Kluwer - Medknow 67

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Upadhyay, et al.: Congenital heart defects
important tool in diagnosing CHD. In developing countries,
the echocardiographic screening may be difficult due to lack of
availability of sonographers and echocardiographic machines.
As a result, CHD in patients can be determined by physical
examinations and clinical presentations such as cardiac
arrhythmia, murmur, cyanosis, chest pain, and palpitation.[12]
Thousands of children die each year because of CHD, and
millions more who survived are in urgent need of treatment.[13]
There is an urgent need of reducing the prevalence of this
disease by knowing the real cause and developing prevention
strategies and effective management.
Types of congenital heart defects
Some studies reports the birth prevalence of eight most common
congenital heart defects subtypes, i.e.  (a) ventricular septal
defect (VSD), (b) atrial septal defect (ASD), (c) pulmonary
stenosis (PS), (d) patent ductus arteriosus (PDA), (e) tetralogy
of Fallot,  (f) coarctation  (Coarc),  (g) transposition of great
arteries (TGA), and (h) aortic stenosis (AoS) [Table 1].[14]
Prevalence
The prevalence generally shows the probability of a person
having a disease in a given population during a given time.
It represents the disease incidences in a given population
at a given time.[12] The birth prevalence of CHD increased
substantially from 0.6/1000 live births between the year 1930
and 1934; to 9.1/1000 live births after 1995. This increase
was S‑shaped overtime initially increase from 1930 to 1960,
then by stabilization around 5.3/1000 live births from 1961
to 1975, then further increase in the year 1970, till 1995, and
then stabilization in the last 15 years, around 9.1/1000 live
births. The prevalence of CHD according to geographical
location was found significantly different. The birth prevalence
of total CHD was reported highest in Asia, i.e.,  9.3/1000
lives births; and lowest in Africa, i.e.,  1.9/1000 live births.
The second highest birth prevalence of CHD was found in
Europe, i.e., 8.2/1000 live births. The high‑income countries
have the highest prevalence of CHD (8.0/1000 live births) as
compared to low‑income countries.[15] Globally, the prevalence
of CHD ranges from 3.7 to 17.5/1000 live births accounting
30%–45% of all the birth defects. There are also some reported
cases of the adult prevalence of CHD that can estimate the
requirement of adult cardiological services. It is very difficult
to diagnose the cases of CHD in adults. Some CHD patients
have recovered spontaneously, the diagnosed cases of adults
with CHD continue to rise, and now, it is higher than diagnosed
pediatric CHD cases.[12]
Etiology
In vertebrates, the development of heart begins at embryonic
day 15 which comprises of an organized series of morphological
and molecular events including the following five primary
steps.[16,17]
• Precardiac cells migration at the myocardial plate from
the cardiac crescents assembly and primitive streak
68 Journal of Indian College of Cardiology  ¦  Volume 9  ¦  Issue 2  ¦  April-June 2019
Table 1: Type of congenital heart defects[14]
Type Defect
VSD This defect occurs in the septum between the ventricles. It is the
commonest type of heart defect. Generally, the left part of heart
pumps blood to the body and right part pumps blood only to the
lungs. In case of VSD, blood gets transferred from the LV to the
RV through a hole and gets out into the lung arteries. If this defect
is large extra blood gets come out into the lung arteries making
lungs and heart work harder and causes congestion of lungs
ASD This defect occurs in the septum between the two upper
chambers of the heart (atria). This opening is normal in the fetus
that allows blood to pass away from the lungs. This opening is
no longer required after birth; it becomes very small or usually
closes after several weeks. In some cases, this opening is larger
than normal and does not gets closed causing this defect. The
reason is not known
PS In this defect narrowing of pulmonary valves occur that causes
the harder pumping of RV to get blood pass the blockage, as
blood flow from RVs to the lungs through pulmonary valves.
The pressure is much higher in the RV and over some time it can
damage the overworked cardiac muscles
PDA Ductus arteriosus is the fetal artery which connects the aorta and
the PA. In this defect, the fetal artery remains open after birth
TOF It has four main characteristics, i.e., VSD, PS, aorta lies
directly over the VSD, and RV develops thickened muscles. It
is the most common type of defect generally occurs in Down
syndrome children
Coarc This defect generally occurs when aorta, i.e., the main artery
carrying blood from heart to the body is narrowed or constricted
TGA In this defect, the aorta and the PA are reversed. The aorta
receives the de‑oxygenated blood from the RV and it carried
the blood back to the body without receiving more oxygen.
Similarly, PA receives oxygenated blood from the LV and carries
it back to the lungs
AS An aortic valve opens when blood flows from LV to the main
aorta. This defect occurs when obstruction or narrowing of the
aortic valve makes the pumping of the LV harder to past the
blockage. Regurgitation occurs when blood which was pumped
through the valve leaks backward into the chamber
VSD: Ventricular septal defect, AS: Aortic stenosis, TGA: Transposition
of great arteries, TOF: Tetralogy of Fallot, PDA: Patent ductus arteriosus,
PS: Pulmonary stenosis, ASD: Atrial septal defect, Coarc: Coarctation,
LV: Left ventricle, RV: Right ventricle, PA: Pulmonary artery
• Formation of the primitive heart tube by cardiac crescents
coalescence
• Alignment of cardiac chambers
• Heart chamber formation and septation
• Cardiac conduction system development and formation
of the coronary vasculature.
Any alteration in the developmental processes of embryonic
structure or failure of structure to develop during an early
embryonic stage leads to congenital heart defects. It is an
anatomical defect influencing the structure and function of
the organ system. The etiology behind the abnormal heart
development in babies remains unclear. Although substantial
knowledge behind the cause of CHD has been made during
the last decade. Genetic disorders may be associated with
the congenital malformations, and also some malformations
are consequences of environmental teratogens or diet. An
alteration in the migration of the cells leads to disorder in the
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Upadhyay, et al.: Congenital heart defects

cardiac development. These findings together emphasize the therapeutic treatment by the health‑care professionals as well
multifactorial and complex etiology of the CHD. Additional as health officers.[12] Table 2 represents the genetic disorders
research is needed to determine the etiology of CHD which will associated with the etiology of CHD and Table 3 shows the
pave the way in understanding the preventive measures and maternal factors causing CHD.

Table 2: Genetic disorders associated with the etiology of congenital heart disease
Serial number Genetic disorders Description References
A Chromosomal About 0.3%‑2% of all live births have chromosomal defects such as aneuploidy and trisomy 21, [12,18]
defect 18, 13
Defects in chromosomes X, 3, 4, 5, 7, 8, 9, 10, 11, 17, and 22
B Single gene A mutation in NKX2‑5 gene causes loss of heart formation in embryo causes atrioventricular [19‑21]
disorder conduction defect, VSD, ASD, or TOF
Microdeletion TBX1 gene causes DiGeorge syndrome, TOF, trunctus arteriosus [22‑24]
TBX5 expressed in embryo heart, mutation causes Holt‑Oram syndrome, causes CHD, i.e., [25‑29]
VSD, ASD, ad TOF
GATA4, it interacts with TBX5 and NKX2‑5 and regulates cardiac gene expressions. These [30,31]
three proteins are required for proper septation of heart. Mutations of these genes cause cardiac
septal defects such as VSD, ASD
TFAP2B, AP‑2 beta gene functions in the differentiation of neural crest cell derivatives causing [32‑35]
embryogenesis of ductus arteriosus. Mutation in this gene causes PDA, facial dysmorphism,
and hand anomalies
ZFPM2/FOG2, modulates the activity of co‑factors with GATA family, regulates [36‑38]
hematopoiesis, and cardiogenesis in mammals. Mutation of this gene results in cardiac
malformations such as TOF, VSD, and ASD
ZIC3, gene encodes member of ZIC family, mutation in this gene which is located in [39‑41]
Xq24‑q27.1 chromosome causes ASD, TGA.
Cell signaling genes
JAG1, Jagged 1 ligand of receptor NOTCH, JAG1 shows high level of expression during heart [42‑45]
and blood vessels developing time, plays an important role in patterning of right heart and
pulmonary vasculature. Mutation causes TOF
NOTCH1, NOTCH2, the NOTCH family receptors interaction of NOTCH gene with Delta [46‑48]
and Jagged ligands performs many cell regulatory functions. Mutation in NOTCH 1 causes
autosomal aortic valve defect and bicuspid aortic valve
PTPN11, encodes protein which is a member of PTP family. Regulates variety of cellular [49‑51]
processes, mutation of this gene causes Noonan syndrome located on 12q24 chromosomes as a
result congenital malformations such as ASD, VSD, and cardiomyopathy occurs
CFC1, cryptic family 1 encodes EGF‑Cripto, Frl‑1, and Cryptic family. Plays a key role in [52‑54]
intercellular signaling pathways during embryogenesis of vertebrates. Mutation of this gene
causes autosomal visceral heterotaxy with complex CHD like TGA, VSD, ASD and systemic
vein anomalies
SOS1, encodes a protein, guanine nucleotide exchange factor for RAS proteins, plays [55]
role in signal transduction pathways. Mutation causes gingival fibromatosis and Noonan
syndrome
PROSIT 240/THRAP2, encodes proteins which regulates embryonic development. Mutation [56]
causes TGA
CRELD1 cysteine rich with EGF like domain, matrix cellular proteins. Mutation causes cardiac [57‑59]
malformations like atrio‑VSD
ECV, ECV2 encodes protein containing leucine zipper and transmembrane domain. Mutation [60‑62]
causes atrio‑VSD
TGFBR1 and TGFBR2 encodes member of Ser/Thr protein kinase family, mutation causes [63,64]
Marfan syndrome, Loeys‑Dietz Aortic Aneurysm syndrome
Extracellular matrix protein genes
ELN elastin, encodes protein of elastin fibers, mutation and deletion results in Williams‑Burren [65‑67]
syndrome, causes nonsyndromic supravalvular AS
FBN1 Fibrillin 1, encodes fibrillin family member, mutation causes Marfan syndrome. [68‑70]
Congenital malformations symptoms involve mitral valve prolapsed and regurgitation in
infants
C Polygenic/ It depends on the concept of threshold limit, i.e., limit of the combined genetic and [12]
multifactorial environmental factors. If limit is reached malformation occur. Below this limit, malformation
inheritance is absent
CHD: Congenital heart disease, PTP: Protein tyrosine phosphatase, VSD: Ventricular septal defect, AS: Aortic stenosis, TGA: Transposition of great arteries, TOF:
Tetralogy of Fallot, ASD: Atrial septal defect, PDA: Patent ductus arteriosus, EGF: Epidermal growth factors, RAS: Reticular activating system, ELN: Elastin-gene

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Table 3: Maternal and environmental factors associated with the etiology of congenital heart disease
Serial number Factors Description References
Maternal factors
A Maternal Health Maternal Diabetes Mellitus, causes TOF, heterotaxy, TGA, ASD, VSD pulmonary [71‑73]
and Medical venous return and outflow obstruction
diseases Possible mechanism: Embryonic hyperglycemia may cause metabolic disturbances of
inositol, arachidonic acid, and formation of oxygen‑free radicals causes activation of
apoptotic pathway and mitochondrial damage
Maternal Phenylketonuria causes TOF, PDA, VSD, Coarc. Increased risk of heart [74,75]
defects due to increased blood levels of phenylalanine and phenyl Pyruvic acid
Maternal connective tissue disease (like systemic lupus erythematosus), causes [76,77]
congenital atrioventricular heart block in offspring. In this case, maternal anti‑Ro and
La autoantibodies transmitted from mother to the fetus causes inflammatory response
in fetus and damages the AV node and cardiac tissue
Maternal rubella causes PDA, PS, ASD. The heart is targeted causes direct damage to [78,79]
the myocardium affecting heart septa and atrium
Maternal febrile illness causes obstructive heart defect in the right side and some left [80‑83]
obstructive heart defect, also causes VSD. Hyperthermia causes biological effects on
apoptosis pathway development. Altered apoptosis involved in cardiac morphogenesis
Maternal stress, causes conotruncal heart defects, and neural tube defects [84,85]
Maternal obesity, causes VSD, ASD, right ventricular outflow obstruction, and [86‑89]
conotruncal defects. Obesity associated with unrecognized diabetes
B Maternal drug Isotretinoin causes VSD and ASD [90,91]
and medical use Trimethadione causes TOF, TGA [92]
Phenytoin causes Coarc, AS, PS, and PDA [93]
Valproic acid causes outflow obstruction, VSD, and TOF [94,95]
Tricyclic antidepressants causes VSD [96]
C Maternal drug Alcohol causes VSD [97]
abuse Cigarette smoking causes VSD, ASD, and TOF [98]
Cocaine and marijuana causes VSD [12,99]
Environmental factors
A Environmental Organic solvents cause TGA, TOF, PS [12,99,100]
factors Pesticides cause TGA, VSD [12,85]
Air pollution [101,102]
Carbon monoxide causes VSD, PS, TOF
Nitrous oxide causes TOF
PDA: Patent ductus arteriosus, TGA: Transposition of great arteries, TOF: Tetralogy of Fallot, ASD: Atrial septal defect, VSD: Ventricular septal defect,
PS: Pulmonary stenosis, AS: Aortic stenosis

Pathophysiology
Shunting lesions
CHD is identified as intracardiac shunting lesions. In a
normal cardiac physiology, there is complete separation of
deoxygenated and oxygenated blood. These two circulations
run in parallel, maintaining one‑to‑one volume relationship
on the pulmonary and systemic region of circulation, each
feeding the other. The deoxygenated blood returns to the right
atrium (RA) and pumped to the lungs as pulmonary blood flow.
After oxygenation, the blood returns from the pulmonary veins
to the left atrium (LA) and is pumped to the aorta, i.e., cardiac
output. “Shunt” refers to the abnormality in the flow of blood
from one side of the circulation to the other side. In left‑to‑right
shunt, the pulmonary venous blood  (oxygenated) return
directly to the lungs, instead of being pumped to the body.
Similarly, in the right‑to‑left shunt, the systemic venous blood
return (deoxygenated) bypass the lungs and return directly to
the body without becoming oxygenated. Circulation in each
shunt become less efficient and increases blood demand on the
ventricles. In most of the cases, the severity of the symptoms
determines the volume of shunted blood.[103]
Left‑to‑right shunting
The normal aerobic respiration is maintained at cellular level,
delivery of oxygen is performed in sufficient quantities to
meet the metabolic demands of the body.[104] In left‑to‑right
shunt, the cardiac output volume gets reduced by the shunted
volume amount. This causes a reduction in the delivery of
oxygen to tissues.[103]
Right‑to‑left shunting
In normal cardiac physiology, the hemoglobin, lung function,
arterial blood oxygen content varies only to a certain
extent when pulmonary oxygenation of alveoli changes.
In right‑to‑left shunt, the systemic venous blood which is
deoxygenated returns directly to the systemic circulation of the
artery. This causes fall in the oxygen content of the systemic
arterial blood in proportion with the systemic venous blood

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volume mixes with the normal venous return from the lungs.
This reduction in the oxygen content even with the normal
cardiac output, the delivery of oxygen to tissue falls and limits
the muscle capacity.[104]
Quantifying shunt volumes
The ratio of the total pulmonary blood flow to the total systemic
blood flow is an important tool in quantifying the net shunt.
The ratio 1:1 is normal and indicates no shunting situation. If
the ratio is >1:1, it indicates that the pulmonary flow is greater
than the systemic flow and it is called as net left‑to‑right shunt.
If this ratio is lesser than 1:1, it indicates net right‑to‑left
shunt. Both such shunting (bidirectional) may be present in
the same patient. When the magnitude of left‑to‑right shunt
equals right‑to‑left shunt, it is possible to have 1:1 ratio of total
pulmonary volume and total systemic volume.[103]
Ventricular septal defect
This defect is based on the complex development of the
ventricular septum during embryogenesis, involving the
fusion of distinct septal components. The site of fusion of all
components resides behind the tricuspid valve septal leaflet
and below the valve of the aorta of the left ventricle  (LV)
outflow tract. The VSD of endocardial cushion is associated
with insufficiency of atrioventricular valve (AV) valve, aortic
insufficiency associated outflow defects, and complicated
physiological lesions. The pathophysiology of VSD and ASD
differs depending on the differences in the hemodynamic effects
of VSD and ASD. In VSD, the ventricular blood flow has two
systolic pathways, i.e.,  usual outflow tract of ventricle and
blood flow through the VSD to the outflow tract of the ventricle.
The volume and direction of systolic blood flow across the
VSD is determined by the ohm’s law, i.e., by comparing the
resistance of each pathway. For example, In patients having
low resistance from the LV to the pulmonary artery compared
with the resistance of low to the systemic circulation, leading
to large left to right systolic flow across the defect. In case
if the VSD is very small, then there will be high resistance at
the defect limiting the shunt (left to right) with low pulmonary
resistance. If resistance of pulmonary circulation is higher than
the resistance of systemic circulation, there will be right‑to‑left
shunt not depending on the defect size.[105] Comparing the blood
volume crossing a VSD in systole, the blood flow in diastole is
very low. The flow across the VSD in a diastole is much similar
to that of flow across the ASD in systole.[106,107]
Atrial septal defect
The atrial septal formation consists of the growth and partial
reabsorption of tissue membrane septum primum and septum
secundum, their fusion causes the formation of membranes
forming endocardial cushions and the fetal sinus venosus
reabsorbed into the structure and forms RA. During the embryonic
development, if any error occurs in this developmental process
will causes a defect in the wall separating the two atria called as
ASD. The ASD includes ostium primum defect, i.e., deficiency
of endocardial cushion tissue and ostium secundum defect,
i.e.,  reabsorption of septum primum in excess and the sinus
Journal of Indian College of Cardiology  ¦  Volume 9  ¦  Issue 2  ¦  April-June 2019
venous defect, i.e., error in introduction of sinus venous chamber
into RA.[106] In the pathophysiology of ASD is multifactorial and
complex and the flow across the defects occur in both the systole
and diastole. In isometric strain, transient right‑to‑left shunt
occurs are common. During diastole, the bulk flow of the shunt
occurs. During this phase, the blood flow occurs in each atrium
through two alternate pathways, i.e., one following the normal
pathway through AV to the ventricle passes through the ASD
and fills the opposite ventricle. The difference in the compliance
and capacity of the two ventricles determines the flow across the
ASD. In normal patient, the pumping of the LV to the systemic
circulation possess larger workload than the right ventricle (RV),
pumping toward the lungs. Hypertrophy of the LV occurs,
showing its work level whereas the RV myocardium remains
thin. Thick‑walled LV contracts to accept additional volume
less readily when compared with thinner RV. This result in the
favoring of left‑to‑right shunt by difference in compliance of
chambers in ASD patients because blood fills more compliantly
in the RV from the LA easily. Congenital obstruction in the
pulmonary arteries or veins resulting from parenchymal disease
or primary hypertension of lungs causes hypertrophy of RV and
increases RV after load. Left‑to‑right shunting is minimal in ASD,
showing little overall difference between the two ventricles.[108,109]
Pulmonary stenosis
PS can be of two types, i.e.,  valvular and subvalvular or
supravalvular. The most common form is valvular stenosis.
In valvular PS, there is a narrow central opening (dome like)
in the pulmonary valve, rudimentary raphes can be observed.
Dysplastic valve with myxomatous thickened leaflets is present
less often. PS can also be associated with other congenital heart
defects such as ASD and TGA. The subvalvular PS, also called
as infundibular or subinfundibular PS. Infundibular PS can be
seen as a part of teratology of Fallot, while isolated infundibular
PS is rare. Hypertrophy of secondary infundibular PS occurs
because of circular muscular structure of the right ventricular
outflow tract. Obstruction in RV outflow occurs because due
to RV hypertrophy. Subinfundibular PS also called double
chambered RV RV cavity has two parts low pressure outlet part
and high pressure inlet part. Local hypertrophy may develop
because of high velocity jet of a small VSD which is directed
at the opposite wall of RV. The supravalvular PS associated
with other cardiac disorders or extracardiac abnormality. It
can be isolated and described in syndromes such as Noonan,
Williams–Beuren, and Alagille syndrome. This stenosis located
in the pulmonary trunk, pulmonary branches, or bifurcation.[110]
Patent ductus arteriosus
During pregnancy, in fetus the ductus allows blood flow
from RV to bypass the lungs  (nonfunctional) and through
the descending aorta, return to the placenta. After 72  h of
birth, the ductus gets closed in maximum newborns by the
arteriolar smooth muscle contraction, mechanism stimulated
by increase in level of the postnatal systemic oxygen.[111]
PDA is a condition in which the lumen of the ductus is not
closed and there are arterial connections between pulmonary
and systemic circulation. In VSD physiology, the PDA size is
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Upadhyay, et al.: Congenital heart defects
resistor in the circuit, and determines the volume of flow. With
large PDA in VSD patients, the left ventricular end‑diastolic
volumes  (preload) increases and allow the stroke volume
supply to both normal cardiac output and left‑to‑right shunt.
The pressure in the LA rises and congestion of pulmonary veins
occur. With large defect of PDA, the diastolic flow “runoff”
results in impairment of coronary and splanchnic perfusion.[107]
Tetralogy of Fallot
It is a complex heart defect having following four
components: (a) PS, i.e., the valve between the RV and lungs
become narrow; (b) hypertrophy of RV, i.e., lower chamber of
the heart become enlarged; (c) VSD; and (d) overriding aorta,
i.e., enlarged aorta located over a VSD. The combination of
all these defects causes poor oxygen blood supply delivery to
the body, which causes cyanosis in babies (due to poor oxygen
supply babies have blue skin color).
Coarctation
There are two theories known in the causation of Coarc
(a) ductus tissue theory, i.e.,  constriction of aberrant ductal
tissue postnatally, (b) hemodynamic theory, i.e., alterations in
the flow of blood (intrauterine) through aortic arch. Deformity
occurs in ductus arteriosus with descending aorta called aortic
isthmus; Coarc is characterized by narrowing of the left
subclavian artery (distal) or proximal aorta.
• Localized stenosis: In the posterior wall of the aorta, a
shelf‑like infolding occurs into the aortic lumen, distal
or proximal to the ductus arteriosus
• Long hypoplastic segment: hypoplasia, i.e., tubular occur
in the aortic arch or the aorta which is distal to the left
subclavian artery origin and ductus area[112]
• Simple Coarc is the Coarc occur in the absence of
lesions[113]
• Complex Coarc involves cardiac and extracardiac lesions.
Bicuspid aortic valve: 50%–60% suffer from this. VSD
and ASD occur along with Coarc
• Coarc and complex CHD includes transposition of arteries,
atrioventricular defect, hypoplastic left heart syndrome.
Coarc can also be present with other types of left heart
obstruction, i.e., mitral stenosis, AoS. Noncardiac anomaly,
i.e., intracranial aneurysm occur in 10% of patients.[113]
In Coarc left ventricular hypertension  (elevated systolic
pressure) occur which is caused by increased resistance to
LV outflow due to narrowing of aorta. The blood pressure of
lower extremity is lower than the upper body blood pressure.
Upper extremity hypertension occur.[113]
Transposition of great arteries
It is the most common cyanotic lesion of the heart present
in neonates by birth. Ventriculoarterial discordance is the
hallmark of TGA in which the pulmonary artery (PA) arises
from morphologic left LV and aorta arises from morphologic
RV. The functioning of systemic and pulmonary circulations
occurs in parallel rather than in series. The pulmonary venous
blood, i.e. oxygenated returns to the LA and LV but again it is
recirculated through the abnormal connection of the PA to the
72 Journal of Indian College of Cardiology  ¦  Volume 9  ¦  Issue 2  ¦  April-June 2019
LV, to the pulmonary vascular bed. The systemic venous blood,
i.e. deoxygenated returns to the RA and RV where it is pumped
to the systemic circulation subsequently by passing through the
lungs effectively. This parallel arrangement causes deficiency
in oxygen supply to the tissues and increase in workload of
the RV and LV. There are three common anatomic regions in
TGA of mixing deoxygenated and oxygenated blood; they are
patent foramen ovale or ASD and VSD, and PDA.[114]
Aortic stenosis
The progression of aortic valve occurs from sclerosis to
stenosis, the LV combat chronic resistance to ejection of blood
during systole. Higher systolic pressure generated by ventricle
than the pressure opposite produced by calcified aortic valve.
Increased resistance during systolic ejection is known as
afterload. The left ventricular myocardial wall gets thickened
to compensate raised afterload, the LV diameter maintains
normal size. LV wall thickening is also called as concentric
hypertrophies, which strengthens left ventricular systolic
contraction and maintain proper stroke volume and cardiac
output. The detrimental effect of high LV afterload includes
decrease in the myocardial elasticity of LV and coronary blood
flow and increases oxygen consumption, myocardial workload,
and mortality. LV hypertrophy increases pressure during
diastole and causing delay of the left ventricular untwisting
as a result a forced atrial contraction is required for sufficient
filling of the LV to maintain stroke volume and cardiac output.
Late symptoms of LV hypertrophy include smaller LV chamber
size decreases preload and aggravate systolic dysfunction.[115]
Diagnosis
Echocardiography
Echocardiography of fetuses is an important tool in
the diagnosis of CHD, which provide information and
improvement in counseling of the parents, guide the patient
about timing and location of delivery. It allows appropriate
planning and consultation by the neonatologists and
cardiologists. It also provides accurate diagnosis of fetal
arrhythmias and its management. Transesophageal and
transthoracic echocardiographies have improved its imaging
quality. New techniques such as tissue strain analysis and
Doppler imaging have been introduced.[116]
Cardiovascular magnetic resonance imaging
For investigating the function and anatomy of adult CHD,
cardiovascular magnetic resonance imaging  (MRI) is an
alternative, frequent, and complementary imaging modality.
It has several advantages over other techniques as it does not
require contrast reagent  (iodinated) or ionizing radiations.
Advances in its software and hardware (coil design, new pulse
sequences, and faster gradients) provide accurate assessment
of anatomy, function, and physiology.[116]
Other imaging modalities
Computed tomography is another useful tool in assessing the
cardiac and extra cardiac structure such as intracardiac anatomy,
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Upadhyay, et al.: Congenital heart defects
aortic dimensions, myocardial function, and coronary artery
anatomy. Position emission tomography is a research tool in
metabolic imaging, pathological and physiological processes.
Fused hybrid coronary computed tomography angiography and
positron emission tomography myocardial perfusion imaging
provide additional benefit in the management of patients with
anomalies of coronary artery and myocardial perfusions.[116]
Biomarkers
Brain natriuretic peptide  (BNP), secreted by cardiac cells
in response to ventricular wall pressure. Its vasodilatory
and diuretic effect determines the effect of heart failure.
BNP values are highly elevated in adults with complex CHD.
Troponins are markers of myocardial damage; also identify
myocardial infarction.[116]
Treatment
Pharmacological treatment
The late complications of CHD are heart failure, arrhythmias,
pulmonary arterial hypertension, and endocarditis. Older CHD
patients may develop acquired cardiovascular complications
such as hypertension, diabetes, and hyperlipidemia.
The treatment of CHD with drugs is mainly based on
pathophysiological conditions or acquired heart disease. For
example, the treatment of systemic right ventricular failure
with digoxin recommended by the European Society of
Cardiology 2010 guideline.[117] Specific groups of population
have been studied like study of beta blocking agents and
angiotensin‑converting enzyme or angiotensin receptors
blockers in patients having systemic RV. For the treatment
of pulmonary arterial hypertension, several trials have been
done to evaluate the hemodynamic and clinical parameters,
biomarkers, and lifestyle modifications. The drugs which
are used in the treatment of pulmonary arterial hypertension
are bosentan, sildenafil, prostacyclin, and riocugat. Other
drugs used in CHD are rosuvastatin in the AoS progression,
ramipril in RV function in Fallot, and losartan in Marfan
syndrome. Additional trials and research is needed to develop
evidence‑based medicine as increased cost of the drugs, lack of
funding, and increasing administrative burden have a negative
impact on this evolution.[116]
Catheter‑based treatment
Surgery is the milestone treatment of CHD patients.
Developments of catheter techniques such as percutaneous
interventions have replaced the surgery. For example
preferred treatment of ASD is percutaneous closure. In
1967, transcatheter closure of PDA was introduced. For the
treatment of aortopulmonary collaterals, venous collaterals,
and pulmonary arteriovenous fistulas, the transcatheter
embolization is the preferred treatment replaces surgery.[118]
Surgery
Previously, patients with dilated aortic root were operated
with total root replacement, but this type of surgery has
bleeding and thromboembolism risks. Valve sparing root
Journal of Indian College of Cardiology  ¦  Volume 9  ¦  Issue 2  ¦  April-June 2019
replacement reported excellent long and short term results. It
offers freedom from risks of bleeding and thromboembolism.
Nowadays, a more advanced approach has been used, i.e., a
personalized aortic root support (external) with a mesh sleeve
which reduces the formation of aneurysm in these patients.
The word total correction or repaired in surgery appears to be
a misconception as many late complications may occur which
require reoperation.[116]
Recent advancement in the treatment of congenital heart
disease
There has been major advancement in the treatment of pediatric
cardiac disorders. Interventional cardiology and catheterization
have evolved as major technological achievement, during the
last 10 years. Cardiac imaging modalities such as intracardiac
echocardiography, transesophageal echocardiography (TEE),
real‑time 3‑dimensional  (3D), MRI, Echo Navigator and
Vessel Navigator systems, and rotational angiography
with holography, 3D roadmap, 3D printing. Due to such
technological advancement, treatment of the many types of
CHDs is possible in cardiac catheter laboratory. The treatment
of lesions involving PS, acute postoperative stenosis, and
obstructive surgical conduits can now be managed with a
greater success rate as they are resistant to interventional
therapies.[119]
Hybrid procedures for the treatment of congenital heart
disease
This procedure involves cooperation between interventions and
surgeons to get better outcome of their individual approaches
and minimize invasiveness.[120]
Hybrid procedure for hypoplastic left heart syndrome
In 1993, first hybrid approach including stenting of the arterial
duct percutaneously and surgical banding of the branch PA
stenosis, for hypoplastic left heart syndrome was reported.[120]
Gissen group modified this method[121] and achieves reduction
in pressure of distal PA (<50%) of the systemic pressure and in
systemic oxygen saturation (80%),[122] which shows the cases of
survival 82% through Stage II palliation. Columbus group[123]
further modified this method by performing PA stenting and
banding of the arterial duct that showed the cases of 83%
survival through Stage III palliation.[124]
Hybrid procedure for ventricular septal defect closure
For the closure of muscular and membranous VSDs in infants
the perventricular approach was used. The main advantage
of this approach was direct access to the heart after surgical
sternotomy for direct placement of closure device across
VSDs. This procedure was conducted under the guidance of
TEE, without the requirement for cardiopulmonary bypass or
radiation.[125,126] Intraoperative stentings,[127] hybrid pulmonic
valve replacement,[128] and hybrid fontan completion[129] are
the other hybrid procedures used.
Regenerative therapy
Stem cell therapy has been extensively studied in the
ischemic heart disease and cardiomyopathy dilation, both by
73
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Upadhyay, et al.: Congenital heart defects
experimental as well as clinical studies. Stem cell therapy is
still at an early stage of development. A recent study shows
that umbilical cord blood mononuclear cell transplantation
preserves the functions of RVs, especially diastolic function
in a model of the right ventricular volume overload.[130] There
are two major mechanisms to be considered in stem cell
therapy, i.e., cardiomyocytes substitution and paracrine effects.
Recently, paracrine effects are the most appropriate mechanism
of action of stem cell therapy. Paracrine effects activation may
leads to decreased apoptosis, increased angiogenesis, improved
ventricular remodeling, and endogenous cardiac progenitor cell
activation. Human embryonic stem cells, cardiac stem cells,
and induced pluripotent stem cells are the cell types which are
currently studied. Stem cell therapy is an important research
topic that will also involve active investigation in CHD.[129]
Conclusion
In the past 4–5 decades, the fate of babies with congenital
heart defects has changed dramatically. Babies born with
CHD are symptomatic and identified soon after birth and
also some of the cases remain undiagnosed until the disease
progresses to a severe conditions. Clinical manifestations
determine the severity of the diseases. Owing to advances in
diagnosis and surgical strategies, there are majority of patients
with CHD. Advanced approaches in surgery have been used
but the increase of late complications requires reoperations,
device implantations and percutaneous interventions to
reduce mortality. The landscape of congenital heart defects
is an ongoing evolving research demanding efforts from
all health‑care professionals to give optimal care to these
expanding, chronically ill CHD patients. Apart from the major
advancement in the field of genetics, with regards to diagnosis
that influences prognosis and genetic counseling, the majority
of the etiology of CHD remains incompletely unknown.
Several experimental and epidemiological studies will provide
us important information related to the anatomy and physiology
of CHD, identifying hypothesis related to its etiology.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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