Contents

o 1 Signs and symptoms

o 1.1 Associated symptoms

o 2 Embryology
o 2.1 Changes at birth

o 3 Causes
o 3.1 Genetics

o 3.2 Environmental

o 4 Classification
o 4.1 Hypoplasia

o 4.2 Obstruction defects

o 4.3 Septal defects

o 4.4 Cyanotic defects

o 4.5 Defects

o 5 Treatment
o 6 Ventricular Septal Defect
o Diagnosis
o Pathophysiology
o Signs and Symptoms
o Treatment
o Epidemiology and Etiology
o Case Study
o 7 Tetralogy Of Fallot
o Anatomic Morphology
o Epidemiology and Etiology
o Pathophysiology and Symptoms
o Diagnosis
o Treatment
o Prognosis
o Case Study

Congenital heart
defect
A congenital heart defect (CHD) is a defect in the structure of the heart and great
vessels which is present at birth. Many types of heart defects exist, most of which either
obstruct blood flow in the heart or vessels near it, or cause blood to flow through the
heart in an abnormal pattern. Other defects, such as long QT syndrome, affect
the heart's rhythm. Heart defects are among the most common birth defects and are the
leading cause of birth defect-related deaths. Approximately 9 people in 1000 are born
with a congenital heart defect. Many defects don't need treatment, but some complex
congenital heart defects require medication or surgery.

Signs and symptoms

Signs and symptoms are related to the type and severity of the heart defect. Symptoms
frequently present early in life, but it's possible for some CHDs to go undetected
throughout life. Some children have no signs while others may exhibit shortness of
breath, cyanosis, syncope, heart murmur, under-developing of limbs and muscles, poor
feeding or growth, or respiratory infections. Congenital heart defects cause abnormal
heart structure resulting in production of certain sounds called heart murmur. These can
sometimes be detected by auscultation; however, not all heart murmurs are caused by
congenital heart defects.
Associated symptoms
Congenital heart defects are associated with an increased incidence of some other
symptoms, together being called the VACTERL association:

 V - Vertebral anomalies
 A - Anal atresia
 C - Cardiovascular anomalies
 T - Tracheoesophageal fistula
 E - Esophageal atresia
 R - Renal (Kidney) and/or radial anomalies
 L - Limb defects

Ventricular septal defect (VSD), atrial septal defects, and tetralogy of Fallot are the most
common congenital heart defects seen in the VACTERL association. Less common
defects in the association are truncus arteriosus, and transposition of the great arteries.
Embryology
There is a complex sequence of events that result in a well formed heart at birth and
disruption of any portion may result in a defect. The orderly timing of cell growth, cell
migration, and programmed cell death ("apoptosis") has been studied extensively and
the genes that control the process are being elucidated. Around day 15 of development,
the cells that will become the heart exist in two horseshoe shaped bands of the middle
tissue layer (mesoderm), and some cells migrate from portion of the outer layer
(ectoderm), the neural crest which is the source of a variety of cells found throughout the
body. On day 19 of development, a pair of vascular elements, the "endocardial tubes",
form. The tubes fuse when cells between then undergo programmed death and cells
from the first heart field migrate to the tube, and form a ring of heart cells (myocytes)
around it by day 21. On day 22, the heart begins to beat and by day 24, blood is
circulating.[7]

At day 22, the circulatory system is bilaterally symmetrical with paired vessels on each
side and the heart consisting of a simple tube located in the midline of the body layout.
The portion that will become the atria and will be located closest to the head are the
most distant from the head. From days 23 through 28, the heart tube folds and twists,
with the future ventricles moving left of center (the ultimate location of the heart) and the
atria moving towards the head.

On day 28, areas of tissue in the heart tube begin to expand inwards; after about two
weeks, these expansions, the membranous "septum primum" and the muscular
"endocardial cushions", fuse to form the four heart chambers of the heart. A failure to
fuse properly will result in a defect that may allow blood to leak between chambers. After
this happens, cells which have migrated from the neural crest begin to divide thebulbus
cordis, the main outflow tract is divided in two by the growth a spiraling septum,
becoming the great vessels—the ascending segment of the aorta and the pulmonary
trunk. If the separation is incomplete, the result is a "persistent truncus arteriosis". The
vessels may be reversed ("transposition of the great vessels"). The two halves of the
split tract must migrate into the correct positions over the appropriate ventricles. A failure
may result in some blood flowing into the wrong vessel (e.g. overriding aorta). The four
chambered heart and the great vessels have features required for fetal growth. The
lungs are unexpanded and cannot accommodate the full circulatory volume. Two
structures exist to shunt blood flow away from the lungs. Cells in part of the septum
primum die creating a hole while muscle cells, the "septum secundum", grow along the
right atrial side the septum primum, except for one region, leaving a gap through which
blood can pass from the right artium to the left atrium, the foramen ovale. A small vessel,
the ductus arteriosus allows blood from the pulmonary artery to pass to the aorta.

Changes at birth
The ductus arteriosus stays open because of circulating factors including prostaglandins.
The foramen ovale stays open because of the flow of blood from the right atrium to the
left atrium. As the lungs expand, blood flows easily through the lungs and the
membranous portion of the foramen ovale (the septum primum) flops over the muscular
portion (the septum secundum). If the closure is incomplete, the result is a patent
foramen ovale. The two flaps may fuse, but many adults have a foramen ovale that stays
closed only because of the pressure difference between the atria.

Causes
The cause of congenital heart disease may be either genetic or environmental, but is
usually a combination of both.

Genetics
Most of the known causes of congenital heart disease are sporadic genetic changes,
either focal mutations or deletion or addition of segments of DNA. Major chromosomal
abnormalities such as trisomies 21, 13, and 18 cause about 5-8% of cases of CHD , with
trisomy 21 being the most common genetic cause. The genes regulating the complex
developmental sequence have only been partly elucidated. Some genes are associated
with specific defects. A number of genes have been associated with cardiac
manifestations. Mutations of a heart muscle protein, α-myosin heavy chain (MYH6) are
associated with atrial septal defects. Several proteins that interact with MYH6 are also
associated with cardiac defects. The transcription factor GATA4 forms a complex with
the TBX5 which interacts with MYH6. Another factor, the homeobox (developmental)
gene, NKX2-5 also interacts with MYH6. Mutations of all these proteins are associated
with both atrial and ventricular septal defects; In addition, NKX2-5 is associated with
defects in the electrical conduction of the heart and TBX5 is related to theHolt-Oram
syndrome which includes electrical conduction defects and abnormalities of the upper
limb. Another T-box gene, TBX1, is involved in velo-cardio-facial syndrome DiGeorge
syndrome, the most common deletion which has extensive symptoms including defects
of the cardiac outflow tract including tetralogy of Fallot.
 Examples of gene products and associated features

NKX2-
MYH6 GATA4 TBX5 TBX1
5

14q11.2- 8p23.1-
Locus 5q34 12q24.1 22q11.2
q13 p22

Syndrome Holt-Oram DiGeorge

Atrial septal defects ✔ ✔ ✔ ✔

Ventricular septal
✔ ✔ ✔
defects

Electrical conduction
✔ ✔
abnormalities

Outflow tract
✔
abnormalities

Small or absent thymus

Non-cardiac Upper limb Small or
manifestations abnormalities absent parathyroids
Facial abnormalities

The notch signaling pathway, a regulatory mechanism for cell growth and differentiation,
plays broad roles in several aspects of cardiac development. Notch elements are
involved in determination of the right and left sides of the body plan, so the directional
folding of the heart tube can be impacted. Notch signaling is involved early in the
formation of the endocardial cushions and continues to be active as the develop into the
septa and valves. It is also involved in the development of the vetricular wall and the
connection of the outflow tract to the great vessels. Mutations in the gene for one of the
notch ligands, Jagged1, are identified in the majority of examined cases of arteriohepatic
dysplasia (Alagille syndrome), characterized by defects of the great vessels (pulmonary
artery stenosis), heart (tetralogy of Fallot in 13% of cases), liver, eyes, face, and bones.
Though less than 1% of all cases, where no defects are found in the Jagged1 gene,
defects are found inNotch2 gene. In 10% of cases, no mutation is found in either gene.
For another member of the gene family, mutations in the Notch1 gene are associated
with bicuspid aortic valve, a valve with two leaflets instead of three. Notch1 is also
associated with calcification of the aortic valve, the third most common cause of heart
disease in adults.

Mutation of a cell regulatory mechanism, the Ras/MAPK pathway are responsible for a
variety of syndromes, including Noonan syndrome,LEOPARD syndrome, Costello
syndrome and cardiofaciocutaneous syndrome in which there is cardiac
involvement. While the conditions listed are known genetic causes, there are likely many
other genes which are more subtle. It is known that the risk for congenital heart defects
is higher when there is a close relative with one.

Environmental
Known antenatal environmental factors include
maternal infections (Rubella), drugs (alcohol, hydantoin, lithium and thalidomide) and
maternal illness (diabetes mellitus, phenylketonuria, and systemic lupus erythematosus).

Classification
A number of differing classification systems exist for congenital heart defects. In 2000
the International Congenital Heart Surgery Nomenclature was developed to provide a
generic classification system.

Hypoplasia
Main articles: Hypoplastic left heart syndrome and Hypoplastic right heart syndrome

Hypoplasia can affect the heart, typically resulting in the underdevelopment of the right
ventricle or the left ventricle. This results in only one side of the heart capable of
pumping blood to the body and lungs effectively. Hypoplasia of the heart is rare but is
the most serious form of CHD. It is called hypoplastic left heart syndrome when it affects
the left side of the heart and hypoplastic right heart syndrome when it affects the right
side of the heart. In both conditions, the presence of a patent ductus arteriosus (and,
when hypoplasia affects the right side of the heart, a patent foramen ovale) is vital to the
infant's ability to survive until emergency heart surgery can be performed, since without
these pathways blood cannot circulate to the body (or lungs, depending on which side of
the heart is defective). Hypoplasia of the heart is generally a cyanotic heart defect.
Obstruction defects
Obstruction defects occur when heart valves, arteries, or veins are abnormally
narrow or blocked. Common defects include pulmonic stenosis, aortic stenosis,
and coarctation of the aorta, with other types such as bicuspid aortic valve
stenosis and subaortic stenosis being comparatively rare. Any narrowing or blockage
can cause heart enlargement or hypertension.

Septal defects
The septum is a wall of tissue which separates the left heart from the right heart. Defects
in the interatrial septum or the interventricular septum allow blood to flow from the left
side of the heart to the right, reducing the heart's efficiency. Ventricular septal
defects are collectively the most common type of CHD, although approximately 30% of
adults have a type of atrial septal defect called probe patent foramen ovale.

Cyanotic defects
Cyanotic heart defects are called such because they result in cyanosis, a bluish-grey
discoloration of the skin due to a lack of oxygen in the body. Such defects
include persistent truncus arteriosus, total anomalous pulmonary venous
connection, tetralogy of Fallot, transposition of the great vessels, and tricuspid atresia.

Defects
• Aortic stenosis
• Atrial septal defect (ASD)
• Atrioventricular septal defect (AVSD)
• Bicuspid aortic valve
• Dextrocardia
• Double inlet left ventricle (DILV)
• Double outlet right ventricle (DORV)
• Ebstein's anomaly
• Hypoplastic left heart syndrome (HLHS)
• Hypoplastic right heart syndrome (HRHS)
• Mitral stenosis
• Pulmonary atresia
• Pulmonary stenosis
• Transposition of the great vessels
o dextro-Transposition of the great arteries (d-TGA)
o levo-Transposition of the great arteries (l-TGA)
• Tricuspid atresia
• Persistent truncus arteriosus
• Ventricular septal defect (VSD)
Some conditions affect the great vessels or other vessels in close proximity to the heart,
but not the heart itself, but are often classified as congenital heart defects.

• Coarctation of the aorta (CoA)

• Interrupted aortic arch (IAA)
• Patent ductus arteriosus (PDA)
• Scimitar syndrome (SS)
o Partial anomalous pulmonary venous connection (PAPVC)
o Total anomalous pulmonary venous connection (TAPVC)

Some constellations of multiple defects are commonly found together.

• tetralogy of Fallot (ToF)

• pentalogy of Cantrell
• Shone's syndrome/ Shone's complex / Shone's anomaly

Treatment
Sometimes CHD improves without treatment. Other defects are so small that they do not
require any treatment. Most of the time CHD is serious and requires surgery and/or
medications. Medications include diuretics, which aid the baby in eliminating water, salts,
and digoxin for strengthening the contraction of the heart. This slows the heartbeat and
removes some fluid from tissues. Some defects require surgical procedures to restore
circulation back to normal and in some cases, multiple surgeries are needed.
Interventional cardiology now offers patients minimally invasive alternatives to surgery.
Device closures can now be performed with a standard transcatheter procedure using a
closure device mounted on a balloon catheter.[19]

Most patients require life-long specialized cardiac care, first with a pediatic cardiologist
and later with and adult congential cardiologist. There are more than 1.8 million adults
living with congenital heart defects

Ventricular Septal Defect

A ventricular septal defect (VSD) is a defect in the ventricular septum, the wall
dividing the left and right ventricles of the heart.

The ventricular septum consists of an inferior muscular and superior membranous portion
and is extensively innervated with conducting cardiomyocytes. The membranous portion,
which is close to the atrioventricular node, is most commonly affected in adults and older
children.

Congenital VSDs are collectively the most common congenital heart defects.

Diagnosis
A VSD can be detected by cardiac auscultation. Classically, a VSD causes a
pathognomonic holo- or pansystolic murmur. Auscultation is generally considered
sufficient for detecting a significant VSD. The murmur depends on the abnormal flow of
blood from the left ventricle, through the VSD, to the right ventricle. If there is not much
difference in pressure between the left and right ventricles, then the flow of blood
through the VSD will not be very great and the VSD may be silent. This situation occurs
a) in the fetus (when the right and left ventricular pressures are essentially equal), b) for a
short time after birth (before the right ventricular pressure has decreased), and c) as a late
complication of unrepaired VSD. Confirmation of cardiac auscultation can be obtained
by non-invasive cardiac ultrasound (echocardiography). To more accurately measure
ventricular pressures, cardiac catheterization, can be performed.

Pathophysiology
During ventricular contraction, or systole, some of the blood from the left ventricle leaks
into the right ventricle, passes through the lungs and reenters the left ventricle via the
pulmonary veins and left atrium. This has two net effects. First, the circuitous refluxing
of blood causes volume overload on the left ventricle. Second, because the left ventricle
normally has a much higher systolic pressure (~120 mm Hg) than the right ventricle
(~20 mm Hg), the leakage of blood into the right ventricle therefore elevates right
ventricular pressure and volume, causing pulmonary hypertension with its associated
symptoms. This effect is more noticeable in patients with larger defects, who may present
with breathlessness, poor feeding and failure to thrive in infancy. Patients with smaller
defects may be asymptomatic. Four different septal defects exist, with perimembranous
most common, outlet, atrioventricular, and muscular less commonly.

Signs and symptoms

Ventricular septal defect is usually symptomless at birth. It usually manifests a few weeks
after birth.

Symptoms

VSD is an acyanotic congenital heart defect, aka a Left-to-right shunt, so there are no
signs of cyanosis.

Signs

• Pansystolic (Holosystolic) murmur (depending upon the size of the defect) +/-
palpable thrill (palpable turbulence of blood flow). Heart sounds are normal.
Larger VSDs may cause a parasternal heave, a displaced apex beat (the palpable
heartbeat moves laterally over time, as the heart enlarges). An infant with a large
VSD will fail to thrive and become sweaty and tachypnoiec (breathe faster) with
feeds [Textbook of Paediatric Emergency Medicine. p116-117 eds Cameron P. et
al Elsevier 2006].

CAUSES: The cause of VSD ( ventricular septal defect) includes the incomplete looping
of the heart during days 24-28 of development. Faults with NKX2.5 gene can cause this.

Treatment
A nitinol device for closing muscular VSDs, 4 mm diameter in the centre. It is shown
mounted on the catheter into which it will be withdrawn during insertion.

Treatment is either conservative or surgical. Smaller congenital VSDs often close on their
own, as the heart grows, and in such cases may be treated conservatively. In cases
necessitating surgical intervention, a heart-lung machine is required and a median
sternotomy is performed. Percutaneous endovascular procedures are less invasive and can
be done on a beating heart, but are only suitable for certain patients. Repair of most VSDs
is complicated by the fact that the conducting system of the heart is in the immediate
vicinity.

Ventricular septum defect in infants is initially treated medically with cardiac glycosides
(e.g., digoxin 10-20mcg/kg per day), loop diuretics (e.g., furosemide 1–3 mg/kg per day)
and ACE inhibitors (e.g., captopril 0.5–2 mg/kg per day).

Epidemiology and Etiology

VSDs are the most common congenital cardiac anomalies. They are found in 30-60% of
all newborns with a congenital heart defect, or about 2-6 per 1000 births. During heart
formation, when the heart begins life as a hollow tube, it begins to partition, forming a
septa. If this does not occur properly it can lead to an opening being left within the
ventricular septum. It is debatable whether all those defects are true heart defects, or if
some of them are normal phenomena, since most of the trabecular VSDs close
spontaneously.Prospective studies give a prevalence of 2-5 per 100 births of trabecular
VSDs that closes shortly after birth in 80-90% of the cases.

Congenital VSDs are frequently associated with other congenital conditions, such as
Down syndrome.

A VSD can also form a few days after a myocardial infarction (heart attack) due to
mechanical tearing of the septal wall, before scar tissue forms, when macrophages start
remodeling the dead heart tissue.

Ventricular septal defect in a child with Alport syndrome: a

case report
Pier Paolo Bassareo , Andrea Raffaele Marras and Giuseppe Mercuro
1
Department of Cardiovascular and Neurological Sciences, University of Cagliari, Cagliari, Italy
2
Study Center for Cardiac Disease in Pediatric Age, University of Cagliari, Cagliari, Italy

Background
Alport syndrome (AS) is a rare inherited disorder characterized by an inflammation of the kidneys and
damage to the glomerular capillaries, ultimately leading to renal failure at an early age. To date, rare
reports of cardiac involvement in AS have been described, due in the majority of cases to the higher risk
of heart conduction abnormalities in these patients, at times requiring implantation of a transcutaneous
pacemaker. An increased risk of hypertension is likewise commonly featured.

Case presentation
A 17-year-old female was referred to our clinical Centre due to difficulty in controlling her blood pressure
by means of treatment with angiotensin-converting enzyme (ramipril 10 mg/day), angiotensin receptor
blockade (losartan 100 mg/day), calcium antagonist (nifedipine 10 mg/day) and alpha lithic (doxazosin 4
mg/day). The patient was affected by an early onset, extremely aggressive form of AS (X-linked type, due
to a nonsense mutation in the COL4A5 gene), with development of severe renal insufficiency requiring
treatment with dialysis (three sessions/week). Additionally, the patient had a history of moderate
membranous VSD treated by surgery at the age of one year. Physical examination underlined the
minuteness of the subject (height 151 cm; weight 44 Kg; BMI 19.3 Kg/m2). Systemic blood pressure was
157/94. The patient presented with perimalleolar oedema of the legs. Heart sounds were rhythmic with no
murmur. Basal lung auscultation revealed crackling wheezes. Electrocardiogram revealed sinus rhythm
with heart rate 92 beats/min. Chest X-ray revealed a normal heart size, and a more marked pulmonary
vasculature, particularly at basal level (Figure 1). Transthoracic echocardiography revealed complete
surgical closure of VSD, with no signs of intracardiac shunt (Figures 2, and 3). The two ventricular
chambers were well balanced and pulmonary arterial pressure - calculated from tricuspid valve
insufficiency - was normal. Surgery performed to close the VSD with a bovine pericardial patch had been
complicated by development of a transient complete atrioventricular block lasting seven days and
promptly treated with a temporary pace maker. The patient was discharged from hospital two weeks after
surgery in good clinical conditions. A 24-hour ambulatory blood pressure monitoring (ABPM) was
performed to better define daily blood pressure variability, in particular to avoid a possible white coat
effect, and evaluate drug-resistance. ABPM analysis (Figure 4) highlighted a persistent elevation in both
systolic and diastolic blood pressure. Physiological decline in nocturnal pressure was also absent (non-
dipper pattern). As treatment prescribed was not capable of adequately controlling the patient's blood
pressure, add-on therapy was introduced (2.5 mg/week transdermal clonidine patch applied to the skin
every 7 days). After two weeks the patient's blood pressure had normalized. Following the development of
cutaneous rush at the site of patch application, after 1 month transdermal clonidine was replaced with oral
clonidine (150 mg × 3/day), achieving the same satisfactory effect in controlling blood pressure.

Figure 1. Chest antero-posterior X-ray showing a normal heart size, and a more marked pulmonary
vasculature, particularly at basal level. A central venous catheter is evident as well.
Figure 2. Transthoracic echocardiogram: parasternal log axis view showing septal paradoxical
movement at M-mode modality.

Figure 3. Closure of the ventricular septal defect by a patch (white arrow).

Figure 4. 24-hour ambulatory blood pressure monitoring profile showing a persistent elevation of
both systolic and diastolic blood pressure. The physiological decline in nocturnal pressure was absent (non-
dipper pattern)

Discussion

Cardiac involvement in AS is very rare. Literature reports refer a higher risk of heart conduction
abnormalities in patients with AS. Even patients with a normal preoperative electrocardiogram or no
conduction system disorders may present some degree of atrioventricular block, including complete
atrioventricular block [19]. Generally speaking, this could reflect [19]:

a. an increase in conduction disorders caused by renal failure due to abnormalities in calcium metabolism
leading to fibrosis and myocardial calcification;

b. high serum potassium levels. Although sinoatrial and atrioventricular nodes are apparently less
sensitive to hyperkalemia than other cardiac fibers - owing to their calcium-dependent electrophysiological
properties - atrioventricular block due to hyperkalemia may occur;

c. an external sympathetic block due to anaesthesia.

Furthermore, surgery for VSD closure is frequently complicated by the development of atrioventricular
blocks. However, AS patients may have an additional risk in developing this surgical complication. In such
cases, including the case described here, a transcutaneous pacemaker provides rapid and effective
treatment in the operating room, thus facilitating the scheduling of definitive treatment. In addition,
isolated case reports of arterial disease in males with AS, including dissection and aneurysm have been
published. Immunohistochemistry bioptic findings have confirmed the abnormal absence of several type IV
collagen chains from the aortic media of these patients. Accordingly, the routine screening of males with
AS for aortic abnormalities may be clinically indicated [20]. To date however, and to the best of our
knowledge no association between AS and any forms of CHD has been described. In our patient, the
presence of a moderate membranous VSD had produced a left to right shunt, initially treated by diuretic
therapy (furosemide 1 mg/Kg × 2/day). At the age of one year, surgical treatment was recommended and
the VSD closed by means of a pericardial patch. As stated above, surgery was complicated by the
development of a transient atrioventricular block, treated with a temporary pace maker. With regard to
the possible pathophysiological mechanism underlying the association of AS and VSD, it should be borne
in mind that the membranous portion of the interventricular septum consists of tough collagenous fibrous
connective tissue, thus suggesting the involvement of collagen formation defects in the pathogenesis of
membranous VSD [21,22]. Even if type IV collagen is mainly involved in glomerulosclerosis of AS kidneys,
it would seem the mutations affecting the Alport gene also have secondary effects on the distribution of
other types of collagen at the level of glomerular basal membrane constituents. These other types, which
may also be involved in the development of VSD, might just be the link between these two so apparently
different pathologies.

However, the above mechanism is merely putative and further studies should be undertaken to better
clarify the relationship between the two disorders. This will likely not be an easy task due to the rarity of
Alport disease. With regard to cardiovascular involvement in AS, high blood pressure is a common feature
manifested secondary to renal failure[23]. In our patient, blood pressure was only normalized following
the addition of clonidine to the previously established pharmacological therapy. Clonidine, which is not a
first line drug in most cases of hypertension, is a direct-acting α2 adrenergic agonist that controls high
blood pressure through stimulation of α2receptors in the brain, leading to a decrease in cardiac output and
peripheral vascular resistance, in turn resulting in a lowering of blood pressure. The drug may however
produce side effects such as lightheadedness, dry mouth, dizziness, constipation, and hypotension.
Clonidine also features peripheral alpha agonist effects, which may lead to the onset of hypertension. The
latter effects may be observed following an overdose in children, as blood pressure increases. As clonidine
is eliminated by the body, its peripheral effects wear off, and central hypotensive effects become visible.
Both hypertensive and hypotensive effects may be harmful. Indeed, sudden discontinuation of the drug
may elicit rebound hypertension due to a rebound in sympathetic outflow [24]. To this regard the utility of
ABPM in monitoring daily blood pressure variability even in patients with end-stage renal disease
undergoing dialysis is evident[25].

Lastly, the present case report is of particular interest in view of the high degree of severity of AS in such
a young female, as the more severe forms of X-linked AS are generally manifested in males, with a later
onset of end-stage renal disease.

Conclusions

In conclusion, this previously unreported association of AS with CHD has contributed towards furthering
insight into this rare disease. A mutation at the level of collagen synthesis may explain the concomitant
presentation of the two pathologies. Even when drug-resistance appears to underlie the failure to control
secondary hypertension in AS, clonidine may represent a safe, effective addition capable of normalizing
high blood pressure [26].

Abbreviations

AS: Alport syndrome; CHD: congenital heart disease; VSD: ventricular septal defect; ABPM: 24-hours
ambulatory blood pressure monitoring

Tetralogy of Fallot
Tetralogy of Fallot (TOF) is a congenital heart defect which is classically understood to
involve four anatomical abnormalities (although only three of them are always present).
It is the most common cyanotic heart defect, and the most common cause of blue baby
syndrome.[1]

It was described in 1672 by Niels Stensen, in 1773 by Edward Sandifort, and in 1888 by
the French physician Étienne-Louis Arthur Fallot, for whom it is named.

Anatomic morphology
Primary four malformations

"Tetralogy" denotes a four-part phenomenon in various fields, including literature, and

the four parts the syndrome's name implies are its four signs. This is not to be confused
with the similarly named teratology, a field of medicine concerned with abnormal
development and congenital malformations, which thereby includes tetralogy of Fallot as
part of its subject matter.

As such, by definition, tetralogy of Fallot involves exactly four heart malformations

which present together:
Tetralogy of Fallot

Normal heart
Condition Description
A narrowing of the right ventricular outflow tract and can occur at the
pulmonary valve (valvular stenosis) or just below the pulmonary valve
(infundibular stenosis). Infundibular pulmonic stenosis is mostly caused
by overgrowth of the heart muscle wall (hypertrophy of the septoparietal
trabeculae), however the events leading to the formation of the
A: Pulmonary overriding aorta are also believed to be a cause. The pulmonic stenosis is
stenosis the major cause of the malformations, with the other associated
malformations acting as compensatory mechanisms to the pulmonic
stenosis. The degree of stenosis varies between individuals with TOF,
and is the primary determinant of symptoms and severity. This
malformation is infrequently described as sub-pulmonary stenosis or
subpulmonary obstruction.
B: Overriding An aortic valve with biventricular connection, that is, it is situated above
aorta the ventricular septal defect and connected to both the right and the left
 ventricle. The degree to which the aorta is attached to the right ventricle
is referred to as its degree of "override." The aortic root can be displaced
toward the front (anteriorly) or directly above the septal defect, but it is
always abnormally located to the right of the root of the pulmonary
artery. The degree of override is quite variable, with 5-95% of the valve
being connected to the right ventricle.
A hole between the two bottom chambers (ventricles) of the heart. The
C: ventricular defect is centered around the most superior aspect of the ventricular
septal defect septum (the outlet septum), and in the majority of cases is single and
(VSD) large. In some cases thickening of the septum (septal hypertrophy) can
narrow the margins of the defect.
The right ventricle is more muscular than normal, causing a
characteristic boot-shaped (coeur-en-sabot) appearance as seen by chest
D: Right X-ray. Due to the misarrangement of the external ventricular septum, the
ventricular right ventricular wall increases in size to deal with the increased
hypertrophy obstruction to the right outflow tract. This feature is now generally
agreed to be a secondary anomaly, as the level of hypertrophy generally
increases with age.

There is anatomic variation between the hearts of individuals with tetralogy of Fallot.
Primarily, the degree of right ventricular outflow tract obstruction varies between patients
and generally determines clinical symptoms and disease progression.

Additional anomalies

In addition, tetralogy of Fallot may present with other anatomical anomalies, including:

1. stenosis of the left pulmonary artery, in 40% of patients

2. a bicuspid pulmonary valve, in 40% of patients
3. right-sided aortic arch, in 25% of patients
4. coronary artery anomalies, in 10% of patients
5. a foramen ovale or atrial septal defect, in which case the syndrome is sometimes
called a pentalogy of Fallot
6. an atrioventricular septal defect
7. partially or totally anomalous pulmonary venous return
8. forked ribs and scoliosis

Tetralogy of Fallot with pulmonary atresia (pseudotruncus arteriosus) is a severe

variant in which there is complete obstruction (atresia) of the right ventricular outflow
tract, causing an absence of the pulmonary trunk during embryonic development. In these
individuals, blood shunts completely from the right ventricle to the left where it is
pumped only through the aorta. The lungs are perfused via extensive collaterals from the
systemic arteries, and sometimes also via the ductus arteriosus.

Epidemiology and etiology

Tetralogy of Fallot occurs in approximately 400 per million live births.

Its cause is thought to be due to environmental or genetic factors or a combination. It is

associated with chromosome 22 deletions and diGeorge syndrome.

Specific genetic associations include:

• JAG1
• NKX2-5
• ZFPM2
• VEGF

It occurs slightly more often in males than in females.

Embryology studies show that it is a result of anterior malalignment of the

aorticopulmonary septum, resulting in the clinical combination of a VSD, pulmonary
stenosis, and an overriding aorta. Right ventricular hypertrophy results from this
combination, which causes resistance to blood flow from the right ventricle.

Pathophysiology and symptoms

Tetralogy of Fallot results in low oxygenation of blood due to the mixing of oxygenated
and deoxygenated blood in the left ventricle via the VSD and preferential flow of the
mixed blood from both ventricles through the aorta because of the obstruction to flow
through the pulmonary valve. This is known as a right-to-left shunt. The primary
symptom is low blood oxygen saturation with or without cyanosis from birth or
developing in the first year of life. If the baby is not cyanotic then it is sometimes referred
to as a "pink tet". Other symptoms include a heart murmur which may range from almost
imperceptible to very loud, difficulty in feeding, failure to gain weight, retarded growth
and physical development, dyspnea on exertion, clubbing of the fingers and toes, and
polycythemia.

Children with tetralogy of Fallot may develop "tet spells". The precise mechanism of
these episodes is in doubt, but presumably results from a transient increase in resistance
to blood flow to the lungs with increased preferential flow of desaturated blood to the
body. Tet spells are characterized by a sudden, marked increase in cyanosis followed by
syncope, and may result in hypoxic brain injury and death. Older children will often squat
during a tet spell, which increases systemic vascular resistance and allows for a
temporary reversal of the shunt.

Diagnosis
The abnormal "coeur-en-sabot" (boot-like) appearance of a heart with tetralogy of Fallot
is easily visible via chest x-ray, and before more sophisticated techniques became
available, this was the definitive method of diagnosis. Congenital heart defects are now
diagnosed with echocardiography, which is quick, involves no radiation, is very specific,
and can be done prenatally.

Treatment
Emergency management of tet spells

Prior to corrective surgery, children with tetralogy of Fallot may be prone to

consequential acute hypoxia (tet spells), characterized by sudden cyanosis and syncope.
These may be treated with beta-blockers such as propranolol, but acute episodes may
require rapid intervention with morphine to reduce ventilatory drive and a vasopressor
such as epinephrine, phenylephrine, or norepinephrine to increase blood pressure.
Oxygen is effective in treating spells because it is a potent pulmonary vasodilator and
systemic vasoconstrictor. This allows more blood flow to the lungs. There are also simple
procedures such as squatting and the knee chest position which increases aortic wave
reflection, increasing pressure on the left side of the heart, decreasing the right to left
shunt thus decreasing the amount of deoxygenated blood entering the systemic
circulation.

Palliative surgery

The condition was initially thought untreatable until surgeon Alfred Blalock, cardiologist
Helen B. Taussig, and lab assistant Vivien Thomas at Johns Hopkins University
developed a palliative surgical procedure, which involved forming an anastomosis
between the subclavian artery and the pulmonary artery (See movie "Something the Lord
Made").It was actually Helen Taussig who convinced Alfred Blalock that the shunt was
going to work. This redirected a large portion of the partially oxygenated blood leaving
the heart for the body into the lungs, increasing flow through the pulmonary circuit, and
greatly relieving symptoms in patients. The first Blalock-Thomas-Taussig
 shunt surgery was performed on 15-month old
Eileen Saxon on November 29, 1944 with dramatic results.

The Potts shunt and the Waterston-Cooley shunt are other shunt procedures which were
developed for the same purpose. These are no longer used.

Currently, Blalock-Thomas-Taussig shunts are not normally performed on infants with

TOF except for severe variants such as TOF with pulmonary atresia (pseudotruncus
arteriosus).

Total surgical repair

The Blalock-Thomas-Taussig procedure, initially the only surgical treatment available for
Tetralogy of Fallot, was palliative but not curative. The first total repair of Tetralogy of
Fallot was done by a team led by C. Walton Lillehei at the University of Minnesota in
1954 on a 11-year-old boy. Successful total repair on infants has had success from 1981,
with research indicating that it has a comparatively low mortality rate.

Total repair of Tetralogy of Fallot initially carried a high mortality risk. This risk has
gone down steadily over the years. Surgery is now often carried out in infants one year of
age or younger with less than 5% perioperative mortality. The open-heart surgery is
designed (1) to relieve the right ventricular outflow tract stenosis by careful resection of
muscle and (2) to repair the VSD with a Gore-Tex patch or a homograft. Additional
reparative or reconstructive surgery may be done on patients as required by their
particular cardiac anatomy.

Prognosis
Untreated, tetralogy of Fallot rapidly results in progressive right ventricular hypertrophy
due to the increased resistance on the right ventricle. This progresses to heart failure
(dilated cardiomyopathy) which begins in the right heart and often leads to left heart
failure. Actuarial survival for untreated tetralogy of Fallot is approximately 75% after the
first year of life, 60% by four years, 30% by ten years, and 5% by forty years.

Patients who have undergone total surgical repair of tetralogy of Fallot have improved
hemodynamics and often have good to excellent cardiac function after the operation with
some to no exercise intolerance (New York Heart Association Class I-II). Surgical
success and long-term outcome greatly depends on the particular anatomy of the patient
and the surgeon's skill and experience with this type of repair.

Ninety percent of patients with total repair as infants develop a progressively leaky
pulmonary valve as the heart grows to its adult size but the valve does not. Patients also
often have damage to the electrical system of the heart from surgical incisions, causing
abnormalities as detected by EKG and/or arrhythmias.

Long-term follow up studies show that patients with total repair of TOF are at risk for
sudden cardiac death and for heart failure. Therefore, lifetime follow-up care by an adult
congenital cardiologist is recommended to monitor these risks and to recommend
treatment, such as interventional procedures or re-operation, if it becomes necessary.

The use of antibiotics is no longer required by cardiologists and varies from case to case.

Tetralogy of Fallot with rheumatic mitral stenosis: A

case report
Cheemalapati Sai Krishna, Gangireddy Venkateswara Reddy2, Mohan Debta and Nanda
Kishore Panigrahi
1
Department of Cardio-Thoracic Surgery, Apollo Heart Institute, Visakhapatnam, Andhra
Pradesh, India
2
Department of Cardiology, King George Hospital, Visakhapatnam, Andhra Pradesh, India
3
Department of Cardiology, Apollo Heart Institute, Visakhapatnam, Andhra Pradesh, India

Introduction
Rheumatic and congenital heart diseases account for the majority of hospital admissions for
cardiac patients in India. Tetralogy of Fallot is the most common congenital heart disease with
survival to adulthood. Infective endocarditis accounts for 4% of admissions to a specialized
unit for adult patients with a congenital heart lesion. This report is unique in that a severe
stenotic lesion of the mitral valve, probably of rheumatic aetiology, was noted in an adult male
with Tetralogy of Fallot.

Case presentation
A male aged 35 years with a history of cyanosis from early childhood was referred for
evaluation of low grade fever and worsening breathlessness on exertion. There was no history
of a recent dental or surgical procedure. General physical examination revealed a moderately
nourished individual with central cyanosis and grade IV clubbing. The jugular venous pulse
was elevated. The pulse was regular with a rate of 100 beats per minute and a collapsing
character. The blood pressure was 120/60 mmHg. On precordial examination the first heart
sound was palpable. Auscultation revealed a loud first heart sound, single second heart sound
and an apical opening snap. Additional findings included ejection systolic and early diastolic
murmurs at the left sternal border and a mid-diastolic murmur with pre-systolic accentuation
at the apex. The lungs were clear. Abdominal examination revealed a tender enlarged liver.
There was no enlarged spleen. Pulse oximetry showed a room air oxygen saturation of 78%.
Chest X-ray revealed enlarged heart, pulmonary oligemia and no evidence of pulmonary
venous hypertension. Electrocardiogram revealed sinus rhythm, normal PR interval, right axis
deviation, left atrial enlargement and right ventricular hypertrophy.

An echocardiogram revealed a large malaligned ventricular septal defect with 60% aortic
override. The aortic valve was trileaflet with a vegetation on the right coronary cusp (Figure
1). The mitral valve was thickened. Diastolic doming of the anterior leaflet, fixed posterior
mitral leaflet with paradoxical motion and two well-formed papillary muscles were noted
(Figure 2). There was no aortic stenosis and grade II aortic regurgitation was noted in addition
to severe infundibular and annular stenosis with confluent branch pulmonary arteries (Figure
3A). Non calcific severe mitral stenosis with commissural fusion and thickening of the sub-
valvular apparatus was noted. The mitral valve area was 1.1 cm2. There was no mitral
regurgitation. The peak and mean gradients across the valve were 36 and 21 mmHg
respectively (Figure 3B) and the echocardiographic mitral valve score was 6/16. Blood cultures
revealed Streptococcus viridans as the infecting organism. The serum antistreptolysin O titers
were within reference range, C-reactive protein was positive and erythrocyte sedimentation
rate was elevated.
Figure 1. Parasternal long axis view showing the malaligned ventricular septal defect,
aortic override (Ao), vegetation on the right coronary cusp (Vrcc) and thickened mitral
valve (M).
Figure 2. Parasternal long axis view demonstrating the papillary muscles (1 and 2),
doming of the anterior mitral leaflet (daml) and fixed posterior mitral leaflet (pml); IVS,
interventricular septum; LA, left atrium.
Figure 3. RVOT morphology and Doppler study of the mitral valve. (A) Short axis image
demonstrating the subaortic ventricular septal defect (arrow), hypoplastic right ventricular outflow
tract (RVOT), main pulmonary artery (M) with confluent branch pulmonary arteries. L, left
pulmonary artery; RA, right atrium; LA, left atrium. (B) Image demonstrating Doppler gradients
across the mitral valve.

A final diagnosis of TF, subacute bacterial endocarditis of the aortic valve and severe mitral
stenosis, probably of rheumatic etiology, was considered. Endocarditis with aortic regurgitation
added to the hemodynamic burden and the patient succumbed to infective complications
during the course of stabilization.

Conclusion

Although there was no definitive evidence of prior streptococcal infection, the clinical profile
and the echocardiographic findings suggest an acquired rheumatic etiology in our patient.
Congenital mitral stenosis can present with some leaflet thickening and commissural fusion;
however, its association with TF is extremely rare [8]. Fifty percent of symptomatic infants
with isolated congenital mitral stenosis are known to die within the first six months of life [5].
The late survival of our patient in the presence of a major associated intracardiac lesion makes
congenital pathology unlikely.

About 50% of patients with rheumatic heart disease may not have a prior history of rheumatic
fever [9] and recurrent subclinical or unsuspected active carditis leading to late mitral stenosis
may occur in the natural history. Histologic evidence of active rheumatic carditis (noted in up
to 40% of patients with unexplained heart failure), raised antistreptolysin O titers and absence
of other features of carditis support this contention [10]. These arguments favor a rheumatic
etiology for the mitral stenosis in our case.

This report draws attention to an interesting association of rheumatic mitral stenosis in TF and
highlights the possibility of a coexistent rheumatic lesion in patients with congenital heart
disease.