B1 – PPT 4

Development of the Heart

 Establishing Laterality

Expressed in the left heart forming field

Serotonin (5HT) signaling molecule

Pitx2c

MAO

Master gene for left-sidedness Suppression of 5HT at the right side

 Establishing of the Primary Heart Field

Master gene for heart development

Human chromosome 5q35.2

NKX-2.5 - expressed
mutation
GATA-protein
ASD, VSD, defects in conduction
system
BMPs 2,4 -expressed
Chordin
Noggin

Inhibition of BMP in the medial

mesoderm
Crescent (FrzB2)

activin WNT 1, 3a,8 inhibited Cerebrus

insulin-like growth factor

FGF8 Shh Dickkopf1 (Dkk-1)

Promote cell survival and proliferation of

cardiogenic cells
expression of cardiac specific proteins
  Elongation of Venous Portion
Irx4 (iroquios)

Determination of formation of ventricles

Expression of Mhc1v

Lower RA

Venous portion
Higher RA
Sinus venosus
Tbx5

mutation

Determination of formation of atria Specified by RA

Holt-Oram Production of own RA

Expression of Mhc1a syndrome

Raldh-2 – limiting enzyme in RA biosynthesis

 Elongation of Arterial Portion

Tbx5, Tbx1
interaction

FGF8

NKX2.5
expression

GATA4
  Cardiac Looping NKX2.5

The signaling mechanisms responsible for cardiac looping are largely unknown.
may play role in deposition of extracellular matrix upregulates expression of
Pitx2c molecules

HAND1 and HAND2 (transcription

downstream target (?) factors)

Flectin (extracellular matrix molecule)

Looping phenomenon Left and right ventricles patterning, expansion

and differentiation

 Septation of the Heart

Tbx5 transcription
factor ChALK2 (activin receptor-like
kinase) zincfinger protein Slug
BMP-2A,4
septation
TGF-ß1,ß2

Epithelial-mesenchymal transformation

 Septation of the Heart

Versican (proteoglican – product of

Endocardial cushion tissue formation Cspg2-gene)
 Cardiac neural crest cells

Give rise to parasympathetic postganglionic neurons of

Pax3 gene - expression the heart (cardiac ganglia)

invade conotruncal
swellings

failure

persistent ductus arteriosus,

VSD

 Formation of the Inner and Outer Layers of Myocardium

Egf receptors Neuregulin ligand

ErbB2+ErbB3 expressed in myocardium expressed in endocardium

Trabecular development + gestational survival

cell proliferation

myocardium

 Fetal RARα (retinoic acid receptors) in Cardiac Fgfs

epicardium

RA
 Ultrasonography
o It is usually performed at 18-22 weeks of gestation
o At this term the size of the fetus heart is big enough for using high-
resolution real-time ultrasonography

 Sudden Infant Death Syndrome (SIDS)

o This is the most common cause of deaths among healthy infants (0.6
per 1000 live births)
o Most likely, no single mechanism is responsible for the sudden and
unexpected deaths of these apparently healthy infants
o Hypotheses:
 Conducting tissue abnormalities
 Autonomic nervous system defect
 Brainstem developmental abnormality

 Congenital Heart Defects (CHDs)

o Frequency is 5-8 cases per 1000 live births
o Causes:
 Single-gene mutations or chromosomal aberrations
(trisomies, monosomies, deletions)
 Exposure to teratogenes (lithium, retinoic acid, alcohol,
talidomide, rubella virus, diabetes)
 Multifactorial (genetic + environmental)
 Unknown causes
o Gene therapy in infants with CHDs is a remote prospect
o Many types of CHDs can be palliated or corrected surgically

 Dextrocardia
o In dextrocardia with situs viscerus inversus totalis the incidence of
accompanying cardiac defects is low
o If there is no other associated vascular abnormality, these hearts
function normally
o Isolated dextrocardia is usually complicated by severe cardiac
anomalies (e.g., single ventricle and transposition of the great vessels)

 Heterotaxy (Isomerism) Syndrome

o It is an abnormality where the internal thoraco-abdominal organs
demonstrate abnormal arrangement across the left-right axis of the
body
o Includes patients with a wide variety of very complex cardiac lesions
o Patients with heterotaxy can be stratified into the subsets of asplenia
syndrome and polysplenia syndrome, or the subsets of heterotaxy
with isomerism of the right atrial appendages and heterotaxy with
isomerism of the left atrial appendages
 o Treatment of patients with isomerism is determined by the nature
and severity of the associated cardiac and extracardiac lesions

 Ectopia Cordis
o It is a rare condition
o The heart is partly or completely exposed on the surface of the thorax
o Established during 4 th week because of nonfusion of the lateral folds
and usually associated with widely separated halves of the sternum
(nonfusion) and an open pericardial sac
o Death occurs in most cases during the first few days after birth,
usually from infection, cardiac failure, or hypoxemia
o Surgical therapy usually consists of covering the heart with skin
o In some cases of ectopia cordis, the heart protrudes through the
diaphragm into the abdomen

 Atrial Septal Defects (ASD)

o Occurs more frequently in females than in males
o Associated with almost all documented autosomal and sex
chromosome aberrations
o The most common form of ASD is patent oval foramen
o A probe patent oval foramen (25% of people) is not clinically
significant and results from incomplete adhesion between the flap-
like valve of the oval foramen and the septum secundum after birth
o Ostium secundum ASDs:
 Closure of the ASD is carried out at open heart surgery, and the
mortality rate is less than 1%
 The defects may be multiple
o Endocardial cushion defects with ostium primum ASDs:
 The septum primum does not fuse with the endocardial
cushions; as a result, there is a patent foramen primum
defect
 In complete failure of the fusion of the endocardial cushions
there is a large defect in the center of the heart - AV septal
defect (persistent AV canal) (in 20% of persons with Down
syndrome)
o The sinus venosus ASDs (high ASDs):
 Are located in the superior part of the interatrial septum close
to the entry of the SVC
 It results from incomplete absorption of the sinus venosus into
the right atrium and/or abnormal development of the septum
secundum
 o Common atrium:
 Is a complete absence of the interatrial septum
 CA occurs as an isolated congenital cardiac anomaly, it might
also occur as part of Ellis van Creveld syndrome (a relatively
rare skeletal dysplasia )

 Ventricular Septal Defects (VSD)

o The VSDs are the most common type of CHD (approximately 25% of
heart defects)
o Occur more frequently in males than in females
o During the first year, 30% to 50% of small VSDs close spontaneously
o Incomplete closure of the IV foramen results from failure of the
membranous part of the IV septum to develop
o Large VSDs with excessive pulmonary blood flow and pulmonary
hypertension result in dyspnea and cardiac failure early in infancy
o Muscular VSD:
 Is a less common type of defect and may appear anywhere in
the muscular part of the interventricular septum
 Multiple small defects (the “Swiss cheese” VSD) probably occur
because of excessive cavitation of myocardial tissue during
formation of the muscular part of the interventricular septum
o Single ventricle (or common ventricle):
 Resulting from failure of the IV septum to form
 It is extremely rare and results in a three- chambered heart
(cor triloculare biatriatum)
 The atria empty through a single common valve or two
separate AV valves into a single ventricular chamber
 The aorta and pulmonary trunk arise from the ventricle

 Persistent Truncus Arteriosus

o Results from failure of the truncal ridges and aorticopulmonary
septum to develop normally
o A single arterial trunk, the TA, arises from the heart and supplies the
systemic, pulmonary, and coronary circulations
o A VSD is always present with a TA defect; the TA straddles the VSD

 Patent Ductus Arteriosus (PDA)

o It is a condition in which the ductus arteriosus does not close
o Affects females more than males

 Aorticopulmonary Septal Defect

o It is a rare condition in which there is an opening (aortic window)
between the aorta and pulmonary trunk near the aortic valve
o Results from localized defect in the formation of the
aorticopulmonary septum
 Tricuspid Atresia
o Involves obliteration of the right AV orifice
o It is characterized by absence or fusion of the cusps of tricuspid valve
o It is always associated with the patency of the oval foramen, VSD,
hypoplasia of the right ventricle and hypertrophy of the left ventricle

 Ebstein Anomaly
o In this condition the tricuspid valve is displaced toward the apex of
the right ventricle
o It result in hypertrophy of the right atrium and hypoplasy of the right
ventricle
o Anterior leaflet of the valve is usually enlarged

 Transposition of the Great Arteries

o It is often associated with other cardiac anomalies (e.g., ASD and VSD)
o The aorticopulmonary septum fails to pursue a spiral course during
partitioning of the bulbus cordis and TA
o The aorta arises from the morphologic right ventricle, and the
pulmonary trunk arises from the morphologic left ventricle
o Without surgical correction of the TGA, these infants usually die
within a few months

 Unequal Divisions of Truncus Arteriosus

o One of the great arteries is large and the other is small
o The aorticopulmonary septum is not aligned with the IV septum and a
VSD results; the vessel with the larger diameter usually straddles the
VSD
o In pulmonary valve stenosis, the cusps of the pulmonary valve are
fused to form a dome with a narrow central opening
o In infundibular stenosis, the conus arteriosus (infundibulum) of the
right ventricle is underdeveloped
o Depending on the degree of obstruction to blood flow, there is a
variable degree of hypertrophy of the right ventricle

 Tetralogy of Fallot
o Consists of 4 defects:
 Pulmonary artery stenosis
 VSD
 Dextroposition of aorta (overriding or straddling aorta),
 Right ventricular hypertrophy
o Cyanosis is an obvious sign of the tetralogy, but it is not usually
present at birth
o Pulmonary atresia with VSD is an extreme form of tetralogy of Fallot.
o In many cases, primary surgical repair is the treatment of choice in
early infancy
 Aortic Stenosis and Aortic Atresia
o In aortic valve stenosis, the edges of the valve are usually fused to
form a dome with a narrow opening
o The valvular stenosis causes hypertrophy of the left ventricle and
heart murmurs
o In subaortic stenosis, there is often a band of fibrous tissue just
inferior to the aortic valve
o The narrowing of the aorta results from persistence of tissue that
normally degenerates as the valve forms
o Aortic atresia is present when obstruction of the aorta or its valve is
complete

 Hypoplastic Left Heart Syndrome (HLHS)

o The left ventricle is small and nonfunctional
o The right ventricle maintains both pulmonary and systemic
circulations
o The blood passes through an atrial septal defect or a dilated oval
foramen from the left to the right side of the heart, where it mixes
with the systemic venous blood
o There are atresia of the aortic or mitral orifice and hypoplasia of the
ascending aorta
o Infants with this severe defect usually die during the first few weeks
after birth

 Holt-Oram Syndrome
o It’s cause is a mutation of Tbx5 gene
o Holt-Oram syndrome is characterized by skeletal abnormalities of the
upper limbs and heart defects (heart chambers malformations,
conduction system defects)
o The most common heart defects in these patients are ASD, VSD

 CHARGE Syndrome
o Caused by a mutation in a single gene, most often CHD7 in the 8th
chromosome
o Involves pharyngeal arches and outflow tract
o The letters in CHARGE stand for:
 Coloboma of the eye
 Heart defects
 Atresia of the choanae
 Retardation of growth and/or development
 Genital and/or urinary abnormalities
 Ear abnormalities and deafness
o Heart defects in this syndrome present in 75% of cases and can be of
any type
o But most are complex, such as tetralogy of Fallot
  DiGeorge (velocardiofacial Syndrome
o Caused by a deletion of the 22q11.2 chromosome
o Loss of Tbx1gene of this chromosome is thought to be responsible for
heart defects in this syndrome
o Mnemonic for diGeorge syndrome:
 Cardiac abnormality (especially tetralogy of Fallot)
 Abnormal facies
 Thymic aplasia
 Cleft palate
 Hypocalcemia/Hypoparathyroidism
o Characteristic signs may include:
 Learning disabilities
 Attention deficit disorder
 Schizophrenia
 Bipolar disorder
 Recurrent infections due to congenital thymic hypoplasia or
aplasia

 Down Syndrome (trisomy 21) and Heart Defects

o The rate of congenital heart defects in newborns with Down
syndrome is around 40%
o Of those with heart disease, about 80% have an AVSD or VSD
o Mitral valve problems become common as people age, even in those
without heart problems at birth
o Other problems that may occur include tetralogy of Fallot and patent
ductus arteriosus

 Single Gene Mutations

o NKX2.5:
 ASD and defects in conducting system
o GATA4:
 ASD and pulmonary valvular stenosis
o CRELD1 (Cysteine- Rich Protein with EGF- Like Domains):
 A cell adhesion molecule – AVSD

Practice Question

A child is born with a VSD and the abnormalities of the upper limbs. Mutation in
which gene caused the development of this syndrome?

A. GATA4
B. Tbx5
C. NKX2.5
D. Pax3
E. Pitx2