Development of the Cardiovascular System

First major system to function in the embryo

Primordial heart and vascular system appear in the middle of the Week 3.
Necessary because the rapidly growing embryo can no longer satisfy its nutritional and oxygen
requirements by diffusion alone
Cardiovascular system is derived mainly from:
o Splanchnic mesoderm which forms the primordium of the heart
o Paraxial and lateral mesoderm near the otic placodes
o Neural crest cells from the region between the otic vesicles and the caudal limits of the third
pair of somites
By day 18 the embryo begins form blood islands that contain hemangioblasts (blood vessels and
blood lines/cells) and prospective myoblasts
Blood islands fusion of the islands to form a single heart tube
Angiogenesis blood vessel development
o Starts at the beginning of the week 3
o Blood vessels first start to develop in the extraembryonic mesoderm of the yolk sac,
connecting stalk, and chorion. Blood vessels begin to develop in the embryo about two days
later.
o Production of blood (hemopoiesis or hematopoiesis) begins first in the yolk sac wall about
Week 3. Erythrocytes produced in the yolk sac have nuclei. Blood formation does not
begin inside the embryo until about the fifth week. Erythrocytes produced in the embryo
do not have nuclei (eunucleated). Hematopoiesis inside in the embryo occurs first in the
liver, then later in the spleen, thymus, and bone marrow

Primitive Heart Tube

Initially, the central portion of the cardiogenic area is anterior to the oropharyngeal membrane and
the neural plate
Closure of the neural tube and formation of the brain vesicles the CNS grows cephalad so rapidly
that it extends over the central cardiogenic area and the future pericardial cavity
Oropharyngeal membrane is then pulled forward, while the heart and
pericardial cavity move first to the cervical region and finally to the
thorax
The heart and pericardial cavity come to lie ventral to the foregut and
caudal to the oropharyngeal membrane
Bilateral cardiogenic cords are formed from the mesenchyme
become canalized and form the paired endocardial heart tubes. These
fuse into a single heart tube forming the primitive heart.
As the heart tubes fuse, the external layer of the embryonic heart-the
primordial myocardium-is formed from splanchnic mesoderm
surrounding the pericardial coelom becomes the muscular wall of
the heart or myocardium

Surrounding mesenchyme thicken to form the myoepicardial mantle which is separated by the
gelatinous cardiac jelly from the endothelial heart tube future endocardium
Mesothelial cells that arise from the external surface of the sinus venosus and spread over the
myocardium visceral pericardium or epicardium

Dilatations
The tubular heart elongates and develops alternate dilations and constrictions

The bulbus cordis (composed of the

truncus arteriosus [TA], the conus
arteriosus, and the conus cordis)

Ventricle
Primordial atrium
Sinus venosus

The TA is continuous cranially with the aortic sac, from which the pharyngeal arch arteries arise.
The sinus venosus receives the
the umbilical veins from the chorion.
the vitelline veins from the yolk sac (umbilical vesicle)
the common cardinal veins from the embryo
3 systems of paired veins drain into the primitive heart:
the umbilical system which degenerates after birth
the vitelline system will become the portal system
the cardinal veins will become the caval system
The arterial and venous ends of the heart are fixed by the pharyngeal arches and septum transversum,
respectively.
Convolution change to primitive 4 chambered heart
Bulboventricular loop

Ventricles moves from the left anteriorly to the right bulbocordis becomes
anterior
Formed because the bulbus cordis and ventricle grow faster than other regions,
the heart bends upon itself, forming a U-shaped
As the primordial heart bends, the atrium and sinus venosus come to lie dorsal to the TA, bulbus
cordis, and ventricle
By this stage the sinus venosus has developed lateral expansions, the right and left
sinus horns.

Atrioventricular loop atrium moves posteriorly to the left

By the end of week 4 coordinated contractions of the heart results in unidirectional flow:
Blood enters the sinus venosus from the vitelline, cardinal and umbilical veins
Blood flows into the primitive ventricle
Upon ventricular contraction, blood flows into the bulbus cordis and the truncus arteriosus into
the aortic sac, passing into the aortic arches and branchial arches
Blood then passes to the dorsal aortae for distribution to the embryo, yolk sac and placenta.
The heart divides into 4-chambered heart between weeks 4 and 7.

Endocardial cushions form on the dorsal and ventral walls of the atrioventricular canal. At week
5, they approach each other and fuse, dividing the atrioventricular canal into right and left
canals.
Atria are partitioned successively by the septum primum and the septum secundum
The latter is an incomplete partition and leaves a foramen ovale. The foramen ovale has a valve
formed from the degeneration of the cranial portion of the septum primum.

Simultaneously structures develop to separate the atria septum

The first, septum primum grows downwards.
It tries to meet the migrating endocardial cushion but there is a small hole in
between called the ostium primum

A second septum forms to the right of septum primum- septum secundum

This grows towards the endocardial cushion but does not reach it WEEK 5
Most times the first time the mother confirms pregnancy-heart very well
developed

At this point blood is going to both atria

Soon all the blood will be shunted to the RIGHT atrium because blood vessels migrate
with the sinus venosus to the RIGHT of the heart and empty into the heart
Blood then flows from RIGHT atria to R&L ventricles to embryo
A second ostium- OSTIUM SECUNDUM forms
Blood is still being shunted from Right to left
Then the Ostium primum closes

Blood is completely shunted to the RIGHT atrium via the left and right venous
valves within that area
Septum secundum continues to grow towards the cushions but leaves an oval
shaped opening- FORAMEN OVALE (has a valve formed from the degeneration
of the cranial portion of the septum primum)
Blood can enter the left atrium from the right atrium via this FORAMEN OVALE
HIGH pressure in right atrium in both fetus and embryo help this phenomenon
Septum primum prevents backflow from left to right atrium

First heartbeat occurs at 21 to 22 days and originates in the muscle,

forming peristalsis-like waves beginning in the sinus venosus
Atrial Septation

The sinus venosus develops a left horn which becomes the coronary sinus and a right horn
which will be incorporated into the right atrium. The smooth part of the right atrium, the sinus
venarum, is derived from the sinus venosus whereas the muscular part, the auricle, is derived
from the primitive atrium. The 2 portions are separated internally by the crista terminalis and
externally by the sulcus terminalis.

At the same time, the heart invaginates into the pericardial cavity. The dorsal mesocardium
which attaches it to the dorsal wall of the pericardial cavity degenerates and forms the
tranverse pericardial sinus

The primitive pulmonary vein and its 4 main branches become partially incorporated into the
left atrium. This results in the 4 pulmonary veins. The portion derived from the original smooth
walled portion of left atrium retains a trabeculated apperance.

Absorption of sinus venosus tissue into the right atrium simulataneously forms posterior atrial
wall and inter atrial septum

As the lungs immediately become functional-rapid blood flow/exchange between heart and
lungs return of blood now through the L. atria sees the rise of pressure > R. side.
The pressure forces septae against each other closes the foramen ovale Adults- fossa ovalis

The ventricles become partitioned by a crescentic fold which is open cranially until the end of
week 7 (interventricular foramen). The interventricular septum is formed of a central
membranous part and a surrounding muscular part. After closure, the right ventricle
communicates with the pulmonary trunk and the left ventricle with the aorta.

During week 5, the bulbus cordis and the truncus arteriosus become divided by
an aorticopulmonary septum into the definitive pulmonary trunk and aorta. Valves develop
from proliferation of the subendocardial tissue.

The primitive atrium acts as a temporary pacemaker. But the sinus venosus soon takes over.

The sinuatrial (SA) node develops during week 5. It is part of the sinus venosus which becomes
incorporated into the right atrium.

The atrioventricular (AV) node also develops from the cells in the wall of the sinus venosus
together with cells from the atrioventricular canal region.

The critical period of development is from day 20 to day 50 after fertilization.

Ventricular Septation

Starts with development of the muscular interventricular septum and the endocardial cushions
The interventricular septum extends until it gets close to the endocardial cushion

Grows and leaves an opening or space between

the two PRIMARY INTERVENTRICULAR
FORAMEN

A second (true) opening remains as the septum

does not quite meet the endocardial cushionSECONDARY INTERVENTRICULAR FORAMEN
(must close to prevent any defect)

Secondary interventricular foramen is

closed by:
Muscular interventricular septum
Endocardial cushion tissue
Conal ridges from the septation of the
truncus and the conus

The bulbar septum - dividing the bulbar cordis into a pulmonary artery and aorta; grows
downward and forms the margin of the secondary interventricular foramen
Bulbus cordis is anterior to the atrium and communicates with the ventricle; following looping.
Aorta is in front of the pulmonary artery Lower - they are side by side Even lower the aorta
is located posterior to the pulmonary artery

Septation of Bulbus Cordis

Week 5 active proliferation of neural crest mesenchymal cells in the walls of the bulbus cordis
formation of bulbar ridges (conotruncal ridges)
Similar ridges that are continuous with the bulbar ridges form in the TA.
Neural crest cells migrate through the primordial pharynx and pharyngeal arches to reach the
ridges; bulbar and truncal ridges undergo a 180 spiraling.
The spiral orientation of the bulbar and truncal ridges, possibly caused in part by the streaming
of blood from the ventricles, results in the formation of a spiral aorticopulmonary septum when
the ridges fuse
This septum divides the bulbus cordis and TA into two arterial channels, the ascending aorta
and pulmonary trunk. Because of the spiraling of the aorticopulmonary septum, the pulmonary
trunk twists around the ascending aorta
The bulbus cordis is incorporated into the walls of the definitive ventricles
o RV conus arteriosus (infundibulum) gives origin to the pulmonary trunk
o LV walls of the aortic vestibule, the part of the ventricular cavity just inferior to the
aortic valve
Extra connections between the atrial and ventricular chambers can
lead to the generation of cardiac arrhythmias.

Cardiac Valve Formation

Semilunar valves develop in the aorta and pulmonary artery as localized swellings of
endocardial tissue.
The atrioventricular valves develop as subendocardial and endocardial tissues and project into
the AV canal.
These bulges are excavated from the ventricular side and invaded by muscle. Eventually,the
valve will be constituted from both connective tissue and myocardial tissue. In addition, muscle
cells will make up a large part of the papillary muscle which attaches to the valve leaflets.
The remodeling of the AV canal cushion tissue results in three cusps of the right AV (tricuspid)
valve, and two cusps of the left AV (mitral) valve.
The atrial myocardium is separated from the ventricular myocardium by connective tissue
except in the region of the AV node and bundle of His.

Development of the Cardiac Conduction System

The conduction system regulates the electrical activity of the heart.

Consists of the sinoatrial node, the atrioventricular node, the atrioventricular bundle (of His),
the left and right bundle branches, and the Purkinje fibers.
The sinoatrial node and the atrioventricular node develop from regions of the heart tube that
have slow conducting properties. This explains why the AV node is a region where conduction
velocities slow before arriving at the AV bundle.
The AV bundle and the Purkinje fibers arise from fast conducting working myocardium. These
cells are found near the developing coronary vessels (and perhaps growth factor endothelin-1
(ET-1), they differentiate into the bundle branches and the Purkinje fibers that connect the AV
bundle to the working myocardium.

Development of the Major Arteries

The six pairs of aortic arches, develop in a cephalo-caudal direction and interconnect the ventral
aortic roots and the dorsal aorta
They are never all present in the developing human heart
Of the six pairs of aortic arches, most of the first, second and fifth arches disappear
As blood flows the first aortic arch degenerates (so all the arches are not present at once);
blood then goes to the second aortic arch etc The third arch will remain

Development of the Major Veins

Initial anterior and posterior cardinal system of veins provides venous drainage for the fetus.
New subcardinal veins and supracardinal veins develop as a consequence of the changes found
in the abdomen of the developing embryo.
The formation of the liver and the mesonephric kidney has profound affects in redirecting blood
flow. The enlarging liver encroaches upon the developing vitelline and umbilical veins and
gradually all the blood will drain to the proximal right vitelline vein.

The distal vitelline veins will give rise to the portal system. The left umbilical vein remains and
drains into the ductus venosus, a shunt that allows blood to bypass the developing liver and
which empties into the proximal right vitelline vein.

FETAL CIRCULATION

Oxygenated blood returns from the placenta by the umbilical vein.

Half of the blood passes through the liver whereas the other half bypasses the liver by
the ductus venosus.
Blood enters into the inferior vena cava and then the right atrium of the heart. This blood is now
partially deoxygenated because it is mixed with returning blood from the lower portion of the
body and the abdominal organs.
Most of the blood in the right atrium passes through the foramen ovale into the left atrium and
mixes with the blood returning from the lungs (deoxygenated) (lungs do not function in the
fetus, the right atrial pressure is higher than the left atrial pressure)
From the left atrium, blood passes into the left ventricle and the ascending aorta. Arteries to the
heart, head and neck, and upper limbs receive well-oxygenated blood.
A small amount of blood from the right atrium mixes with blood from the superior vena cava
and coronary sinus. It passes into the right ventricle and leaves via the pulmonary trunk. Most of
it passes into the ductus arteriosus into the aorta. A small amount passes into the lungs.
50% of the blood passes via the umbilical arteries into the placenta for reoxygenation, the rest
supplies the viscera and the inferior 1/2 of the body.
The fetal circulation is designed to carry oxygenated blood from the placenta to the fetal
circulation, bypassing the lungs.

birth the lungs become inflated and O now enters the blood in the lung tissue dilation of the
At
2

pulmonary vasculature Right atrial pressure is reduced especially in relation to left atrial pressure. The
left atrial pressure results in the valve of the foramen ovale, the old septum primum, becoming

pressed
against the septum secundum and the communication between left and right atria becomes

eliminated
with the formation of an intact interatrial septum.

The umbilical artery is constricted and this results in the constriction of the ductus venosus.

After
birth the elevated oxygen levels plus the release of bradykinins from the lungs, act to promote the

constriction of the ductus arteriosus. This vessel closes during the few weeks after birth

Defects will commonly involve a patent foramen ovale and/or patent ductus arteriosus

CVS Defects
Improper partitioning of the heart may result in defects of the cardiac septa, of which the ventricular
septal defects are most common (25% of congenital heart disease).

Membranous ventricular septal defect (most common)

o Involves the oval membranous portion of the interventricular septum which fails to develop.
o Due to the failure of extensions of subendocardial tissue growing from the right side of the
fused endocardial cushions and fusing with the aorticopulmonary septum and the muscular
part of the interventricular septum.
Muscular septal defect
o Perforation may appear anywhere in the muscular part of the interventricular septum
(multiple defects = Swiss cheese type of ventricular septal defect) due perhaps to excessive
resorption of myocardial tissue during formation of the muscular part of the interventricular
septum.
The Tetralogy of Fallot consists of:
o pulmonary valve stenosis: the cusps of pulmonary valve are fused together to form a dome
with a narrow central opening.
o ventricular septal defect
o overriding aorta
o hypertrophy of right ventricle

Cyanosis is an obvious sign but may not be present at birth.

Foramen Ovale Defect (Ostium Secundum Defect)

o Occurs when ostium secundum becomes too large as the result of the loss of too much
septum primum tissue or too little growth of septum secundum.

Leaves an opening in the region of fossa ovalis that permits blood flow between the atria.
Interatrial Septal Defect (Sinus Venosus Defect)
o Occurs when the sinus venosus is not properly incorporated into the right atrium and
interatrial septum or sinus venosus may be incompletely incorporated or else may not shift
to the right enough to be fully incorporated into the septum.
o Another possibility is that the septum secundum may not develop or may become
reabsorbed.
Low interatrial septal defect (ostium primum)
o Occurs when there is the retention of the foramen primum.
o This may be due to the inadequate growth of septum primum, or it can be due to a
malformation of endocardial cushion tissue; abnormal valve formation also may accompany
this defect (mitral valve cleft slit-like or elongated hole in one of the leaflets (anterior
leaflet) that form the mitral valve)
Atrium or Cor Triloculare Biventriculare
o Results of the lack of septum primum and septum secundum formation. An interatrial
septum is not present and the atria form one large chamber.
Pars membranaceum defect of the interventricular septum
o Occurs as the result of the abnormal contribution of endocardial cushion tissue, a lack of
connective tissue from the muscular interventricular septum, or the lack of
aorticopulmonary tissue.
o Associated with other congenital cardiac abnormalities.
Pars muscularis defects (defects in the muscular interventricular septum)
o During normal development there are numerous sinuses or canals between the two
ventricular chambers. Normally they are obliterated with the final formation of the
interventricular septum.
Cor triloculare biatriatum
o Occur with the complete absence of the interventricular septum. In this defect there are
two atrial chambers that both empty into a single ventricular chamber (3-chambered heart)
Bulbus Cordis Defects
o One type of bulbus cordis defect is the absence of part or all of the aorticopulmonary
septum.
o Partial Persistent Truncus Arteriosus defect the caudal part of the septum is absent
o Common Truncus Arteriosus complete absence of the aorticopulmonary septum
o There is an accompanying IV defect which results from the lack of a contribution of the
bulbar septum to the IV septum