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Development of the Heart
Thomas A. Marino, Ph.D.
Temple University School of Medicine
Stages of Development of the
Heart
1.
2.
3.
4.
5.
6.
7.
The horseshoe-shaped pericardial cavity.
The formation of the single heart tube.
The convolution of the heart tube.
The primitive 4-chambered heart.
Atrial septation.
Ventricular septation
Aorticopulmonary septation
Development of the HorseshoeShaped Pericardial Cavity
By day 18 the embryo
begins form blood
islands that contain
hemangioblasts and
prospective myoblasts.
Development of HorseshoeShaped Pericardial Cavity
Endocardial Heart tubes
These blood islands coalesce in a precephalic
area that is in front of the developing brain.
The cells form a horseshoe shaped tube called
the endocardial heart tube. The ends of the
tube are located in the region of the
developing septum transversum which will
become part of the diaphragm.
Development of HorseshoeShaped Pericardial Cavity
Lateral body folding occurs
as well as head folding
and brings the two ends of
the heart tube together.
They approach each other
in front of the developing
gut tube.
Endocardial heart tube
This view shows that as lateral body folding occurs the head
folding also shifts the heart tubes caudally so that they come to
lie in the region of the future neck.
Blood
islands
Heart
tube
Heart
Development of HorseshoeShaped Pericardial Cavity
If a section is taken
in the region of the
black line.
n
ssio
xpr
e
WNT inhibitors
(crescent & cerberus)
NK
BMP expression
Xe
BMP expression
GATA4 is important at the beginning of cardiogenesis. BMP 2,4 secreted by endoderm Crescent and cerberus inhibit WNT proteins NKX2.5 is upregulated. FGF8 is also important for heart specific proteins
MEF2C Controls cardiac
morphogenesis and
myogenesis,
Development
of HorseshoeShaped
Pericardial
Cavity
And if you were to look at the
embryo from the caudal
region.
Mesoderm
You would see that the heart tubes fuse and
that the ventricles fuse first. The single heart
tube fuses at day 21 of gestation.
Mesoderm
As the heart tubes fuse they become surrounded by the myocardial mantle. This
group of cells will form one of the heart fields that gives rise to some of the
myocardial cells in the heart. It also gives rise to connective tissue cells that will
be part of the cardiac jelly.
Mesoderm
cardiac jelly
Cardiac jelly will become the subendocardial connective tissue. It will also give rise to
the precursors of the valves. In addition these cells will form the connective tissue of
the interatrial and interventricular septa.
Mesoderm
Foregut
Dorsal Aorta
The heart has three
layers:
1. Endocardial layer
2. Cardiac jelly
3. Myocardial layer.
!
The heart tube at this
point lies in front of
the foregut and
suspended in the
body cavity by the
mesocardium.
Heart
Body
Cavity
Amniotic Cavity
Embryonic Circulation
• There are three vascular circuits being set
up early in development:
– An embryonic circuit
– Two extraembryonic circuits
• Vitelline
• Umbilical
16
Embryonic Circulation
Common Cardinal Vein
Dorsal Aorta
Brain and Spinal Cord
Posterior
Cardinal Vein
Anterior
Cardinal
Vein
Umbilical Artery
Umbilical Vein
Yolk
Sac
Aortic Arches
Ventricle
Atria
Vitelline Artery
& Vein
Endocardial Heart Tube
aortic arches
II
III
aortic sac
I
bulbus cordis
truncus art.
conus cordis.
primitive ventricle
atrium
r. sinal horn
l. sinal horn
The heart tube can be subdivided into several different regions. Nkx2.5 is
important in the differentiation of different regions of the heart tube.
• Hand 1 important in conotruncus and
left ventricle
• Hand 2 important in right ventricle.
– Cells in RV from different source than LV
• Tbx5 important is specification of
atria.
Isotretinoin (vitamin A)
Vitamin A embryopathy: small, abnormally
shaped ears, mandibular hypoplasia, cleft
palate, heart defects
• Retinoic Acid from
mesoderm
• Atria and sinus
venosus then
produces RA
• Commits region
• Bulbus and ventricles
produce lower levels
of RA
RA
2nd heart field
Myogenic
progenitor
Myocardial
progenitor
Myocardial
progenitor
Im
m ma
yo tu
cy re
te
Precardiac
mesoderm
Im
m ma
yo tu
cy re
te
Differentiated atrial myocyte
Endothelial
cells
Immature
myocyte
r
ula
sc
Va oothe
m
s uscl nitor
M oge
pr
Differentiated ventricular myocyte
LV
Differentiated ventricular myocyte
RV
Blood
Cells
Conduction
tissue
Vascular smooth muscle
The point of this slide is to note the precursors of the heart cells and origin of
the different cell types.
Endocardial Heart Tube
The atrial end of the heart tube
receives new vessels that form
in the yolk sac (vitelline) and in
the placenta (umbilical). They
also are connected to the
embryonic circuit (not shown
here).
Umbilical Vein
Vitelline Vein
Convolution of the Heart Tube
The hear tube then undergoes looping.
Looping depends on laterality-inducing
genes
Convolution of the Heart Tube
There are two loops that are formed.
1. a Bulboventricular loop that has
the truncus and conus moving
ventrally and to the right.
2. An atrioventricular loop that has
the atria moving posteriorly and
superiorly.
Aortic Sac
Ventricle
Truncus
Conus
Sinus
Venosus
Atria
Convolution of the Heart Tube
Truncus
This puts the conus and the primitive
ventricle on the ventral surface.
These chambers extend caudally.
The atria are the most cephalic
chambers of the heart and also the
most posterior.
R.
Atrium
L. Atrium
Conus
Primitive
Ventricle
Primitive Four-Chamber Heart
To understand septation of the heart you need
to visualize the three dimensional architecture
of the heart. So if we take a sagital section of
the convoluted heart tube and look from the
side we would see the image in the next slide.
Primitive 4 Chamber Heart
Here the truncus and
conus are in the front
and the atria are
posterior. Note the
flow of blood from the
atria to the ventricles to
the conus and then out
the truncus.
truncus
atrium
conus
ventricle
Primitive 4 Chamber Heart
If a coronal section is
then take and viewed
from the front the next
slide shows the view youtruncus
would see.
atrium
conus
ventricle
Primitive Four-Chamber Heart
T
C
AV
V
on the left the coronal section reveals the ventricle, the conus, the truncus and the
black atrioventricular canal.
The AV canal has to shift to the right and as it does so
thebulboventricular flange regresses This will put the AV canal in
continuity with the conus and the ventricle.
Bulboventricular
flange
RA
LA
LV
RV
AV canal
Primitive Four-Chamber Heart
If a sagital section is made again
and viewed from the side you
see the following section.
Primitive 4 Chamber Heart
truncus
atrium
conus
ventricle
This is the primitive four chambered heart prior to septation.
Primitive 4 Chamber Heart
truncus
atrium
conus
ventricle
A common way to look at the septating heart is to take a section through the atria
and the ventricles like the green line.
Primitive 4 Chamber Heart
truncus
atrium
conus
ventricle
Then looking from the front you would see the next image.
Primitive 4 Chamber Heart
superior
R. Atrium
L. Atrium
Common A-V
Canal
Left Ventricle
Right Ventricle
inferior
Note the two atria above, the left and right ventricles below. The right ventricle is
the structure that develops from the conus. The conus gives rise to the reight
ventricle and its outflow tract.
Going back to the sagital section, the nest event that occurs
is the expansion of the cardic jelly in the region of the AV
canal. The develop in the anterior and posterior part of the
canal.
Endocardial
cushions
Atrial Septation
The first event is atrial septation is the downward growth of a septum that is in
between the two atrial chambers. This is called septum primum.
Septum
primum
R. Atrium
L. Atrium
Foramen Primum
Left Ventricle
Right Ventricle
Atrial Septation
Septum primum grows downward toward the endocardial cushions which are in the
process of fusing. Before they reach the cushions they leave an opening called the
ostium primum.
Septum
primum
Ostium
Primum
R. Atrium
L. Atrium
Endocardial
Cushion
Atrial Septation
Here in horizontal (left) and sagital (right) section the endocardial cushion, the
ostium primum and the septum primum are seen.
Septum
Primum
R. Atrium
L. Atrium
Ostium
primum
Endocardial
cushions
Atrial Septation
As septum primum reaches the endocardial cushions a new ostium forms in the
septum.
R. Atrium
L. Atrium
Atrial Septation
This is called ostium secumdum. This allows blood to
continue to flow from the right atrium to the left atrium (arrow).
Ostium
Secundum
R. Atrium
L. Atrium
Ostium
Primum
Atrial Septation
As septum primum fuses with the endocardial cushion a second septum
(septum secundum) develops to the right of ostium secundum.
Septum
Secundum
R. Atrium
L. Atrium
Atrial Septation
As septum secundum develops the blood now all flows into the right atrium in between
the right and left venous valves.
Septum
spurium
L. venous
valve
R. venous
valve
Atrial Septation
Blood then enters the right atrium and can go either directly to the right ventricle or
else flow thru foramen ovale (in septum secundum), thru ostium secundum (in
septum primum) to the left ventricle.
Foramen
Ovale
Atrial Septation
The sinus venosus tissue gets reabsorbed into the right atrium up to the incorporation
of the superior vena cava, the inferior vena cava and the coronary sinus.
Coronary sinus
SVC
IVC
foramen
ovale
Pulmonary
veins
Valve of the
foramen ovale
Atrial Development
From pulmonary
vein tissue
From sinus
venosus tissue
The sinus venosus tissue forms the smooth wall portion of the right atriumfrom the
crista termalis up to and including septum secundum of the interatrial septum.
Left Atrial Development
Here we see the primitive left atrium
superior
R. Atrium
L. Atrium
Common A-V
Canal
Left Ventricle
Right Ventricle
inferior
Left Atrial Development
As the pulmonary vein develops it empties into the left atrium.
R. Atrium
Pulmonary
vein
L. Atrium
Left Atrial Development
Pulmonary
veins
The pulmonary vein gets reabsorbed into the left atrium up to the first bifurcation. It
then continues to get incorporated into the left atrium.
Left Atrial Development
The incorporation of left pulmonary vein tissue continues until the second bifurcation
and this accounts for the four pulmonary veins emptying into the left atrium.
Pulmonary
veins
Atrial Development
From pulmonary
vein tissue
From sinus
venosus tissue
The incorporated pulmonary vein tissue gets reabsorbed and forms the smooth wall
portion of the left atrium.
Ventricular Septation
superior
R. Atrium
L. Atrium
Common A-V
Canal
Left Ventricle
Right Ventricle
inferior
As atrial septation is taking place the septation of the ventricle is also occurring. Early
on the two ventricular chambers are in direct communication with each other.
Ventricular Septation
Endocardial
Cushion
Interventricular
Foramen
Interventricular
Septum
AS the endocardial cushion grow in the midline dividing the atrioventricular canal
into a left and right AV canal, there is a growth of tissue between the two ventricles.
This is the muscular interventricular septum.
Ventricular Septation
E
E
IVS
IVS
I
V
I
V
The interventricular septum (IV) grows toward the endocardial cushion (E). The
space in between the two is the primary IV septum (IVS).
Ventricular Septation
Secondary
Interventricular
Foramen
RV
LV
As the muscular interventricular septum reaches the endocardial cushion a small
foramen remains and it is called the secondary interventricular foramen.
Ventricular Septation
• The secondary interventricular foramen is
closed by the
– Connective tissue from the muscular
interventricular septum.
– Endocardial cushion tissue.
– Conal ridges from the septation of the truncus
and the conus.
Ventricular Septation
Endocardial
cushion tissue
RV
I
V
LV
Here in green the contribution from the endocardial cushion is depicted. It will grow
toward the IV septum.
Ventricular Septation
If you take a midsagital section through the
interventricular septum and the endocardial
cushion you would see the image above. Note
the location of the aorta and pulmonary artery
as they develop from the truncus and conus.
The bulbar septum will septate the conus and
truncus and also contribute to the IV septum.
Ventricular Septation
Aorta
SVC
Pulmonary Artery
Bulbar Septum
IV Foramen
IVC
Foramen
Ovale
Coronary
Sinus
Endocarial
Cushion
Muscular IV
Septum
Here you can see the formation of the membranous interventricular septum by the
muscular IV septum connective tissue, the endocardial cushion and the bulbar
septum.
Aorta
Pulmonary Artery
Conal Ridges
IV Foramen
Membranous
Interventricular
Septum
Endocarial
Cushion
Muscular IV
Septum
SeptaIon of the Bulbus Cordis
Bulbus Cordis
AV Canal
Ventricle
Looking at a sagital secIon of the heart early in development the bulbus cordis is conInuous with the ventricle which is conInuous with the atria. As the AV canal shiOs to the right the bulbus move to the right as well. SeptaIon of the Bulbus Cordis
A
PA P
The next three slides make the point via cross secIons that the aorta and pulmonary arteries rotate around each other. This means the septum between them changes posiIon from superior to inferior as well. SeptaIon of the Bulbus Cordis
A
P P
A
SeptaIon of the Bulbus Cordis
P
A
P
A
MigraIon of neural crest cells
Neural crest cells migrate from the 3ed, 4th and 6th pharyngeal arches to form some of the populaIon of cells forming the aorIcopulmonary septum.
SeptaIon of the Bulbus Cordis
Truncal (Conal) Swellings
Bulbus Cordis
The cardiac jelly in the region of the truncus and conus adds the neural crest cells and expands as truncal swellings.
SeptaIon of the Bulbus Cordis
Aorticopulmonary septum
These swellings grow toward each other to meet and form the septum between the aorta and pulmonary artery.
Aorta
Pulmonary Artery
SeptaIon of the Bulbus Cordis
Anterior
1
2
3
1
2
3
The aorIcopulmonary septum then rotates as it moves inferiorly. However, the exact mechanism for that rotaIon remains unclear. SeptaIon of the Bulbus Cordis
Aorta
Pulmonary Artery
Conal Ridges
IV Foramen
Membranous
Interventricular
Septum
Endocarial Cushion
Muscular IV Septum
However, the aorIcopulmonary septum must form properly for the IV septum to be completed. Embryonic CirculaIon
Common Cardinal Vein
Dorsal Aorta
Brain and Spinal Cord
Posterior Cardinal Vein
Anterior Cardinal Vein
Umbilical Artery
Umbilical Vein
Yolk Sac
AorIc Arches
Ventricle
Atria
Vitelline Artery & Vein
Blood leaves the truncus and moves to the aorIc arches. There is an aorIc arch for each pharyngeal arch.
http://php.med.unsw.edu.au/embryology/index.php?
title=File:Advanced_Heart_Development_Timeline.jpg
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