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Home , Aorticopulmonary septum, Aortic sac, Blood islands, Bulbus cordis, Dorsal aorta, Endocardial cushions

Development of the

Thomas A. Marino, Ph.D.

Temple University School of Medicine Stages of Development of the Heart 1. The horseshoe-shaped pericardial cavity. 2. The formation of the single heart tube. 3. The convolution of the heart tube. 4. The primitive 4-chambered heart. 5. Atrial septation. 6. Ventricular septation 7. Aorticopulmonary septation Development of the Horseshoe- Shaped Pericardial Cavity By day 18 the begins form that contain hemangioblasts and prospective myoblasts. Development of Horseshoe- Shaped 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 Horseshoe- Shaped 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 Horseshoe- Shaped Pericardial Cavity

If a section is taken in the region of the black line. BMP expression

WNT inhibitors NKX expression (crescent & cerberus) BMP expression BMP

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 and myogenesis,

Development of Horseshoe- Shaped Pericardial Cavity

And if you were to look at the embryo from the caudal region.

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 The heart has three layers: 1. Endocardial layer 2. Cardiac jelly 3. Myocardial layer. ! The heart tube at this point lies in front of Heart the foregut and suspended in the body cavity by the Body mesocardium. 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

Umbilical Vein Yolk Sac

Ventricle Vitelline Artery Atria & Vein Endocardial Heart Tube

aortic arches I II III truncus art. conus cordis. primitive

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 then produces RA • Commits region • Bulbus and ventricles produce lower levels RA of RA 2nd heart field Precardiac Myogenic Myocardial mesoderm progenitor progenitor Myocardial progenitor Differentiated atrial myocyte

Immature myocyte

Immature Immature myocyte myocyte Endothelial Vascular cells smooth Muscle progenitor

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 (vitelline) and in the (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 Aortic Sac the truncus and conus moving Ventricle ventrally and to the right. 2. An atrioventricular loop that has Truncus the atria moving posteriorly and superiorly.

Conus Atria

Sinus Venosus Convolution of the Heart Tube

Truncus This puts the conus and the on the ventral surface. These chambers extend caudally. R. L. Atrium The atria are the most cephalic Atrium chambers of the heart and also the most posterior.

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 truncus atria to the ventricles to atrium the conus and then out the truncus. 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 . 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

LA RA

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 R. Atrium L. Atrium Foramen Primum

Left Ventricle Right Ventricle Atrial Septation

Septum primum grows downward toward the which are in the process of fusing. Before they reach the cushions they leave an opening called the ostium primum. Septum primum R. Atrium Ostium L. Atrium Primum 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 () 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 R. venous valve L. venous valve Atrial Septation Blood then enters the right atrium and can go either directly to the right ventricle or else flow thru (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 Pulmonary IVC veins Valve of the foramen foramen ovale 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 . 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.

Pulmonary vein R. Atrium 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

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 LV I V

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 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 Pulmonary Artery SVC Bulbar Septum

IV Foramen

IVC

Foramen Muscular IV Ovale Endocarial Septum Coronary Cushion Sinus 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 Muscular IV Endocarial Septum Interventricular Cushion Septum Septaon of the Bulbus Cordis

Bulbus Cordis

AV Canal

Ventricle

Looking at a sagital secon of the heart early in development the bulbus cordis is connuous with the ventricle which is connuous with the atria. As the AV canal shis to the right the bulbus move to the right as well. Septaon of the Bulbus Cordis

A P A P

The next three slides make the point via cross secons that the aorta and pulmonary arteries rotate around each other. This means the septum between them changes posion from superior to inferior as well. Septaon of the Bulbus Cordis

P A A P Septaon of the Bulbus Cordis

P A P A Migraon of cells

Neural crest cells migrate from the 3ed, 4th and 6th pharyngeal arches to form some of the populaon of cells forming the aorcopulmonary septum. Septaon 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. Septaon 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 Septaon of the Bulbus Cordis

Anterior

1

2

3 1 2 3

The aorcopulmonary septum then rotates as it moves inferiorly. However, the exact mechanism for that rotaon remains unclear. Septaon of the Bulbus Cordis

Aorta Pulmonary Artery

Conal Ridges

IV Foramen

Membranous Muscular IV Endocarial Septum Interventricular Cushion Septum However, the aorcopulmonary septum must form properly for the IV septum to be completed. Embryonic Circulaon Common Cardinal Vein Brain and Spinal Cord

Posterior Anterior Cardinal Vein Cardinal Vein Umbilical Artery

Umbilical Vein Yolk Aorc Arches Sac

Ventricle Vitelline Artery Atria & Vein

Blood leaves the truncus and moves to the aorc arches. There is an aorc arch for each pharyngeal arch. http://php.med.unsw.edu.au/embryology/index.php? title=File:Advanced_Heart_Development_Timeline.jpg 71