Development of the Heart 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 embryo begins form blood islands 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 BMP expression WNT inhibitors (crescent & cerberus) NKX 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 Horseshoe- Shaped 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. Body Cavity Heart 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 Anterior Cardinal Vein Brain and Spinal Cord Posterior Cardinal Vein Umbilical Artery Aortic Arches Yolk Sac Umbilical Vein Ventricle Atria Vitelline Artery & Vein
Endocardial Heart Tube aortic arches II aortic sac III truncus art. conus cordis. I bulbus 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.
Retinoic Acid from mesoderm Atria and sinus venosus then produces RA Commits region Bulbus and ventricles produce lower levels of RA Isotretinoin (vitamin A) Vitamin A embryopathy: small, abnormally shaped ears, mandibular hypoplasia, cleft palate, heart defects RA
2 nd heart field Precardiac mesoderm Myogenic progenitor Myocardial progenitor Immature myocyte Differentiated atrial myocyte Myocardial progenitor Endothelial cells Vascular smooth Muscle progenitor Immature myocyte Immature myocyte 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 Truncus Ventricle Conus Atria Sinus Venosus
Convolution of the Heart Tube 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 Truncus 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 conus atrium ventricle
Primitive 4 Chamber Heart If a coronal section is then take and viewed from the front the next slide shows the view you would see. truncus 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 RV LV 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.
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
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 Right Ventricle Left 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 Right Ventricle Left 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. Ostium Primum R. Atrium L. Atrium Septum 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 (septum secundum) develops to the right of ostium secundum. Septum Secundum R. Atrium L. Atrium
Septum spurium L. venous valve Atrial Septation As septum secundum develops the blood now all flows into the right atrium in between the right and left venous valves. 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 sinus venosus tissue From pulmonary vein 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 Right Ventricle Left Ventricle inferior
Left Atrial Development As the pulmonary vein develops it empties into the left atrium. R. Atrium L. Atrium Pulmonary vein
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 sinus venosus tissue From pulmonary vein 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 Right Ventricle Left 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 IVS I V E IVS 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 SVC Aorta 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 P A 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 A P
SeptaIon of the Bulbus Cordis A P 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 1 2 Anterior 3 1 2 3 The aoricopulmonary septum then rotates as it moves inferiorly. However, the exact mechanism for that rotaion remains unclear.
However, the aoricopulmonary septum must form properly for the IV septum to be completed. SeptaIon of the Bulbus Cordis Aorta Pulmonary Artery Conal Ridges IV Foramen Membranous Interventricular Septum Endocarial Cushion Muscular IV Septum
Embryonic CirculaIon Common Cardinal Vein Dorsal Aorta Anterior Cardinal Vein Brain and Spinal Cord Posterior Cardinal Vein Umbilical Artery AorIc Arches Yolk Sac Umbilical Vein Ventricle Atria Vitelline Artery & Vein Blood leaves the truncus and moves to the aoric arches. There is an aoric arch for each pharyngeal arch.
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