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 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 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 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 Anterior Cardinal Vein Cardinal Vein Umbilical Artery Umbilical Vein Yolk Aortic Arches Sac Ventricle Vitelline Artery Atria & Vein Endocardial Heart Tube aortic arches I II aortic sac III 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 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 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 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 primitive ventricle 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 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 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. 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 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 (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 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 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 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 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. 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.