AL-Qassim University Faculty of Medicine (second year- 1431) Development of the cardiovascular system Part I- development of the heart Prepared by Dr / Amani Almallah

Our objectives today are: 1- Formation and sequence of the normal development of the heart tube. 1.Septal formation in atrioventricular canal, autrium, ventricle, and truncus and bulbus; 2.Congenital Anomalies in each stage: the embryological origin of Atrial septal defects (ASD), Tetrology of Fallot and Eisenmenger ُُs syndrome

Angiogenesis The vascular system appears in the middle of the third week. Cardiac progenitor cells lie immediately lateral to the primitive streak. From there, they migrate to lie cranial to the buccopharyngeal membrane and neural folds. Here they reside in the splanchnic layer of the lateral plate mesoderm. At this time, they are induced by the underlying pharyngeal endoderm to form cardiac myoblasts. Blood islands also appear in this mesoderm will form blood cells and vessels by the process of vasculogenesis. This region is known as the cardiogenic area the intraembryonic cavity over it later develops into the pericardial cavity. Mesenchymal cells in the cardiogenic area form two angioblastic cords. These cords canalized to form two endothelial heart tubes. Tubes fuse to form a single endothelial heart tube.

primitive blood cells.

Within this network, the following main blood vessels are differentiated : 1- primitive aorta: one on each side. It begins in the septum transversum and extends caudally close to the middle line. At first, it turns ventrally to the pericardium and then along side the notochord and primitive streak. It then extends into the connecting stalk where it form the umbilical artery. 2- Vitelline vein: one on each side. It is formed by collection of veins from the wall of the yolk sac and later the gut. This vein will joins the umbilical vein to form the vitello-umbilical vein. 3- umbilical vein: one on each side. It turn close to the margin of the embryonic plate. Posteriorly, the two umbilical veins pass into the connecting stalk where they unite to form a single vein called vena umbilicalis impare. Anteriorly, the umbilical vein joins the vitelline vein in the septum transversum to form the vitello-umbilical trunk one on each side.

The vitello-umbilcal trunk ends by joining the caudal end of primitive aorta. 4- Common cardinal veins : return poorly oxygenated blood from the body of the embryo.

As a result of folding of embryonic plate, the primitive aorta on each side is differentiated into three parts: 1- ventral aorta: this is the part of the aorta enclosed in the head fold and lies ventral to the foregut. 2- the dorsal aorta: this is the greater caudal part of the primitive aorta which lies dorsal to the gut. At a later stage, the two dorsal aortae fuse together to form a single median dorsal aorta. 3- First aortic arch: this is the primitive aorta connecting the ventral and dorsal aortae. Later, five aortic arches will appear caudal to the first. The two ventral aortae fuse together in the middle to form a single tube called heart tube. The heart tube is connected cranially with the first aortic arch, and at its caudal end with the vitello-umbilical trunk.

Formation and Position of the Heart Tube Initially, the cardiogenic area is anterior to the buccopharyngeal membrane and the neural plate. With growth of the nervous system, it extends over the central cardiogenic area and the future pericardial cavity. As a result of this growth, the buccopharyngeal membrane is pulled forward, while the heart and pericardial cavity move first to the cervical region and finally to the thorax. The developing heart tube bulges more and more into the pericardial cavity. However, the tube remains attached to the dorsal side of the pericardial cavity by a fold of mesodermal tissue called (dorsal mesocardium). No ventral mesocardium is ever formed. With further development, the dorsal mesocardium disappears, creating the transverse pericardial sinus, which connects both sides of the pericardial cavity.

The heart is now suspended in the cavity by blood vessels at its cranial and caudal poles. During these events, the myocardium thickens and secretes a thick layer of extracellular matrix, rich in hyaluronic acid, that separates it from the endothelium cardiac jelly. In addition, mesothelial cells from the region of the sinus venosus migrate over the heart to form the epicardium. Thus the heart tube consists of three layers: (a) the endocardium, forming the internal endothelial lining of the heart. (b) the myocardium, forming the muscular wall. (c) the epicardium or visceral pericardium, covering the outside of the tube. is derived from mesothelial cells of the sinus venosus and spread over the myocardium. This outer layer is responsible for formation of the coronary arteries.

Formation of the Cardiac Loop A constriction divides the heart tube into two chambers, the bulbus cordis cranially and atrio-venticular chamber caudally. A second constriction appears caudal to the first one, this constriction divides the atrio-ventricular chamber into the ventricle cranially and the atrium caudally.

The second constriction marks the atrio-ventricular (a-v) canal. The atrium recieves the vitello-umbilical trunk. The heart tube continues to elongate and bend on day 23, at a higher rate than pericardium. The heart tube undergoes bending. The result of bending: 1- the heart tube forms spiral S-shaped tube. 2- The atria acquired a dorso-cranial and to right position. The a trial portion, initially a paired structure outside the pericardial cavity, forms a common atrium and is incorporated into the pericardial cavity. 3- The bulbus cordis and the ventricle form a U-shaped loop ventral to the atria. This bending, which may be due to cell shape changes, creates the cardiac loop. It is complete by day 28.

4- The atrioventricular junction forms the atrio-ventricular canal, which connects the common atrium and common ventricle shifted to the left. 5- The junction between the ventricle and the bulbus cordis, externally indicated by the bulboventricular sulcus, remains narrow. 6- The bulbus cordis is narrow except for its proximal third. a- its proximal portion will form the trabeculated part of the right ventricle. B- its middle portion, the conus cordis, will form the outflow tracts of both ventricles. C- The distal part of the bulbus, the truncus arteriosus, will form the roots and proximal portion of the aorta and pulmonary artery.

The developing Heart Bends on its self to form an S- shaped hear.

FROM TUBE TO FOUR CHAMBERS EXTERNAL VIEW

Abnormalities of Cardiac Looping 1- Dextrocardia, in which the heart lies on the right side of the thorax, is caused because the heart loops to the left instead of the right. Dextrocardia may coincide with situs inversus, a complete reversal of asymmetry in all organs.

Congential malformations Bifid apex of heart: This is a rare condition indicating a tendency for doubling of the heart. Acardia Absence of heart Ectopic Cordis Heart is located outside the thoracic cavity, through a sternal fissure or Into the neck or Down through a diaphragmatic hernia.

Development of the Sinus Venosus The last chamber to appear in the heart tube is the sinus venosus in the middle of 4 th week. It is the most caudal chamber, receives venous blood from the right and left sinus horns, Each horn receives blood from three important veins: (a) the vitelline vein. (b) the umbilical vein. (c) the common cardinal vein (duct of cuvier). Soon, however, the entrance of the sinus shifts to the right( due to the changes in the arrangement of the veins and direction of the vitello-umbilical blood flow by the development of liver). So a crescent constriction is seen in the left side, this constriction lead to the blood reach more to the right side. With obliteration of the right umbilical vein and the left vitelline vein during the fifth week, the left sinus horn rapidly loses its importance.

When the left common cardinal vein is obliterated at 10 weeks, all that remains of the left sinus horn is the oblique vein of the left atrium and the coronary sinus. As a result of left-to-right shunts of blood, the right sinus horn and veins enlarge greatly. The right horn, which now forms the only communication between the original sinus venosus and the atrium, is incorporated into the right atrium to form the smooth-walled part of the right atrium. Its entrance, the sinuatrial orifice with right and left venous valves on each side. Dorsocranially the valves fuse, forming a ridge known as the septum spurium. Initially the right sinus horn is incorporated into the wall of the Rt atrium and forms: (a) the valve of the inferior vena cava. (b) the valve of the coronary sinus. ( c) The crista terminalis

which forms the dividing line between the original trabeculated part of the right atrium and the smooth-walled part (sinus venarum), which originates from the right sinus horn.

Division of the atrio-ventricular canal By the end of the 4 th week, cardial cushions are formed in the ventral and dorsal wall of the a-v canal. They are formed by active growth of a single tissue mass that continues to expand until it reaches the opposite side of the lumen. Formation of such tissue masses depends on synthesis and deposition of extracellular matrices and cell proliferation. Fusion of the endocardial cushions in the atrioventricular canal forms the (septum intermedium). Formation of this septum resulting in a complete division of the canal into right and left atrioventricular orifices by the end of the 5 th week, Endocardial cushions are formed also in the conotruncal regions. In these locations. They assist in formation of the atrial and ventricular (membranous portion) septa, the atrioventricular canals and valves, and the aortic and pulmonary channels.

Endocardial Cushions and Heart Defects Because of their key location, abnormalities in endocardial cushion formation contribute to many cardiac malformations, including atrial and ventricular septal defects and defects involving the great vessels (i.e., transposition of the great vessels and tetralogy of Fallot).

Formation of the Cardiac Septa SEPTUM FORMATION IN THE COMMON ATRIUM: At the end of 4th week, a sickle-shaped crest grows from the roof of the common atrium into the lumen. This crest is the first portion of the septum primum. The two limbs of this septum extend toward the endocardial cushions in the atrioventricular canal. The opening between the lower rim of the septum primum and the endocardial cushions is the ostium primum. With further development, extensions of the superior and inferior endocardial cushions grow along the edge of the septum primum, closing the ostium primum. Before closure is complete, however, cell death (apoptosis) produces perforations in the upper portion of the septum primum.

Coalescence of these perforations forms the ostium secundum, ensuring free blood flow from the right to the left primitive atrium. When the lumen of the right atrium expands new fold, the septum secundum. Its anterior limb extends downward to the septum in the atrioventricular canal. When the left venous valve and the septum spurium fuse with the right side of the septum secundum, the free concave edge of the septum secundum begins to overlap the ostium secundum. The opening left by the septum secundum is called the oval foramen (foramen ovale). When the upper part of the septum primum gradually disappears, the remaining part becomes the valve of the oval foramen. The blood passes from the right atrium flows to the left side. After birth, when lung circulation begins and pressure in the left atrium increases, the valve of the oval foramen is pressed against the septum secundum, obliterating the foramen ovale.

The septum primum forms the floor of the fossa ovalis. The inferior edge of the septum secundum forms a rounded fold, the limbus fossae ovalis (anulus ovalis).

Differentiation of the Atria While the primitive right atrium enlarges by incorporation of the right sinus horn, the primitive left atrium is likewise expanding. Initially, a single embryonic pulmonary vein develops as an outgrowth of the posterior left atrial wall, just to the left of the septum primum This vein gains connection with veins of the developing lung buds. During further development, the pulmonary veins are incorporated into the left atrium, forming the large smooth-walled part of the adult atrium. In the fully developed heart, the original left atrium is represented by the trabeculated atrial appendage, while the smooth-walled part originates from the pulmonary veins. The right atrium becomes the trabeculated right atrial appendage containing the pectinate muscles, and the smooth-walled sinus venarum originates from the right horn of the sinus venosus.

Abomalies in the atrial septation 1- complete ansence of the interatrial septum: due to complete absence of the two septa. 2- Atrial septal defect (ASD):One of the most significant defects is the ostium secundum defect, characterized by a large opening between the left and right atria. It is caused either by excessive cell death and resorption of the septum primum or by inadequate development of the septum secundum. 3- Patent foramen ovale: remains after birth due to the two septa are not fused together after birth. 4- premature closure of the oval foramen: leads to massive hypertrophy of the right atrium and ventricle and underdevelopment of the left side of the heart. Death usually occurs shortly after birth. 5- persistance of the atrio-ventricular canal

ATRIAL SEPTAL DEFECTS- “Fossa Ovalis” type

ATRIAL SEPTAL DEFECTS Unrelated to Foramen Ovale

Formation of the interventricular septum By the end of the 4 th week, the two primitive ventricles begin to expand. This is accompanied by trabecula formation on the inside. The medial walls of the expanding ventricles gradually merge, forming the muscular interventricular septum. The space between the free rim of the muscular ventricular septum and the fused endocardial cushions permits communication between the two ventricles. The interventricular foramen, During development, outgrowth of tissue from the endocardial cushion along the top of the muscular interventricular septum closes the foramen. Complete closure of the interventricular foramen forms the membranous part of the interventricular septum. The proximal bulbar septum develops as two ridges which fuse together. This septum divides the bulbus cordis longitudinally into;

Into the infundibulum of the Rt ventricle and vestibule of the Lt ventricle. This septum share in the closure of the interventricular foramen. Distal bulbar septum Four endocardial cushions (anterior, posterior and two lateral) are developed in the distal part of the bulbus cordis. - A ridge is developed in the middle of each of the two lateral cushion, these two ridges fuse to form a complete septum called the distal bulbar septum. So the distal end of the bulbus cordis is divided into two Pulmonary orifice anteriorly and the aortic orifice posteriorly. -Formation of the distal bulbar septum divides each of the lateral cushion into two. As a result, the pulmonary and aortic orifices is guarded by three cusps. -Originally, the cusps of pulmonary are one anterior and two posterior, but after rotation the two cusps are anterior and the one is posterior.

Originally, the cusps of aorta are one posterior and two anterior, but after rotation the two cusps are posterior and the one is anterior. Spiral aortopulmonary septum: Two opposite ridges are developed in the wall of the truncus arteriosus during the 5 th week of development. The two ridges have varying positions in the different part of the truncus arteriosus. In the lower part of the truncus, the ridges are right and left. In the middle, the right becomes anterior and the left become posterior. In the upper part, the anterior ridge becomes left and the posterior ridge becomes right. When the two ridges fuse together, a spiral septum is formed. This septum is called aorticopulmonary septum. This septum divides the truncus arteriosus into The ascending aorta and pulmonary trunk.

The upper border of the spiral septum fuse with the posterior wall of the aortic sac between the attachment of the 4 th and 6 th aortic arch. As a result descending aorta becomes continuous with the upper part of the aortic sac and the upper four aortic arches but the pulmonary trunk becomes continuous only with 6 th aortic arch which form the pulmonary arteries and the ductus arteriosus on the Lt side

Spiral aortopulmonary septum

Development of the conotruncal ridges (cushions) and closure of the interventricular foramen. Proliferations of the right and left conus cushions, combined with proliferation of the inferior endocardial cushion, close the interventricular foramen and form the membranous portion of the interventricular septum. A. 6 weeks. B. Beginning of the seventh week. C. End of the seventh week

Abnormal division of Trancus Arteriosus

Atrioventricular Valves After the atrioventricular endocardial cushions fuse, each atrioventricular orifice is surrounded by local proliferations of mesenchymal tissue. When the bloodstream hollows out and thins tissue on the ventricular surface of these proliferations, valves form and remain attached to the ventricular wall by muscular cords. Finally, muscular tissue in the cords degenerates and is replaced by dense connective tissue. The valves then consist of connective tissue covered by endocardium. They are connected to thick trabeculae in the wall of the ventricle, the papillary muscles, by means of chordae tendineae. In this manner two valve leaflets, constituting the bicuspid, or mitral, valve, form in the left atrioventricular canal, and three, constituting the tricuspid valve, form on the right side.

Formation of atrioventricular valves

Endocardial cushions of the atrioventricular canal participate in formation of the membranous portion of the interventricular septum and in closure of the ostium primum. Whenever the cushions fail to fuse, the result is: 1- A persistent atrioventricular canal, combined with a defect in the cardiac septum. This septal defect has an atrial and a ventricular component, separated by abnormal valve leaflets in the single atrioventricular orifice. 2- Tricuspid atresia, which involves obliteration of the right atrioventricular orifice, is characterized by the absence or fusion of the tricuspid valves. Tricuspid atresia is always associated with (a) patency of the oval foramen, (b) ventricular septal defect, (c) underdevelopment of the right ventricle, and (d) hypertrophy of the left ventricle.

Semilunar Valves When partitioning of the truncus is almost complete, primordia of the semilunar valves become visible as small tubercles found on the main truncus swellings. One of each pair is assigned to the pulmonary and aortic channels, respectively. A third tubercle appears in both channels opposite the fused truncus swellings. Gradually the tubercles hollow out at their upper surface, forming the semilunar valves. Recent evidence shows that neural crest cells contribute to formation of these valves.

Septation anomalies in the ventricle and truncus arteriosus 1- Ventricular septal defect (VSD) involving the membranous portion of the septum is the most common congenital cardiac malformation. Although it may be found as an isolated lesion, VSD is often associated with abnormalities in partitioning of the conotruncal region

2- Tetralogy of Fallot T he most frequently occurring abnormality of the conotruncal region, is due to an unequal division of the conus resulting from anterior displacement of the conotruncal septum. Displacement of the septum produces four cardiovascular alterations: (a) a narrow right ventricular outflow region, a pulmonary infundibular stenosis; (b) a large defect of the interventricular septum; (c) an overriding aorta that arises directly above the septal defect; and (d) hypertrophy of the right ventricular wall because of higher pressure on the right side. 3- Trilogy of Fallot 1- Pulmonary Stenosis. 2- ASD 3- Right ventricular hypertrophy

2- Tetralogy of Fallot (cyanotic congenital heart). Unequal division of conus cordis; 4 defects: pulmonary stenosis, overriding aorta, ventricular septal defect, hypertrophy of right ventricle.

4- Eisenmanger Complex. Characterized by: a) Pulmonary hypertension b) Dilatation of the Pulmonary trunk. C )Hypertrophy of the right ventricle Some times in addition to ASD & VSA

5- Persistent truncus arteriosus results when the ridges fail to fuse and to descend toward the ventricles. In such a case, the pulmonary artery arises some distance above the origin of the undivided truncus. Since the ridges also participate in formation of the interventricular septum, the persistent truncus is always accompanied by a defective interventricular septum. 6- Transposition of the great vessels occurs when the conotruncal septum fails to follow its normal spiral course and runs straight down. As a consequence, the aorta originates from the right ventricle, and the pulmonary artery originates from the left ventricle. sometimes is associated with a defect in the membranous part of the interventricular septum. It is usually accompanied by an open ductus arteriosus. Since neural crest cells contribute to the formation of the truncal cushions, insults to these cells contribute to cardiac-defects involving the outflow tract.

5- Persistent truncus arteriosus ridges fail to fuse and descend ; Truncus overrides both ventricles; Accompanied by ventricular septal defect; Cyanosis, blood to lungs increased.

6- Transposition of great vessels Truncoconal septum failing to follow its spiral course and descending straight downward; Aorta originates from right ventricle, pulmonary artery from left; Usually combined with patent ductus arteriosus

Patent ductus arteriosus Ductus arteriosus fails to be closed after birth; Isolated or combined with other defects.

7- Valvular stenosis of the pulmonary artery or aorta occurs when the semilunar valves are fused for a variable distance. In the case of a valvular stenosis of the pulmonary artery, the trunk of the pulmonary artery is narrow or even atretic. The patent oval foramen then forms the only outlet for blood from the right side of the heart. The ductus arteriosus, always patent, is the only access route to the pulmonary circulation. In aortic valvular stenosis, fusion of the thickened valves may be so complete that only a pinhole opening remains. The size of the aorta itself is usually normal. 8- Valvular atresia: When fusion of the semilunar aortic valves is complete– aortic valvular atresia the aorta, left ventricle, and left atrium are markedly underdeveloped. The abnormality is usually accompanied by an open ductus arteriosus, which delivers blood into the aorta.

7 &8- Tricuspid atresia Absence or fusion of tricuspid valves; Patent oval foramen & ventricular septal defect; Underdeveloped right ventricle

7 &8Pulmonary valvular atresia (or stenosis) Pulmonary valves are fused for variable distance. Hypoplastic right heart; Patent oval foramen and patent ductus arteriosus

Aortic valvular atresia and stenosis Aortic valves are fused for variable distance; Aorta, left ventricle, left atrium underdeveloped; Accompanied by patent ductus arteriosus.

Formation of the Conducting System of the Heart Initially the pacemaker for the heart lies in the caudal part of the left cardiac tube. Later the sinus venosus assumes this function, and as the sinus is incorporated into the right atrium, pacemaker tissue lies near the opening of the superior vena cava. Thus, the sinuatrial node is formed. The atrioventricular node and bundle (bundle of His) are derived from two sources: (a) cells in the left wall of the sinus venosus, and (b) cells from the atrioventricular canal. Once the sinus venosus is incorporated into the right atrium, these cells lie in their final position at the base of the interatrial septum.