EMBRYO-LC14-Embryonic Development of the Cardiovascular System.pdf

III. CARDIOGENIC FIELD OUTLINE I. Cardiac Cell Lines II. Cardiovascular System III. Cardiogenic Field A. Pr...

III. CARDIOGENIC FIELD OUTLINE I. Cardiac Cell Lines II. Cardiovascular System III. Cardiogenic Field A. Progenitor Heart Cells B. Primary Heart Field C. Secondary Heart Field D. Vasculogenesis E. Horseshoe Shaped Endothelial-Lined Cells F. Dorsal Aortae IV. Formation and Position of the Heart Tube V. Formation of Cardiac Loop A. Atrial Portion B. Atrioventricular Junction C. Bulbus cordis D. Bulboventricular Junction VI. What happens after looping is completed? Figure 1. A. Dorsal View of a Late Presomite. Embryo [approximately 18 days] VII. Development of Sinus Venosus after removal of the amnion. Progenitor heart cells have migrated and formed VIII. Formation of the Cardiac Septa the horseshoe-shaped PHF located in the splanchnic later of lateral plate IX. Septum Formation in the Common Atrium mesoderm. As they migrate, PHF cells are specified to develop the L & R sides of X. Formation of the Left atrium and Pulmonary Vein the heart, including the [LV] Left Ventricle, and parts of both [A] Atria. The [RV] XI. Septum formation in the atrioventricular canal Right Ventricle, outflow tract [C] Conus Cordis & [T] Truncus Arteriosus and XII. Septum formation in the atrioventricular canal (End of 5th remainder of both atria also exhibit L & R patterning and are formed by the SHF. week) B. Transverse section through a similar-staged embryo to show the position of XIII. Atrioventricular Valves Formation PHF cells in the visceral mesoderm layer XIV. Septum formation in the Truncus Arteriosus and Conus Cordis XV. Septum formation in the Ventricles A. Progenitor Heart Cells XVI. Semilunar Valves Lie in the Epiblast XVII. Formation of the conducting system of the heart Immediately adjacent to the cranial end of the primitive XVIII. Vascular Development streak XIX. Arterial System: Aortic Arches They migrate cranially through the streak and into the XX. Venous System (5th week) visceral layer of the lateral plate mesoderm XXI. Clinical Correlations Establishing the primary heart field B. Primary Heart Field I. CARDIAC CELL LINES Cranial to the neural folds Form a horseshoe-shaped cluster of cells Composed of LEFT and RIGHT PRIMARY HEART FIELD Mesoderm - has majority contribution to the formation of cardiac which ends will fuse together to form part of ATRIA and muscle ENTIRE LEFT VENTRICLE Ectoderm - neural crest came from ectodermal origin ○ Minority of the cardiac cell lines are derived C. Secondary Heart Field Resides visceral (splanchnic) mesoderm ventral to the Note: when a patient has a problem in neural crest especially those with Spina pharynx bifida where in the neural tube is not exactly closed, you’ll expect also that the Forms the Right Ventricle & Outflow Tract ( Right: Conus patient may also have a problem with the heart which is most probably part of Cordis and Left: Truncus Arteriosus) the blood vessels problems such as Tetralogy of Fallot and Truncus Arteriosus. Contributes cells to formation of the atria at the caudal end of the heart Endoderm - to form the blood vessels ○ Other cardiac lines that make up the heart during the D. Vasculogenesis development Process where Blood Cells and Vessels are formed ← Cardiac Myoblasts & Blood Islands ← PHF induced by pharyngeal endoderm II. CARDIOVASCULAR SYSTEM When the primary heart field is established, the pharyngeal endoderm induces PHF to form bloodlines. Vascular System Cardiac myoblast will proliferate to become blood cells and vessels Appear in the mid of 3rd week age of gestation AOG Formed when the embryo is no longer able to satisfy its nutritional E. Horseshoe Shaped Endothelial Lined Tube requirements by diffusion alone. It needs to have nutrition coming Formed from the union of blood islands unite from circulation (surrounded by myoblasts) They need vascular system for the embryo to fully develop From the Cardiogenic Region Pericardial cavity (from intraembryonic cavity) surrounds Note: Nutrition by diffusion → diffusion replaced by circulation the cardiac region Fuse on its ends to form a single tube later on Page 1 of 19 [EMBRYOLOGY] 1.14 EMBRYONIC DEVELOPMENT OF THE CARDIOVASCULAR SYSTEM – Dr. Leslie A. Viado F. Dorsal Aortae Longitudinal vessels form the blood islands Will be formed posteriorly coming from the blood islands Figure 2. Showing the SHF that lies visceral mesoderm at the posterior of the pharynx. The SHF provides cells that lengthen the arterial and venous poles of the heart, which includes the Right Ventricle and the Outflow Tract [Conus Cordis & Truncus Arteriosus] and Atria and Sinus Venosus respectfully. Figure 4. Showing formation of a single heart tube from paired primordia. Disruption of the SHF causes shortening of the outflow tract region, resulting in A. Early presomite embryo [17 days]. B. Late presomite embryo [18 days]. outflow tract defects C. Eight—somite stage [22 days]. Fusion occurs only in the caudal region of the horseshoe—shaped tube. The outflow tract and most of the ventricular region IV. FORMATION AND POSITION OF THE HEART TUBE form by expansion and growth of the crescent portion of the horseshoe. Receives venous drainage at its caudal pole and begins to pump Initially, the central portion of the cardiogenic area is anterior to the blood out of the first aortic arch into the dorsal aorta at its cranial oropharyngeal membrane and the neural plate pole. Closure of the neural tube and formation of the brain vesicles Tube remains attached to the dorsal side of the pericardial cavity by a Central nervous system grows cranially so rapidly that it extends over fold of mesodermal tissue (dorsal mesocardium) from the SHF the central cardiogenic region and the future pericardial cavity No ventral mesocardium is ever formed. Figure 3. Showing the cardiogenic area and the pericardial cavity are in front of the oropharyngeal membrane Figure 5. Frontal view of an embryo showing the heart in the pericardial cavity and the developing gut tube with the anterior and posterior intestinal portals. Growth of the brain and cephalic folding of the embryo The original paired tubes of the heart primordia have fused into a single tube ○ The oropharyngeal membrane is pulled forward except at their caudal ends, which remain separate. These caudal ends of the ○ The heart and pericardial cavity move first to the cervical heart tube are embedded in the septum transversum, whereas the outflow tract region and finally to the thorax leads to the aortic sac and aortic arches. The embryo grows and bends cephalocaudally, and laterally Central part of the horseshoe shaped tube expands to form the Middle section of the dorsal mesocardium disappears. future outflow tract and ventricular regions. ○ Creating the transverse pericardial sinus connecting both Heart becomes a continuous expanded tube consisting of an inner sides of the pericardial cavity endothelial lining and an outer myocardial layer. Heart is now suspended in the cavity by blood vessels at its cranial (Truncus Arteriosus) and caudal (Sinus Venosus) poles Myocardium thickens and secretes a layer of extracellular matrix, rich in hyaluronic acid called cardiac jelly which separates it from the endothelium. Mesenchymal cells proliferate and migrate over the surface of the myocardium to form the epicardium Page 2 of 19 [EMBRYOLOGY] 1.14 EMBRYONIC DEVELOPMENT OF THE CARDIOVASCULAR SYSTEM – Dr. Leslie A. Viado Epicardium responsible for formation of the coronary arteries is very important so that the whole cardiac region will be placed in the pericardial cavity. B. Atrioventricular Junction Forms the atrioventricular canal Connects the common atrium and the early embryonic ventricle C. Bulbus cordis Proximal 1/3 — trabeculated part of the right ventricle Midportion — a.k.a. the conus cordis form the outflow tracts of both ventricles (no division between right and left outflow tract) Distal 1 /3 — a.k.a. truncus arteriosus form the roots and proximal portion of the aorta and pulmonary artery D. Bulboventricular Junction junction between the ventricle and the bulbus cordis Called the primary interventricular foramen Note: Thus, the cardiac tube is organized by regions along its craniocaudal axis from the conotruncus to the right ventricle to the left ventricle to atrial region, Figure 6. Single tube of pericardial cavity will receive oxygenated blood in the respectively. Sinus venosus and deoxygenated blood in Truncus arteriosus. The blood will pass thru Sinus venosus to Primitive atrium, Ventricle, Bulbus cordis, and goes out to Truncus arteriosus. Single tube that was joint together with the use of blood VI. WHAT HAPPENS AFTER LOOPING IS COMPLETED? lines and cells coming from splanchnic mesosderm. Smooth-walled heart tube form primitive trabeculae in 2 sharply V. FORMATION OF CARDIAC LOOP defined areas proximal & distal to the primary interventricular foramen Bulbus temporarily remains smooth-walled (smooth walled will The heart tube continues to elongate as cells are added from the SHF become the right ventricle) to its cranial end Primitive ventricle now trabeculated is called the primitive left This lengthening process is essential: ventricle ○ For normal formation of the right ventricle and the Proximal third of the bulbus cordis is called the primitive right outflow tract region (conus cordis and truncus arteriosus) ventricle (trabeculated) ○ For the looping process that will occur later Cardiac tube begins to bend on day 23 and ends on day 28 ages of gestation Cephalic portion of the tube bends ventrally, caudally, and to the right Atrial (caudal) portion shifts dorsocranially and to the left What will happen if the cardiac looping is halted? There will be a transposition of the vessels or the right ventricle will be place on the left ventricle. If the right ventricle which is part of Bulbus cordis will not go to the right, then, the part of the right ventricle will be on left side. Figure 8. Frontal section through the heart of a 30—day embryo showing the primary interventricular foramen and entrance of the atrium into the primitive left ventricle. Note the bulboventricular flange. Arrows, direction of blood flow. Conotruncal portion of the heart tube: Figure 7. Formation of the cardiac loop. A. 22 days. B. 23 days. C. 24 ○ Initially on the right side of the pericardial cavity ○ As the looping is completed it will shifts gradually to a more medial position A. Atrial Portion ○ Change in position is the result of formation of two Forms a common atrium and is incorporated into the pericardial transverse dilations of the atrium bulging on each side of cavity. the bulbus cordis The reason why the heart will also loop is that it needs to be encapsulated in the pericardial cavity. Therefore, the cardiac looping Page 3 of 19 [EMBRYOLOGY] 1.14 EMBRYONIC DEVELOPMENT OF THE CARDIOVASCULAR SYSTEM – Dr. Leslie A. Viado VII. DEVELOPMENT OF SINUS VENOSUS Middle 4th week of AOG Sinus venosus receives venous blood from the right and left sinus horns attached posteriorly to the right atrium. Eventually all of the branches in the left horn will disappear. Right horn will receive the venous blood. Each horn receives blood from three important veins: ○ Vitelline or the Omphalomesenteric vein ○ Umbilical vein ○ Common cardinal vein Figure 10. Final stage in development of the sinus venous and great veins. L-R shunt: The right horn will become enlarged, 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, it will become the main cavity. Initially, the blood is coming from the right side to the left. As the embryo develops there will be shunting of blood from the primitive left atrium to the right side. So, the right horn and right atria will become dilated and enlarged. Sinuatrial orifice: flanked on each side by the right and left venous valves. Septum spurium: ridge formed when the valves fused dorsocranially. Left valve and septum spurium fused then the superior part of the right valve disappears. Inferior portion: where IVC Valve and Coronary Sinus Valve developed. Crista terminalis: divides trabeculated part of the right atrium and Figure 9. Dorsal view of two stages in the development of the sinus venosus at the smooth-walled part (sinus venarum), which originates from the approximately 24 days [A] and 35 days [B]. Broken line, the entrance of the sinus sinus horn. venosus into the atrial cavity. Each drawing is accompanied by a scheme to show in the transverse section the great veins and their relation to the atrial cavity. ACV, anteriorcardinal vein; PCV, posteriorcardinal vein; UV, umbilical vein; V/T V,vite|line vein; CCV, common cardinal vein. At first the communication between the sinus and the atrium is wide. 4th and 5th week There are left to right shunts of blood coming from the primitive left atrium to the primitive right atrium. Left venous flow will go to the right side of the cavity. Therefore, the left horn will no longer receive blood coming from the periphery, making the right atrium more dilated. All the venous circulation will go to the right horn. Hence, the entrance of the sinus shifts to the right. 5th week Obliteration of the right umbilical vein & left vitelline vein. Veins coming from the right sinus horn will be the only one present and the left sinus horn rapidly loses its importance. Figure 11. Ventral view of coronal sections through the heart at the level of the atrioventricular canal to show development of the venous valves. A. 5 weeks. B. 10th week Fetal stage. The sinus venarum [blue] is smooth— walled; it derives from the Left common cardinal vein is obliterated. right sinus horn. Arrows, blood flow. *Note: All that remains of the left sinus horn is the OBLIQUE VEIN of the left atrium and the coronary sinus. VIII. FORMATION OF THE CARDIAC SEPTA 27th and 37th days of development Methods by which a septum may be formed: ○ Two actively growing masses of tissue that approach each other until they fuse, dividing the lumen into two separate canals. Page 4 of 19 [EMBRYOLOGY] 1.14 EMBRYONIC DEVELOPMENT OF THE CARDIOVASCULAR SYSTEM – Dr. Leslie A. Viado ○ Formed by active growth of a single tissue mass that continues to expand until it reaches the opposite side of the lumen. ENDOCARDIAL CUSHIONS ○ Tissue masses that are formed centrally are endocardial cushions. ○ Develop in the atrioventricular and conotruncal regions ○ Form atrial and ventricular (membranous portion) septa, Figure 13. Atrial septa at 30 days (6mm). the atrioventricular canals and valves, and aortic and Septum secundum pulmonary channels. ○ Formed after the formation of ostium secundum ○ Lumen of the right atrium plus incorporation of the sinus ATRIOVENTRICULAR CUSHIONS horn ○ derived from endocardial cells that detach from the ○ New crescent-shaped fold surrounding and move into the matrix ○ Never forms a complete partition in the right and left atrial cavity. CONOTRUNCAL CUSHIONS ○ Anterior limb extends downward to the septum in the ○ derived from neural crest cells migrating from the cranial atrioventricular canal. neuron atrioventricular cushions, cells are derived from ○ Fused with left venous valve and septum sprimum on its cranial folds to the outflow tract region. right side → free concave edge of the septum secundum ○ Any problems in the conotruncal cushion may have been to overlap the ostium secundum. caused by the abnormal fusion of the neural tube which ○ Once septum secundum is closed, there will be an comes from the neural crest. opening left by septum secundum and becomes Foramen Ovale. Cushions are populated by in conotruncal cushions. Cells are derived from migrating and proliferating cells going into the Upper part of the septum primum disappears and becomes the Valve matrix. of Foramen Ovale. During fetal circulation, the oxygenated part is on the right side and the deoxygenated part is on the left side. The valve of the foramen ovale is the opening where the oxygenated blood transfers to the left side of the heart. Foramen ovale becomes fossa ovalis in adults. Figure 12. Drawings show development of endocardial cushions. Initially, the heart tube consists of the myocardium and endocardium separated by a layer of extracellular matrix (B) Endocardial cushions form in the atrioventricular canal Figure 14. Atrial septa at 33 days (9mm). and the outflow tract as exp the ECM (C) Cells migrate into the cushions and proliferate. X. FORMATION OF THE LEFT ATRIUM AND PULMONARY VEIN Primitive right and left atria enlarge by incorporation of the right IX. SEPTUM FORMATION IN THE COMMON ATRIUM sinus horn through diffusion Since there is a lot of blood going to the atria via right sinus horn, End of the 4th week these two chambers will enlarge Septum primum (first portion) Mesenchyme at the caudal end of the dorsal mesocardium begins to ○ Sickle-shaped crest grows from the roof of the common proliferate atrium into the lumen. Proliferating mesenchyme forms of the dorsal mesenchymal ○ Ostium primum: opening between the lower rim of the protrusion (DMP) and this grows with the septum primum toward septum primum and the endocardial cushions. the atrioventricular canal it will form pulmonary vein. ○ Extensions of the superior and inferior endocardial Within the DMP is the developing pulmonary vein that is positioned cushions grow along the edge of the septum primum, in the left atrium by the growth and movement of the DMP closing the ostium primum. Because of the movement of DMP, the pulmonary veins of the left ○ Before closure is complete, apoptosis produces atrium are developed. perforations in the upper portion of the septum primum. Remaining portion of the DMP at the tip of the septum primum ○ When there is a complete closure of septum primum, contributes to endocardial cushions formation in the atrioventricular there is cell death in the upper portion of septum canal primum, wherein there will be an opening before the Main stem of the pulmonary vein that opens into the left atrium complete closure. sends two branches to each lung ○ Cells that were coming from the apoptosis coalescence of these perforations forms the ostium secundum, ensuring free blood flow from the right to the left primitive atrium. Page 5 of 19 [EMBRYOLOGY] 1.14 EMBRYONIC DEVELOPMENT OF THE CARDIOVASCULAR SYSTEM – Dr. Leslie A. Viado XI. SEPTUM FORMATION IN THE ATRIOVENTRICULAR CANAL Four atrioventricular endocardial cushions appear, fused together to form the right and left atrioventricular canal. End of 4th week One on each side plus one at the dorsal (superior) and one at the ventral (inferior) border of the atrioventricular canal Initially, the atrioventricular canal gives access only to the primitive left ventricle and is separated from the bulbus cordis by the bulbo (cono) ventricular flange. To form the atrioventricular canal with the aid of blood flow to the cardiac cavity, the heart will try to elongate and it pushes the ventricle by diffusion and this cushion will try to coalesce. The inferior and anterior cushion will be coaptating until it forms two separate canals (Right and Left atrioventricular canal). Figure 15. A. Drawing showing the heart tube suspended into the pericardial Figure 17. Formation of the septum in the atrioventricular canal.From left to cavity by the dorsal mesocar­dium, a mesentery attached to mesoderm right, days 23,26,31,and35. The initial circular opening widens transversely. surrounding the gut tube, that is derived from the SHF. At this stage, the central portion of the mesocardium breaks down such that only the two ends of the heart tube remain attached. B,C. At the atrial pole, a portion of the dorsal mesocardium proliferates to form the dorsal mesenchymal protrusion [DMP] that penetrates the atrial wall to the left of the septum primum. The pulmonary vein forms within the mesenchyme of the DMP and becomes positioned in the posterior wall of the left atrium as the DMP grows downward with the septum primum. D. Initially, only the main stem of the pulmonary vein enters the left atrium, but, as the atrial walls expand, this stem is incorporated into the left atrium to the point where its four branches diverge to go to the lungs. Consequently, once the process of atrial expansión is complete, there are four openings for pulmonary veins into the left atrium. The remaining portion of the DMP remains at the tip of the septum primum and contributes to endocardial cushion formation around the atrioventricular canal. Fully developed heart Figure 18. Frontal section through the heart of a day-35 embryo. At this stage of ○ Original embryonic right atrium becomes the development, blood from the atrial cavity enters the primitive left ventricle as trabeculated right atrial appendage containing the well as the primitive right ventricle. Note develop­ment of the cushions in the pectinate muscles (only found in the appendages). atrioventricular canal. Cushions in the truncus and conus are also visible. Ring, ○ Smooth-walled sinus venarum become the main cavity, primitive interventricular foramen; arrows, blood flow. originates from the right horn of the sinus venosus ○ Original embryonic left atrium is represented by little more than the trabeculated atrial appendage. XII. SEPTUM FORMATION IN THE ATRIOVENTRICULAR CANAL (End of ○ Left primitive atrium becomes the left atrial appendage. 5th week) ○ Smooth-walled part originates from the pulmonary vein The posterior extremity of the flange terminates almost midway coming from the DMP. along the base of the dorsal endocardial cushion and is much less prominent than before Two lateral atrioventricular cushions appear on the right and left borders of the canal The dorsal and ventral cushions project further into the lumen and fuse, resulting in a complete division of the canal into right and left atrioventricular orifices XIII. ATRIOVENTRICULAR VALVES FORMATION Each atrioventricular orifice is surrounded by local proliferations of Figure 16. Coronal sections through the heart to show development of the mesenchymal tissue derived from the endocardial cushions smooth-walled portions of the right and left atria. Both the wall of the right Bloodstream hollows out and thins tissue on the ventricular surface sinus horn [blue] and the pulmonary vein [red] are incorpo­rated into the heart to of these proliferations form the smooth-walled parts of the atria. Mesenchymal tissue becomes fibrous and forms the AV valves AV valves remain attached to the ventricular wall by muscular cords Page 6 of 19 [EMBRYOLOGY] 1.14 EMBRYONIC DEVELOPMENT OF THE CARDIOVASCULAR SYSTEM – Dr. Leslie A. Viado Muscular tissue in the cords replaced by dense connective tissue, which is the fibrous skeleton and it is where the base is attached Connected to papillary muscles through the chordae tendinae 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. Figure 19. Formation of the atrioventricular valves and chordae tendineae. The valves are hollowed out from the ventricular side but remain attached to the Figure 20. Development of the conotruncal ridges [cushions] and closure of the ventricular wall by the chordae tendineae. interventricular foramen. Proliferations of the right and left conus cushions, combined with proliferation of the anterior endocardial cushion, cióse the interventricular foramen and form the membranous portion of the XIV. SEPTUM FORMATION IN THE TRUNCUS interventricular septum. A. 6 weeks [12 mm], B. Beginning of the seventh week [14.5 mm], C. End of the seventh week [20 mm). During the fifth week pairs of opposing ridges appear in the truncus NOTE: Lie on the right superior wall (will be the right superior truncus 1. Cardiac neural crest cells contribute to endocardial cushion formation in both swelling) And on the left inferior wall (will be the left inferior truncus the conus cordis and truncus arteriosus. swelling) 2. Because neural crest cells also contribute to craniofacial development, it is The Truncus will be one tube. As they grow distally, they twist common to see facial and cardiac abnormalities in the same individual Due to the enlargement or expanding of tissue in the area, (congenital anomalies, spina bifida) aorticopulmonary septum will be formed. The distal portion of bulbus cordis, is where the conus cordis is located and in this area, the outflow tract will be formed. Attached to the conus cordis the truncus arteriosus and there will be twisting of this vessel. As they twist distally outward, it will also cause the formation of the aorticopulmonary septum. As they twist, there will be separation of the conotruncal area and the truncus arteriosus becoming the right outflow tract forming the pulmonary trunk. The left outflow tract will connect the aorta. What will happen if there will be no development or no twisting between conus cordis and truncus arteriosus? There will be an inversion of the outlet. Both the pulmonary trunk and the aorta will be placed in the right ventricle and wil become a double outlet ventricle but if the twisting will halt medially, the truncus arteriosus will lie in the middle of interventricular septum then there will be overriding of the aorta. Sometimes, the great arteries will be found on the left side. If this great vessel will not twist the level of the conus cordis, there Figure 21. Drawing showing the origin of neural crest cells in the hindbrain and will be transposition of the great vessel. The right ventricle will give their migration through pharyngeal arches 3, 4, and 6 to the out- flow tract of off blood to the aorta and the left ventricle will give off blood to the the heart. In this location, they contribute to septation of the conus cordis and pulmonary trunk. truncus arteriosus. XV. SEPTUM FORMATION IN THE VENTRICLES End of the fourth week, the two primitive ventricles begin to expand (because of the circulation of blood to the primitive ventricles, the ventricle will become more hollow and will be pushed downward. Continuous growth of the myocardium on the outside and continuous diverticulation and trabecula formation on the inside so it will become bigger and the myocardial cells will become enlarged from the outside and more trabecula or sponge-like structures will be formed inside If Trabeculation is not developed during this process Non- compacted Right Ventricle or Left Ventricle will be formed as the baby will be delivered. Muscular interventricular septum: formed by medial walls of the expanding ventricles which become apposed and then merge Page 7 of 19 [EMBRYOLOGY] 1.14 EMBRYONIC DEVELOPMENT OF THE CARDIOVASCULAR SYSTEM – Dr. Leslie A. Viado Two walls do not merge completely Membranous ventricular septum comes from the endocardial cushion. Whereas XIX. ARTERIAL SYSTEM: AORTIC ARCHES the muscular interventricular septum comes from the expanding ventricles. Apical cleft between the two ventricle appears Fourth and fifth weeks of development Space between the free rim of the muscular ventricular septum and Each arch receives its own cranial nerve and its own artery. the fused endocardial cushions permits communication between the Aortic arches arise from the aortic sac the most distal part of the two ventricles truncus arteriosus Interventricular foramina shrink on completion of the conus septum Aortic arches are embedded in the mesenchyme of the pharyngeal Complete closure of the interventricular foramen forms the arches and terminate in the right and left dorsal aortae. membranous part of the interventricular septum Aortic sac contributes a branch to each new arch: giving rise to a total of five pairs of arteries. XVI. SEMILUNAR VALVES The fifth arch never forms or forms incompletely and then regresses: number I, II, III, IV and VI Partitioning of the truncus is almost complete Arterial pattern becomes modified, and some vessels regress - Primordia of the semilunar valves become visible as small tubercles completely as they develop. found in the main truncus swellings Neural crest cells regulate the pattern of development. One of each pair is assigned to the pulmonary and aortic channels Division of the truncus arteriosus by the aorticopulmonary septum: Tubercles hollow out at their upper surface, forming the semilunar divides the outflow channel of the heart into the ventral aorta and valves the pulmonary trunk. The aortic sac then forms right and left horns, Neural crest cells contribute to formation of these valves. which subsequently give rise to the brachiocephalic artery and the prox- imal segment of the aortic arch, respectively, as shown in figure 24, B and C. Aortic sac then forms the right horn becoming the brachiocephalic artery and the left horn becoming the proximal segment of the aortic arch. Figure 22. Longitudinal sections through the semilunar valves at weeks 6 (A), 7 Right: distal part of the sixth aortic arch and the fifth aortic arch disappears, the (B), and 9 (C) of development. The upper surface is hollowed [orrows] to form recurrent laryngeal nerve moves up and hooks around the right subclavian the valves. artery. Left: the nerve does not move up because the distal part of the sixth aortic arch persists as the ductus arteriosus later forms the ligamentum arteriosum. XVII. Formation of the conducting system of the heart Figure 23. A. Aortic arches and dorsal aortae before transformation into the All myocardial cells in the heart tube have pacemaker activity definitive vascular pattern. B. Aortic arches and dorsal aortae after the Heart begins to beat at approximately 21 days of gestation transformation. C. The great arteries in the adult. Pacemaker is restricted to the caudal part of the left side of the cardiac tube (initially the pacemaker is on the left side, but once the baby is born, the pacemaker will be on the right side, because of the twisting of cardiac tube) Later, the sinus venosus assumes this function. Why? Because there will be Left To- Right shunting. Then the right atrium will enlarge, the sinus venosus will be well developed and sinus venosus will be on the right side, and the pacemaker will be on the right side. Pacemaker tissue lies near the opening of the SVC as the sinus is incorporated into the right atrium then sinoatrial node (SAN) is formed. Table 1. Derivatives of the Aortic Arches. Atrioventricular node begins as a collection of cells located around the atrioventricular canal that coalesce to form the AVN, Impulses from the AVN (will pass through and pierce in to the septal VITELLINE ARTERIES leaflet of the tricuspid valve) pass to the atrioventricular bundle and A number of paired vessels supplying the yolk sac, gradually fuse and left and right bundle branches then pierce into the ventricular wall to form the arteries in the dorsal mesentery of the gut. the Purkinje fiber network. In Adults: the celiac (supply foregut) and superior mesenteric (supply midgut) arteries. XVIII. VASCULAR DEVELOPMENT UMBILICAL ARTERIES Blood vessel development occurs by two mechanism: Becomes inferior mesenteric arteries (supply hindgut). 1. Vasculogenesis in which vessels arise by the coalescence of the Initially paired ventral branches of the dorsal aorta, course to the angioblast placenta in close association with the allantois. - The major vessels (dorsal aorta and cardinal veins) During the fourth week, each artery acquires a secondary connection 2. Angiogenesis whereby vessels sprout from existing vessels with the dorsal branch of the aorta, the common iliac artery, and - The remainder of the vascular system then forms by loses its earliest origin. angiogenesis After birth, the proximal portions of the umbilical ar- teries persist as - Branches of aorta the internal iliac and superior vesical arteries, and the distal parts are Vascular endothelial growth factor - Important role for vascular obliter- ated to form the medial umbilical ligaments. development. CORONARY ARTERIES Derived from epicardium. Page 8 of 19 [EMBRYOLOGY] 1.14 EMBRYONIC DEVELOPMENT OF THE CARDIOVASCULAR SYSTEM – Dr. Leslie A. Viado Differentiated from the proepicardial organ located in the caudal portion of the dorsal mesocardium: derivative of the SHF. Epicardial cells undergo an epithelial to mesenchymal transition induced by the underlying myocardium. Neural crest cells also may contribute smooth muscle cells along the proximal segments of these arteries and may direct connection of the coronary arteries to the aorta. Connection occurs by ingrowth of arterial endothelial cells from the arteries into the aorta causing the coronary arteries to “invade” the aorta. The aortic cusp will give of the coronary arteries, except the noncoronary cusp or the posterior aortic cusp. Figure 24. Development of the vitelline and umbilical veins during the [A] fourth XX. VENOUS SYSTEM (5TH WEEK) and [B] fifth weeks. Note the plexus around the duodenum, formation of the hepatic sinusoids, and initiation of left—to—right shunts between the vitelline veins. Three pairs of major veins: CARDINAL VEINS A. Vitelline veins, or Omphalomesenteric veins Form the main venous drainage system of the embryo. - Carrying blood from the yolk sac to the sinus venosus (drains to right Consists of anterior, which drain the cephalic part of the embryo, atrium) posterior, which drain the rest of the embryo, and common cardinal veins. B. Umbilical veins 4th week: form a symmetrical system. - Originating in the chorionic villi and carrying oxygenated blood to the 5th week to the seventh weeks: subcardinal veins, sacrocardinal embryo veins, supracardinal veins. 1. Subcardinal veins, which mainly drain the kidneys; C. Cardinal veins 2. Sacrocardinal veins, which drain the lower extremities; - Draining the body of the embryo proper and 3. Supracardinal veins, which drain the body wall by way of There are only 2 venous segments that will carry oxygenated blood to the the intercostal veins, taking over the functions of the embryo, they are the umbilical veins. posterior cardinal veins. Formation of the vena cava system is characterized by the On adult circulation, the vein that will carry the oxygenated blood will be the appearance of anastomoses between left and right: pulmonary trunk. ○ Blood from the left is channeled to the right side Left brachiocephalic vein: anastomosis between the anterior cardinal VITELLINE VEINS veins. Before entering the sinus venosus they form a plexus around the Superior vena cava: right common cardinal vein and the proximal septum transversum portion of the right anterior cardinal vein. The liver cords growing into the septum interrupt the course of the The cardinal veins is usually formed by the anastomosis of the veins, and an extensive vascular network, the hepatic sinusoids, different veins forms. External jugular veins: plexus of venous vessels in the face Reduction of the left sinus horn, blood from the left side of the liver Left renal vein: anastomosis between the subcardinal veins is rechanneled with enlargement of right vitelline vein and form Renal segment of the inferior vena cava: right subcardinal vein hepatocardiac portion of the inferior vena cava. becomes the main drainage channel. Proximal part of the left vitelline vein disappears. Left common iliac vein: anastomosis between the sacrocardinal Superior mesenteric vein derives from the right vitelline vein. veins. The distal portion of the left vitelline vein also disappears. UMBILICAL VEINS XXI. CLINICAL CORRELATIONS The umbilical veins pass on each side of the liver but some connect to the hepatic sinusoids, shown in figure 25, A, B. LATERALITY AND HEART DEFECTS The proximal part of both umbilical veins and the remainder of the Establishing laterality during gastrulation is essential for normal heart right umbilical vein then disappear. development because it specifies cells contributing to and patterning Left vein is the only one that carry oxygenated blood from the the right and left sides of the heart. placenta to the liver (oxygenated blood because the placenta acts as The process requires a signaling cascade that includes serotonin the lungs in the fetal circulation) [5-HT] as a key molecule in initiating the pathway (See Figure n) Increase of the placenta circulation, a direct communication forms 5HT is concentrated on the left side of the embryo, in part because of between the left umbilical vein and the right hepatocardiac channel: a high concentration of its degrading enzyme, monoamine oxidase The Ductus Venosus (MAO), on the right side near the primitive node. After birth: form the ligamentum teres hepatis and ligamentum Nodal and FGF also accumulate on the left side and together with venosum. 5HT propagate signals that culminate in expression of PITX2, the master gene for left sidedness. The right side is also specified, but signals responsible for this event have not been as well established. Cardiac progenitor cells are also specified at this time both for the parts of the heart they will form and their left—right sidedness by the laterality pathway. This period [days 16 to 18] is critical for heart development and individuals with laterality defects, such as heterotaxy, often have many different types of heart defects, including ○ dextrocardia [right-sided heart], Page 9 of 19 [EMBRYOLOGY] 1.14 EMBRYONIC DEVELOPMENT OF THE CARDIOVASCULAR SYSTEM – Dr. Leslie A. Viado ○ ventricular septal defects [VSDs], HEART DEFECTS ○ atrial septal defects [ASDs], Heart and vascular abnormalities make up the largest category of ○ double outlet right ventricle [DORV; both the aorta and human birth defects and are present in 1% of live born infants. The pulmonary artery exit the right ventricle], incidence among stillborns is 10 times as high. It is estimated that 2% outflow tract defects of babies with heart defects have a chromosomal abnormality and, transposition of the great vessels conversely, that 33% of babies with a chromosomal abnormality have pulmonary stenosis, and others. a heart defect. In some conditions, such as trisomy 18, the incidence ○ Laterality defects of the heart of heart defects is 100%. atrial and ventricular isomerisms: both atria or Approximately 2% of heart defects are due to environmental agents, both ventricles have similar characteristics but most are caused by a complex interplay between genetic and instead of the normal left-right differences environmental influences (multifactorial causes). inversions: the characteristics of the atria or Classic examples of cardiovascular teratogens include rubella virus ventricles are reversed and thalidomide. Others include RA (Accutane), alcohol, and many Selective serotonin reuptake inhibitor [SSRI] class, an antidepressant, other compounds. Maternal diseases, such as insu-lin-dependent has been linked to an increase in heart defects. The mechanism for diabetes, have also been linked to cardiac defects. this teratogenic effect appears to be a disruption of 5-HT signaling Targets for genetic or teratogen-induced heart defects include heart important in the laterality pathway. progenitor cells from the PHF and SHF, neural crest cells, endocardial cushions, and other cell types important for heart development. The fact that the same malformation can result from disrupting different targets (e.g Transposition of the great arteries can result from disruption of the SHF or neural crest cells) means that heart defects are heterogeneous in origin and difficult to classify epidemiologically. Genes regulating cardiac development are being identified and mapped, and mutations that result in heart defects are being discovered. For example, mutations in the heart-specifying gene NKX2.5, on chromosome 535, can produce ASDs (secundum type), tetralogy of Fallot, and atrioventricular conduction delays in an autosomal dominant fashion. HOLT-DRAM SYNDROME Is a result of mutations in the TBX5 gene, characterized by preaxial [radial] limb abnormalities and ASDs. Defects in the muscular portion of the interventricular septum may also occur. It is one of a group of heart-hand syndromes illustrating that the same genes may participate in multiple developmental processes. For example, TBX5 regulates forelimb development and plays a role in septation of the heart. Figure 25. Dorsal view of a drawing of a 16-day embryo showing the laterality It is inherited as an autosomal dominant trait with a frequency of pathway. The pathway is expressed in lateral plate mesoderm on the left side 1/100,000 live births. and involves a number of signaling molecules, including serotonin (5HT), which result in expression of the transcription factor PITX2, the master gene for left HYPERTROPHIC CARDIOMYOPATHY sidedness. This pathway specifies the left side of the body and also programs caused by a mutation in a number of genes regulating production of heart cells in the primary and SHFs. The right side is specified as well, but genes sarcomere proteins that may result in sudden death in athletes and responsible for this patterning have not been completely determined. Disruption the general population. of the pathway on the left results in laterality abnormalities, including many The disease is inherited as an autosomal dominant, and most heart defects. mutations (45%) target the ꞵ-myosin heavy-chain gene (14q11.2). The result is cardiac hypertrophy due to disruption in the organization of cardiac muscle cells (myocardial disarray), which may ABNORMALITIES OF CARDIAC LOOPING: DEXTROCARDIA adversely affect cardiac output and/or conduction. A condition where the heart lies on the right side of the thorax and it occurs when the heart loops to the left instead of the right. VENTRICULAR INVERSION The defect may be induced during gastrulation, when laterality is is a defect in which the morphologic left ventricle is on the right and established, or slightly later when cardiac looping occurs. connects to the right atrium through a mitral valve. The morphologic It occurs with situs inversus, a complete reversal of asymmetry in all right ventricle is on the left side and connects to the left atrium organs, or may be associated with laterality sequences in which only through the tricuspid valve. some organ positions are reversed. The defect is sometimes called L-transposition of the great arteries because the pulmonary artery exits the morphologic left ventricle TOTAL ANOMALOUS PULMONARY VENOUS RETURN (TAPVR) and the aorta exits the morphologic right ventricle. However, the a rare birth defect where the pulmonary veins drain into other arteries are in their normal positions, but the ventricles are reversed. vessels or directly into the right atrium. The abnormality arises during the establishment of laterality and A deviation of the DMP to the right places the pulmonary vein in the specification of the left and right sides of the heart by the laterality right atrium instead of the left [20% of cases] or if deviation to the pathway. right is more pronounced, the vein can enter the superior vena cava or the brachiocephalic vein [50% of cases]. HYPOPLASTIC RIGHT HEART SYNDROME (HRHS) AND HYPOPLASTIC LEFT Because the dorsal mesocardium is normally a midline structure, it is HEART SYNDROME (HLHS) not surprising that TAPVR often occurs in individuals with heterotaxy. Are rare defects that cause an underdevelopment of the right or left sides of the heart, respectively. Page 10 of 19 [EMBRYOLOGY] 1.14 EMBRYONIC DEVELOPMENT OF THE CARDIOVASCULAR SYSTEM – Dr. Leslie A. Viado On the right, the ventricle is very small, the pulmonary artery is affected and may be atretic or stenosed, and the atrium may be small; On the left, the ventricle is very small, the aorta may be atretic or stenotic, and the atrium may be reduced in size. The laterality associated with these defects suggests an adverse effect on specification of the left and right cardiac progenitor cells at an early stage of cardiac morphogenesis. The defects can also arise when the helix-loop helix transcription factors Hand1 [left ventricle] and Hand2 [left ventricle] that regulate ventricular growth are misexpressed. Figure 28. A Normal atrial septum formation. B,C. Ostlum secundum defect caused by excessive resorption of the septum primum. D,E. Similar defect caused by failure of development of the septum secundum. F. Common atrium, or cor triloculare blventrlculare, resulting from complete failure of the septum primum and septum secundum to form. RV, right ventricle COR TRILOCULARE BIVENTRICULARE The most serious abnormality in this group It is a complete absence of the atrial septum This condition known as common atrium is associated with serious defect elsewhere in the heart Figure 26. Hypoplastic right heart syndrome (HRHS) PREMATURE CLOSURE OF THE OVAL FORAMEN Occasionally the oval foramen closes during prenatal life Leads to massive hypertrophy of the right atrium and ventricleand under development of the left side of the heart Death usually occurs shortly after birth PERSISTENT ATRIOVENTRICULAR CANAL Whenever the atrioventricular cushions fail to fuse, 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 Figure 27. Hypoplastic left heart syndrome (HLHS) ATRIAL SEPTAL DISORDER (ASD) One of the most significant defects is the ostium secundum defect, characterized by a large opening between the left and right atria. It may be caused by excessive cell death and resorption of the septum primum or by inadequate development of the septum secundum. The secundum type is caused by mutations in the heart- specifying gene NKX2.5, on chromosome 5q35, that can produce tetralogy of Fallot, and atrioventricular conduction delays in an autosomal dominant fashion. Figure 29. A. Persistent common atrioventrical canal. This abnormality is always accompanied by a septum defect in the atrial as well as in the ventricular portion of the cardiac partitions. B. Valves in the atrioventricularorifices under normal Page 11 of 19 [EMBRYOLOGY] 1.14 EMBRYONIC DEVELOPMENT OF THE CARDIOVASCULAR SYSTEM – Dr. Leslie A. Viado conditions. C. Split valves in a persistent atrioventricular canal. D,E. Ostium Membranous VSDs usually represent a more serious defect and are primum defect caused by incomplete fusion of the atrioventricular endocardial often associated with abnormalities in partitioning of the cushions conotruncal region. Depending on the size of the opening, blood carried by the pulmonary artery may be 1.2 to 1.7 times as abundant OSTIUM PRIMUM DEFECT as that carried by the aorta Occasionally, endocardial cushions in the atrioventricularcanal partially fuse. The result is a defect in the atrial septum, but theinterventricular septum is closed Usually combined with a cleft in the anterior leaflet of thetricuspid valve TRICUSPID ATRESIA Involves obliteration of the right atrioventricular orifice Is characterized by the absence or fusion of the tricuspidvalves. Tricuspid atresia is always associated with (1) patency of the oval foramen, (2) VSD (3) underdevelopment of the rightventricle, (4) hypertrophy of the left ventricle Figure 32. A. Normal heart B.Isolated defect in the membranous portion ofthe interventricular septum. Blood from the left ventricle flows to the right through the interventricular foramen TERATOLOGY OF FALLOT The most frequently occurring abnormality of the conotruncal region It is due to an unequal division of the conus resulting from anterior displacement of the septum Displacement of the septum produces four cardiovascular alterations: ○ Pulmonary infundibular stenosis - a narrow right Figure 30. A.NormalheartB.Tricuspidatresia.Notethe small rightventricle and the ventricular outflow region large left ventricle. ○ A large defect of the interventricular septum ○ An overriding aorta that arises directly above the septal EBSTEIN ANOMALY defect A condition where the apex of the right ventricle, and as a result, ○ Hypertrophy of the right ventricular wall because of there is an expanded right atrium and a small right ventricle. higher pressure on the right side The valve leaflets are abnormally positioned, and the anterior one is Occurs in 9.6/10,000 births but occurs as a common feature in usually enlarged. individuals with Alagille syndrome In addition to the heart defect, these people have abnormalities in other organs, including the liver, and a characteristic face with a broad prominent forehead, deep set eyes, and a small pointed chin. In 90% of cases, there is a mutation in JAG1, the ligand for NOTCH signaling that regulates neural crest cells forming the conotruncal (outflow tract) septum. Figure 33. Teratology of Fallot. A Surface View B. The four components of the defect; pulmonary stenosis, overriding aorta, interventricular septal defect, and Figure 31. Ebstein anomaly. The tricuspid valve leaflets are displaced toward the hypertrophy of the right ventricle apex of the right ventricle, and there is expansion of the right atrial region. PERSISTENT (COMMON) TRUNCUS ARTERIOSUS VSDs Occurs in 0.8/10,000 births, Involving the membranous or muscular portion of the septum re the Results when the conotruncal ridges fail to form such that no division most common congenital cardiac malformation, occurring as an of the outflow tract occurs. The undivided truncus thus overrides isolated condition in 12/10,000 births. both ventricles and receives blood from both sides. The pulmonary Most (80%) occur in muscular region of the septum and resolve as artery arises some distance above the origin of the undivided the child grows truncus. Page 12 of 19 [EMBRYOLOGY] 1.14 EMBRYONIC DEVELOPMENT OF THE CARDIOVASCULAR SYSTEM – Dr. Leslie A. Viado The persistent truncus is always accompanied by a defective interventricular septum since the ridges also participate in formation of the interventricular septum. Figure 36. Example of DeGeorge syndrome showing small mouth, nearly smooth Figure 34. Persistent truncus arteriosus. The pulmonary artery originates from a philtrum, micrognathia, prominent nasal bridge, and posteriorly rotated ears. common truncus. A. The septum in the truncus and conus has failed to form. B. This abnormality is always accompanied by an interventricular septal defect VALVULAR STENOSIS Approximately 3 to 4/10,000 births. TRANSPOSITION OF THE GREAT VESSELS Occurs at pulmonary artery or aorta when semilunar valves are fused Occurs in 4.8/10,000 births for a variable distance Occurs when the conotruncal septum fails to follow its normal spiral course and runs straight down. As a consequence, the aorta A. PULMONARY ARTERY VALVULAR STENOSIS originates from the right ventricle, and the pulmonary artery - Trunk is narrow or atretic originates from the left ventricle. - Patent oval foramen forms the only outlet for blood from the right It is sometimes associated with a defect in the membranous part of side of the heart. And the Ductus arteriosus, always patent, the only the interventricular septum and usually accompanied by an open access route to the pulmonary circulation ductus arteriosus. For the reason that SHF and neural crest cells contribute to the formation and septation of the outflow tract, B. AORTIC VALVULAR STENOSIS respectively, insults to these cells contribute to cardiac defects Fusion of thickened valves may be so complete that only pinhole involving the outflow tract. opening remains size of aorta is usually normal a. aortic valvular atresia – fusion of the semilunar aortic valve is complete — the aorta, left ventricle, and left atrium are markedly underdeveloped and usually accompanied by an open ductus arteriosus. Figure 35. A. transposition of the great vessels. B. Pulmonary valvular atresia with normal aortic root. The only access route to the lungs is by way of a patent ductus arteriosus. DiGEORGE SEQUENCE Example of the 22q11 deletion syndrome (DiGeorge syndrome, DiGeorge anomaly, velo-cardio-facial syndrome, Shprintzen syndrome, conotruncal anomaly face syndrome, and congenital thymic aplasia), where the defects are the result of a deletion on the Figure 37. A. Aortic valvular stenosis. B. HLHS with aortic valvular atresia. Arrow long arm of chromosome 22. in the arch of the aorta indicates the direction of blood flow. The coronary Characterized by a pattern of malformations that have origin in arteries are supplied by this reverse blood flow. *Note: small left ventricle and large right ventricle abnormal neural crest development These children have facial defects, thymic hypoplasia, parathyroid ECTOPIA CORDIS dysfunction, and cardiac abnormalities involving the outflow tract, Rare anomaly such as persistent truncus arteriosus and tetralogy of Fallot. heart lies on the surface of the chest and caused by failure of the Craniofacial malformations are often associated with heart defects embryo to close the ventral body wall because neural crest cells play important roles in the development of both the face and heart. Page 13 of 19 [EMBRYOLOGY] 1.14 EMBRYONIC DEVELOPMENT OF THE CARDIOVASCULAR SYSTEM – Dr. Leslie A. Viado Aortic arches Neural crest Patterning the Anomalous right (days 22-42) cell migration, arches into the pulmonary proliferation and great artery: IAA type viability arteries B Table summarizes the target tissues and the birth defects that can be caused when different processes and stages of heart development are adversely affected. Days give an appropriate estimation of the period of vulnerability and calculated from the time of fertilization. PHF, Primary Heart Field DORV, Double VSD, Ventricular Septal DefectAVC, Figure 38. Ectopia cordis. The heart lies outside the thorax, and there is a cleft in Outlet Right Ventricle Atrioventricular Canal IVS, the thoracic wall. TGA, Transposition of the Interventricular Septum SHF, GreatArteries l-TGA, Left Transposition Secondary Heart Field IAA, HEART DEVELOPMENT: SUSCEPTIBLE STAGES FOR THE INDUCTION OF CARDIAC of the Great Interrupted Aortic Arch BIRTH DEFECTS Arteries ASD, Atrial Septal Defect Target Tissue Cell Process Normal Effect Birth Defects ARTERIAL SYSTEM DEFECTS PHF Establish of Formation of DORV, TGA, I- Normal: ductus arteriosus is functionally closed through contraction (days 16-18) laterality and the 4 TGA, ASD, VSD, of its muscular wall shortly after birth to form ligamentum patterning chambered atrial isomerism arteriosum heart , Anatomical closure by intima proliferation: 1 – 3 months ventricular inversion, PATENT DUCTUS ARTERIOSUS (PDA) dextrocardia One of the most frequent abnormalities of the great vessels (8/10,000 births) Premature infants May be isolated or accompany other heart defects (e.g. Tetralogy of Heart tube Genetic signaling Looping Dextrocardia Fallot and Transposition of the Great Vessels) (days 22-28) Cascade for Defects that cause large differences between aortic and pulmonary normal looping pressures may cause increased blood flow through the ductus, preventing normal closure. AVC Cushion Division of the VSD, mitral & Endocardial formation: cell AVC into the tricuspid valve COARCTATION OF THE AORTA cushions proliferation and left and right defects (mitral (days 26-35) migration channels; insufficiency, Occurs in 3.2/10,000 births Formation of tricuspid Aortic lumen below the origin of left subclavian artery is narrowed mitral and atresia); (constriction) tricuspid positioning and Cause of aortic narrowing is primarily an abnormality in the media of valve