Cardiac Embryology PDF

(005) CARDIAC EMBRYOLOGY DR. LESLIE ASUNCION-VIADO| 01/11/21 OUTLINE Spina Bifida will also hav...

(005) CARDIAC EMBRYOLOGY DR. LESLIE ASUNCION-VIADO| 01/11/21 OUTLINE Spina Bifida will also have Cardiac abnormality (E.g. Tetraloggy of Fallot and Truncus Arteriosus) I. Cardiac cell lines II. Cardiovascular system CARDIOVASCULAR SYSTEM III. Cardiogenic field VASCULAR SYSTEM A. Progenitor heart cells Appear in the mid of 3rd week age of gestation AOG B. Primary heart field Formed when embryo no longer able to satisfy its C. Secondary heart field nutritional requirements by diffusion alone D. Vasculogenesis Embryo needs circulation to develop fully E. Horseshoe shaped endothelial-lined tube Vascular system will develop F. Dorsal aortae Embryo needs to have a diffusion. IV. Formation and position of the heart tube NOTE: nutrition by diffusion *diffusion replaced by circulation V. Formation of the cardiac loop A. Atrial portion CARDIOGENIC FIELD B. Atrioventricular junction C. Bulbus cordis D. Bulboventricular junction PROGENITOR HEART CELLS VI. What happens after looping is completed By the first few weeks of development, Progenitor Heart Cells VII. Development of the sinus venosus are present VIII. Formation of the cardiac septa Lie in the epiblast. IX. Septum formation in the common atrium Immediately adjacent to the cranial end of the primitive streak X. Formation of the left atrium and pulmonary vein They migrate cranially through the streak and into the visceral XI. Septum formation in the atrioventricular canal layer of lateral plate mesoderm. XII. Septum formation in the atrioventricular canal (end of 5th week) XIII. Atrioventricular valves formation PRIMARY HEART FIELD (PHF) XIV. Septum formation in the truncus arteriosus and Lateral to the Progenitor Heart Cells conus cordis XV. Septum formation in the ventricles Found cranial to the neural folds XVI. Semilunar valves Form a horseshoe-shaped cluster of cells XVII. Formation of the conducting system of the heart Composed of the Left and Right Primary Heart Field which XVIII. Vascular development ends will fuse together to form part of atria and entire Left XIX. Arterial system: aortic arches ventricle A. Vitelline arteries Heart will be developed after birth and is composed of the Left B. Umbilical arteries and Right field C. Coronary arteries XX. Venous system (5th week) A. Vitelline veins B. Umbilical veins C. Cardinal veins XXI. Clinical Correlations CARDIAC CELL LINES Figure 1. Dorsal view of a late presomite embryo (approximately - made up of 3 Germ Layers 18 days] after removal of the amnion. Mesoderm –what majority of the cardiac cell lines are made of Ectoderm – preferentially from the neural crest SECONDARY HEART FIELD (SHF) - where some/ few of the cardiac cell lines Resides visceral (splanchnic) mesoderm ventral to the come from pharynx Endoderm – preferentially from the blood vessels Form the right ventricle and outflow tract (Right: Conus - other cardiac lines that make up the Cordis and Left: Truncus Arteriosus) heart during the development Contributes cells to formation of the atria at the caudal end NOTE: The Heart also has an Ectoderm formed by the Neural of the heart. Crest especially the blood vessels. Most of the time, patients with Page 1 of 19 CMED 1D  (005) CARDIAC EMBRYOLOGY DR. LESLIE ASUNCION-VIADO| 01/11/21 Figure 2. Drawing showing the SHF that lies in splanchnic mesoderm at the posterior of the pharynx. Figure 4. Cross sections through early presomite embryo, showing formation of a single heart tube from paired primordia. Receives venous drainage at its caudal pole and begins to pump blood out of the first aortic arch into the dorsal aorta at its cranial pole. Tube remains attached to the dorsal side of the pericardial cavity by a fold of mesodermal tissue (dorsal mesocardium) from the SHF. No ventral mesocardium is ever formed. Figure 3. Dorsal view of a drawing of a 16-day embryo showing the laterality pathway. VASCULOGENESIS Process where blood cells and vessels are formed  cardiac myoblasts and blood islands  PHF induced by pharyngeal endoderm Once the Primary Heart Field is being established, the Pharyngeal Endoderm will induce the formation of Cardiac Myoblast and Blood Islands that will form blood vessels. Figure 5. Frontal view of an embryo showing the heart in the pericardial HORSESHOE SHAPED ENDOTHELIAL-LINED TUBE cavity and the developing gut tube with the anterior and posterior intestinal portals. Formed from the union of blood islands unite (surrounded by Once the Cardiac cavity is formed, it becomes an elongated myoblasts) tube with some constriction. Form the cardiogenic region Above is the Truncus Arteriosus followed by the Bulbus Around it will form the Pericardial cavity (from intraembryonic Cordis, Ventricle, Right Atrium and the Sinus Venosus cavity) surrounds the cardiac region Middle section of the dorsal mesocardium disappears. Fuse on its ends to form a single tube later on - Creating the transverse pericardial sinus connecting both sides of the pericardial cavity DORSAL AORTAE Heart is now suspended in the cavity by blood vessels at its Longitudinal vessels form the blood islands. cranial (Truncus Arteriosus) and caudal (Sinus Venosus) poles Myocardium thickens and secretes a layer of extracellular FORMATION AND POSITION OF THE HEART TUBE matrix, rich in hyaluronic acid called cardiac jelly which Initially, the central portion of the cardiogenic area is anterior separates it from the endothelium. to the oropharyngeal membrane and the neural plate Mesenchymal cells proliferate and migrate over the surface Closure of the neural tube and formation of the brain of the myocardium to form the epicardium. vesicles Epicardium responsible for formation of the coronary arteries - Central nervous system grows cranially so rapidly that it NOTE: Coronary Arteries come from the Epicardium. extends over the central cardiogenic region and the future pericardial cavity. - When it grows cranially, it becomes one central tube. Page 2 of 19 CMED 1D  (005) CARDIAC EMBRYOLOGY DR. LESLIE ASUNCION-VIADO| 01/11/21 Figure 7. Formation of the cardiac loop. (A) 22 days. (B) 23 days. (C) 24 days. The primitive ventricle is moving ventrally and to the Figure 6. Formation of the cardiac loop at 22 days. right, whereas the atrial region is moving dorsally and to the left. ATRIAL PORTION FORMATION OF THE CARDIAC LOOP Forms a common atrium and is incorporated into the The heart tube continues to elongate as cells are added from pericardial cavity. the SHF to its cranial end This lengthening process is essential: ATRIOVENTRICULAR JUNCTION - For normal formation of the right ventricle and the Forms the atrioventricular canal outflow tract region (conus cordis and truncus Connects the common atrium and the early embryonic arteriosus) ventricle - Responsible for the looping process which takes place afterwards Cardiac tube begins to bend on day 23 and ends on day 28 BULBUS CORDIS is when the Cardiac Looping will occur Proximal 1/3 — trabeculated part of the right ventricle NOTE: The heart is a continuous tube with some Midportion — a.k.a. the conus cordis form the outflow tracts constrictions. Cardiac Looping occurs so that the Ventricles of both ventricles will position more anteriorly to the right and more ventrally. NOTE: Initially, there is only one Outflow tract. The Pulmonary Outflow tract and Aortic Outflow tract is from one tube from the Cephalic portion of the tube bends ventrally, caudally, and Ventricles. to the right Distal 1 /3 — a.k.a. truncus arteriosus form the roots and NOTE: This particular position will be responsible for some proximal portion of the aorta and pulmonary artery Congenital Heart Diseases. When the D- looping (normal Responsible for the outflow tract and Proximal potion of the looping towards the right) does not occur, L-looping will Aorta and Pulmonary Artery. happen. L- looping - Results in the Right Ventricle looping to the BULBOVENTRICULAR JUNCTION left Will become the junction between the ventricle and the - Transposition of the right ventricle will be bulbus cordis found on the left side of the heart Called the primary interventricular foramen As the heart begin to twist, the Right Ventricle will be positioned on the anterior surface towards the right. Left Ventricle on the other hand will be positioned backward Left Atrium (caudal) portion shifts dorsocranially (posterior and up) and to the left and becomes the base of the posterior portion of the heart Figure 8. Formation of the cardiac loop. A. 22 days. B. 23 days. C. 24 days. 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, respectively. The Cardiac tube should be twisted towards the right side (D- looping) so that the ventricles are on the correct sides. Page 3 of 19 CMED 1D  (005) CARDIAC EMBRYOLOGY DR. LESLIE ASUNCION-VIADO| 01/11/21 Depending on the position of the valves, we can determine if the ventricles are positioned correctly, Right Ventricle: 3 valves; Left Ventricle: Transposition of the ventricles. WHAT HAPPENS AFTER THE LOOPING IS COMPLETED? Smooth-walled heart tube form primitive trabeculae Figure 10. Heart of a 5-mm embryo [28 days). The bulbus cordis is in 2 sharply defined areas proximal & distal to the divided into the truncus arteriosus, conus cordis, and trabeculated part of primary interventricular foramen the right ventricle. Broken Une, pericardium. Bulbus temporarily remains smooth-walled Primitive ventricle now trabeculated is called the DEVELOPMENT OF SINUS VENOSUS primitive left ventricle Proximal third of the bulbus cordis is called the Middle 4th week primitive right ventricle (trabeculated) - sinus venosus receives venous blood from the right NOTE: Previously, the proximal third of the Bulbus Cordis and left sinus horns attached posteriorly to right becomes trabeculated during the cardiac looping. Therefore, atrium it becomes the Primitive Right Ventricle. Whereas the Each horn receives blood from three important veins: Primitive Ventricle will be the Primitive Left Ventricle. vitelline or the omphalomesenteric vein umbilical vein common cardinal vein Figure 9. 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. Figure 11. Dorsal view of two stages in the development of the sinus Conotruncal portion of the heart tube: venosus at approximately 24 days (A) and 35 days (B). Broken line, the - Initially on the right side of the pericardial cavity entrance of the sinus venosus into the atrial cavity. prior to the looping - After looping, it shifts gradually to a more medial At first the communication between the sinus and position the atrium is wide thus, the sinus horns will be - Change in position is the result of formation of attached to the atrium and the communication or two transverse dilations of the atrium bulging on opening of that area is wide. each side of the bulbus cordis 4th and 5th week - There is left to right shunts of blood coming from the primitive left atrium to the primitive right atrium. Therefore, there will be a shifting of blood to the right, making the right atrium more dilated. Hence, entrance of the sinus shifts to the right 5th week - Obliteration of the right umbilical vein & left vitelline vein Page 4 of 19 CMED 1D  (005) CARDIAC EMBRYOLOGY DR. LESLIE ASUNCION-VIADO| 01/11/21 - Veins coming from the right sinus horn will be the venous valves. (A) 5 weeks (B) Fetal stage. The sinus venarium only one present and the left sinus horn rapidly [blue] is smooth walled; it derives from the right sinus horn. loses its importance. 10th week FORMATION OF CARDIAC SEPTA - Left common cardinal vein is obliterated 27th and 37th days of development Methods by which a septum maybe formed: Two actively growing masses of tissue that approach each other until they fuse, dividing the lumen into two separate canals. formed by the active growth of a single tissue mass that continues to expand until it reaches the opposite side of the lumen Endocardial cushions Figure 12. Final stage development of the sinus venosus and great veins. - Tissue masses that are formed centrally are Note: all that remains of the left sinus horn is the OBLIQUE VEIN of endocardial cushions. the left atrium and the coronary sinus - Developed in the atrioventricular and conotruncal regions L-R shunt: The right horn will become enlarged, forms the only - Form atrial and ventricular septa (membranous portion communication between the original sinus venosus and the or more proximal portion only not the muscular portion atrium, is incorporated into the right atrium to form the smooth- of the septum), the atrioventricular canals and valves, walled part of the right atrium, it will become the main cavity. aortic and pulmonary channels Sinuatrial orifice: flanked on each side by the right and left Cushions are populated by in conotruncal cushions venous valves. Cells are derived from cells migrating and proliferating cells Septum spurium: ridge formed when the valves fused going into the matrix. dorsocranially Atrioventricuar cushions Left valve and septum spurium fused then superior part - Derived from endocardial cells that detach from of right valve disappear. surrounding and move into the matrix. INFERIOR PORTION: where IVC VALVE AND Conotruncal cushions CORONARY SINUS VALVE occur. - Derived from neural crest cells migrating from the Crista terminalis: divides trabeculated part of the right cranial neuron atrioventricular cushions, cells are atrium and the smooth-walled part (sinus venarum), derived from cranial folds to the outflow tract region. which originates from the sinus horn. - Any problems in the conotruncal cushion may have There are two sinus horn attached to the atrium. However, cause by the abnormal fusion of neural tube which the left sinus horn will be obliterated and the right sinus horn comes from the neural crest.. will the only one left that will have communication between the sinus venosus and the right atrium. Once there is a L-R shunting, the right horn will be incorporated with the right atrium and it will form the main cavity of the right atrium- the smooth walled part of the right atrium. Figure 14. 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 and the outflow tract as exp the ECM (C) Cells migrate into the cushions and proliferate. Figure 13. Ventral view of coronal sections through the heart at the level of the atrioventricular canal to show development of the Page 5 of 19 CMED 1D  (005) CARDIAC EMBRYOLOGY DR. LESLIE ASUNCION-VIADO| 01/11/21 SEPTUM FORMATION IN THE COMMON ATRIUM ovale is the opening where the oxygenated blood transfers to the left side of the heart. End of the fourth week - Sickle-shaped crest (first portion of septum primum) grows from the roof of the common FORMATION OF THE LEFT ATRIUM AND atrium into the lumen. PULMONARY VEIN Ostium primum: opening between the lower rim of the septum primum and the endocardial cushions. Primitive right and left atria enlarge by incorporation of the right sinus horn. Since there is a lot of blood going to the atria via right sinus horn, these two chambers will enlarged. Mesenchyme at the caudal end of the dorsal mesocardium begins to proliferate Proliferating mesenchyme forms of the dorsal mesenchymal protrusion (DMP) and this grows with the Figure 15. Atrial septa at 30 days (6 mm). septum primum toward the atrioventricular canal it will form pulmonary vein. Extensions of the superior and inferior endocardial cushions grow along the edge of the septum primum, closing the ostium primum. Before closure is complete, apoptosis produces perforations in the upper portion of the septum primum. When there is a complete closure of spetum primum, there is cell death in the upper portion of septum primum, wherein there will be an opening befoe the complete closure. Cells that was cominf from the apoptosis coalescence of these perforations forms of the ostium secundum, ensuring free Figure 17. Atrial septa at the atrial pole, a portion of the dorsal blood flow from the right to the left primitive atrium. 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 grows downward with the septum primum. Within the DMP is the developing pulmonary vein that is positioned in the left atrium by the growth and movement of the DMP Figure 16. Atrial septa at 33 days [9 mm]. Because of the movement of DMP, the pulmonary veins Septum secundum of the left arium are developed. - formed after the formation of ostium secundum. Remaining portion of the DMP at the tip of the septum - Lumen of the right atrium plus incorporation of the sinus primum contributes to endocardial cushions formation in horn the atrioventricular canal - New crescent-shaped fold Main stem of the pulmonary vein that opens into the - Never forms a complete partition in the right and left atrial left atrium atrium sends two branches to each lung. cavity. these opening will form branches, two from left - Anterior limb extends downward to the septum in the pulmonary circulation, otherl will be coming from right atrioventricular canal. pulmonary circulation and all will be drained in left - Fused with left venous valve and septum sprimum on its atrium. right side → free concave edge of the septum secundum to overlap the ostium secundum. - Once septum secundum is closed, there will be opening left by septum secundum and becomes Foramen Ovale. Upper part of septum primum disappears and become Valve of foramen ovale. During fetal circulation, the oxygenated part is on the right side and deoxygenated is on the left side. Valve of foramen Page 6 of 19 CMED 1D  (005) CARDIAC EMBRYOLOGY DR. LESLIE ASUNCION-VIADO| 01/11/21 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 Figure 18. Atrial septa. Initially, only the main stem of the pulmonary vein ATRIOVENTRICULAR VALVES FORMATION enters the left atrium, but, as the atrial walls expand, this stem is Each atrioventricular orifice is surrounded by local incorporated into the left atrium to the point where its four branches proliferations of mesenchymal tissue derived from the diverge to go to the lungs. endocardial cushions Bloodstream hollows out and thins tissue on the ventricular Fully developed heart surface of these proliferations - Original embryonic right atrium becomes the Mesenchymal tissue becomes fibrous and forms the AV trabeculated right atrial appendage containing the valves pectinate muscles (only found in the appendages). AV valves remain attached to the ventricular wall by - Smooth-walled sinus venarum will become the muscular cords main cavity, it originates from the right horn of the Muscular tissue in the cords replaced by dense sinus venosus connective tissue, the fibrous skeleteon - Original embryonic left atrium is represented by Connected to papillary muscles through the chordae little more than the trabeculated atrial appendage. tendinae Left primitive atrium become the left atrial appendage. - Smooth-walled part originates from the pulmonary vein coming from the DMP. SEPTUM FORMATION IN THE TRUNCUS ARTERIOSUS AND CONUS CORDIS SEPTUM FORMATION IN THE ATRIOVENTRICULAR CANAL During the fifth week pairs of opposing ridges appear in the truncus Four atrioventricular endocardial cushions appear, fuse Lie on the right superior wall (will be the right superior together to form the right and left atrioventricular canal. truncus swelling) And on the left inferior wall (will be the End of 4th week left inferior truncus swelling) One on each side plus one at the dorsal (superior) and The Truncus will be one tube. As they grow distally, they twist one at the ventral (inferior) border of the atrioventricular The Left aorta will be twisting above going to the right side. canal And the right pulmonary trunk will be twisting distally, then it will be part of the left side of the heart. So, if the valve is in the right side, the pulmonary trunk is on the right side. But during development when you auscultate the patient after delivery, the pulmonary trunk as it goes upward, the valve will be heard on the left side of the intercostal space or the Figure 19. Formation of the septum in the atrioventricular canal. sternum. Whereas the aortic valve closure will be heard on From left to right. Days 23, 26, 31 and 35. The intial circular the right side of the sternum. opening widens transversely. But in here, what is important here is that, when the truncus arteriosus will twist, it will put your vessels on the right position so that pulmonary trunk will be on the right side and it will come from the right ventricle, and the aorta will be SEPTUM FORMATION IN THE ATRIOVENTRICULAR coming from the left ventricle. CANAL (END OF 5th WEEK) This is important because when the fetus’ heart will not twist The posterior extremity of the flange terminates almost distally, the aorta will remain in the right ventricle (which is midway along the base of the dorsal endocardial cushion and not supposedly there) and the pulmonary trunk will be coming is much less prominent than before from the left ventricle => TRANSPOSITION OF THE GREAT VESSELS Page 7 of 19 CMED 1D  (005) CARDIAC EMBRYOLOGY DR. LESLIE ASUNCION-VIADO| 01/11/21 Another important thing is that, when the truncus arteriosus will fail to twist, or there will be halt or stopping of the twisting (embryonically), the heart may have 1 great vessel between the ventricles. So there will be 1 vessel in between the right and left ventricle, or sometimes the great vessel, both the aorta and pulmonary trunk will be on the right side => DOUBLE OUTLET CONGENITAL HEART DISEASE (both Figure 22. Drawing showing the origin of neural crest in the hindbrain and vessels are found at the right side.) their migration through pharyngeal arches 3, 4 and 6 to the outflow tract of After complete fusion the ridges form The the heart. In this location, they contribute to septation of the conus cordis Aorticopulmonary Septum: divides the truncus into an and truncus arteriosus. aortic and a pulmonary channel NOTE: 1. Cardiac neural crest cells contribute to endocardial cushion formation in both the conus cordis and truncus arteriosus. 2. Because neural crest cells also contribute to craniofacial development, it is common to see facial and cardiac abnormalities in the same individual (congenital anomalies, spina bifida) SEPTUM FORMATION IN THE VENTRICLES Figure 20. Development of the conotruncal ridges [cushions] and End of the fourth week, the two primitive ventricles closure of the interventricular foramen. Proliferations of the right begin to expand (because of the circulation of blood to and left conus cushions, combined with proliferation of the the primitive ventricles, the ventricle will become more anterior endocardial cushion, close the interventricular foramen hollow and will be pushed downward and form the membranous portion of the interventricular septum. Continuous growth of the myocardium on the outside (A) 6 weeks [12mm], (B) Beginning of the 7th week [14.5]. and continuous diverticulation and trabecula formation Truncus swelling developed along the right dorsal and on the inside so it will become bigger and the myocardial left ventral walls of the conus cordis so this will become cells will become enlarged from the outside and more your outflow tract trabecula or sponge-like structures will be formed inside Conus swellings grow toward each other and distally to If Trabeculation is not developed during this process Non- unite with the truncus septum to form your great vessels compacted Right Ventricle or Left Ventricle will be formed as 2 conus swelling fused, the septum divides the conus: the baby will be delivered. - Anterolateral portion will form the right ventricular Muscular interventricular septum: formed by medial outflow tract (the outflow tract of the right ventricle) walls of the expanding ventricles which become apposed (Meaning: the right ventricular outflow tract will be and then merge anterior to the left ventricular outflow tract. So that Two walls do not merge completely when you cut the heart cross-sectionally at the level of Membranous ventricular septum comes from the endocardial the great vessel, you will know that the pulmonary cushion. Whereas the muscular interventricular septum comes valve is anterior to your aorta. from the expanding ventricles. - Posteromedial portion (the outflow tract of the left Apical cleft between the two ventricle appears ventricle) Space between the free rim of the muscular ventricular septum and the fused endocardial cushions permits communication between the two ventricles Interventricular foramens shrink on completion of the conus septum Complete closure of the interventricular foramen forms the membranous part of the interventricular septum Figure 21. Frontal section through the heart of an embryo at the SEMILUNAR VALVES end of the seventh week. The conus septum Is complete, and Partitioning of the truncus is almost complete blood from the left ventricle enters the aorta. Note the septum in - Primordia of the semilunar valves become visible as small the atrial region. tubercles found in the main truncus swellings Page 8 of 19 CMED 1D  (005) CARDIAC EMBRYOLOGY DR. LESLIE ASUNCION-VIADO| 01/11/21 One of each pair is assigned to the pulmonary and aortic Vascular endothelial growth factor – important role for channels vascular development Tubercles hollow out at their upper surface, forming the semilunar valves ARTERIAL SYSTEM: AORTIC ARCHES Neural crest cells contribute to formation of these valves Fourth and fifth weeks of development Each arch receives its own cranial nerve and its own artery. Aortic arches arise from the aortic sac the most distal part of the truncus arteriosus Aortic arches are embedded in mesenchyme of the pharyngeal arches and terminate in the right and left dorsal Figure 23. Longitudinal sections through the semilunar valves at aortae. weeks (A) 6, (B) 7, and (C) 9 of development. The upper surface Aortic sac contributes a branch to each new arch: giving rise is hollowed to form the valves. to a total of five pairs of arteries. The fifth arch never forms or forms incompletely and then regresses: number I, II, III, IV and VI Arterial pattern becomes modified, and some vessels regress FORMATION OF THE CONDUCTING SYSTEM OF completely as they develop. THE HEART Neural crest cells regulate pattern of development. Division of the truncus arteriosus by the aorticopulmonary All myocardial cells in the heart tube have pacemaker activity septum: ventral aorta and pulmonary trunk Heart begins to beat at approximately 21 days of gestation Aortic sac then forms right horn becoming the Pacemaker is restricted to the caudal part of the left side of the brachiocephalic artery and left horn becoming proximal cardiac tube (initially the pacemaker is on the left side, but segment of the aortic arch. 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 sinoatrial node (SAN) is formed Atrioventricular node begins as a collection of cells located around the atrioventricular canal that coalesce to form the Figure 24. Aortic arches and dorsal aortae before transformation AVN, into the definitive vascular pattern. Impulses from the AVN (will pass through and pierce in to the septal leaflet of the tricuspid valve) pass to the atrioventricular bundle and left and right bundle branches then pierce into the ventricular wall to the Purkinje fiber network VASCULAR DEVELOPMENT Blood vessel development occurs by two mechanisms: 1. Vasculogenesis in which vessels arise by the coalescence of angioblasts - The major vessels (dorsal aorta and cardinal veins) Table 1. Derivatives of the Aortic Arches. 2. Angiogenesis whereby vessels sprout from existing Right: distal part of the sixth aortic arch and the fifth aortic arch vessels disappears, the recurrent laryngeal nerve moves up and hooks - The remainder of the vascular system then around the right subclavian artery. forms by angiogenesis - Branches of aorta Page 9 of 19 CMED 1D  (005) CARDIAC EMBRYOLOGY DR. LESLIE ASUNCION-VIADO| 01/11/21 Left: the nerve does not move up because the distal part of the The aortic cusp will give of the coronary arteries, except the non- sixth aortic arch persists as the ductus arteriosus later coronary cusp or the posterior aortic cusp. forms the ligamentum arteriosum VENOUES SYSTEM (5TH WEEK) Three pairs of major veins: 1. Vitelline veins, or Omphalomesenteric veins - Carrying blood from the yolk sac to the sinus venosus 2. Umbilical veins - Originating in the chorionic villi and carrying oxygenated blood to the embryo 3. Cardinal veins - Draining the body of the embryo proper There are only 2 venous segments that will carry oxygenated Figure 25. The great arteries in the adult. blood to the embryo, they are the umbilical veins. On adult circulation, the vein that will carry the oxygenated blood VITELLINE ARTERIES will be the pulmonary trunk. A number of paired vessels supplying the yolk sac. Gradually fuse and form the arteries in the dorsal mesentery of the gut. VITELLINE ARTERIES In Adults: the celiac (supply foregut) and superior mesenteric Before entering the sinus venosus they form a plexus around (supply midgut) arteries the septum transversum The liver cords growing into the septum interrupt the course of the veins the hepatic sinusoids forms. UMBILICAL ARTERIES Reduction of the left sinus horn, blood from the left side of the Becomes inferior mesenteric arteries (supply hindgut) liver is rechanneled with enlargement of right vitelline vein and Initially paired ventral branches of the dorsal aorta form hepatocardiac portion of the inferior vena cava. Course to the placenta in close association with the allantois Proximal part of the left vitelline vein disappears. during the fourth week acquires a secondary connection with Superior mesenteric vein derives from the right vitelline vein. the dorsal branch of the aorta, the common iliac artery, and The distal portion of the left vitelline vein also disappears. loses its earliest origin. After birth: the umbilical arteries will become your common iliac artery UMBILICAL VEINS - Proximal portions persist as the internal iliac and superior The umbilical veins pass on each side of the liver but some vesical arteries. connect to the hepatic sinusoids - Distal portion obliterated forming medial umbilical ligaments. The proximal part of both umbilical veins and the remainder of the right umbilical vein then disappear. Left vein is the only one that carry oxygenated blood from the CORONARY ARTERIES placenta to the liver (oxygenated blood because the placenta Derived from epicardium. acts as the lungs in the fetal circulation) Differentiated from the proepicardial organ located in the Increase of the placenta circulation, a direct communication caudal portion of the dorsal mesocardium: derivative of the forms between the left umbilical vein and the right SHF. hepatocardiac channel: The Ductus Venosus Epicardial cells undergo an epithelial to mesenchymal After birth: form the ligamentum teres hepatis and ligamentum transition induced by the underlying myocardium. venosum. 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. CARDINAL VEINS Connection occurs by ingrowth of arterial endothelial cells Form the main venous drainage system of the embryo. from the arteries into the aorta causing the coronary arteries to Consists of anterior, posterior and common cardinal veins. “invade” the aorta. Page 10 of 19 CMED 1D  (005) CARDIAC EMBRYOLOGY DR. LESLIE ASUNCION-VIADO| 01/11/21 4th week: form a symmetrical system. defects. The mechanism for this teratogenic effect appears to 5th week: subcardinal veins sacrocardinal veins, supracardinal be a disruption of 5-HT signaling important in the laterality veins pathway Formation of the Vena Cava System is characterized by the appearance of anastomoses between left and right: - Blood from the left is channeled to the right side ABNORMALITIES OF CARDIAC LOOPING: Left brachiocephalic vein: anastomosis between the anterior DEXTOCARDIA cardinal veins It is a condition where the heart lies on the right side of the Superior vena cava: right common cardinal vein and the thorax and it occurs when the heart loops to the left instead of proximal portion of the right anterior cardinal vein the right. The cardinal veins is usually formed by the anastomosis of the The defect may be induced during gastrulation, when laterality different veins is established, or slightly later when cardiac looping occurs. External jugular veins: plexus of venous vessels in the face It occurs with situs inversus, a complete reversal of asymmetry Left renal vein: anastomosis between the subcardinal veins in all organs, or may be associated with laterality sequences Renal segment of the inferior vena cava: right subcardinal vein [heterotaw] in which only some organ positions are reversed. becomes the main drainage channel Left common iliac vein: anastomosis between the sacrocardinal veins TOTAL ANOMALOUS PULMONARY VENOUS RETURN (TAPVR) a rare birth defect where the pulmonary veins drain into other CLINICAL CORRELATIONS vessels or directly into the right atrium. A deviation of the DMP to the right places the pulmonary vein LATERALITY AND HEART DEFECTS in the right atrium instead of the left [20% of cases] or if Establishing laterality during gastrulation is essential for deviation to the right is more pronounced, the vein can enter normal heart development because it specifies cells the superior vena cava or the brachiocephalic vein [50% of contributing to and patterning the right and left sides of the cases]. Because the dorsal mesocardium is normally a midline heart. structure, it is not surprising that TAPVR often occurs in The process requires a signaling cascade that includes individuals with heterotaxy. serotonin [5-HT] as a key molecule in initiating the pathway which is concentrated on the left side of the embryo and, by signaling through the transcription factor MAD3, restricts HEART DEFECTS Nodal ex- pression to the left where this gene initiates a Heart and vascular abnormalities make up the largest signaling cascade culminating in expression of PITXZ, the category of human birth defects and are present in 1% of live master gene for left sidedness. born infants. The incidence among stillborns is 10 times as Cardiac progenitor cells are also specified at this time both for high. It is estimated that 12% of babies with heart defects have the parts of the heart they will form and their left—right a chromosomal abnormality and, conversely, that 33% of sidedness by the laterality pathway. babies with a chromosomal abnormality have a heart defect. This period [days 16 to 18] is critical for heart development Targets for genetic or teratogen-induced heart defects include and individuals with laterality defects, such as heterotaxy, heart progenitor cells from the PHF and SHF, neural crest often have many different types of heart defects, including cells, endocardial cushions, and other cell types important for o dextrocardia [right-sided heart], heart development. o ventricular septal defects [VSDs], o atrial septal defects [ASDs], o double outlet right ventricle [DORV; both the aorta and pulmonary artery exit the right ventricle], HOLT-DRAM SYNDROME outflow tract defects, such as Is a result in a mutations in the TBX5 gene, characterized by o transposition of the great vessels, preaxial [radial] limb abnormalities and ASDs. o pulmonary stenosis, and others. It is one of a group of heart-hand syndromes illustrating that the same genes may participate in multiple developmental Laterality defects of the heart, such as processes. For example, TBX5 regulates forelimb o atrial and ventricular isomerisms and development and plays a role in septation of the heart. o inversions It is inherited as an autosomal dominant trait with a frequency Selective serotonin reuptake inhibitor [SSRI] class, an of 1/100,000 live births. antidepressant, have been linked to an increase in heart Page 11 of 19 CMED 1D  (005) CARDIAC EMBRYOLOGY DR. LESLIE ASUNCION-VIADO| 01/11/21 HYPERTROPHIC CARDIOMYOPATHY is caused by a mutation in a number of genes regulating production of sarcomere proteins that may result in sudden death in athletes and the general population. The disease is inherited as an autosomal dominant, and most mutations [45%] target the B—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 adversely affect cardiac output and/or conduction. VENTRICULAR INVERSION It is a defect in which the morphologic left ventricle is on the right and connects to the right atrium through a mitral valve. Figure 26. Hypoplastic right heart syndrome. The morphologic right ventricle is on the left side and connects to the left atrium through the tricuspid valve. The defect is sometimes called L-transposition of the great arteries because the pulmonary artery exits the morphologic left ventricle and the aorta exits the morphologic right ventricle. However, the arteries are in their normal positions, but the ventricles are reversed. The abnormality arises during the establishment of laterality and specification of the left and right sides of the heart by the laterality pathway. HYPOPLASTIC RIGHT HEART SYNDROME (HRHS) AND HYPOPLASTIC LEFT HEART SYNDROME (HLHS) Are rare defects that cause an underdevelopment of the right or left sides of the heart, respectively. On the right, the ventricle is very small, the pulmonary artery is affected and may be atretic or stenosed, and the atrium may Figure 26. Hypoplastic left heart syndrome. 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. AUTISM SPECTRUM DISORDER (ASD) One of the most significant defects is the ostium secundum The laterality associated with these defects suggests an defect, characterized by a large opening between the left and adverse effect on specification of the left and right cardiac right atria. It may be caused by excessive cell death and progenitor cells at an early stage of cardiac morphogenesis. resorption of the septum primum or by inadequate The defects can also arise when the helix-loop-helix development of the septum secundum. transcription factors Hand1 [left ventricle] and Hand2 [left The secundum type is caused by a mutations in the heart- ventricle] that regulate ventricular growth are misexpressed specifying gene NKX2.5, on chromosome 5q35, that can produce tetralogy of Fallot, and atrioventricular conduction delays in an autosomal dominant fashion. Page 12 of 19 CMED 1D  (005) CARDIAC EMBRYOLOGY DR. LESLIE ASUNCION-VIADO| 01/11/21 Figure 27. 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. Figure 28. A. Persistent common atrioventrical canal. This abnormality is Common atrium, or cor triloculare blventrlculare, resulting from complete always accompanied by a septum defect in the atrial as well as in the failure of the septum primum and septum secundum to form. RV, right ventricular portion of the cardiac partitions. B. Valves in the atrioventricular ventricle. orifices under normal conditions. C. Split valves in a persistent atrioventricular canal. D,E. Ostium primum defect caused by incomplete fusion of the atrioventricular endocardial cushions. COR TRILOCULARE BIVENTRICULARE The most serious abnormality in this group It is a complete absence of the atrial septum OSTIUM PRIMUM DEFECT this condition known as common atrium is associated with Occasionally, endocardial cushions in the atrioventricular serious defect elsewhere in the heart canal partially fuse. The result is a defect in the atrial septum, but the PREMATURE CLOSURE OF THE OVAL FORAMEN interventricular septum is closed Occasionally the oval foramen closes during prenatal life Usually combined with a cleft in the anterior leaflet of the leads to massive hypertrophy of the right atrium and ventricle tricuspid valve and under development of the left side of the heart Death usually occurs shortly after birth TRICUSPID ATRESIA PERSISTENT ATRIOVENTRICULAR CANAL Involves obliteration of the right atrioventricular orifice Whenever the atrioventricular cushions fail to fuse, combined Is characterized by the absence or fusion of the tricuspid with a defect in the cardiac septum. valves. Tricuspid atresia is always associated with (1) patency This septal defect has an atrial and a ventricular component, of the oval foramen, (2) VSD (3) underdevelopment of the right separated by abnormal valve leaflets in the single ventricle, (4) hypertrophy of the left ventricle atrioventricular orifice Figure 29. A. Normal heart B. Tricuspid atresia. Note the small right ventricle and the large left ventricle. Page 13 of 19 CMED 1D  (005) CARDIAC EMBRYOLOGY DR. LESLIE ASUNCION-VIADO| 01/11/21 EBSTEIN ANOMALY It is due to an unequal division of the conus resulting from A condition where the apex of the right ventricle, and as a anterior displacement of the septum result, there is an expanded right atrium and a small right Displacement of the septum produces four cardiovascular ventricle. alterations: The valve leaflets are abnormally positioned, and the anterior Pulmonary infundibular stenosis- a narrow right one is usually enlarged. ventricular outflow region A large defect of the interventricular septum An overriding aorta that arises directly above the septal defect Hypertrophy of the right ventricular wall because of higher pressure on the right side Occurs in 9.6/10,000 births but occurs as a common feature in 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 30. Ebstein anomaly. The tricuspid valve leaflets are displaced toward the apex of the right ventricle, and there is expansion of the right atrial region VSDs Involving the membranous or muscular portion of the septum re the most common congenital cardiac malformation, occurring as an isolated condition in 12/10,000 births. Most (80%) occur in muscular region of the septum and resolve as the child grows Membranous VSDs usually represent a more serious defect and are often associated with abnormalities in partitioning of Figure 32. Teratology of Fallot. A Surface View B. The four components the conotruncal region. Depending on the size of the opening, of the defect; pulmonary stenosis, overriding aorta, interventricular septal blood carried by the pulmonary artery may be 1.2 to 1,7 times defect, and hypertrophy of the right ventricle as abundant as that carried by the aorta PERSISTENT (COMMON) TRUNCUS ARTERIOSUS Results when the conotruncal ridges fail to form such that no division of the outflow tract occurs. occurs in 0.8/10,000 births, the pulmonary artery arises some distance above the origin of the undivided truncus. Because the ridges also participate in formation of the interventricular septum, the persistent truncus is always accompanied by a defective interventricular septum. The undivided truncus thus overrides both ventricles and Figure 31 A. Normal heart B.Isolated defect in the membranous portion of receives blood from both sides. the 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 Page 14 of 19 CMED 1D  (005) CARDIAC EMBRYOLOGY DR. LESLIE ASUNCION-VIADO| 01/11/21 Ductus arteriosus: always patent, the only access route to the pulmonary circulation AORTIC VALVULAR STENOSIS Fusion of thickened valves may be so complete: o only pinhole opening remains size of aorta is usually normal fusion of the semilunar aortic valve is complete – aortic valvular atresia – the aorta, left ventricle, and left atrium are markedly underdeveloped Figure 33. Persistent truncus arteriosus. The pulmonary artery originates from a 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 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. Occurs in 4.8/10,000 births, sometimes associated with a defect in the membranous part of the interventricular septum accompanied by an open ductus arteriosus A. Aortic valvular stenosis. B. HLHS with aortic valvular atresia. Arrow in It is usually accompanied by an open ductus arteriosus. the arch of aorta indicates direction of blood flow. The coronary arteries Because the SHF and neural crest cells contribute to the are supplied by this reverse blood flow. formation and septation of the outflow tract, respectively, *Note: small left ventricle and large right ventricle insults to these cells contribute to cardiac defects involving the outflow tract. ECTOPIA CORDIS rare DiGEORGE SEQUENCE heart lies on the surface of the chest example of the 22q11 deletion syndrome failure of the embryo to close the ventral body wall Characterized by a pattern of malformations that have origin in abnormal neural crest development These children have facial defects, thymic hypoplasia, HEART DEVELOPMENT: parathyroid dysfunction, and cardiac abnormalities involving the outflow tract, such as persistent truncus arteriosus and SUSCEPTIBLE STAGES FOR THE INDUCTION OF teratology of Fallot. CARDIAC BIRTH DEFECTS Craniofacial malformations are often associated with heart Heart defects are the most common birth defects defects because neural crest cells play important roles in the Related to the complexity of heart development that provides a development of both the face and heart. number of targets for genetic mutations and environmental insults to disrupt normal embryological processes Heart development can be altered very early in gestation and VALVULAR STENOSIS insults at different times can product the same birth defects Target Tissue Cell Process Normal Effect Birth Defects Occurs at pulmonary artery or aorta PHF Establish of Formation of DORV, TGA, I- o Incidence is similar at 3-4/10,000 births (days 16-18) laterality and the 4 TGA, ASD, Semilunar valves are fused for a variable distance patterning chambered VSD, atrial heart isomerism, ventricular PULMONARY ARTERY VALVULAR STENOSIS inversion, Trunk is narrow or atretic dextrocardia Patent oval foramen forms the only outlet for blood from right Heart tube Genetic Looping Dextrocardia side of heart (days 22-28) signaling Page 15 of 19 CMED 1D  (005) CARDIAC EMBRYOLOGY DR. LESLIE ASUNCION-VIADO| 01/11/21 cascade for COARCTATION of the AORTA normal looping occurs in 3.2/10,000 births AVC Cushion Division of the VSD, mitral & aortic lumen below the origin of left subclavian artery is Endocardial formation: cell AVC into the tricuspid valve narrowed (constriction) cushions proliferation left and right defects (mitral Cause of aortic narrowing is primarily an abnormality in the (days 26-35) and migration channels; insufficiency, Formation of tricuspid media of the aorta and intima proliferations mitral and atresia); Preductal: ductus arteriosus persists above tricuspid positioning and Postductal: more common; obliterated ductus arteriosus below valves and leaflet defects o Collateral circulation between proximal and distal aorta is IVS SHF Splanchnic Lengthening Tetralogy of established by way of large intercostal and internal thoracic (days 22-28) mesoderm and Fallot, TGA, arteries ventral to the partitioning pulmonary o Lower part of body is supplied with blood pharynx and the outflow atresia and Classic clinical signs: hypertension in right arm concomitant signaling from tract into stenosis with lowered blood pressure in legs neural crest aortic and cells pulmonary channels Outflow tract Neural crest Formation of Common (conotruncus) cell migration, the truncus (days 36-49) proliferation conotruncal arteriosus and and viability cushions for other outflow division of the tract defects outflow tract Aortic arches Neural crest Patterning the Anomalous right (days 22-42) cell migration, arches into pulmonary proliferation the great artery: IAA type and 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 period of vulnerability and Coarctation of aorta. A. Preductal. B. Postductal. The caudal part of the calculated from the time of fertilization. body is supplied by large hypertrophied intercostal and internal thoracic PHF, Primary Heart Field VSD, Ventricular Septal Defect arteries. DORV, Double Outlet Right Ventricle AVC, Atrioventricular Canal TGA, Transposition of the Great IVS, Interventricular Septum Arteries SHF, Secondary Heart Field l-TGA, Left Transposition of the Great IAA, Interrupted Aortic Arch Arteries ABNORMAL ORIGIN OF THE RIGHT ASD, Atrial Septal Defect SUBCLAVIAN ARTERY artery formed by the distal of right dorsal aorta and 7th intersegmental artery ARTERIAL SYSTEM DEFECTS Right 4th aortic arch and proximal of right dorsal aorta are Normal: ductus arteriosus is functionally closed through obliterated contraction of its muscular wall shortly after birth to form With shortening of aorta between the left common carotid and ligamentum arteriosum left subclavian arteries, origin of abnormal right subclavian Anatomical closure by intima proliferation: 1 – 3 months artery settles below left subclavian artery Its stem is from the right dorsal aorta, it must cross the midline behind the esophagus to reach the right arm PATENT DUCTUS ARTERIOSUS (PDA) Does not usually cause problems with swallowing or breathing one of the most frequent abnormalities of the great vessels because neither the esophagus/trachea is severely (8/10,000 births) compressed premature infants may be isolated or accompany other heart defects (e.g. Tetralogy of Fallot and Transposition of the Great Vessels) defects that cause large differences between aortic and pulmonary pressures may cause increased blood flow through the ductus, preventing normal closure Page 16 of 19 CMED 1D  (005) CARDIAC EMBRYOLOGY DR. LESLIE ASUNCION-VIADO| 01/11/21 Abnormal origin of right subclavian artery. A. Obliteration of right 4th aortic Ventricular Septal Defect (VSD) is also present because the arch and proximal of right dorsal aorta with persistence of distal of right conotruncal septum responsible for septating the outflow tract dorsal aorta. B. The abnormal right subclavian artery crosses the midline fails to extend and fuse with the ventral endocardial cushion in behind esophagus and may compress it. the AVC Type B IAA is often present in children with DiGeorge syndrome (part of 22q11 deletion syndrome complex) DOUBLE AORTIC ARCH right dorsal aorta persists between origin of 7th intersegmental artery and its junction with the left dorsal aorta vascular ring surrounds trachea and esophagus and commonly compresses these, causing difficulties in breathing and swallowing Double aortic arch. A. Persistence of distal of right dorsal aorta. B. The double aortic arch forms a vascular ring around trachea and esophagus. RIGHT AORTIC ARCH A. Abnormal regression patterns in the 4th aortic arch on the left results in left 4th arch & left dorsal aorta are obliterated and replaced by 3 different types of IAA. These interruptions represent the ultimate the corresponding vessels on the right side expression of coarctation of the aorta where the vessel is split in two instead of simply constricted. B. Type A IAA C. Type B IAA D. Type C Occasionally, when ligamentum arteriosum lies on the left side IAA and passes behind the esophagus o complaints with swallowing. VENOUS SYSTEM DEFECTS complicated development of the vena cava may account for INTERRUPTED AORTIC ARCH (IAA) the fact that deviations from the normal pattern are common very rare (3/1,000,000 live births) original pattern of venous return is established bilaterally and o occurs in 50% children w/ DiGeorge syndrome (part of shifts to the right probably accounts for the vena cava 22q11 deletion syndrome complex) abnormalities observed in individuals with laterality (sided- abnormal regression patterns in the right and left 4 th aortic ness) defects arches result to an interruption between the aortic arch and descending aorta DOUBLE INFERIOR VENA CAVA accompanied by a VSD and PDA that allow blood to reach left sacrocardinal vein fails to lose its connection with the left lower part of body subcardinal vein types depends on where the break occurs: left common iliac vein may or may not be present, but the left o Type A: (3-40%) bet. left subclavian artery & descending gonadal vein remains as in normal conditions A. Double inferior vena cava at the lumbar level arising from the aorta persistence of the left sacrocardinal vein. B. Absent inferior vena cava. o Type B: (50-60%) bet. left common carotid & left The low/er half of the body is drained by the azygos vein, v^hich enters subclavian arteries the superior vena cava. The hepatic vein enters the heart at the site of the o Type C: (4%), bet. right & left common carotid arteries inferior vena cava. Patent Ductus Arteriosus (PDA) is present to allow blood to reach descending aorta to the lower parts of the body Page 17 of 19 CMED 1D  (005) CARDIAC EMBRYOLOGY DR. LESLIE ASUNCION-VIADO| 01/11/21 ABSENCE OF THE INFERIOR VENA CAVA arises when the right subcardinal vein fails to make its connection with the liver and shunts its blood directly into the right supracardinal vein bloodstream from the caudal part of the body reaches the heart by way of the azygos vein and superior vena cava hepatic vein enters into the right atrium at the site of the in- ferior vena cava associated with other heart malformations LEFT SUPERIOR VENA CAVA persistence of the left anterior cardinal vein and obliteration of the common cardinal and proximal part of the anterior cardinal veins on the right blood from the right is channelled toward the left by way of the brachiocephalic vein left superior vena cava drains into the right atrium by way of the left sinus horn, that is, the coronary sinus A. Left superior vena cava draining into the right atrium by way of the coronary sinus (dorsal view). B. Double superior vena cava. The communicating [brachiocephalic) vein between the two anterior cardinals has failed to develop (dorsal view). DOUBLE SUPERIOR VENA CAVA characterized by the persistence of the left anterior cardinal vein and failure of the left brachiocephalic vein to form The persistent left anterior cardinal vein, the left superior vena cava, drains into the right atrium by way of the coronary sinus. Page 18 of 19 CMED 1D  (005) CARDIAC EMBRYOLOGY DR. LESLIE ASUNCION-VIADO| 01/11/21 TEST YOUR KNOWLEDGE d) NOTA 13. It is the master gene for left sidedness. 1. Coronary artery is derived from what germ layer a) Serotonin (5-HT) __________. b) PITX2 a) Endocardium c) transcription factor MAD3 b) Myocardium d) NOTA c) Epicardium 14. This is a condition where the heart lies on the right side 2. Common carotid arteries are derived from what of the thorax instead of the left and it occurs when the embryonic structure heart loops to the left instead of the right. a) 3rd aortic arch a) Dextrocardia b) 4th aortic arch b) Situs inversus c) Left distal 6th aortic arch c) Levocardia 3. It forms a horseshoe-shaped cluster of cells. d) NOTA a) Progenitor Hear Cells 15. Which of the three primary germ layers forms the b) Primary Heart Field histologically definitive endocardium of the adult heart? c) Secondary Heart Field a) Ectoderm