Cardiovascular Development PDF Notes 2024-25

Cardiovascular Development Dr. Bruce Berkowitz Page 1 of 43 DEVELOPMENT OF THE CARDIOVASCULAR SYSTEM Lecture Learning Objectives 1. Describe the development of the heart. Describe...

Cardiovascular Development Dr. Bruce Berkowitz Page 1 of 43 DEVELOPMENT OF THE CARDIOVASCULAR SYSTEM Lecture Learning Objectives 1. Describe the development of the heart. Describe the early origin of the heart from the cardiogenic area through the formation of the endocardial tubes. Describe the formation of the primitive heart tube Describe the morphology of the newly-formed heart including its divisions and layers Describe the formation and functions of cardiac jelly. Describe the attachment of the heart tube to the dorsal wall of the pericardial cavity. Describe the process of cardiac looping. Describe the development of the cardiac conduction system. Describe the early circulatory system including the vitelline, umbilical, and general circulations. Describe the heart tube remodeling that results in the formation of the definitive atria. Describe the incorporation of the sinus venosus into the right atrium. Describe the process of shunting the bilateral venous return to the right atrium Describe the development of the left atrium. Describe the partitioning of the heart tube. Describe the partitioning of the atrioventricular canal. Describe the partitioning of the developing primitive atrium, including the role of the septum primum, foramen primum, foramen secundum, endocardial cushions, septum secundum, and foramen ovale. Describe the partitioning of the primitive ventricle. Describe the formation of the muscular interventricular septum. Describe the formation of the membranous interventricular septum. Describe the partitioning of the bulbus cordis and the truncus arteriosus. 2. Describe the development of blood vessels associated with the heart. Describe the development of the veins associated with the heart. Describe the formation of the aortic arches. Name the derivatives of the following aortic arches: 1st, 2nd, 3rd, left 4th, right 4th, 5th, 6th. 3. Describe the fetal circulation. 4. Describe the changes in fetal circulation that occur at birth. 5. Describe congenital defects of the heart and major vessels. Describe the most vulnerable period of cardiovascular development for congenital defects. Describe the two types of strial septal defects and their causes: secundum atrial septal defect and endocardial cushion defect with primum atrial septal defect (priimum atrial septal defect). Cardiovascular Development Dr. Bruce Berkowitz Page 2 of 43 Describe the two most common ventricular septal defects and their causes. Describe the condition and cause of the following defects related to the division of the truncus arteriosus: Persistent truncus arteriosus, transposition of the great vessels, tetrology of Fallot, and aortic or pulmonary stenosis. Describe the condition and cause of the following malformations of the great vessels: Persistent ductus arteriosus, coarctation of the aorta. Describe dextrocardia and its cause. Lecture Content Outline I. Development of the heart A. Formation of the endocardial tubes B. Formation of the primitive heart tube C. Cardiac looping D. Development of the conduction system E. Early circulatory system F. Heart tube remodeling: Formation of the definitive atria G. Partitioning of the heart tube II. Development of blood vessels associated with the heart A. Development of veins associated with the heart B. Development of aortic arches C. Clinical considerations III. Fetal circulation A. Flow of blood from placenta B. Flow of blood from inferior vena cava within heart C. Fate of blood entering the ascending aorta D. Flow of deoxygenated blood from upper extremities E Fate of blood entering the pulmonary trunk F. Fate of blood in the descending aorta IV. Changes in fetal circulation at birth A. Impact of first breath B. Impact of cutting the umbilical cord C. Closure of foramen ovale V. Congenital defects of the heart and major vessels A. Background B. Atrial septal defects (ASD) C. Ventricular septal defects (VSD) D. Defects related to abnormal division of the truncus arteriosus E. Malformations of the great arteries F. Abnormalities of position: Dextrocardia FOR A LINK TO THE VIDEOS AND OTHER LEARNING AIDS visit http://berkowitzlab.wayne.edu/ and go to “Medical Student Information” tab. Cardiovascular Development Dr. Bruce Berkowitz Page 3 of 43 DEVELOPMENT OF THE CARDIOVASCULAR SYSTEM I. Development of the heart A. Formation of the endocardial tubes (Day 19): 1. Endocardial tube formation begins in the cardiogenic plate region of the embryo, located cranial and lateral to the neural plate (Figure 1). Figure 1. Superior view of embryo at 16-17 days, showing the cardiogenic plate and angioblastic cell clusters. From “Heart Development” on Loyola University Medical Education Network (LUMEN). 2. Responding to signals from the underlying endoderm, the splanchnic mesodermal cells in the cardiogenic plate region aggregate into two longitudinal angioblastic cell clusters ventrolateral to the neural plate (Figure 1). 3. These cell clusters then canalize to become the two endocardial tubes. 4. The endocardial tubes are formed via vasculogenesis. a. In vasculogenesis, endothelial cells differentiate from precursor cells and angioblasts, then link together to form vessels. Cardiovascular Development Dr. Bruce Berkowitz Page 4 of 43 b. In contrast, in angiogenesis, new vessels originate from pre-existing blood vessels. 5. This plexus initially lies anterior to the prochordal (prechordal) plate and neural plate. 6. At the same time the endocardial tubes are forming, the outflow and inflow tracts of the future heart form. a. Outflow tract i. Outflow tract is formed by the dorsal aortae. ii. The tract is connected with the endocardial tubes before folding begins. b. Inflow tract: i. Inflow tract is formed by the sinus venosus (left and right horns). ii. Receives blood from three pairs of vessels (common cardinal veins, vitelline veins, and umbilical veins). B. Formation of the primitive heart tube 1. Cephalic folding of the embryo brings the two endocardial tubes into the thoracic region (Figure 2). 2. Lateral folding brings the endocardial tubes close together (Figure 3), where they fuse to form a single heart tube (Figure 4). a. Fusion is facilitated by apoptosis in contacting surfaces. Cardiovascular Development Dr. Bruce Berkowitz Page 5 of 43 Figure 3. Results of cranial (cephalocaudal) and lateral Figure 2. Cranial (cephalocaudal) folding of the embryo. folding of the embryo at the end of the third week: 20 days Figure 13-9 in Moore et al., “The Developing Human”, (top) and 21 days (bottom). Figures 7-2A and B in Larsen, 10th ed. (2016). “Essentials of Human Embryology”, 2nd ed. (1998). Figure 4. Fusion of endocardial tubes. Left: Diagram showing right and left endocardial tubes approaching each other during embryo folding. Right: Scanning electron micrograph (SEM) of fusing endocardial tubes within the pericardial cavity – ventral view. From “Heart Development” on Loyola University Medical Education Network (LUMEN). Cardiovascular Development Dr. Bruce Berkowitz Page 6 of 43 b. Heart tube bulges into the pericardial cavity. 3. As a result of folding, the dorsal aortae form the first aortic arch. 4. Once the heart tube has formed (around day 21), the fused tube elongates and develops dilatations and constrictions, defining key regions (Figure 5). 5. Heart tube begins to beat somewhat ineffectively. Figure 5. Diagram showing key regions defined by the elongation and reshaping of the heart tube around day 21. 6. Fates of regions of heart tube in the adult a. Truncus arteriosus: outflow origin of pulmonary artery and aorta b. Bulbis cordis: forms bulk of right ventricle c. Primitive ventricle: forms bulk of left ventricle d. Primitive atria: form right and left atria 7. Formation of 3 layers in heart tube a. Initially the heart tube is comprised only of endothelium, and this layer will become the endocardium of the heart wall. Cardiovascular Development Dr. Bruce Berkowitz Page 7 of 43 b. Around day 22, a thick mass of splanchnic mesoderm invests the heart tube (Figure 6) and differentiates into two layers: i. Myocardium: Figure 6. Investment of primitive heart tube by cardiac muscle myocardium and cardiac jelly around day 22. Loyola University Medical Education Network (LUMEN). (future myocardium of heart wall) ii. Cardiac jelly: a layer of acellular matrix, composed of glycosaminoglycan and matrix proteins. c. The future epicardium of the heart wall or visceral pericardium is derived from cells of the dorsal mesocardium (dorsal mesoderm in Figure 6) that begin to cover the outside of the heart tube. 8. Cardiac jelly a. The cardiac jelly separates the myocardium and the endothelium of the heart tube. b. Functions of the cardiac jelly i. Serves as a substrate for cell migration in cardiac septation and valve formation. ii. Accumulates to form the endocardial cushions at the atrio-ventricular (A-V) junction and in the outflow tract. Cardiovascular Development Dr. Bruce Berkowitz Page 8 of 43 iii. Stimulates endothelial cells to migrate into the cushion matrix, where they transform into mesenchyme that will form the fibrous basis of the mitral and tricuspid valves. 9. Attachment of heart tube to dorsal wall of pericardial cavity. a. The newly formed heart tube bulges into the pericardial cavity (Figure 7). b. It is attached to the Figure 7. Diagram of transverse section through embryo dorsal side of the around day 22, showing attachment of heart tube to the dorsal wall of the pericardial cavity via the dorsal pericardial cavity via a mesocardium. fold of mesodermal tissue, the dorsal mesocardium, a derivative of the foregut splanchnic mesoderm (Figure 7; dorsal mesoderm in Figure 6). c. Formation and rupture of dorsal mesocardium (Figure 8) i. As the heart pushes into the empty pericardial sac, it becomes surrounded to such a degree that two layers of the dorsal pericardial tissue become opposed and are given the name, the dorsal mesocardium (meso = mesentery, cardium = heart). ii. The dorsal mesocardium suspends the heart for a time but soon breaks down (ruptures), leaving the heart suspended at its cranial and caudal surfaces but not at the back. Cardiovascular Development Dr. Bruce Berkowitz Page 9 of 43 Figure 8. Diagram showing the formation and ultimate rupture of the dorsal mesocardium. iii. The gap which persists where the dorsal mesocardium once was is called the transverse sinus. iv. Dorsal mesocardium ruptures around day 22 together with start of irregular beating. C. Cardiac looping 1. As noted, by day 22, the heart has begun to beat, however this is irregular and somewhat ineffective at first. 2. Blood enters via the sinus venosus and leaves via the dorsal aorta. Cardiovascular Development Dr. Bruce Berkowitz Page 10 of 43 Figure 9. Diagram showing an overview (frontal views) of the four components of normal cardiac looping: (1) ventral bending transforms a straight tube into a curved tube whose outer curvature is formed by its ventral wall; (2) torsion around its original cranio-caudal axis transforms a curved tube into a helically wound loop which appears as a c-shaped loop in frontal views; (3) caudal shift of the ventricular segment; (4) untwisting is characterized by ventral and leftward shift of the proximal outflow tract and ventral shift of the primitive right ventricle.. A: common atrium (primitive atria); LV: embryonic left ventricle; O: outflow tract; RV: embryonic right ventricle. Figure 8 in Männer J, Clinical Anatomy 22:21-35 (2009). 3. Formation of the cardiac loop, i.e., cardiac looping, begins around day 23 and will result in the following changes in the components of the heart tube (Figure 9): a. Site of blood inflow (sinus venosus and primitive atria) will move to a more cranial position relative to the structures that will form the ventricles (primitive ventricle, bulbus cordis). b. Left ventricle will shift to the left. c. Right ventricle will shift to the right d. Blood comes out of the right ventricle. 4. Details of cardiac looping (Figure 10) a. Position of the heart tube on day 23 (Figure 10a) i. The cardiac tube is constrained at the sinus venosus by the septum transversum, and at the truncus region by its connection with the aortic arches. Cardiovascular Development Dr. Bruce Berkowitz Page 11 of 43 ii. Between these constraints, the tube is free to move. Figure 10. Diagram showing the process of cardiac looping. (a) Heart tube before cardiac looping. (b): Expansion and looping of heart tube result in formation of the bulboventricular loop. Regions that become right and left atria (RA and LA) are shown. (c)-(e): Further changes that occur during cardiac looping. Ao: aorta; AVC: atrioventricular canal; BC: bulbus cordis; CC: conus cordis; LA: left atrium; LV: left ventricle; PLV: presumptive left ventricle; PRV: presumptive right ventricle; PT: pulmonary trunk; RA: right atrium; RV: right ventricle; S: aortic sac; TA: truncus arteriosus; V: primitive ventricle. Figure 13.2 from “The Heart” (Ch. 13), Henderson, D, Hutson, MR, and Kirby, ML in Embryos, Genes and Birth Defects, eds. Ferretti, P et al., 2nd ed., John Wiley & Sons, 2006. b. Around day 23, the heart tube bends upon itself and to the right to form the bulboventricular loop (Figures 10b and c). c. The atrium and sinus venosus are now located dorsal and cranial to the ventricle (Figure 10c). d. The heart is the first asymmetrical structure to appear in the embryonic body. Cardiovascular Development Dr. Bruce Berkowitz Page 12 of 43 5. What causes cardiac looping? Probably multifactorial involving asymmetrical distribution of actin bundles, pressure of cardiac jelly, cell deformation, and hemodynamic factors. D. Development of the conduction system 1. Development of the cardiac conduction system remains a somewhat controversial area. 2. The conduction system consists of modified myocardial cells. 3. Nodal tissue develops in the sinus Figure 11. Diagram showing the location where nodal tissue develops within the heart tube (rings). venosus (Figure 11). 4. After inclusion of the sinus venosus within the right atrium, nodal tissue condenses in two locations: a. At the entry of the superior vena cava, which gives rise to the sinoatrial ring, which includes the SA node (beat originates). b. Near the right atrioventricular orifice, which gives rise to the atrioventricular ring that develops into the atrioventricular conduction system including the AV node. 5. The development of the AV node is accompanied by the appearance of a bundle of specialized conducting cells, bundle of His, which sends one branch into the right ventricle and the other into the left ventricle. Cardiovascular Development Dr. Bruce Berkowitz Page 13 of 43 6. Problems with looping lead to problems with conduction. E. Early circulatory system 1. Inflow and outflow to and from heart a. Inflow track: The sinus venosus, the intake end of the heart, receives blood from six vessels - the paired umbilical, vitelline, Figure 12. Diagram showing the inflow track of the heart. The sinus venosus receives blood and common cardinal from the three pairs of vessels: umbilical veins (UV), vitelline veins (VV), and common veins (Figure 12). cardinal veins (CC). The sinus venosus remains a paired structure with right (RSH) and left (LSH) horns. LA: left atrium; RA: right atrium; SA: sinoatrial orifice. From “Heart b. Outflow track Development” on Loyola University Medical Education Network (LUMEN). i. The truncus arteriosus opens into the aortic sac, from which arise the aortic arches that in turn open into the paired dorsal aortae. ii. The dorsal aortae have formed in the paraxial mesoderm, and soon unite from behind the heart to the level of lumbar vertebra 4. 2. Vitelline circulation (Figure 13) a. Vitelline arteries arising from the dorsal aortae bring blood to the yolk sac and future gut. b. They are represented in the adult by the celiac, superior mesenteric, and inferior mesenteric arteries. Cardiovascular Development Dr. Bruce Berkowitz Page 14 of 43 Figure 13. Diagram showing early embryonic circulatory system. c. Blood returns to the heart via the vitelline veins, which later form the portal and hepatic veins. 3. Umbilical circulation (Figure 13) a. Two umbilical arteries arise from the dorsal aortae and conduct 50% of the cardiac output to the placenta. b. Oxygenated blood from the placenta returns to the heart via the umbilical vein. c. Note artery/vein reversal: Umbilical arteries carry deoxygenated blood, while umbilical vein carries oxygenated blood. 4. General Circulation a. Blood is distributed by dorsal intersegmental branches of the dorsal aortae to the neural tube and Cardiovascular Development Dr. Bruce Berkowitz Page 15 of 43 somites, and by lateral segmental arteries to the developing kidneys and gonads. b. Blood returns to the heart via the anterior and posterior cardinal veins, which join to become the common cardinal vein (Figure 13). F. Heart tube remodeling: Formation of the definitive atria 1. Up to about day 24, sinus venosus is centrally located, and there is bilateral symmetry (Figure 12). a. Sinus venosus remains a paired structure with right and left horns. b. Each horn receives venous blood from three vessels: vitelline vein, umbilical vein, and common cardinal vein. c. Communication between the sinus venosus and the primitive atrium, the sinoatrial orifice, is originally centrally located. 2. Incorporation of the sinus venosus into the right atrium a. Gradually, as the heart undergoes looping and the interatrial septa form, the entrance of the sinus venosus (sinoatrial orifice) Figure 14. Diagram showing a superior view of the left atrium (right) and right atrium (left). shifts to the right and Note the shift of the sinoatrial orifice (SA) to the right. LVV: left venous valve; RVV: right communicates with only the venous valve; SA: sinoatrial orifice; SS: septum spurium. From “Heart Development” right atrium (Figure 14). on Loyola University Medical Education Network (LUMEN). Cardiovascular Development Dr. Bruce Berkowitz Page 16 of 43 b. As a result of left to right shunts, the right horn of the sinus venosus enlarges, and the left horn shrinks. i. The left horn remains as the coronary sinus of the heart. ii. The right horn is incorporated into the right atrium. iii. Thus all blood returning to the heart via the inferior vena Figure 15. Diagram showing a superior view of the left atrium (right) and right atrium (left). cava, superior vena Note the formation of the orifice of the inferior vena cava (Inf. V.C.) and the orifice of the cava, and coronary superior vena cava (Sup. V.C.) within the previous sinoatrial orifice. CT: crista sinus enters the right terminalis; RAu: pectinate auricular appendage in right atrium. From “Heart atrium (Figure 15). Development” on Loyola University Medical Education Network (LUMEN). c. The right venous valve of the sinoatrial orifice forms the crista terminalis, the valve of the inferior vena cava, and the valve of the coronary sinus (Figure 15). d. The original embryonic right atrium becomes the pectinate auricular appendage (Figure 15). e. The incorporated sinus venosus forms the smooth walled sinus venarum of the definitive right atrium, while the primitive atrium (original embryonic atrium) is represented by the trabeculated part of the right atrium, i.e., the pectinate auricular appendage (Figure 16). Cardiovascular Development Dr. Bruce Berkowitz Page 17 of 43 3. Left atrium development a. Left atrium development occurs concurrently with that of the right atrium. b. Early in the fourth week, the left atrium is Figure 16. Diagram showing the sources of the smooth- greatly expanded by walled parts of the definitive right and left atria. incorporation of the primitive pulmonary vein and its branches (Figure 17). Figure 17. Left: Diagram showing a superior view of the left atrium (right) and right atrium (left). Note that the left atrium has incorporated the primitive pulmonary vein (PV). Right: Posterior view of heart tube. LA: left atrium; PV: pulmonary vein. From “Heart Development” on Loyola University Medical Education Network (LUMEN). c. Thus, the larger smooth-walled part of the definitive left atrium is derived from pulmonary vein tissue, while the original embryonic left atrium is represented by the auricular appendage, i.e., the trabeculated portion of the definitive atrium (Figure 16). Cardiovascular Development Dr. Bruce Berkowitz Page 18 of 43 G. Partitioning of the heart tube (4th -7th weeks) 1. Partitioning of the atrioventricular canal a. On day 28, the common atrium communicates with the ventricle through a narrow passage, the atrioventricular canal (Figure 18). Figure 18. Diagram of the heart tube showing a view of the left ventricle (LV) and the bulbus b. About day 35 two thickenings cordis (BC) on ~day 28. Note the presence of the atrioventricular canal (AVC), through form on the dorsal and ventral which the common atrium (into the page) communicates with the ventricle. From “Heart walls of the atrioventricular Development” on Loyola University Medical Education Network (LUMEN). canal. i. Thickenings are called endocardial cushions. Cardiac jelly and neural crest cells contribute to the formation of endocardial cushions. ii. The cushions begin to divide the atrioventricular canal into a left and a right orifice. Figure 19. Diagram of the heart tube on ~day c. The endocardial cushions 35 showing the formation of the right (RAVC) and left (LAVC) atrioventricular canals. They continue to grow and approach formed when the endocardial cushions fused to divide the atrioventricular canal. LV: left each other. ventricle; RV: right ventricle. From “Heart Development” on Loyola University Medical Education Network (LUMEN). d. At approximately day 42, the dorsal (superior) and ventral (inferior) endocardial cushions fuse dividing the single atrioventricular canal into a right and a left atrioventricular canal (Figure 19). Cardiovascular Development Dr. Bruce Berkowitz Page 19 of 43 e. Formation of atrioventricular valves 1. Large proteoglycan particles (adherons) produced by the myocardial cells accumulate in the endocardial cushion tissue and induce the overlying endothelium to transform into mesenchymal cells which migrate into the cardiac jelly. ii. These mesenchymal cells participate in the formation of the definitive mitral and triscupid valves. 2. Partitioning of the primitive atrium a. The primitive atrium is divided into right and left atria by the formation of the interatrial septum. b. At about day 28, the sickle-shaped septum primum (S1 in figures) grows from the roof (dorsal wall) of the atrium toward Figure 20. Diagram showing formation of foramen primum (O1) by growth of septum primum (S1) toward the endocardial the endocardial cushions. LA: left atrium. From “Heart Development” on Loyola University Medical Education cushions (Figure 20). Network (LUMEN). c. The opening (foramen) between the lower edge of the septum primum and the atrioventricular (endocardial) cushions is called the foramen primum (O1 in figures) (Figure 20). Cardiovascular Development Dr. Bruce Berkowitz Page 20 of 43 d. The foramen primum becomes progressively smaller and is obliterated when the septum primum fuses with the fused atrioventricular cushions. e. Before the foramen primum is obliterated, genetically programmed cell death (apoptosis) creates perforations in the septum primum Figure 21. Diagram showing creation of perforations (Perf.) in the septum primum (S1). EC: endocardial (Figure 21), which cushions; O1: foramen primum; SAO: sinoatrial orifice ; SS: septum spurium. From “Heart Development” on coalesce to form the Loyola University Medical Education Network. foramen secundum (Figure 22). i. Thus, blood continues to flow freely from the right to the left Figure 22. Diagram showing the growth of the septum atrium. secundum (S2) to the right of the septum primum (S1). EC: endocardial cushions; O1: foramen primum; LVV: left venous valve; SS: septum spurium. From “Heart Development” on Loyola University Medical Education ii. This avoids Network (LUMEN). loading of the pulmonary circulation. f. Another septum, septum secundum (S2 in figure), grows from the roof (dorsal wall) of the atrium toward the atrioventricular (endocardial) cushions (Figure 22). i. It appears to the right of the septum primum and overlaps the foramen secundum. Cardiovascular Development Dr. Bruce Berkowitz Page 21 of 43 ii. Septum secundum does not fuse with the endocardial cushions (Figure 23). Figure 23. Diagram showing continued growth of the g. The opening between septum secundum (S2) forming the foramen ovale (FO). O1: foramen primum; S1: septum primum. From “Heart the lower edge of the Development” on Loyola University Medical Education Network (LUMEN). septum secundum and the endocardial cushions is called the foramen ovale (FO in figure) (Figure 23). h. The persistent part of the septum primum, below the foramen secundum, is also known as the valve of foramen ovale. i. In postnatal life, it forms the floor of fossa ovalis. ii. The overlapping edges of the septa fuse to form the limbus of fossa ovalis. i. Blood flow between atria i. Blood flows from the right atrium, through the foramen ovale, and between the overlapping edges of the septum secundum and septum primum into the left atrium. ii. The septum primum acts as a one way flutter valve over the foramen ovale allowing blood to flow only from right to left. Cardiovascular Development Dr. Bruce Berkowitz Page 22 of 43 3. Partitioning of the primitive ventricle a. A muscular interventricular septum results from expansion of the ventricles on each side of it (Figure 24). Figure 24. Formation of the muscular interventricular septum. b. The septum then grows actively toward, but does not reach, the fused atrioventricular cushions leaving an interventricular foramen (Figure 25). Figure 25. Diagram showing the formation of the interventricular foramen. c. The membranous part of the interventricular septum completes the septum. i. Thin-walled structure that closes the interventricular foramen. ii. It is derived from atrioventricular cushion tissue that fuses with the aortico-pulmonary septum and the muscular interventricular septum (Figure 26). Cardiovascular Development Dr. Bruce Berkowitz Page 23 of 43 Figure 26. Development of aortico-pulmonary septum and closure of the interventricular septum. The twisting aortico-pulmonary septum is formed by the fusion of ridges that appear in the bulbus and the truncus. Fusion of the developing aortico-pulmonary septum with the proliferating anterior atrioventricular (endocardial) cushion closes the interventricular foramen and forms the membranous portion of the interventricular septum d. Cavitation of the ventricular walls leads to formation of trabeculae carneae, papillary muscles, and chordae tendineae. 4. Partitioning of the bulbus cordis and the truncus arteriosus a. Formation of aortico-pulmonary septum i. The aortico-pulmonary septum is largely derived from neural crest mesenchyme that migrates into the truncus arteriosus and bulbus cordis and forms ridges (truncal and conus swellings or truncoconal swellings). ii. The aortico-pulmonary septum is formed by the fusion of these ridges (truncal and conus swellings or truncoconal swellings) in the bulbus and the truncus (Figure 27). Cardiovascular Development Dr. Bruce Berkowitz Page 24 of 43 iii. It divides the bulbus cordis and truncus arteriosus into the ascending aorta and the pulmonary trunk. Figure 27. Diagram showing formation of ridges (truncal and conus swellings) within the bulbus cordis and truncus arteriosus. The spiraling ridges b. The spiral nature of form the aortico-pulmonary septum that divides the bulbus cordis and truncus arteriosus into the septum results in the ascending aorta and the pulmonary trunk. LITS: left inferior truncal swelling; LVCS: left ventral conus "twisting" of the swelling; RDCS: right dorsal conus swelling; RSTS: right superior truncal swelling. Modified pulmonary trunk with from “Heart Development” on Loyola University Medical Education Network (LUMEN). respect to the aorta. c. The aortico-pulmonary septum fuses with the atrioventricular cushions and participates in the formation of the membranous interventricular septum (Figure 26). d. Mesenchymal cells of the neural crest migrate to the wall of the outflow channel of the heart, and form the tunica media of the ascending aorta and pulmonary trunk, and contribute connective tissue to the leaflets of the aortic and pulmonary valves which form at the base of the bulbus cordis. Continued on next page. Cardiovascular Development Dr. Bruce Berkowitz Page 25 of 43 II. Development of blood vessels associated with the heart A. Development of veins associated with the heart 1. An anastomosis develops between the left and right anterior cardinal veins (ACV, which drain blood from the brain) shunts blood to the right anterior cardinal vein. a. The left ACV below the anastomosis disappears. b. The anastomotic channel is the left brachiocephalic vein which joins the right ACV. c. The small segment of right ACV between the junction of the right and left brachiocephalic veins and the right atrium becomes the superior vena cava. Thus all blood returning from the head, neck, and upper limbs enters the superior vena cava. 2. Posterior cardinal veins largely disappear. In the thorax, terminal portion of right posterior cardinal vein persists as the azygos vein, which enters the superior vena cava. 3. During incorporation of the sinus venosus into the right atrium, the left horn of the sinus venosus becomes the coronary sinus of the heart. 4. Fate of umbilical and vitelline veins a. The right umbilical vein, and the left vitelline vein and left umbilical vein between the liver and sinus venosus disappear. b. Only the right vitelline vein between the liver and sinus venosus persists to form the inferior vena cava in this region. Cardiovascular Development Dr. Bruce Berkowitz Page 26 of 43 c. The left umbilical vein shunts 80% of its blood via the ductus venosus to the inferior vena cava. The remainder circulates through the liver and returns to the inferior vena cava via the hepatic veins. 5. All of these changes are completed in the eighth week of gestation. B. Development of aortic arches 1. Remember $1.25 rule: 1st, 2nd, and 5th aortic arches largely disappear (Figure 28). Figure 28. Diagram showing aortic arches during embryonic development. 2. Formation and regression of 1st pair of aortic arches (Figures 29 and 30) a. First pair of aortic arches is formed between day 22 and 24, during embryonic folding. b. Largely disappears, but remainder forms maxillary arteries. 3. Formation and regression of 2nd pair of aortic arches (Figures 29 and 30) a. Second pair of aortic arches appears in week four, developing from angioblasts that migrate from the surrounding splanchnic mesoderm. b. Second arch regresses rapidly (on ~day 29), except for a small remnant giving rise to the stapedial artery. Cardiovascular Development Dr. Bruce Berkowitz Page 27 of 43 Figure 29. Development of the six pairs of aortic arches. Figure 30. Diagram showing the six pairs of aortic arches (left) and their fates (right). 4. Formation of 3rd pair of aortic arches (Figures 29 and 30) a. Third pair appears around the end of the fourth week (~day 28), while the first arch is regressing. b. Develops from angioblasts that migrate from the surrounding splanchnic mesoderm. c. In the adult, third arch gives rise to common carotid arteries and proximal portion of the internal carotid arteries. Cardiovascular Development Dr. Bruce Berkowitz Page 28 of 43 d. The distal portions of the internal carotid arteries are formed by the cranial portions of the dorsal aorta. 5. Formation of 4th pair of aortic arches (Figures 29 and 30) a. Fourth pair develop soon after the third arch arteries (~day 28), while the first arch is regressing. b. Develops from angioblasts that migrate from the surrounding splanchnic mesoderm. c. In the adult: i. Left side persists, connecting the ventral aorta to the dorsal aorta, forming the aortic arch. ii. Right side forms the proximal portion of the right subclavian artery. 6. Formation and regression of 5th pair of aortic arches (Figures 29 and 30) a. Fifth pair of aortic arches develops at the end of week four from angioblasts that migrate from the surrounding splanchnic mesoderm. b. It regresses completely and is not known to contribute to any vascular structure. c. The fifth aortic arch is absent in about 50% of embryos. Cardiovascular Development Dr. Bruce Berkowitz Page 29 of 43 7. Formation of 6th pair of aortic arches (Figures 29 and 30) a. Sixth pair appears around the middle of the fifth week from angioblasts that migrate from the surrounding splanchnic mesoderm. b. In the adult: i. Proximal portion of sixth arch gives rise to right and left pulmonary arteries. ii. Distal portion gives rise to ductus arteriosus. 8. Review: Derivatives of the aortic arches (Figure 30) a. First: Largely disappears, but remainder forms maxillary arteries. b. Second: Largely disappears, but remnant gives rise to stapedial arteries. c. Third: Give rise to common carotid and part of internal carotid arteries. d. Left fourth: Give rise to arch of the aorta. e. Right fourth: i. Forms proximal part of the right subclavian artery. ii. The distal part of the right subclavian artery is derived from the right dorsal aorta and the right 7th intersegmental artery. Cardiovascular Development Dr. Bruce Berkowitz Page 30 of 43 f. Sixth Arch: i. On the right, the distal part of the 6th arch artery disappears, but the proximal portion gives rise to right and left pulmonary arteries. ii. On the left, it persists as the ductus arteriosus and then the ligamentum arteriosum. III. Fetal circulation (Figure 31) End of 7th week, heart has reached its final stage of development. A. Flow of blood from placenta 1. The umbilical vein carries highly oxygenated blood from the placenta to the fetus. 2. Fate of umbilical vein blood a. Almost all of the blood is shunted through the Figure 31. Fetal (pre-natal) circulation. Figure 13-46 in Moore et ductus al., “The Developing Human”, 10th ed. (2016). venosus to the inferior vena cava (IVC), which also conducts some deoxygenated blood from the lower trunk, lower limbs, and liver. Cardiovascular Development Dr. Bruce Berkowitz Page 31 of 43 b. Some blood from umbilical vein is shunted to the portsal vein to supply the liver, and ultimately reaches the inferior vena cava. B. Flow of blood from inferior vena cava within heart 1. The inferior vena cava delivers the blood to the right atrium. 2. Almost all of the IVC blood courses through the foramen ovale to the left atrium, where it mixes with a small amount of deoxygenated blood from the lungs. 3. This high oxygen content blood then courses through the left ventricle and is pumped into the ascending aorta. C. Fate of blood entering the ascending aorta 1. Most of this oxygenated blood entering the ascending aorta is immediately distributed to the heart, head and neck, and upper limbs. 2. The remainder continues along the aorta, where it is mixed with deoxygenated blood from the ductus arteriosus (see below). 3. This mixed blood with medium oxygen content continues to the descending aorta. D. Flow of deoxygenated blood from upper extremities 1. Deoxygenated blood returning from the upper body via the superior vena cava enters the right atrium, where it mixes with a small amount of blood coming from the inferior vena cava (see above). Cardiovascular Development Dr. Bruce Berkowitz Page 32 of 43 2. This mixed blood with medium oxygen content flows into the right ventricle and is pumped into the pulmonary trunk. E. Fate of blood entering the pulmonary trunk 1. Only a small amount of this blood enters the lungs, because of the high pulmonary resistance to flow. a. This small amount that enters the lungs to supply the lung tissues. b. The deoxygenated blood from the lungs returns to the left atrium via the pulmonary veins. c. This blood mixes with oxygenated blood coming from the right atrium (see above). 2. Most of the blood entering the pulmonary trunk flows through the ductus arteriosus to the descending aorta (see above). F. Fate of blood in the descending aorta 1. About 35% of the blood in the descending aorta supplies the lower limbs and the lower trunk. 2. About 65% is distributed to the placenta via the umbilical arteries. Note: Patency of the ductus arteriosus and ductus venosus in the fetus is maintained by prostaglandins and bradykinin. Cardiovascular Development Dr. Bruce Berkowitz Page 33 of 43 IV. Changes in fetal circulation at birth (Figure 32) A. Impact of first breath 1. The first inspiratory effort opens up the pulmonary vascular bed so that blood in the pulmonary trunk enters the lungs. 2. Pressure in the ductus arteriosus drops markedly, and it constricts within minutes after birth. 3. The large amount of blood now leaving the lungs via the Figure 32. Post-natal (neonatal) circulation. Figure 13-47 in Moore et al., “The Developing Human”, 10th ed. (2016). pulmonary veins enters the left atrium. 4. As a result of the large amount of blood entering the left atrium, pressure in the left atrium increases markedly. B. Impact of cutting the umbilical cord 1. Cutting the umbilical cord results in an immediate cessation of blood entering the body via the umbilical vein, and thus greatly reduces the amount of blood entering the right atrium. 2. Pressure in the right atrium drops immediately. Cardiovascular Development Dr. Bruce Berkowitz Page 34 of 43 C. Closure of foramen ovale 1. As a result of these events (first breath and cutting of umbilical cord), pressure in the left atrium exceeds that of the right atrium. 2. The valve of the foramen ovale (persistent part of the septum primum) is pushed tightly against the septum secundum, and the foramen ovale is functionally closed. 3. Adherence of the septum primum to the edge of the septum secundum is initially secured by fibrin deposits along the line of contact. 4. Subsequently the fibrin is replaced by fibrous connective tissue over several months. V. Congenital defects of the heart and major vessels A. Background 1. Cardiovascular system defects are the most frequent group of serious malformations, with an incidence of around 8 per 1,000 live births. 2. Etiology: a. Single gene defects b. Chromosomal abnormalities (10%) - Examples: Down's syndrome, trisomies 18, 13. c. Environmental factors - Examples: thalidomide, rubella virus, anti-convulsant drugs, heavy alcohol intake. Cardiovascular Development Dr. Bruce Berkowitz Page 35 of 43 d. Unknown - regarded as multifactorial, i.e., produced by a genetic predisposition acting in concert with unknown environmental factors. 3. Most vulnerable period of cardiovascular development is 3rd through 7th week of development. 4. The following account for about 80% of cardiovascular malformations: a. Atrial septal defects b. Ventricular septal defects c. Pulmonary and aortic stenosis d. Fallot's tetralogy e. Persistent ductus arteriosus f. Coarctation of the aorta g. Abnormalities of Position B. Atrial Septal Defects (ASD, Figure 33) 1. ASD results in mixing of oxygenated (systemic) and deoxygenated (pulmonary) blood. Figure 33. Diagram illustrating an atrial septal defect (right). From University of Kansas (1996). Cardiovascular Development Dr. Bruce Berkowitz Page 36 of 43 2. May lead to pulmonary hypertension, right ventricle and pulmonary trunk enlargement and heart failure. 3. Two types of atrial septal defect (ASD): a. Secundum ASD b. Endocardial cushion defect with primum ASD (Primum ASD) 4. Secundum ASD (Figure 34) a. Defect in fossa ovalis. Figure 34. Diagram illustrating a secundum ASD. Left: b. Defect can result right sagittal view. Right: frontal cross section. FO: foramen ovale; S1: septum primum; S2: septum from: secundum. From “Heart Development” on Loyola University Medical Education Network (LUMEN). i. Excessive resorption of septum primum. ii. Defective formation of septum secundum. c. In both cases, the result is a patent foramen ovale. 5. Endocardial Cushion Defect with Primum ASD (Figure 35) a. Incomplete fusion of the AV endocardial cushions prevents Figure 35. Diagram illustrating an endocardial cushion proper fusion of defect with primum ASD (primum ASD). Left: right sagittal view. Right: frontal cross section. FO: foramen septum primum with ovale; IEC: inferior endocardial cushion; O1: foramen primum; SEC: superior endocardial cushion. From the cushions. “Heart Development” on Loyola University Medical Education Network (LUMEN). Cardiovascular Development Dr. Bruce Berkowitz Page 37 of 43 b. Thus, a foramen primum persists. c. Defect is often associated with abnormal mitral valve and interventricular septum defect, as often occurs in Down's Syndrome. C. Ventricular Septal Defects (VSD, Figure 36) 1. Most common type of cardiac defect (25%). 2. VSD results in massive left to right shunting of blood and, if vessel Figure 36. Diagram illustrating ventricular septal defect diameters are normal, (right). From University of Kansas (1996). pulmonary hypertension. 3. Two types of ventricular septal defect (Figure 37): a. Membranous VSD: Defect in formation of membranous part of interventricular Figure 37. Diagram illustrating the two types of VSD: membranous VSD (left) and muscular VSD (right). Mem: septum caused membranous septum; Musc: muscular septum From “Heart Development” on Loyola University Medical Education by failure of the Network (LUMEN). muscular portion of the interventricular septum to fuse with the free edge of the cushions. Cardiovascular Development Dr. Bruce Berkowitz Page 38 of 43 b. Muscular VSD: Defect in formation of muscular part of interventricular septum caused by excessive cavitation of myocardial tissue during formation of muscular interventricular septum. D. Defects related to abnormal division of the truncus arteriosus 1. Persistent truncus arteriosus (Figure 38) a. A persistent truncus arteriosus results when the truncoconal swellings fail to Figure 38. Diagram illustrating a persistent truncus arteriosus (right). From University of Kansas (1996). grow. i. The aortico-pulmonary septum does not properly form. ii. The membranous interventricular septum does not form, resulting in a ventricular septal defect. b. The single artery, the truncus arteriosus, arises from both ventricles above the ventricular septal defect, allowing pulmonary and systemic blood to mix. c. Distally, the single artery is divided into the aorta and pulmonary trunk by an incomplete septum. Cardiovascular Development Dr. Bruce Berkowitz Page 39 of 43 2. Transposition of the great vessels (Figure 39) a. Transposition is a condition in which the aorta arises from the right ventricle and the pulmonary trunk arises from the left ventricle. b. This anomaly is due to the failure of the truncoconal swellings to grow in the normal spiral direction. c. A ventricular septal defect Figure 39. Diagram illustrating transposition of the great vessels. and a patent ductus arteriosus are often present. These secondary defects make life possible, as they provide a way for some oxygenated blood to reach the entire body. 3. Tetralogy of Fallot (Figure 40) a. Most common cause of "blue baby." b. This condition results from a single error: the Figure 40. Diagram illustrating tetralogy of Fallot (right). From University of Kansas (1996). conus septum develops too far anteriorly giving rise to two unequally proportioned vessels: a large aorta and a smaller stenotic pulmonary trunk. Cardiovascular Development Dr. Bruce Berkowitz Page 40 of 43 c. The four main characteristics of tetralogy of Fallot are: i. pulmonary stenosis ii. Ventricular septal defect (VSD) of the membranous portion: The septum is displaced too far anteriorly to contribute to the septum. iii. Overriding aorta: The aorta straddles the VSD. iv. Right ventricular hypertrophy due to the shunting of blood from right to left: The pressure in the right ventricle is increased due to pulmonary stenosis causing the walls of the right ventricle to expand. 4. Aortic or Pulmonary Stenosis (Figure 41) a. The aortic or pulmonary valve is thickened and narrowed, leading to the development of abnormally high pressure in the left or right ventricle, respectively. b. The left or right ventricular wall, respectively, becomes thickened ("hypertrophied"). c. Stenosis (narrowing) of the valve restricts flow. d. This leads to the presence of a heart "murmur". Cardiovascular Development Dr. Bruce Berkowitz Page 41 of 43 Figure 41. Diagrams illustrating an aortic stenosis (left) and a pulmonary stenosis (right). e. Complications i. Often the narrowing is mild and does not put significant strain on the heart. However, the narrowing frequently worsens with growth. ii. If the obstruction is severe, symptoms may develop, or the heart may show evidence of "strain". The valve may require treatment to open it up. E. Malformations of the Great Arteries 1. Persistent ductus arteriosus (Figure 42) a. Normally functional closure of the ductus arteriosus occurs Figure 42. Diagram illustrating persistent (or patent) ductus within a few days arteriosus (right). From University of Kansas (1996). Cardiovascular Development Dr. Bruce Berkowitz Page 42 of 43 after birth and anatomical closure within a few weeks. b. If the ductus arteriosus remains patent, blood flows from aorta to pulmonary artery. c. Failure of ductus arteriosus to close accounts for 10% of cardiovascular malformations in infancy. d. Often associated with premature birth, and rubella. 2. Coarctation of the aorta (Figure 43) a. Narrowing of the aorta. b. Usually the narrowing is located proximal to the ductus arteriosus (preductal coarctation, Figure 43). c. May remain unidentified Figure 43. Diagram illustrating a preductal until early childhood. coarctation of the aorta. d. When the ductus closes, blood reaches the lower part of the body through collateral pathways: i. Scapular anastomosis, which connects with intercostal arteries and thus blood flows into the thoracic aorta. ii. Internal thoracic ─ superior epigastric ─ inferior epigastric arteries ─ femoral arteries. Cardiovascular Development Dr. Bruce Berkowitz Page 43 of 43 e. Always suspect in young adults with hypertension. i. Femoral pulses are reduced and delayed. ii. May be able to hear blood flow through epigastric arteries with a stethoscope, and observe enlarged intercostal arteries. f. Accounts for 10% of major cardiovascular malformations. F. Abnormalities of Position: Dextrocardia (Figure 44) 1. Dextrocardia is an anomaly in which the primitive heart tube folds to the left instead of to the right. 2. Results in a mirror image of a normal bulboventricular loop. Figure 44. Diagram illustrating dextrocardia, an anomaly 3. This usually occurs when in which the primitive heart tube folds to the left instead of to the right. BC: bulbus cordis; LA: left atrium; RA: all the organ systems are right atrium; RV: right ventricle. From “Heart Development” on Loyola University Medical Education reversed, a condition Network (LUMEN). called situs inversus.