This session discusses the development of the cardiovascular system and includes: 1. Development of the heart 2. Development of the arterial system 3. Development of the venous system 4. Development of lymphatics, overview of fetal circulation, and changes in fetal circulation at birth

2. Origin of the Heart Tube
 The cardiac progenitor cells originate lateral to the primitive streak and invaginate through it to
migrate cranially to the cardiogenic field where they lie within splanchnic mesoderm, rostral to the
buccopharyngeal membrane, as two separate groups, one on each side; each group is stimulated by
the endoderm of the pharynx to form cardiac myoblasts;
 Blood islands also appear in the splanchnic mesoderm and form a horseshoe-shaped endothelial
tube for each group of cardiac myoblasts; hence the endocardium is derived from the blood islands,
while the myocardium is derived from the cardiac progenitor cells
 With lateral folding of the embryo, the two groups come together and begin fusion craniocaudally; a
complete heart tube thus is formed

3. Fusion of the Heart Tubes and Pericardial Coeloms

4. The Dorsal Mesocardium
 The heart tube bulges more into the pericardial cavity; initially it remains attached to the dorsal wall
of the cavity by the dorsal mesocardium (connection between the splanchnic and somatic layers of
the pericardial cavity); later the dorsal mesocardium breaks down, connecting both sides of the
cavity together, and forming the transverse pericardial sinus in the adult; the heart is then
suspended by blood vessels at its cranial and caudal ends

5. Fusion of Heart Tubes
 With lateral folding of the embryo, the two groups come together and begin fusion craniocaudally; a
complete heart tube thus is formed
 Blood islands appear in the splanchnic mesoderm and form a horseshoe-shaped endothelial tube
for each group of cardiac myoblasts; hence the endocardium is derived from the blood islands, while
the myocardium is derived from the cardiac progenitor cells

6. Looping of the Heart
 The heart tube continues to elongate and bend at the beginning of the 4th week; the cephalic
portion of the tube bends ventrocaudally and to the right, while the caudal portion bends
dorsocranially and to the left; this process is called dextral looping, which is complete by the 28th
day; opposite bending leads to dextrocardia
 Local expansions in the tube appear dividing it, from caudal to cranial, into: sinus venosus, common
atrium, AV junction, left ventricle, primary interventricular foramen, and bulbus cordis
 Bulbus cordis is divided into three parts, from proximal (i.e. caudal) to distal: trabeculated part of
right ventricle, conus cordis (future outflow tracts, or smooth parts of both ventricles), and truncus
arteriosus (roots and proximal ends of aorta and pulmonary artery)

7. Looping of the Heart
 Local expansions in the tube appear dividing it, from caudal to cranial, into: sinus venosus, common
atrium, AV junction, left ventricle, primary interventricular foramen, and bulbus cordis

8. Ventricles and Atria
 When looping is complete, trabeculae begin to appear on both sides of the primary interventricular
foramen, forming the trabeculated part of both ventricles
 Formation of two transverse dilations of the common atrium on either side of the bulbus cordis,
causes shifting of the conotruncus from the right side to a more median position

9. The Sinus Venosus
 Sinus venosus has two sinus horns, each receiving blood from three veins: umbilical, common
cardinal, and vitelline (or omphaloenteric); later the left common cardinal and left vitelline veins
are obliterated, causing shunting of blood to the right horn (left-to-right shunts) which results in its
enlargement; only remnant of left horn is the coronary sinus and oblique vein of left atrium
 Connection of the sinus with the common atrium is initially wide, but later shifts to the right and the
right horn is incorporated into the right atrium as the sinuatrial orifice, guarded by right and left
venous valves; the valves fuse dorsocranially forming the septum spurium

10. The Sinus Venosus
 The right horn is incorporated into the right atrium as the sinuatrial orifice, guarded by right and
left venous valves; the valves fuse dorsocranially forming the septum spurium; then the left valve
and the septum spurium fuse with the septum secundum on their left side; the superior portion of
the right venous valve disappears completely, while the inferior portion develops into the valves of
the inferior vena cava and coronary sinus
 In the adult, the crista terminalis on the inside (sulcus terminalis on the outside) is the dividing line
between the original trabeculated part of the right atrium and the smooth part (sinus venarum)
derived from the sinuatrial orifice

11. Conducting System of the Heart
 Initially the pacemaker is located in the caudal part of the left heart tube; later it lies within the
sinus venosus; later when the sinus is incorporated into the right atrium, the sinuatrial node is
established; the AV node and bundle arise from the left wall of the sinus venosus and the AV canal
and eventually come to lie in the interatrial septum

12. Formation of Septa
 The ways by which a septum may be formed are three:
 Two masses of tissue growing towards each other until they fuse
 One mass of tissue growing towards another mass until it fuses with it
 Presence of a narrow strip of tissue which fails to grow in an expanding wall, resulting in expansion of the walls on its sides

13. Formation of AV Septum
 Initially blood passes through AV canal only to the left ventricle in a direct manner because it is
separated from the bulbus cordis by a mass of tissue, the bulbocono ventricular flange; later this
flange is obliterated and blood can then pass directly to both ventricles
 Two mesenchymal cushions, the superior and inferior AV endocardial cushions appear in the wall of
the canal and grow towards each other until they fuse and divide the canal into right and left parts

14. Formation of AV Septum
 Initially blood passes through AV canal only to the left ventricle in a direct manner because it is
separated from the bulbus cordis by a mass of tissue, the bulbocono ventricular flange; later this
flange terminates at the superior border of the canal and blood can pass directly to both ventricles
 Two mesenchymal cusions, the superior and inferior AV endocardial cushions appear in the wall of
the septum and grow towards each other until they fuse and divide the septum into right and left

15. Formation of AV Septum

16. Formation of AV Valves
 After fusion of the AV septa, each orifice is surrounded by local proliferations of mesenchymal
tissue which are hollowed and thinned by blood on the ventricular side, forming valves which lose
their muscular tissue and are filled with dense connective tissue covered by endocardium
 These valves (tricuspid on the right and biscuspid on the left) are connected by chordae tendinae to
the papillary muscles in the wall of the ventricles

17. Formation of the Atrial Septum
 First, a sickle-shaped crest, the septum primum, grows from the roof of the atrium; its limbs grow
down to the AV cushions; the opening between the lower rim of septum and cushions is the ostium
primum; as this opening is filled by tissue from the cushions, other foramina appear in the upper
part of the septum and fuse to form another opening, the ostium secundum

18. Formation of the Atrial Septum
 First, a sickle-shaped crest, the septum primum, grows from the roof of the atrium; its limbs grow
down to the AV cushions; the opening between the lower rim of septum and cushion is the ostium
primum; as this opening is filled by tissue from the cushions, other foramina appear in the upper
part of the septum and fuse to form another opening, the ostium secundum

19. Formation of the Atrial Septum
 Then another septum, the septum secundum, appears from the roof of the atrium, to the right of
the septum primum; it also has limbs that extend down to the AV septum, but it never forms a
complete septum, leaving the foramen ovale; when the septum secundum fuses with the septum
spurium and left venous valve, it overlies the ostium secundum; when the upper part of the septum
primum disappears, it forms the valve of the foramen ovale

20. Formation of the Atrial Septum
 Then another septum, the septum secundum, appears from the roof of the atrium, to the right of
the septum primum; it also has limbs that extend down to the AV septum, but it never forms a
complete septum, leaving the foramen ovale; when the septum secundum fuses with the septum
spurium and left venous valve, it overlies the ostium secundum; when the upper part of the septum
primum disappears, it forms the valve of the foramen ovale

21. Fate of Foramen Ovale
 After birth, pressure on the left atrium increases because of respiration, and the valve of the
foramen ovale is pressed against the septum secundum until they fuse, forming the fossa ovalis; in
about 20% of individuals, fusion never occurs and a narrow oblique cleft remains, which is called
probe patent foramen ovale, but does not allow shunting of blood between the atria

22. Further Differentiation of Atria
 Initially, a single pulmonary vein grows from the wall of the left atrium, to the left of the septum
primum, and connects with veins of the developing lungs; similar to incorporation of right sinus horn
into right atrium, this pulmonary vein is later incorporated into the wall of the left atrium along
with three other pulmonary veins formed later
 In the adult heart, the original portions of the atria are respresented by the trabeculated
appendages, while the incorporated portions represent the smooth parts

23. Formation of the Conotruncal Septum
 A pair of opposing ridges appear in the truncus arteriosus; these are the right superior and left
inferior truncus swellings; both of them grow distally (i.e. upwards) in opposite directions, thus
twisting around each other and forming the aorticopulmonary septum
 Meanwhile, two conus swellings also appear; these are the right dorsal and left ventral conus
swellings; they grow towards each other and fuse to form the conus septum which divides the conus
into an anterolateral portion (outflow tract for the right ventricle) and a posteromedial portion (for
the left ventricle); the conus swellings also grow distally (i.e. upwards) toward the truncus swellings

24. Formation of the Conotruncal Septum
 Neural crest cells from the hindbrain region also contribute to the formation of this septum; since
they also contribute to craniofacial skeleton, it is not uncommon to see abnormalities in the face and
the heart in the same patient

25. Formation of the Semilunar Valves
 When partitioning of the truncus is near completion, a pair of small tubercles becomes visible on
each of the two truncus swellings; one of each pair is assigned to each of the aorta and the
pulmonary trunk; then a third tubercle appears in each channel opposite the fused main truncus
swellings; thus three cusps are formed which are hollowed on their upper surface to form the
semilunar valves of the aorta and the pulmonary trunk

26. Formation of the Ventricular Septum
 Continuous growth of the two ventricles causes their medial walls to fuse and form a muscular
interventricular septum that does not completely separate them; the interventricular foramen
above the septum is bounded above by the conus septum and behind by the AV septum
 Later, cells proliferating from the inferior AV endocardial cushion close the foramen and form the
membranous part of the interventricular septum thus completely separating the two ventricles

27. Layers of the Heart
 The endocardium, inner layer of the heart, is derived from the blood islands forming in the
splanchinic mesoderm
 The myocardium, middle muscular layer, forms from the cardiac progenitor cells originating lateral
to the primitive streak and invaginating towards the cardiogenic field
 The epicardium, outer layer, is derived from two sources:
 Proepicardial cells derived from the septum transversum near the sinus venosus
 Mesothelial cells originating in the outflow tract region

28. Formation of the Arterial System
 In addition to the cardiogenic field, other blood islands appear bilaterally parallel to the midline of
the embryo; these form the dorsal aortae; later in development, the truncus arteriosus is divided by
the aorticopulmonary septum into the ventral aorta and the pulmonary trunk
 The most distal portion of the truncus arteriosus, called the aortic sac, gives rise to two horns: the
right one forms the brachiocephalic artery, while the left one forms the aortic arch
 Each pharyngeal arch receives its own artery from the ventral arteries arising from the aortic sac and
terminating dorsally at the dorsal aorta; six arches form sequentially; the fifth arch either never
forms or forms and then disappears

29. Fate of the Arch Arteries
 The first arch disappears and only a small part of it persists as the maxillary
artery
 The second arch disappears and only contributes to the hyoid and stapedial
arteries
 The third arch forms the common carotid and part of the internal carotid
arteries (the rest of the internal carotid is derived from the dorsal aortae;
the external carotid is formed by sprouting from the third arch)

30. Fate of the Arch Arteries
 The forth arch on the right side forms the proximal portion of the
subclavian artery while on the left side it forms the part of the aortic arch
between the common carotid and the left subclavian
 The rest of the right subclavian artery and entire left subclavian artery are
derived from the 7th intersegmental artery, which is a branch of the dorsal
aortae
 The proximal portion of the aortic arch is derived from the left horn of the
aortic sac, the right horn of which forms the brachiocephalic artery

31. Fate of the Arch Arteries
 The fifth arch either never forms, or forms incompletely and then
disappears
 The sixth arch on both sides gives an important pulmonary branch that
grows towards the developing lungs; however, on the right side the distal
portion of the arch disappears and loses connection with its dorsal aorta,
while on the left side it persists as the ductus arteriosus (ligamentum
arteriosum in the adult) which connects it to the future descending
thoracic aorta

32. Other Changes in the Arterial System
 The portion of dorsal aorta between entry of 3rd and 4th arches, called the
carotid duct, is obliterated
 The portion of the right dorsal aorta disappears that lies between the right
7th intersegmental artery and its union with the left dorsal aorta
 As a result of the descent of the heart, the carotid and brachiocephalic
arteries elongate considerably and the left subclavian shifts its origin close
to the left common carotid

33. Other Changes in the Arterial System
 Because of the difference in the fate of the 6th
arches on the right and left, the recurrent
laryngeal nerve on the left hooks around the
ductus arteriosus (ligamentum arteriosum in the
adult) while on the right it hooks around the
right subclavian artery

34. Vitelline and Umbilical Arteries
 The paired vitelline arteries, which arise from the ventral aspect of the dorsal aorta, later form three
vessels which supply the gut: the celiac, superior mesenteric, and inferior mesenteric, supplying the
foregut, midgut, and hindgut, respectively
 The paired umbilical arteries arise from the dorsal aorta; later the proximal portion of each one
acquires a secondary connection with the common iliac artery, branch of dorsal aorta, and loses its
original connection; in the adult the proximal portions contribute to the internal iliac and form the
superior vesical arteries while the distal portions form the medial umbilical ligaments

35. The Coronary Arteries
 The coronary arteries are derived from two sources:
 Angioblasts formed at other places and distributed over the heart by the migration of the proepicardial cells
 The epicardium of the heart itself, by undergoing an epithelial-to-mesenchymal transition, induced by underlying myocardium,
and then contributing to both the endothelial lining and the muscular coat of the coronary arteries
 Neural crest cells also contribute to the muscular wall of these arteries
 Their connection with aorta occurs by the arteries invading the wall of the aorta

36. Formation of the Venous System
 Initially, three pairs of veins can are recognized in the embryo and drain into the sinus venosus: the
vitelline veins, the umbilical veins, and the cardinal veins (each receiving anterior and posterior
cardinal branches)

37. The Vitelline Veins
 The vitelline veins, on their way to the sinus venosus, form a plexus around the duodenum and
pierce the septum transversum; later, when the liver cords penetrate the septum transverum, they
interrupt the course of the veins and form the hepatic sinusoids that connect with the vitelline veins
 With the left-to-right shunting of blood, the right vitelline vein, now called the right hepatocardiac
channel, enlarges and forms the hepatocardiac portion of the inferior vena cava; the left vitelline
disappears completely; the superior mesenteric vein also derives from the right vitelline vein

38. The Vitelline Veins
 The vitelline veins, on their way to the sinus venosus, form a plexus around the duodenum and
pierce the septum transversum; later, when the liver cords penetrate the septum transverum, they
interrupt the course of the veins and form the hepatic sinusoids that connect with the vitelline veins
 With the left-to-right shunting of blood, the right vitelline vein, now called the right hepatocardiac
channel, enlarges and forms the hepatocardiac portion of the inferior vena cava; the left vitelline
disappears completely; the superior mesenteric vein also derives from the right vitelline vein

39. The Umbilical Veins
 Both veins initially pass on either side of the liver to the sinus venosus; later they acquire connection
with the liver; gradually the proximal parts of both veins and the remainder of the right vein are
completely obliterated, leaving only the distal part of the left umbilical vein which becomes the
definitive umbilical vein that carries nutrition from the placenta to the fetus
 With further development, a direct connection forms between the left umbilical vein and the
hepatocardiac portion of inferior cava through the ductus venosus, which allows blood to bypass
the sinusoidal plexus and reach the heart faster; after birth, both veins are obliterated (umbilical vein
becomes ligamentum teres hepatic and ductus venosus becomes ligamentum venosum)

40. The Umbilical Veins
 Both veins initially pass on either side of the liver to the sinus venosus; later they acquire connection
with the liver; gradually the proximal parts of both veins and the remainder of the right vein are
completely obliterated, leaving only the distal part of the left umbilical vein which becomes the
definitive umbilical vein that carries nutrition from the placenta to the fetus
 With further development, a direct connection forms between the left umbilical vein and the
hepatocardiac portion of inferior cava through the ductus venosus, which allows blood to bypass
the sinusoidal plexus and reach the heart faster; after birth, both veins are obliterated (umbilical vein
becomes ligamentum teres hepatic and ductus venosus becomes ligamentum venosum)

41. The Cardinal Veins
 The anterior and posterior cardinal veins on each side drain into the common cardinal veins; later,
other vein pairs develop: subcardinal veins (draining the kidneys mainly), sacrocardinal veins
(draining the lower limbs), and supracardinal veins (draining the posterior body wall)
 Later, anastomosis occurs between the veins such that most of the blood from the left is shunted to
the right; anastomosis of the anterior cardinal veins forms the left brachiocephalic vein; only a small
portion of the left posterior cardinal vein persists as the left superior intercostal vein

42. The Brachiocephalic Vein
 Anastomosis of the anterior cardinal veins forms the left brachiocephalic vein; only a small portion
of the left posterior cardinal vein persists as the left superior intercostal vein which drains into the
left brachiocephalic vein and drains the 2nd and 3rd intercostal spaces

43. The Cardinal Veins
 The superior vena cava is formed from the right common cardinal vein and the proximal portion of
the right anterior cardinal vein
 Most of the posterior cardinal veins are obliterated; the right supracardinal vein forms the azygos
vein which drains the 4th to 11th intercostal spaces and enters the superior vena cava, while the left
supracardinal forms the hemiazygos vein which drains the 4th to 7th intercostal spaces and enters
the azygos vein

44. The Cardinal Veins
 The anastomosis of the subcardinal veins forms the left renal vein; then only the distal portion of
the left subcardinal vein persists as the left gonadal vein; the right subcardinal enlarges and forms
the subcardinal portion of the inferior vena cava
 This is the reason why in the adult the left gonadal vein enter the renal vein while the right gonadal
vein enters the inferior vena cava directly

45. The Cardinal Veins
 The anastomosis of the sacrocardinal veins forms the left common iliac vein; the right sacrocardinal
becomes the sacrocardinal portion of the inferior vena cava; thus the inferior vena cava is complete,
formed from three portions: hepatocardiac, subcardinal, and sacrocardinal

46. The Lymphatic System
 The lymphatic system may either develop from mesenchyme in situ or as outgrowth from the veins;
six main lymph sacs form: two jugular, two iliac, one retroperitoneal, and one cisterna chyli
 Of the many lymphatic channels that form, two main thoracic ducts form; later, anastomosis
between these two ducts results in the formation of the definitive thoracic duct from the distal
portion of the right duct, the anastomosis, and the proximal portion of the left duct, and the
formation of the right lymphatic duct from the proximal end of the right duct

47. Fetal Circulation
 Read the explanation in the book. Give attention to the sites where oxygenated and deoxygenated
blood mix.

48. Circulatory Changes at Birth – Neonatal Circulation
 Changes that occur at birth or soon thereafter are: closure of umbilical arteries and vein, closure of
ductus venosus and arteriosus, and closure of oval foramen; details in the book are required