Embryology Learning Modules
Duke University Medical School
UNSW Embryology (awesome site!)

Cardiovascular System Development

Suggested readings from Langman's Medical Embryology (11th. ed.):
Ch. 12, pp. 165-200

Lecture videos, PowerPoints, and notes may be accessed using the drop-down menu above.


I.  Development of the Heart
A.  Generation and fusion of the developing heart tubes

  • The heart fields are of mesodermal origin and established in the cranial-most end of the embryo (ahead, or "anterior" of the future brain).
  • The heart fields are patterned into primary and secondary heart fields:
    • primary heart field will develop into left and right atria and the left ventricle
    • the secondary heart field will become the right ventricle and outflow tract

Patterning of the heart fields is a retinoic acid-dependent process, so exogenous retinoids (such as prescription acne treatments) or disruption of retinoid signaling can produce heart defects due to mis-specification of these tissues (e.g. not enough secondary heart field tissue develops so the right ventricle or outflow tracts are hypoplastic).

B.  Repositioning the cardiogenic fields

  1. Lateral folding brings the forming heart tubes to the midline to fuse into a single tube
  2. Cranio-caudal folding swings the heart tube into a position just ventral to the foregut pocket in the neck of the embryo with the inflow oriented toward the tail of the embryo and outflow oriented toward the head.  The heart tube is suspended from the body wall by a sling of connective tissue called the dorsal mesocardium.
  3. Differential growth of the embryo causes the heart to be displaced toward the tail of the embryo such that the heart ends up in the chest.

C.  Folding of the developing heart

  • Degeneration of the central portion of the dorsal mesocardium leaves the primitive heart attached at the outflow and inflow ends (this is how the tranverse pericardial sinus forms).
  • The heart grows rapidly, but it is still fixed at both ends so it loops.
  • Heart looping is NOT random but instead is a finely controlled process (by a variety of factors NOT discussed) such that the ventricle almost always moves ventrally and to the right.

Reversal of heart looping can occur in cases where the left-right axis is fully perturbed (situs inversus) or partially perturbed (heterotaxy) resulting in a condition called dextrocardia where the left ventricle ends up pointing to the right rather than the left.  This can be picked up on ECG as a right axis deviation with very little upward deflection of QRS in the lateral precordial leads (V4, 5, and 6).

D.  Partitioning the Atrio-Ventricular Canal

  • The atrio-ventricular canal is divided by the fusion of the dorsal and ventral AV cushions.
  • The AV cushions are formed by the conversion of endogenous (i.e. NOT neural crest) heart tissue in the endocardium of the AV canal into mesenchyme that proliferates to form the two "cushions" or swellings that grow toward each other.
  • The cushions fuse in the middle of the AV canal to form a left and a right AV canal.  However, the two canals initially empty into the future left ventricle –with additional growth and remodeling, the canals shift toward the middle such that the left AV canal lines up with the left ventricle and the right AV canal lines up with the right ventricle.
  • The formation and subsequent remodeling of the AV cushions is retinoic acid-dependent, so disruption of retinoid signaling often produces AV canal defects:
    • persistent AV canal –the left and right AV canals are not fully divided (this is also pretty common in Down syndrome, not necessarily because of disrupting retinoid signaling but because of other genes involved that are on Chromosome 21)
    • double inlet left ventricle –the left and right AV canals are separated, but they BOTH empty into the left ventricle.

E.  Partitioning the Atria

  • A septum, the septum primum ("first" septum) grows down from the roof of the primitive atrium toward the AV cushions that have fused into a block of tissue dividing the left and right AV canals.
  • The foramen primum is the space between the free edge of the septum primum and AV cushions –it becomes progressively smaller as the septum primum grows toward the AV cushions and eventually closes off completely when the septum primum fuses with the AV cushions.
  • As the foramen primum is closed off, programmed cell death in the wall of the septum primum near the roof of the atrium opens up a second foramen, the foramen secundum.
  • A second, more rigid, septum called the septum secundum grows down on the right side of the septum primum from the roof of the atrium toward the AV cushions.  However, the septum secundum does not grow all the way down to the cushions, but leaves an oval opening, the foramen ovale, located toward the lower back wall of the right atrium (near the opening of the inferior vena cava):
    • during embryonic development oxygenated blood from the placenta delivered via the inferior vena cava is shunted from the right atrium to the left atrium via the foramen ovale into the left atrium.
    • immediately after birth, functional closure of the foramen ovale occurs because of pressure differences between the two atria:
      • pressure drops in the right atrium because of decreased flow from the placenta
      • pressure increases in the left atrium due to increased pulmonary venous return
  • Over time, the tissues of the two septa grow together such that they typically become anatomically fused.  However, in about 25% of the population, this fusion is not complete and said to be "probe patent" (meaning a probe pushed into the foramen ovale would push open the septum secundum and pass into the left atrium).  Usually, this does not cause a problem as pressure is normally high enough in the left atrium to keep the septum functionally closed.  However, if pressure drops in the left atrium (e.g. pulmonary embolism or respiratory insufficiency), then the septum will open allowing blood from the right atrium to get into the left atrium.  This can be bad in the setting of thrombosis because clots from the systemic veins that would normally end up in the lungs can get out into the systemic circulation and go the brain.
  • The septum primum and secundum are formed via contributions from the atrial wall and AV cushions.  Disruption of either can therefore cause Atrial Septal Defects (ASDs).  So, ASDs are common in Down's Syndrome (AV cushion development is incomplete) as well as mutations in genes normally expressed in the atria (such as NKX2.5 and TBX5).  Development of the AV node is also dependent on proper atrial development, so ASDs are often accompanied with AV bundle block.  

F.  Partitioning the ventricles

  • A ridge of muscular tissue from the wall of ventricles proliferates at the transition from the future left ventricle and future right ventricle to form the "muscular interventricular septum" that almost completely separates the right and left ventricles.
  • The upper portions of the left and right ventricles (near the AV valves and semilunar valves) are divided by a much thinner septum known as the "membranous interventricular septum."
  • The membranous septum is formed via contributions from the muscular interventricular septum, the atriventricular cushions, and the truncoconal cushion (discussed below).  Failure of any one of these tissues can therefore cause a defect; hence, most ventricular septal defects (VSDs) are "Membranous VSDs" (holes in the membranous septum).

G.  Partitioning the Outflow Tract

  • Neural crest cells associated with pharyngeal arches 4 and 6 migrate into the truncus arterosus (undivided outflow tract) and conus cordis (aka bulbus cordis, which is the conical-shaped outflow portion of the primitive right ventricle) and transform into mesenchymal tissue that proliferates to form two so-called truncoconal or truncobulbar cushions (or ridges).
  • The two truncoconal ridges grow toward each other and fuse first at the truncoconal transition and then "zip" distally (toward the outflow tract) and proximally (toward the ventricles.
  • As the ridges zip together, they spiral in a right-handed twist such that the pulmonary trunk ends up anterior to the aorta.
  • As the truncoconal ridges grow toward the ventricles, they also contribute a portion of the membranous interventricular septum.
  • Failure of the truncoconal neural crest tissue to migrate and/or differentiate appropriately can cause outflow tract defects such as:
    • persistent truncus arteriosus (failure of the aorta and pulmonary trunk to fully divide)
    • transposition of the great vessels (pulmonary trunk attached to the left ventricle and the aorta is attached to the right ventricle)
    • aortic stenosis (narrowing or occlusion of the aortic valve)
    • pulmonary stenosis (narrowing or occlusion of the pulmonary valve) –pulmonary stenosis is usually accompanied by a set of findings called the Tetrology of Fallot:
      • Pulmonary stenosis
      • Membranous interventricular septal defect
      • Aorta shifted to the right, or overriding, the septal defect
      • Right ventricular hypertrophy
      • patent ductus arteriosus

Patients with pulmonary stenosus usually exhibit respiratory distress that can be relieved by pulling the legs into the chest, cyanosis in hands and feet that can eventually result in ”clubbing" (swelling at the phalangeal tips), and a boot-shaped heart (Coeur en sabot) on chest X-rays.

H.  Formation of valves in the heart

  • Semilunar (pulmonary and aortic) valves are formed via cavitation of truncoconal ridge tissue to form three triangular valve leaflets in each of the outflow vessel in a highly stereotypical pattern:
    • the pulmonary semilunar valve develops three cusps: left, right, and anterior
    • the aortic semilunar valve also develops three cusps: left, right and posterior

Disruption of neural crest that contribute to the trucnoconal cushions can result in aortic or pulmonary valve defects.

  • Atrioventricular (tricuspid and mitral, or bicuspid) valves are formed via cavitation of atrioventricular cushion tissue and ventricular walls to form valve leaflets attached via chordae tendinae to myocardium (i.e. papillary muscles).

Disruption of AV cushion tissue or ventricular myocardium can result in tricuspid or mitral valve defects such as mitral stenosis:
-mitral valve does not form properly and is stenotic (partially or fully occluded)
-reduced flow causes left ventricle and usually the aortic valve to become hypoplastic
-OK in fetus since blood is oxygenated by the placenta and pumped out of the right ventricle into the systemic circulation via the ductus arteriosus
This arrangement does NOT work well postnatally, so one approach to fix this surgically is the Fontan Procedure:
-close off vena cava inputs into the R atrium and instead attach pulmonary trunk to the vena cava to reroute systemic venous blood to lungs for oxygenation (0-5mmHg venous  pressure is generally enough to perfuse lungs)
-Typically, there is already an atrial septal defect that allows blood to flow from L atrium to R atrium; this ASD is maintained so that oxygenated blood from the lungs is shunted over the R atrium and eventually to the R ventricle
-R ventricular outflow is rerouted to the aorta such that the R ventricle is now providing outflow to the systemic circulation.

II. Formation of the Arterial Vasculature

  • the arterial system develops from bilaterally symmetrical pairs of aortic arches that undergo remodeling to form the adult pattern.  For a review of aortic arch development, the University of Indiana School of Medicine has an excellent website (http://www.indiana.edu/~anat550/cvanim/aarch/aarch.html) with animations showing the fate of each component.          

A. Aortic Arches
1.  During development of the head and neck, paired arches of tissue form that encircle the forming pharynx.  Six pharyngeal arches start to form, but the 5th arch regresses, so the arches are numbered 1, 2, 3, 4, and 6.  Each pharyngeal (or "branchial" due to the similarity to gills) arch has an associated arterial or aortic arch of the same number (aortic arch 1 goes with pharyngeal arch 1, etc.).  Each pharyngeal arch also has an associated cranial nerve (this wasn't discussed in lecture, but good to know or future reference):

    • arch 1: trigeminal nerve (CN V)
    • arch 2: facial nerve (CN VII)
    • arch 3: glossopharyngeal nerve (CN IX)
    • arch 4: superior laryngeal branch of the vagus nerve (CN X)
    • arch 6: recurrent branch of the vagus nerve (CN X)

Blood from the heart flows from the outflow tract into a vascular trunk called the aortic sac located ventral to the pharynx.  The aortic arches branch from this trunk, wrap around the pharynx, and then connect to paired dorsal aortae that merge into a single aorta caudal to the pharynx.

2.  Fates of the aortic sac and arches 1-3: 

    • Aortic sac: proximal (ascending) segment of the aortic arch and brachiocephalic trunk.
    • 1st aortic arch: maxillary artery (in the face)
    • 2nd aortic arch: stapedial artery (in middle ear)
    • 3rd aortic arch: common carotid and initial segments of internal carotid artery

3.  Fates of arches 4 and 6: these arches have different fates on the left and right sides; also, the proximal segment of the 6th arch (closest to the aortic sac) has a different fate than the distal segment (the portion closest to the paired aortae).

  • 4th RIGHT arch: becomes the initial segment of the R subclavian artery
  • 4th LEFT arch: is incorporated into the arch of the aorta.
  • 6th RIGHT arch: the proximal segment is incorporated into the R pulmonary artery; the distal segment (the portion attached to the paired dorsal aorta in the neck) regresses.
  • 6th LEFT arch: the proximal segment is incorporated into the L pulmonary artery; the distal segment persists as the ductus arteriosus

The ductus arteriosus functions to augment the right to left shunting of oxygenated blood coming from the venous input to the heart to the systemic circulation.  Most of this blood is shunted from the R atrium to the L atrium via the foramen ovale.  However, that which makes it into the right ventricle is then shunted to the dorsal aorta via the ductus arteriosus.  The ductus arteriosus closes off postnatally in the first few weeks after birth (prostaglandins induce the vascular smooth muscle in the ductus arteriosus to constrict) and eventually becomes the fibrous ligamentum arteriosum.

The fact that the distal segment of the 6th arch regresses on the right but persists on the left affects the course of the recurrent laryngeal branches of the vagus nerves that innervate the intrinsic muscles of the larynx associated with the 6th pharyngeal arch.  The recurrent laryngeal nerves run INFERIORLY to the 6th aortic arches when they initially grow out to innervate the muscles of the larynx.  With differential growth, the heart and great vessels move downward into the upper thorax whereas the larynx moves upward into the neck and "drags" its innervation with it.  On the LEFT side, the proximal AND distal segments of the 6th aortic arch persist and "trap" the left recurrent laryngeal nerve such that it is found in the adult wrapping under the ligamentum arteriosum.  On the RIGHT side, however, the distal segment of the 6th aortic arch regresses such that the right recurrent laryngeal nerve is not "trapped" until it encounters the 4th aortic arch such that it is found in the adult wrapping under the brachiocephalic trunk. 

4.  Fates of the paired dorsal aortae

  • on the RIGHT, the proximal segment of the right dorsal aorta persists and is incorporated into the R subclavian artery whereas the distal segment regresses.
  • on the LEFT, both the proximal and distal segments are retained and incorporated into the descending arch of the aorta.

Aberrations of this developmental pattern can cause aortic arch anomalies:

    • Double aortic arch: occurs when there is abnormal persistence of the distal segment of the RIGHT aortic arch.  This is often associated with dysphagia (difficulty in swallowing) and dyspnea (difficulty in breathing) due to entrapment of the esophagus and trachea between the left and right arches.
    • Aberrant origin of the Right Subclavian Artery: occurs when there is abnormal persistence of the RIGHT distal segment and abnormal regression of the RIGHT proximal segment.  The result is that the R subclavian originates directly from the descending aorta rather than the brachiocephalic trunk and runs behind the esophagus to get over to the right side. This is often associated with dysphagia and a slightly weaker pulse in the right arm.
    • Right aortic arch: occurs when there is abnormal persistence of the RIGHT distal segment and abnormal regression of the LEFT distal segment.  In this instance, the aorta arches to the right rather than to the left.  This is usually asymptomatic and generally detected when imaging studies are performed for some other reason.
    • Interrupted Aortic Arch: occurs due to abnormal regression of the proximal LEFT arch.  Output to the right arm and head is via the ascending aorta, which is still intact.  The descending arch, however, is missing, so output to the left arm, trunk, and both legs is from the pulmonary trunk which is connected to descending aorta via the ductus arteriosus.  This pattern is not a problem in the fetus and in the first week or so postnatally (the left arm, trunk, and legs are still being perfused –the blood is not well oxygenated, but the overall metabolic demands are not that great, so this is tolerable).  However, closure of the ductus arteriosus that occurs after about two weeks will compromise blood flow to the left arm, trunk, and legs, so the interruption in the aortic arch needs to be surgically repaired by then.  IAA is VERY rare in the general population (1:50,000), but quite common (10-15%) in patients with DiGeorge syndrome (chromosome 22 deletion).
    • Coarctation of the Aorta: occurs when the descending arch of the aorta is abnormally constricted.  Usually occurs AFTER the junction of the ductus arteriosus, or "postductal."  Collateral circulation via the internal thoracic and intercostal arteries allows for perfusion of the trunk and lower limbs, but at lower pressure compared to the head and arms (i.e. the carotid and brachial/radial pulses will be strong on both sides, but the femoral and pedal pulses will be noticeably weaker).  Coarctation of the aorta is relatively rare overall (1:3000), but very often associated with Turner's syndrome (present in 20% of Turner's patients) and neural crest disorders.


III. Development of the Venous Vasculature

  • The venous system develops from three, bilaterally symmetrical sets of veins in the embryo: the cardinal veins, the vitelline veins, and the umbilical veins.
  • In general, left-to-right shunting of venous blood to the right atrium causes the remodeling of the bilaterally symmetrical veins into the asymmetric pattern observed in the adult.

A. Right and Left Vitelline Veins (associated with the yolk sac)

  • The liver develops at the site where the vitelline veins empty into the sinus venosus and thus incorporates the proximal portions of the left and right vitelline veins into its extensive network of hepatic sinusoids.
  • Due to left-to-right shunting of blood, the portion of the left vitelline vein distal to the liver regresses.  The right vitelline vein, however, enlarges to form the hepatic, splenic, superior mesenteric and inferior mesenteric veins of the hepatic portal system.

B. Right and Left Umbilical Veins (associated with the placenta)

  • Initially, the left and right umbilical veins are bilaterally symmetrical and connected to the sinus venosus.  With the expansion and dominance of the right vitelline veins, the entire right umbilical vein (proximal and distal portions) regresses entirely (the remnants of which, along with the right umbilical artery, form the right medial umbilical ligament found in the anterior abdominal wall in the adult)
  • As the liver grows and impinges on the remaining left umbilical vein, a channel in the liver called the ductus venosus develops that allows blood to flow from the distal portion of the left umbilical vein through the liver and into the sinus venosus.  This essentially bypasses the proximal portion of the left umbilical vein, which therefore regresses.  The net result of this remodeling is that oxygenated blood flows from the placenta into the left umbilical vein, through the ductus venosus in the liver, and then into the inferior vena cava and right atrium of the heart.  After birth, the left umbilical vein regresses along with the left umbilical artery to form the left medial umbilical ligament on the anterior abdominal wall and round ligament of the liver (ligamentum teres hepatis) where the left umbilical vein was connected to the liver.  The ductus venosus within the liver regresses to form the ligamentum venosum.

C. Cardinal Veins (associated the body wall)

  • Anterior cardinal veins drain the head and armsPosterior cardinal veins drain the trunk and legs.
  • Later in development, the posterior cardinal veins are supplemented by two additional sets of bilaterally symmetrical veins: the subcardinal and supracardinal veins.
  • Left-to-right shunting of blood causes the formation of the left brachiocephalic anastomosis in the anterior cardinal veins and remodeling of the anterior veins such that the superior vena cava is usually a singular structure on the right side in the adult.
  • In the posterior veins, left-to-right shunting causes the right subcardinal vein in the thorax and right supracardinal vein in the abdomen to develop into the inferior vena cava.
  • In the thorax, the supracardinal veins develop into the azygous and hemiazygous veins.

This is a highly variable process, so it is quite common to have alterations in the adult venous pattern:

  • left superior vena cava: the brachiocephalic anastomosis shunts blood right to left rather than left to right, so the SVC forms on the left and connects to the right atrium via the oblique sinus.
  • double superior vena cava: no brachiocephalic anastomosis forms, so there is NO left brachiocephalic vein.  Instead, there are two superior vena cavae: the right SVC drains into the right atrium in the usual manner and the left SVC connects via the oblique sinus.
  • double inferior vena cava: occurs when the left supracardinal vein persists, forming an additional inferior vena cava below the level of the kidneys.
  • absent inferior vena cava: occurs when the subcardinal veins in the thorax regress, causing a failure of the thoracic portion of the IVC to form.  The thorax is instead drained entirely by the azygous and hemiazygous veins.  The lower limbs and truck are drained via connection of the abdominal IVC to the azygous vein.

1. Which of the flowing correctly describes the possible route a red blood cell might take to get from the placenta to the developing stomach in the fetus?  (the choices below are not in any particular order; they only describe a segment of a possible route)

  1. passing from the arch of the aorta to the pulmonary trunk via the ductus venosus
  2. passing from the inferior vena cava to the umbilical vein via the ductus arteriosus
  3. passing from the abdominal aorta to the celiac artery
  4. passing from the left atrium to the right atrium via the foramen ovale
  5. passing from the abdominal aorta to the superior mesenteric artery
  6. ALL of the above
  7. NONE of the above



2. Cardiac neural crest cells contribute significantly to:

  1. formation of the interatrial septa (i.e. septum primum and secundum).
  2. division of the atrioventricular canal.
  3. formation of the muscular interventricular septum.
  4. division of the outflow tract.
  5. ALL of the above.



3. During vascular development, the hepatic portal venous system arises from:

  1. posterior cardinal veins.
  2. umbilical veins.
  3. vitelline veins.
  4. subcardinal veins.
  5. supracardinal veins.



4. During vascular development:

  1. the condition of having a double superior vena cava can develop if the left brachiocephalic vein fails to form.
  2. the thoracic supracardinal veins normally give rise to the azygous and hemiazygous veins.
  3. the condition of having a double inferior vena cava can form if the left supracardinal vein fails to regress.
  4. the right umbilical vein normally regresses in the fetus.
  5. ALL of the above
  6. NONE of the above



5. Which of the following does NOT contribute to the formation of the membranous interventricular septum of the heart?

  1. outflow tract cushions
  2. atrioventricular cushions
  3. interventricular myocardium
  4. neural crest
  5. septum primum


Questions 5 AND x6 refer to the following case:
 A 25-year-old male is admitted to a hospital for treatment of a broken left leg and left arm resulting from a motor vehicle crash.  One of the routine work-ups includes an assessment of the pulse and blood pressure in all limbs to make sure there is no vascular involvement, during which it is noticed that the pulse is weaker and blood pressure is lower in the right arm compared to all of the other limbs.  To follow up on these findings, the attending physician asks the patient if he ever has difficulty swallowing, and he answers that he does.

5. The most likely reason for these findings is:

  1. interrupted aortic arch
  2. coarctation of the aorta
  3. double aortic arch
  4. pulmonary stenosis / Tetralogy of Fallot
  5. aberrant origin of the right subclavian artery


6. The most likely embryological cause of this condition is:

  1. abnormal persistence of the distal segment of the right dorsal aorta.
  2. abnormal persistence of the distal segment of the right dorsal aorta coupled with regression of the proximal segment.
  3. abnormal persistence of the distal segment of the right 6th arch.
  4. abnormal regression of the proximal segment of the left  dorsal aorta.
  5. failure of cardiac neural crest cells to migrate and/or differentiate appropriately
  6. abnormal incorporation of the distal segment of the right 6th arch into the aorta.




For items 7-9, select the one lettered option from the following list that is most closely associated with each numbered item below.  Options in the list may be used once, more than once, or not at all.
                a.  foramen ovale
                b.  ductus arteriosus
                c.  ductus venosus
                d.  tricuspid valve
                e.  aortic valve

7. shunts blood from the right atrium to the left atrium   ANSWER

8. shunts blood from the umbilical vein to the inferior vena cava   ANSWER

9. derived in part from atrioventricular cushion tissue   ANSWER


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Updated 10/09/11 - Velkey