By Dr. Thomas Burnell and Dr. Bethany Turner
Next Lesson - Congenital Heart Defects
Core
The cardiovascular system begins to develop in the third week after fertilisation. The heart is the first functional organ to develop. It starts to beat by about week 4 after fertilisation. A heartbeat can sometimes be seen on a transvaginal ultrasound scan (a scan with the probe placed in the vagina) at around 6 weeks of pregnancy. Pregnancy weeks are counted from the first day of the last period.
Formation of the Primitive Heart Tube
At the start of its development, the cardiovascular system exists as two regions near the cranial end of the embryo. These regions are called cardiogenic fields and they are derived from the mesoderm layer of the embryo (the middle of the three early cell layers). The cells that will go on to form the cardiovascular system reside here.
The cardiogenic fields consist of blood islands (clusters of primitive cells that form the first blood cells and blood vessels). They mark the beginning of blood, vessel and heart development. These areas develop further and fuse to form two tubes, which are called endocardial tubes, one on each side of the embryo.
From about the end of the third week after fertilisation, the embryo begins to fold. This puts the heart tissue in the correct position to form the primitive heart tube, which is surrounded by the pericardial sac (the fluid-filled bag around the heart). The embryo folds in two directions:
- Cephalo-caudal folding (head-to-tail folding) brings the cardiogenic fields from the cranial end towards the centre of the embryo to sit in the thoracic region where the heart will be.
- Lateral folding fuses the two lateral sides of the embryo. This brings the two cardiogenic fields into the midline so they can fuse and form the primitive heart tube.
This primitive heart tube is formed at around day 22 after fertilisation. It is divided into six parts, listed from the outflow end to the inflow end:
- Aortic sac (the widened end of the tube from which the arteries arise)
- Gives rise to the aortic arches (paired embryonic arteries)
- Truncus arteriosus (the common arterial trunk, which later splits into the aorta and pulmonary trunk)
- Involved in the formation of the pulmonary trunk and aorta (outflow from the heart)
- Bulbus cordis
- Forms most of the right ventricle (the trabeculated, ridged part) and the smooth-walled outflow region that leads to the pulmonary trunk and aorta (the conus arteriosus)
- Primitive ventricle
- Forms most of the left ventricle (its trabeculated, ridged part)
- Primitive atrium
- Forms the trabeculated parts of both atria, including the auricles (small pouches on the atria)
- Sinus venosus (the end of the tube that receives blood from the veins)
- Forms the smooth part of the right atrium and the coronary sinus (the vein that drains blood from the heart wall into the right atrium)
Diagram - Shows how the embryo folds, and endocardial tubes fuse to form the primitive heart tube in the pericardial cavity. The heart tube sits in the thoracic region of the embryo
SimpleMed original by Dr. Bethany Turner
The newly formed heart tube is surrounded by the pericardial sac. As the heart tube grows and elongates, differential growth produces looping (different parts of the tube grow at different rates).
During looping, the tube changes shape. The primitive ventricle moves ventrally and to the right, while the primitive atrium moves dorsally and to the left. This puts the inflow portion of the heart (veins and atria) behind the outflow portion (ventricles and arteries). This is the same shape and orientation as in mature hearts.
Breakdown of the dorsal mesocardium, which initially suspends the heart tube, creates the transverse pericardial sinus. In the mature heart, this passage lies behind the aorta and pulmonary trunk and in front of the superior vena cava. Looping moves the chambers into position, but it is the breakdown of the dorsal mesocardium that forms this passage.
Diagram - The changing position of the heart tube during looping, with the primitive atrium moving behind the primitive ventricle. The dorsal mesocardium and its breakdown, which forms the transverse pericardial sinus, are not shown
SimpleMed original by Dr. Bethany Turner
Development of the Right Atrium
The right atrium develops from most of the primitive atrium, and part of the sinus venosus.
The sinus venosus receives blood from the right and left sinus horns (its two arms), which bring blood into the primitive heart tube. The right sinus horn is partially absorbed by the primitive atrium as the atrium grows. The absorbed horn forms the smooth-walled sinus venarum of the right atrium, and not the superior and inferior vena cava. The left sinus horn becomes the coronary sinus which drains venous blood from the coronary vessels into the right atrium.
Diagram - The blue represents the sinus venosus. The light blue portion represents the right sinus horn, which is incorporated into the right atrium to form its smooth-walled sinus venarum. The right sinus horn does not form the superior and inferior vena cava. The dark blue portion represents the left sinus horn which becomes the coronary sinus
SimpleMed original by Dr. Bethany Turner
Development of the Left Atrium
The left atrium develops from a small part of the primitive atrium, and the proximal portions of the pulmonary veins.
The pulmonary veins begin as a single vein entering the left atrium. This vein is formed from four branches which converge to form one vein draining into the developing left atrium. As the left atrium grows, it absorbs the single pulmonary vein, as far as the point where it splits into its four branches. This means that when the left atrium has finished growing, it is receiving blood from four pulmonary veins, as seen in mature hearts.
The part of the mature left atrium that came from the primitive atrium is trabeculated (ridged, with muscle bundles on the inner wall). This part forms the left auricle in the mature heart, which is a little pouch in the wall of the left atrium. The part derived from the pulmonary veins (which makes up most of the future left atrium) is smooth. The auricle is an important feature of the mature heart because with atrial fibrillation (a condition where the atria do not contract efficiently) blood can collect here. This stasis (blood standing still) can go on to cause blood clots. A clot can travel to the brain and cause a stroke, or to other organs and cause infarction.
Diagram - The proximal parts of the pulmonary veins become absorbed into the wall of the left atrium. The contribution of the pulmonary veins is shown in blue, and the primitive left atrium is shown in pink
SimpleMed original by Dr. Bethany Turner
The lining of the dorsal and ventral aspects of the developing heart grow small bumps called endocardial cushions. These grow to meet in the middle of the heart and are key in the separation of the left and right sides of the heart. The septa that divide the atria and the ventricles each grow towards the cushions, which is where the last gap between each pair of chambers closes.
The atrial septum is formed from two septa which grow in a specific order:
- A septum of tissue grows down from the top of the developing atria towards the endocardial cushions. This is the septum primum, and as it grows down, the communicating hole between the atria is called the ostium primum.
- Just before the septum primum meets the endocardial cushions and the ostium primum is closed, a hole forms in the middle of the septum. This is the ostium secundum.
- The septum primum meets the endocardial cushions, and the ostium secundum allows blood to continue to move from the right atrium to the left.
- Another septum grows down from the top of the atria, called the septum secundum.
- As the septum secundum grows down, it leaves another hole just below the ostium secundum.
These two septa and two holes together form the foramen ovale, a right to left shunt allowing blood to flow from the right atrium into the left. The two holes (the ostium secundum in the septum primum and the opening in the septum secundum) are staggered, so the septum primum acts as a one-way flap valve. This shunt will cease after birth, when higher pressure in the left atrium pushes the septum primum against the septum secundum and the septa functionally close (are held shut by pressure, without yet fusing), as discussed later.
Diagram - The formation of the septum. Also shown is the expansion of the atria by the contributions of the veins
SimpleMed original by Dr. Bethany Turner
The formation of the ventricular septum takes place in two steps.
First, a muscular portion of heart tissue grows upwards from the floor of the primitive ventricle towards the endocardial cushions. It does not quite reach the cushions. The gap that is left is the primary interventricular foramen (the opening between the two developing ventricles).
The remaining gap closes where the muscular septum, the developing outlet septum (the part of the septum in the outflow region of the ventricles) and the atrioventricular cushion tissue (endocardial cushion tissue between the atria and ventricles) meet. The membranous portion (the thin, non-muscular upper part of the septum) derives from cushion tissue at this junction as the outflow tract aligns with the ventricles. Closure is not simply downward growth from the cushions. A defect in the formation of the membranous portion is a common reason for ventricular septal defects, as discussed in the Congenital Heart Defects article.
Diagram - The formation of the interventricular septum. The muscular portion grows upwards from the base of the ventricles. The membranous portion forms from cushion tissue at the junction with the muscular and outlet septal structures as the aorta and pulmonary trunk become connected to the correct ventricles. Also shown in the diagram is the septum separating the ventricles
SimpleMed original by Dr. Bethany Turner
Septation of the Outflow Tract
The bulbus cordis and truncus arteriosus form one tube allowing outflow from the heart. This tube needs to be split in order to form the aorta and pulmonary trunk.
The outflow tract develops paired endocardial cushions. These contain mesenchymal cells (loose embryonic connective tissue cells) derived from the endocardium, with an additional contribution from migrating neural crest cells (cells that migrate from the edge of the developing nervous system). These cushions extend in a spiral arrangement through the proximal and intermediate outflow tract; they are not made solely of neural crest cells.
The outflow cushions grow towards one another and fuse to form a spiral septum through the proximal and intermediate outflow tract. The spiral septum and the distal aorticopulmonary partition together make up the aorticopulmonary septum (the dividing wall between the aorta and pulmonary trunk). With later remodelling, this process separates the aorta and pulmonary trunk and aligns each with its respective ventricle.
Diagram - The formation of the aorticopulmonary septum. It shows the development of the pulmonary artery and the arch of the aorta with its branching vessels
SimpleMed original by Dr. Bethany Turner
Formation of the Great Vessels
Vessels connecting the aortic sac to the dorsal aortae (the two embryonic aortas that run down the back) develop as aortic arches. The five pairs are conventionally numbered I, II, III, IV and VI, because the fifth arch either never forms or forms incompletely and then regresses (shrinks away). These arches, along with the truncus arteriosus, contribute to the formation of large arteries:
- Truncus arteriosus: divided by the aorticopulmonary septum to contribute to the pulmonary trunk and the proximal ascending aorta.
- Sixth arch (also called the pulmonary arch): the proximal portions contribute to the right and left pulmonary arteries. The distal left portion persists as the ductus arteriosus, connecting the pulmonary circulation to the descending aorta, while the distal right portion regresses. After birth, closure of the ductus removes this arterial connection.
- Fourth arch: on the left it forms a segment of the arch of the aorta, between the left common carotid and left subclavian arteries. On the right it forms the proximal part of the right subclavian artery. The rest of that artery comes from other embryonic vessels.
- Third arch: becomes the common carotids and the first part of the internal carotids.
- Second and first arches: largely regress. They still leave contributions including the maxillary arteries from the first arch and transient stapedial arteries (short-lived vessels near the stapes, a tiny ear bone) from the second.
Diagram - Shows the development of the vessels from aortic arches, to the final arrangement of the vessels. Also shows the final position of the right and left vagus nerves and recurrent laryngeal nerves (branches of the vagus nerve that supply most of the muscles of the larynx). The left recurrent laryngeal nerve loops under the arch of the aorta while the right recurrent laryngeal nerve loops under the right subclavian artery
SimpleMed original by Dr. Bethany Turner
The fetal circulation works very differently to adult circulation. The following steps outline the flow of blood from the placenta to the systemic circulation of the fetus:
- Oxygenated blood is carried from the placenta into the fetal circulation via the umbilical vein.
- Part of this blood bypasses the liver through the ductus venosus (a vessel that links the umbilical vein to the inferior vena cava). The rest passes through the liver. Blood in the inferior vena cava mixes with deoxygenated blood from the lower body.
- The liver is very metabolically active. Blood that bypasses it keeps a higher oxygen saturation as it travels to the heart and then to the rest of the body, most importantly the brain.
- Blood enters the right atrium. Some of it passes into the left atrium via the foramen ovale, so it bypasses the pulmonary circulation (the blood flow through the lungs). Blood can shunt from the right to the left side of the heart because pressure on the right side is higher than on the left in the fetus.
- The fetal lungs are not used for gas exchange. The fetus gets its oxygen from the mother's blood across the placenta. Blood therefore does not need to go to the alveoli, so most of it bypasses the pulmonary circulation.
- The blood is pumped from the left ventricle into the aorta.
- Some blood does not cross the foramen ovale. It is pumped from the right ventricle into the pulmonary trunk. Only a small part of it goes to the lungs, which are not used for gas exchange. Instead, most of this blood flows through the ductus arteriosus into the descending aorta, just beyond the arch of the aorta. This means that, in the fetus, the right ventricle pumps more than half of the blood leaving the heart. In the developing heart, the rule of 'use it or lose it' applies. If the right ventricle has no blood passing through it, the ventricle will be underdeveloped in the mature heart. This is relevant in congenital heart defects such as tricuspid atresia (the tricuspid valve fails to form, so blood cannot flow directly from the right atrium to the right ventricle).
Diagram - The fetal circulation. Blood comes in through the umbilical vein, around the fetal body, and back to the placenta via the two umbilical arteries
Creative commons source by OpenStax college [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)]
Changes to the Circulation After Birth
- When the baby takes its first breath, the partial pressure of oxygen (pO2, the amount of oxygen dissolved in the blood) increases. This change, together with a fall in prostaglandin levels (prostaglandins are chemicals that help keep the ductus open before birth), causes the ductus arteriosus to close. At first this is functional closure (the duct narrows and shuts, but is not yet sealed by scar tissue). Fibrosis (scarring) later closes it permanently.
- Ductus arteriosus becomes the ligamentum arteriosum.
- As the lungs fill with air, the resistance to blood flow through the lungs falls. More blood now flows through the pulmonary circulation, and less blood leaves the pulmonary trunk through the ductus arteriosus. This increases venous return (blood returning to the heart) to the left atrium, leading to an increase in left atrial pressure. The pressure in the left atrium then exceeds that of the right. This pushes the septum primum against the septum secundum and closes the foramen ovale functionally. In most people the two septa later fuse. In roughly a quarter to a third of people they do not, which leaves a patent foramen ovale (a small opening that persists).
- Foramen ovale becomes the fossa ovalis (a shallow depression in the septum between the atria, seen from the right atrium).
- When the umbilical cord is cut, there is no longer blood flowing through the umbilical vein, causing the ductus venosus to collapse.
- Ductus venosus becomes the ligamentum venosum (a fibrous cord).
Diagram - The changes that have occurred after the baby has been born. The changes shown are the ligamentum arteriosum (closed ductus arteriosus) and fossa ovalis (closed foramen ovale)
Creative commons source by BruceBlaus [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)]
Edited by: Dr. Ben Appleby
Reviewed by: Dr. Marcus Judge
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