Cardiovascular Development

The cardiovascular system consists of the heart, blood vessels and lymphatic vessels. The heart is a central pump that pushes blood into arteries that supply tissues and cells of the body by oxygen and nutrients. Deoxygenate blood and tissue waste products are taken back from tissues by veins and lymphatic vessels. The first indication of development of the cardiovascular system (CVS) is the appearance of blood islands in the yolk sac extraembryonic mesoderm outside the embryo, in the 3^rd week of embryonic development in the 16^th or 17^th day of development.

Fig. 13.1. The illustration on the left shows the dorsal view of an 18-days old embryo showing location of the blood islands in the extraembryonic splanchnopleure of the yolk sac, whereas the one on right shows their location in a cross section of the embryonic disc.

Development of the Heart

In the 3^rd week of development of the heart begins with the appearance of the mesodermal cardiogenic fields. The process involves differentiation of splanchnic mesodermal cells into myoblasts and cardiac myocytes that arrange themselves into a tube, which by complicated bending, folding, and partitioning yield the known 4-chambered heart.

The splanchnic mesodermal cells in close proximity to the primitive pharynx are induced by the endodermal cells of the pharynx to form a pair of bilateral crescentic horseshoe-shaped tubes lined by endothelium called the cardiogenic fields. These bilateral endocardial heart tubes appear in the third week of embryonic development. The lateral folding of the embryonic body brings these endocardial heart tubes ventrally and towards the midline. Gradually they come in contact with each other and fuse form a single tube called the primordial heart tube. Fusion of the paired tubes begins close to their cranial ends and proceed caudally. Cranially, the pair of tubes remain unfused and will develop into arteries that carry blood away from the heart. Likewise, the in caudal end of the primordium the tubes remain unfused and develop into veins that bring blood into the heart; that is to say the tubular heart primordium receives venous blood at its caudal pole and pumps out arterial blood at its cranial pole.

Fig. 13.2. The illustrations show how the pair of endocardial tubes (left) move towards each other and fuse together (middle) forming the single tubular heart (right).

In the beginning of the 4^th week of embryonic development, the tubular heart protrudes into the pericardial cavity and hangs in the cavity suspended by blood vessels at its cranial and caudal ends. During this period splanchnic mesodermal cells surrounding the tube differentiate into cardiac myocyte that join each other by intercalated disc form cardiac muscle fibers and the muscular layer of the heart wall called the myocardium. Mesodermal cells surrounding the myocardium differentiate into fibroblasts that lay down a connective tissue investment, the epicardium. Concomitant with these changes, the first cardiac constriction rings (folds) and dilatation occur forming the first divisions of the tubular heart, which are the truncus arteriosus, the bulbus cordis, the primitive ventricle, the primitive atrium, and the sinus venous. The atrial part of the primitive heart tube develops into the definitive atrium, the bulbus cordis divides into three parts; its proximal part forms the right ventricle, its middle part becomes the conus cordis, whereas the truncus arteriosus gives rise to the arterial roots of the proximal aorta and the pulmonary artery. Cardiac looping which is a key part of cardiac morphogenesis, starts in the 4^th week of embryonic development and is completed in the fifth week of development. Due to lack of space enough to accommodate the lengthening of the cardiac tube, the heart starts to bend as it grows longer and larger. The simultaneous growth of the bulbus cordis and the primitive ventricle forces the heart to bend ventrally and rotate to the right. The cephalic part of the heart bends ventrally, caudally, and to the right, Whereas the caudal part of the tubular heart moves craniodorsally and towards the left.

Fig. 13.3.  The illustration shows the appearance of the cardiac constriction rings and compartmentation of the tubular heart into five chambers. Blood flows into the heart from its caudal end (venous pole) and is pumped in a cranial direction consecutively through the sinus venosus, the primitive atrium, the primitive ventricle, the bulbus cordis, the truncus arteriosus, and out of the heart at the arterial pole.

In the next stage of development, septations occur within the developing heart; this occurs in the 4^th week of embryonic development and results in the appearance of two atria, two ventricles, two atrioventricular valves, and two separate outflow tracts. Still the caudocranial arrangement of the cardiac compartments is maintained essentially in the same sequence as before. The paired branchial arteries along with the two aortae progressively regress, resulting in a persistent left aortic arch and its corresponding bifurcations. On the venous side, several paired veins regress and fuse to develop into the systemic venous system where the hepatic veins and superior vena cava and the inferior venae cava are the principle tributaries. The tubular heart contracts in a pulsatile manner pumping blood in a caudocranial direction. At the same time the heart tube bends and rotates to the right and ventrally along its longitudinal axis, resulting the d-looped heart.  Accordingly, the ventricle is pushed downwards and to the right whereas the atrium is pushed upwards to a position posterior to the ventricles. Due to further elongation of the tube, the heart bends on itself forming the s-shaped heart.

Fig. 13.4. The illustration shows constrictions and twisting of the heart during development from a tubular structure into a 4-chambered structure. The venous pole which is situated caudally receives blood from several major veins that include the umbilical veins, the vitelline veins, and the cardinal veins.

Septation of the atrium takes place in the 7^th and 8^th weeks of development, where the primitive atrium divides into two parts by the development of two septa in succession; these septa are the septum primum and the septum secundum. The septum primum develops first as an evagination from the roof of the primitive atrium that grows towards the endocardial cushions. Throughout the process of development and elongation of the septum premium, an opening persists ensuring communication between the newly forming right and left atria; this opening is the interatrial the foramen primum or the ostium premium. The foramen premium obliterates, and second foramen called the foramen secundum appears before the foramen premium obliterates. Then a second septum called the interatrial septum secundum develops to the right of the septum primum, grows in the reverse direction ventrodorsally and assumes a crescentic shape. The septum secundum remains incomplete and almost covers the free rim of the septum primum. An ovale opening called the foramen ovale or the foramen secundum is present in the septum secundum. The two septa (the septum premium and the septum secundum) fuse and make a partition between the left and right atria except for the foramen ovale (ostium secundum), which remains patent for shunting blood from right atrium to left atrium. The free flap of the septum primum acts as a valve for the foramen ovale that prevents backflow of blood from the left atrium into the right atrium. is seen on ultrasound within the left atrium as the foramen ovale flap. The foramen ovale remains patent throughout the fetal life; the complete closure of the foramen ovale occurring postnatally, after birth when the increased pressure within the left atrium forces the septum primum against the septum secundum.

Fig. 13.5.  The illustration shows the septum premium and the septum secundum separating between the right and left atria. The foramen ovale and foramen secundum are window in the interatrial septa that allow communication between the right and left atria. Most of the blood reaching the right atrium via the vena cava passes through the foramen ovale and the foramen secundum (thick, red-dashed arrows) into the left atrium. From there blood passes into the left ventricle via the atrioventricular canal (AV canal). The lower part of the septum premium acts as a valve that prevents backflow of blood from the left atrium to the right atrium. A small amount of blood (thin, red-dashed arrow) reached the right ventricle.

The primitive ventricle separates into a left ventricle and a right ventricle by the interventricular septum, commonly referred to as the ventricular septum. It is a thick Musculo-membranous septum that begins to develop in the 5^th week of embryonic development and is fully formed by the 8^th week of embryonic development. The septum is formed by the fusion of three independent septa, namely the muscular septum, outlet or Conal or infundibular septum, and the inlet septum. The muscular septum develops from the bulboventricular fold, expanding inward as the ventricles deepen. The Conal septum, which is also known as the bulbar or infundibular septum, develops from the conus, and contributes to the right ventricle and the pulmonary outflow. On the other hand, the inlet septum develops from the atrioventricular canal and fuses with the other two septa. The membranous part of the interventricular septum is that parts of the septum which connects the muscular septum to the atrioventricular canal and the aorticopulmonary septum. 

Concomitant with the development of the interventricular septum, an atrioventricular septum develops separating the atria from the ventricles and forming the atrioventricular canals. The endocardial cushions, which are specialized mesenchymal cells originating from the endocardium, play an important role in the development of these septa and in the formation of the heart valve. In this manner, internal partitioning of the four chambered heart is accomplished.

Fig. 13.6.  The internal features of the heart showing the four chambers (two atria and two ventricles) that resulted from the partitioning processes.

By continued elongation and looping, the atria are brought a cranial position above the ventricles surrounding the bulbus cordis which forms the outflow tract and the truncus arteriosus which give rise to the aorta and the pulmonary trunk.

Fig. 13.7. The illustrations show how the tubular heart of 4-weeks old embryo, that has five parts namely the sinus venosus, the atrium, the ventricle, the bulbus cordis, and the truncus arteriosus in a caudocranial sequence (illustration on the left) transforms by looping, partitioning, and twisting (illustration in the middle) into a unique-shaped heart of 6-weeks old embryo, where the atria is brought cranial to the ventricles (illustration on the right).

By continued development and morphogenesis, the heart takes its usually mature shape with its characteristic external features where the smaller upper chambers (the atria) are demarcated from the lower larger ventricles by the coronary sulcus, and where the ventricles are demarcated from each other by the inter ventricular sulcus. Internally, the four chambers are clearly demarcated from each other and have specific apertures, valves, and orifices of the major blood vessels entering and leaving the chambers.

Fig. 13.8. The illustration shows the external features of the fully developed heart. The four heart chambers, the boundaries between them, and the major blood vessels entering and leaving the heart are evident.

Heart Valve Development

Development of the heart valves commences in 7th week of gestation when endocardial cells in the atrioventricular canal or the bulbar ridges under the influence of BMP differentiate to form structures known as the endocardial cushions. The endocardial cushions elongate, and the cushion and interstitial cells differentiate and remodel the cushions giving rise of valve leaflets with distinct features. Cells of the endocardial cushions give rises to the atrioventricular valves (mitral and tricuspid), whereas the bulbar ridges and subendocardial cells develop into the semilunar valves.

The Aortic Arches

Six pairs of aortic arches develop in association with the pharyngeal (brachial) arches in the early stages of embryonic development. They are temporary vessels that play significant roles in the development of the major blood vessel of thorax and neck. To begin with, they are present on the left and right sides of body in a symmetrical fashion. They connect between the paired ventral and dorsal aortae.  The first artic arch is the first of the aortic arches to develop; this takes place in the beginning of the 4^th week of embryonic development. The two ventral aortae develop from the heart tube and grow cranially (upwards) forming the primitive or first aortic arch along the 1^st branchial arch and continue caudally along the dorsal surface of the branchial or pharyngeal arches thus forming a pair of dorsal aortae that eventually unite to form the descending aorta. Five additional pairs of vessel appear caudal to the first aortic arch connect each dorsal aorta with the corresponding ventral aorta, each pair aligned and traversing a branchial (pharyngeal) cleft.

Fig. 13.9. The illustration on the left is of a lateral view of an embryo in its 5^th week of development showing aortic extending between the ventral aorta and the dorsal aorta; the first aortic arch is at the level of the 1^st branchial arch. The illustration on the left is a dorsal view of the pair of the ventral and dorsal aortae and the six pairs of aortic arches connecting them; the short-lived aortic arches (1^st&5^th arches) are shown in a pale colour.

Derivatives of the Aortic Arches

Of the six pairs of aortic arches that develop in the region of the pharyngeal arches and pouches, the fifth pair degenerates and disappears soon after its formation thus leaving the 1^st, 2^nd, 3^rd, 4^th, and 6^th arches to participate in the development of major blood vessels of the chest and neck regions. The 1^st and 2^nd arches disappear shortly after their formation. Remnants of the first arch contributes to the formation of the maxillary artery and the meningeal artery. The 3^rd aortic arch constitutes the carotid arch, which is the initial segment of internal carotid artery. The ventral aorta cranial to carotid arch forms the external carotid artery, whereas the carotid arch itself and dorsa aorta cranial to carotid arch (the 3^rd aortic arch) develop into internal carotid. The dorsal aorta between the 3^rd and 4^th artic arches disintegrates. The ventral aorta between the 4^th and 3^rd aortic arches develop into the common carotid artery supplying the internal and external carotid arteries. The left 4^th aortic arch develops into the adult aortic arch, whereas the right 4^th aortic arch develops into the proximal part of the right subclavian artery. The fifth aortic arch does not show up and does not contribute to the formation of any of the adult blood vessels. The proximal part of the 6^th right arch persists forming the proximal part of the right pulmonary artery, whereas the distal part of this disintegrates; a branch of the 6^th left arch develops into the left pulmonary artery, whereas the segment of the 6^th arch between the origin of the left pulmonary artery and dorsal aorta constitutes the ductus arteriosus. The ductus arteriosus remains a patent duct throughout the prenatal life shunting blood of the lung which is not yet functioning. It closes in the first few days after birth.

Fig. 13.10. The illustration shows the six pairs of aortic arches and their derivatives, the external carotid, the internal carotid, the common carotid, the definitive aortic arch, the pulmonary artery, the subclavian artery, and the ductus arteriosus.

Fig. 13.11.  The illustration shows the definitive derivatives of the six embryonic aortic arches, namely the common carotid arteries, the brachiocephalic trunk, the subclavian arteries, the aorta, and the pulmonary arteries. The internal and external carotid arteries, which are derivatives of the embryonic aortic arches are not shown  

Vasculogenesis and Angiogenesis

Embryonic development of blood vessels involves vasculogenesis and angiogenesis. These are two distinct methods of blood vessel formation, differing in their starting point and process. Thus, whereas vasculogenesis is the formation of blood vessels from precursor cells known as angioblasts, angiogenesis on the other hand is the growth of new blood vessels from already existing blood vessels. Vasculogenesis means creation of new blood vessels in the absence of existing blood vessels; it involves the recruitment mesenchymal or other primitive cell and their differentiation into endothelial progenitor cells and then to endothelial cells. In developing embryos, it is essential for establishing the initial vascular network, followed by angiogenesis to expand these newly formed network. Several signaling biomolecules are involved in regulating vasculogenesis and angiogenesis; these include vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), which stimulate mitosis in different types of cells.

Embryonic vasculogenesis involves the differentiation of angioblasts into endothelial cells and assembly of the latter into a primitive vascular network. It starts after gastrulation in the 3^rd week of embryonic development, wherein the mesoderm formed, and appearance of the blood islands in the splanchnic mesoderm. Blood islands are aggregations of mesodermal cells into hemocytoblasts surrounded by angioblasts. The angioblasts differentiate into endothelial cells the arrange themselves in tubular structures forming the walls of new blood vessel, whereas hemocytoblasts develop into blood cells.

Fig. 13.12.  The illustration shows the process of angiogenesis, blood islands formation and development of blood vessels.

The newly formed endothelial-lined blood vessels elongated branch and anastomose forming primitive vascular networks which extends towards the developing heart within the embryo. The vascular wall thicken due to formation of new layers of connective tissue and smooth muscle fibers around the endothelial lining thus forming muscular arteries. Veins accompanying the arteries have thinner and less muscular walls. Larger arteries known as elastic arteries develop in a similar manner but the fibroblasts and smooth muscle which differentiate from the mesenchyme synthesize and secrete elatin.

Fig. 13.13.  The illustration shows a small artery (on the left) made up of endothelium, smooth muscle fibers and connective tissue, and a small vein (on the right) made up of endothelium and connective tissue. All elements of the arterial and venous wall are of mesodermal origin. Mesenchyme differentiates to give rise to smooth muscle and connective tissue elements.

Fetal Circulation

The fetus has a distinct circulatory system that differs from that of the adult in that in addition to the systemic circulation, it has an additional arc that facilitates supply of oxygen and nutrients to embryo and called the placental or umbilical circulation. There is yet a third arc called the vitelline circulation that facilitates blood flow between the embryo and the yolk sac in the early stages of embryonic development. The vitelline circulation crucial for supplying nutrients and oxygen to the developing embryo until the placenta fully develops. Blood flows from the embryo to the yolk sac via the vitelline arteries derived from the dorsal aorta and drained back to the embryo through the vitelline veins that open into the cardinal vain. The heart acts as a common central pump for all three circulations, the systemic, the vitelline and the umbilical arcs. In all three circulations, arteries carry blood away from the heart and veins carry blood back towards heart whereas capillaries are thin-walled tiny vessels that connect arteries to veins; they are the sites where nutrients, gases and waste are exchanged between the blood and cells and tissues surrounding the capillaries.

Fig. 13.14.  The illustration shows the human fetal circulation in a 4-week embryo. The systemic circulation supplies blood to various organs of the fetus, the vitelline circulation has the yolk sac at its core and supplies nutrients and oxygen to the developing embryo in the early stages of embryonic development, whereas the umbilical circulation has the placenta at its core and supplies oxygen and nutrients to the embryo and fetus until birth.

After involution of the yolk sac blood is pumped by the heart into to aorta and pulmonary arteries. Blood passing to pulmonary arteries is shunted of from the lungs. Blood pumped into the aorta supplies the head, neck and arms by branches of the common carotid arteries and the subclavian artery. Abdominal organs including the liver, stomach, and intestines are supplied by branches of the abdominal aorta mainly the coeliac and mesenteric arteries, whereas the kidneys are supplied by the renal arteries.

The umbilical circulation consists of the umbilical arteries, umbilical vein, and placental blood vessels.   The umbilical arteries are branches of the internal iliac arteries at the caudal end of the dorsal aorta. The carry deoxygenated blood from the fetus to the placenta.

Fig. 13.15. The illustration shows the major components of the fetal systemic and umbilical circulation at term.

The right atrium receives oxygenated venous blood from the inferior vena cava; a small proportion of the blood received at the right atrium passes through the right atrioventricular canal into the right atrium to be pumped into the pulmonary truck, but most of this blood is shunted away from the lungs into the aorta by the ductus arteriosus that connects the pulmonary trunk to the aortic arch. The vast majority of the blood reaching the right atrium is directed towards the left atrium via the foramen ovale to pass down the left atrioventricular canal into the left ventricle to be pumped into the aorta. Blood from the aorta reaches the head, neck and upper limbs by the common carotid arteries and the subclavian arteries. The abdominal organs are supplied by the coeliac and mesenteric arteries that originate from the abdominal aorta. At its caudal end the aorta bifurcates into the internal iliac arteries. An umbilical artery originates from each of the iliac arteries and passes to the placenta via the umbilical cord. Within the placenta they break up into placental arteries and capillary networks. Within these capillaries, exchange of substances and gasses between the maternal and fetal bloods takes place. Fetal blood loaded with oxygen and nutrients passes from these capillary networks into placenta venules and veins into the umbilical vein that passes via the umbilical cord into the abdominal cavity, and through the liver into the inferior vena cava. A direct connection between the umbilical vein and the inferior vena cava known as the ductus venosus, bypasses the hepatic capillary networks thus carrying most of the oxygenated blood coming from the placenta into the inferior vena cava that drains into the right atrium. The human placenta is a hemochorial placenta where the maternal blood is in direct contact with the fetal chorionic epithelium

Fig. 13.16. The illustration shows the placental and endometrial blood interrelations. Th umbilical arteries and vein reach carried within the umbilical cord reach the placenta and branch into placental vessels. The placental arterioles open into placental capillaries present within the chorionic villi which are submerged in maternal blood that flows out of the spiral maternal endometrial arteries. Exchange of gases, nutrients, and waste products between the fetal and maternal bloods takes places across the chorionic epithelium and the capillary fetal capillary endothelium. Blood laden with nutrients and oxygen is carried from the fetal capillaries, into the placental veins and into the umbilical on its way towards the heart. The umbilical vein (in red colour) carries oxygenated blood.

Postnatal Circulatory Changes

The fetus depends on the placenta for providing its oxygen and nutrients needs and according to the fetal circulation is modified to accommodate for a supply of oxygen and nutrients from the placenta. There is a foramen and two right-to-left shunts that direct blood that needs to be oxygenated. The foramen and the two shunts are designed to bypass the lungs and liver. The foramen is the foramen ovale; it moves about 2/3^rd of the blood from the right atrium of the heart to the left atrium. The shunts are ductus arteriosus and ductus venosus; the ductus arteriosus moves blood out of the pulmonary artery to the aorta whereas the ductus venosus shunts blood away from the liver sinusoids and direct to inferior vena cava.

Fig. 13.17. The illustration on the left shows the interatrial foramen ovale that facilitates passage of blood from the right atrium to the left atrium diverting blood from reaching the lungs via the pulmonary arteries as shown by the dark green arrows. The illustration on the right shows the ducts arteriosus which further shunts blood from reaching the lungs (not yet functioning) by allowing blood to pass from the pulmonary artery to the aorta.

The umbilical cord is clamped during parturition, and the baby no longer receives oxygen and nutrients from the placenta via the umbilical vein. Inhalation with the breaths of life cause the lungs to expand. With the expansion of the lungs the blood pressure increases accompanied by a significant reduction in the pulmonary pressure that make the ductus arteriosus redundant. The lumen of the ductus obliterates and the ductus arteriosus transforms into a ligament called the ligamentum arteriosum. Moreover, these changes increase the pressure in the left atrium of the heart and a concurrent decrease in the pressure of the right atrium that together lead to the closure of the foramen ovale. A depression in the interatrial septum called the fossa ovalis marks the site of the fetal foramen ovale. In a similar way, the ductus venosus obliterates and transforms into the ligamentum venosum. The closure of the ductus arteriosus, ductus venosus, and foramen ovale completes the transition of fetal circulation into the newborn’s circulation.

Fig. 13.18.  The illustration shows the umbilical circulation and its relation to the fetal systemic circulation. The ductus venosus which shunts the liver by connecting the umbilical artery directly to the inferior vena cava is highlighted by a surrounding dashed rectangle.

Developmental Anomalies of CVS

Anomalies of the cardiovascular system could anomalies affecting blood vessels or anomalies affecting the heart. Congenita anomalies of blood vessel range from simple variations to more severe conditions such as vascular rings that occur from developmental defects of the aortic arches. .  that can compress the trachea or esophagus. Anomalies of the aortic arches include double aortic arches, interrupted aortic arch and right aortic arch.

Anomalies of the heart are more renowned and more common constituting about 1% of live births, and often more serious than anomalies of other organs. They include aortic valve stenosis, patent foramen ovale, defects of the interventricular septum, patent ductus arteriosus, pulmonary valve stenosis, tetralogy of Fallot, tricuspid atresia, and  atresia of the pulmonary artery.

In congenital aortic valve stenosis, the tricuspid aortic valve does not open properly causing narrowing the passage. It often results from failure of development of one the cusps (leaflets) the valve being bicuspid instead of the normal tricuspid valve. The condition could be mild  without symptoms or with severe symptoms and complication including heart failure that result from severe obstruction of valve.

Patent foramen ovale is an anomalies that occurs postnatally due to failure of closure of the interatrial foramen. The foramen ovale which functions in directing blood from the right to the atrium during the fetal life becomes redundant postnatally and closes off permanently when the lungs take over the responsibility of blood oxygenation. However, the foramen remains open in about 25% of the newborns a patent foramen ovale. most people with a patent foramen ovale are asymptomatic but show severe symptoms that necessitate surgical correction.

Fig. 13.19. The illustration compares and a normal intact interatrial septum (on the left) with one that has a patent foramen ovale (right).

Tetralogy of Fallot is a congenital anomaly with four specific cardiac defects that result in low levels of oxygen due to abnormal functioning of the heart. The four (tetra) defects of Fallot are pulmonary valve stenosis, ventricular septal defect, overriding aorta, and ventricular hypertrophy. Pulmonary heart stenosis is narrowing of the aperture of the pulmonary valve that reduces blood flow to the lungs leading to deficiency in blood oxygenation causing a blue skin in newborns. Narrowing of the pulmonary valve puts more pressure on the right ventricle causing thickening of the right ventricular wall. Ventricular septal defect is the presence of hole in the interventricular septum that results in passage of oxygenated blood from the left ventricle to right ventricle reducing the amount of oxygenated blood passing through the aorta to the various body organs an tissue causing malfunctioning of organs and skin bluing. Overriding aorta is a congenital heart deft where the aorta is shifted from its normal left position rightwards to be situated right on a defective interventricular septum. In this case, the aorta receives blood from both the left and right ventricles augmenting the problem properly oxygenated blood reaching body organs and tissues. Ventricular hypertrophy is the thickening of the wall of the ventricles.  In case of tetralogy of Fallot, ventricular hypertrophy refers to the thickening of the wall of the right ventricle, which is a consequence of the increased workload on the right ventricle that result the pulmonary stenosis and the ventricular septal defect.

Fig. 13.20. The illustration shows the four birth defects that characterize the tetralogy of Fallot.

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