The Complex Process of Cardiovascular System Development: From Formation to Septation

The cardiovascular system, comprising the heart, blood vessels, and blood cells, originates from the mesodermal germ layer. Throughout its ontogenetic evolution, both the heart and vascular system undergo successive transformations. The heart undergoes changes driven by the shift from branchial to pulmonary respiration, necessitating a configuration where systemic and pulmonary blood flow are distinct. Concurrently, alterations in the vascular system are intricately tied to the nutritional sources for the embryo and fetus.

During the embryonic stage, a vascular network forms when the embryo receives nourishment from the umbilical vesicle, vitelline or omphalomesenteric circulation. Subsequently, another network emerges when the embryo gains nourishment from maternal blood through the placenta, known as umbilical or uteroplacental circulation. This latter network undergoes adaptation after birth, as the newborn initiates pulmonary respiration and begins processing ingested food independently.

The formation of the vascular system initiates in the first half of the third week when the embryo's nutritional demands surpass diffusion alone. Initially, primitive cardiac cells reside in the epiblast, positioned immediately lateral to the primitive streak, and subsequently migrate through it.

The migration process commences with cells responsible for the cranial segments of the heart (effluent tract), followed in sequence by cells contributing to the more caudal portions, ultimately giving rise to the right ventricle, left ventricle, and venous sinus. As cells progress toward the cephalic extremity, they align rostral to the buccopharyngeal membrane and neural folds, situated in the splanchnic layer of the lateral plate mesoderm.

In the advanced presomitic stage, these cells respond to stimulation from the underlying pharyngeal endoderm, undergoing transformation into cardiac myoblasts. Concurrently, blood islands emerge in the local mesoderm, fostering the development of blood cells and blood vessels through vasculogenesis.

As time unfolds, these blood islands amalgamate, forming a horseshoe-shaped tube surrounded by myoblasts and lined with endothelium—this region is termed the cardiogenic field. The pericardial cavity subsequently takes shape above it. Additionally, on each side of the body, supplementary blood islands emerge parallel to the embryonic body's midline, giving rise to a pair of longitudinal vessels known as the dorsal aortas.

In organisms where the heart solely propels blood into the gills, it adopts the form of a single tube consisting of four segments: the venous sinus, caudal segment receiving venous blood, single atrium, single ventricle, and the cardiac bulb from which the aorta originates. Initially, there might have been separate hearts for pulmonary and systemic circulation, explaining the existence of two cardiac tubes. Throughout phylogenetic evolution, these tubes fuse, but in the common path of the heart, the two blood flows remain separate through cavity septation (in amphibians and reptiles, septation is incomplete, with a single ventricle for both pulmonary and systemic circulation).

During gastrulation, specifically on days 18-19, a conglomerate of mesenchymal cells from the splanchnopleure comes together to form a cell cluster designated as the cardiogenic plate. This plate is situated in the precordial region, where clefts in the mesoderm give rise to the pericardial cavity. From the cells of the cardiogenic plate, two strips form, giving rise to two endothelial tubes. As the embryo laterally folds, the pericardial cavities on both sides merge, initiating the fusion of the two endothelial tubes. This fusion results in the formation of a single pulsating endocardial tube.

As the embryo elongates, the pericardial cavity and endocardial tube are pushed ventrally ahead of the anterior intestine, concealed by the brain vesicles. The elongation and subsequent bending of the embryo include the endocardial tube into the pericardial cavity. Initially connected to the posterior wall of the pericardial cavity by the dorsal mesocardium, the middle portion of this suspensory ligament regresses over time, creating a narrow opening known as the transverse sinus of the pericardium, allowing communication between the right and left sides of the pericardial cavity.

Unlike the formation of a ventral mesocardium, the surrounding splanchnopleure contributes to the development of a thick myocardial-epicardial covering around the endocardial tube. This covering includes a layer of gelatinous connective tissue, with the epicardium's mesothelial cells and myocardial myoblasts originating from the outer layer. Simultaneously, the gelatinous connective tissue gives rise to subendocardial tissue. The cardiac primordium, with its relatively large extent, significantly influences the external shape of the embryo.

Initially, two separate cardiac tubes exist, but by the 22nd day of development, they merge into a single, slightly curved cardiac tube. This tube comprises an inner layer of endocardial cells and an outer layer of myocardial tissue. Between the 4th and 7th weeks of development, the cardiac cavity undergoes division, leading to the establishment of the typical four-chambered structure of the heart.

The central part of the cardiogenic field is initially situated anterior to the buccopharyngeal membrane and neural plate. As the neural tube closes and brain vesicles form rapidly in the cephalic direction, nervous tissue covers the cardiogenic area and the future pericardial cavity.

Following the development of the brain and the cephalic folding of the embryo, the buccopharyngeal membrane shifts anteriorly. Simultaneously, the heart and pericardial cavity move initially to the cervical region and eventually to the thorax. The cephalo-caudal folding of the embryo, coupled with lateral folding, leads to the union of the caudal regions of the paired heart primordia, forming a continuous tube with a horseshoe-shaped expansion. This tube comprises an endothelial lining on the interior and a myocardial layer on the exterior. Venous blood enters through the caudal pole, and at the cranial pole, the tube initiates blood circulation through the first aortic arch into the dorsal aorta.

As the developing cardiac tube extends further into the pericardial cavity, it remains initially attached to the dorsal surface of the pericardial cavity by the dorsal mesocardium. The disappearance of the dorsal mesocardium coincides with the appearance of the transverse pericardial sinus, connecting the two parts of the pericardial cavity. Blood vessels support the heart at its cranial and caudal poles within the pericardial cavity.

The myocardium develops, and myocardial cells secrete a thick layer of extracellular matrix rich in hyaluronic acid, creating a separation between the myocardium and the endothelium. The proepicardium, originating from mesothelial cells on the surface of the transverse septum, migrates to the heart's surface, forming the majority of the epicardium. Additional mesothelial cells from the effluent tract region contribute to the rest of the epicardium. The wall of the cardiac tube is composed, from the inside out, of three layers: endocardium, myocardium (constituting the muscular wall), and epicardium or visceral pericardium, responsible for the formation of coronary arteries, including their endothelial and smooth muscle components.

Initially, the endocardial tube is a relatively straight structure, with its unidirectional venous circulation stabilized by the transverse septum, and the arterial circulation directed outward fixed by the branchial arches. As it undergoes rapid growth in length, various loops, expansions, and thickenings emerge, delineating distinct segments from caudal to cranial: the venous sinus (convergence point for veins of the vitelline sac, umbilical veins, and cardinal veins), the atrial segment, the ventricular segment, the cardiac bulb, and the arterial trunk.

The ventricular part of the cardiac loop comprises a descending arm and an ascending arm, with the inflection point marking the future apex of the heart. Both arms enclose a shared space termed the primary cardiac chamber. Through a twisting motion of the cardiac loop, the atrial part positions itself posteriorly to the arterial trunk, slightly ascending, while the ventricular part remains anterior. A groove emerges between the atrial and ventricular parts, ultimately defining the atrioventricular boundary, near which the atrioventricular canal develops.

Initially, the drainage of the venous sinus is centrally located in the common atrium, ensuring equal sizes for the two sinus horns. However, as the veins of the vitelline sac and umbilical veins transform, and anastomoses form between the anterior cardinal veins, blood flow gradually shifts from left to right. Consequently, the right sinus horn enlarges, shifting its drainage to the right side of the atrium and incorporating it into the atrial wall. The boundary between the sinus and atrium can be identified externally in the adult heart at the sulcus terminalis and internally at the terminal crest. Meanwhile, the left sinus horn transforms into the coronary sinus. As the embryo grows, and the cervical region develops, the cardiac primordium descends into the future thoracic cavity, a process known as the descent of the heart.

On day 23, the elongation and bending of the cardiac tube persist, with the cephalic portion moving ventro-caudally and to the right, while the atrial (caudal) portion shifts dorso-cranially and to the left. The bending, likely influenced by changes in cell shape, culminates in the creation of the cardiac loop by day 28. As the cardiac loop forms, local expansions become evident throughout the entire cardiac tube. The atrial portion, initially situated outside the pericardial cavity, transforms into a common atrium and integrates into the pericardial cavity. The atrioventricular junction remains narrow, giving rise to the atrioventricular canal, connecting the common atrium and the embryonic heart's primitive ventricle. The cardiac bulb, except for its proximal third, remains narrow and forms the trabecular component of the right ventricle.

From the middle portion, known as the cardiac cone, the efferent tracts of both ventricles take shape. The distal portion of the bulb, the arterial trunk, gives rise to the roots and proximal segments of the aorta and pulmonary artery. The junction between the ventricle and the cardiac bulb, identified externally as the bulboventricular groove, remains narrow and is termed the primary interventricular foramen. Along the craniocaudal axis, the cardiac tube exhibits distinct regions: the conical region, right ventricle, left ventricle, and atrial region. Homeotic genes regulate the organization of these regions, akin to the craniocaudal axis of the embryo.

Following the completion of the cardiac loop formation, primitive trabeculae emerge on the smooth inner surface of the cardiac tube, occurring in two well-defined areas proximal and distal to the primary interventricular foramen. The inner surface of the bulb remains smooth initially. The primitive ventricle displays trabeculae, termed the primitive left ventricle, while the proximal third of the cardiac bulb, exhibiting trabeculation, is known as the primitive right ventricle.

Initially positioned on the right side of the pericardial cavity, the conical region of the cardiac tube gradually shifts medially due to the formation of two transverse dilations of the atrium, notable on each side of the cardiac bulb.

The venous sinus, by the middle of the fourth week, receives venous blood from the right and left sinus horns, each horn collecting blood from three major veins: the vitelline or omphalo-mesenteric vein, the umbilical vein, and the common cardinal vein. Initially, the communication between the venous sinus and the atrium is broad, but later the entrance orifice of the sinus shifts to the right. This shift primarily results from the left-to-right shunt of blood in the venous system during the fourth and fifth weeks of development.

In the fifth week, the obliteration of the right umbilical vein and the left vitelline vein reduces the significance of the left sinus horn. By the tenth week, when the common left cardinal vein undergoes obliteration, only the oblique vein of the left atrium and the coronary sinus persist from the left sinus horn.

Due to the left-to-right blood shunt, the volume of the right sinus horn and its veins significantly increases. The right horn becomes the sole communication pathway between the initial venous sinus and the atrium, integrating into the right atrium and forming the smooth portion of its wall. The sinoatrial orifice, represented by the entrance orifice of the right horn, features valvular folds on each side—the right and left venous valves. These valves fuse in the dorso-cranial zone, creating a bridge known as the spurious septum. Initially large, the valves reduce in size as the right sinus horn incorporates into the atrial wall, and the left venous valve and false septum merge with the developing atrial septum. The upper portion of the right venous valve disappears entirely, while the lower portion gives rise to the valve of the inferior vena cava and the valve of the coronary sinus. The terminal crest serves as the demarcation between the trabecular portion of the right atrium and the smooth portion (sinus venarum) derived from the right sinus horn.

Initially, the atrial and ventricular segments of the endocardial tube are divided by the atrioventricular cushion. In a subsequent stage, this division transforms into a right half and a left half through the atrial and ventricular septa. Additionally, the aorta and pulmonary trunk are segregated by an aortopulmonary septum (septum pulmonale). The development of heart septa coincides with the emergence of cardiac valves, crucial for regulating blood circulation direction.

Between day 27 and day 37 of development, as the embryo's length increases from 5 mm to 16-17 mm, the primary septa of the heart take shape. The cardiac septum can form either from two growing tissue masses that converge and fuse, dividing the lumen into distinct channels, or through the continuous growth of a single tissue mass that extends until it reaches the opposite side of the lumen. This process depends on factors like the synthesis and deposition of extracellular matrix and cell proliferation. Known as endocardial ridges, these tissue masses develop in the atrioventricular and cono-truncal regions, contributing to the formation of atrial and ventricular septa (the membranous portion), atrioventricular channels and valves, as well as aortic and pulmonary channels.

Alternatively, a cardiac septum can form without the appearance of endocardial ridges. In this scenario, a thin tissue blade from the atrial or ventricular wall remains unchanged, while the surrounding tissue areas grow rapidly. A narrow crest forms between the two developed regions, and as the lateral regions expand on each side of the narrowing zone, the walls approach each other and eventually fuse. This creates a septum that doesn't completely divide the initial lumen, leaving a narrow communication pathway between the two lateral regions. The opening is later sealed by tissue from adjacent areas undergoing cell proliferation. This type of septum results in the partial separation of the atria and ventricles.

From the ceiling of the common atrial cavity, a crescent-shaped ridge starts developing towards the lumen at the end of the fourth week. This ridge marks the initial section of the primary septum, with its two arches extending towards the endocardial primordia at the atrioventricular canal level. The opening, known as ostium primum, is delimited by the lower edge of the primary septum and endocardial folds. Extensions of the upper and lower endocardial folds along the edge of the primary septum eventually close the ostium primum. Before complete closure, several perforations appear in the upper part of the primary septum due to apoptosis of cells in that region. These perforations coalesce to form the ostium secundum, allowing free blood flow from the primitive right atrium to the primitive left atrium.

The secondary septum emerges as a crescent-shaped prominence when the right atrium's lumen widens due to the incorporation of the sinus venosus. It never entirely separates the two atrial cavities. The anterior arch descends towards the atrioventricular canal septum. Fusion of the left venous valve and the septum spurium with the right part of the secondary septum leads to the free concave edge of the secondary septum covering the ostium secundum. The uncovered portion of the secondary septum forms the oval hole, and as the upper part of the primary septum gradually disappears, the remaining portion becomes the valve of the oval orifice. The communication between the atrial cavities is represented by an oblique and elongated slit through which blood flows from the right atrium to the left atrium.

After birth, pulmonary circulation establishes, increasing pressure in the left atrium. The valve of the oval orifice is pushed towards the secondary septum, closing the oval orifice and thus separating the atrial cavities. In some cases with a catheter-permeable oval orifice, incomplete fusion of the primary and secondary septa leaves a narrow oblique gap between the two atria, preventing intracardiac blood shunting. During atrial differentiation, the primitive right atrium enlarges by incorporating the primitive right sinus venosus, while the primitive left atrium's dimensions also increase. Initially, a single embryonic pulmonary vein develops from the posterior wall of the left atrium, adjacent to the primary septum, contacting the veins of the lung primordia. Over time, the pulmonary vein and its branches merge into the left atrium, forming the smooth portion of the atrial wall in adults. Initially, a single vein enters the left atrium, and eventually, four pulmonary veins open into the atrium due to the incorporation of various venous branches into the developing atrial wall.

In the fully developed heart, the trabecular atrial appendage on the left serves as a remnant of the embryonic left atrium. The smooth portion of the left atrial wall originates from the pulmonary veins. On the right side, the embryonic right atrium forms the trabecular right atrial appendage containing pectinate muscles (myocardial muscle fibers with a comb-like appearance). The venous sinus, with a smooth wall, originates from the right horn of the venous sinus.

At the level of the atrioventricular canal, four endocardial cushions are present. The merging of the upper and lower cushions divides the canal into two atrioventricular canals, left and right. The tissue of these cushions undergoes fibrous transformation, forming the mitral (bicuspid) valve on the left and the tricuspid valve on the right. Common atrioventricular canal persistence and abnormal canal division are frequently encountered heart malformations.

At the end of the fourth week, two mesenchymal prominences representing atrioventricular endocardial cushions appear at the upper and lower margins of the atrioventricular canal. Initially, the canal communicates solely with the primitive left ventricle and is separated from the cardiac bulb by the bulboventricular ridge. By the end of the fifth week, the posterior end of this structure reaches near the midpoint of the base of the upper endocardial cushion, appearing less prominent than before. As the atrioventricular canal widens to the right, blood flowing through the atrioventricular orifice gains direct access to both the primitive left and right ventricles.

At the right and left margins of the canal, two lateral atrioventricular cushions, in addition to the upper and lower endocardial cushions, emerge. These cushions project into the lumen, ultimately merging and fully separating the canal into right and left atrioventricular orifices by the end of the fifth week.

Following the fusion process of the atrioventricular endocardial cushions, which results in the formation of the intermediate septum, each atrioventricular orifice is surrounded by local proliferations of mesenchymal tissue. Subsequent resorption and thinning of the tissue on the ventricular surface of these structures, induced by blood flow, lead to the development of atrioventricular valves. These valves remain attached to the ventricular wall through muscular chordae, with the muscular tissue at the chordae level being replaced by dense connective tissue. The valves, now composed of connective tissue covered by endocardium, are connected to the thick trabeculae of the ventricular wall, known as papillary muscles, through chordae tendineae. In the left atrioventricular canal, two valvular leaflets form the bicuspid (mitral) valve, while in the right atrioventricular canal, three valvular leaflets form the tricuspid valve.

The cardiac septum is partially formed by the development of endocardial cushions from the atrioventricular canal, known as atrioventricular endocardial cushions, and prominences in the cono-truncal region, termed cono-truncal prominences.

In the fifth week, a pair of ridges, identified as the endothelial prominences of the arterial trunk, emerges diametrically opposite each other. The upper-right prominence is situated at the upper part of the right wall, while the lower-left prominence is located at the lower part of the left wall. The growth pattern involves the upper-right primordium of the arterial trunk extending distally and to the left, while the lower-left prominence extends distally and to the right. As these prominences develop toward the aortic sac, they twist around each other, establishing the spiral trajectory of the future septum. Following complete fusion of the margins, the aortopulmonary septum forms, dividing the arterial trunk into an aortic canal and a pulmonary canal.

Primordia of the arterial trunk along the right dorsal wall and the left ventral wall of the cardiac conus lead to the creation of two similar conal prominences. These conal prominences grow towards each other and distally, eventually uniting with the septum of the arterial trunk. Upon fusion of the two prominences of the cardiac conus, the formed septum divides the conus into an anterolateral portion (outflow tract of the right ventricle) and a posteromedial portion (outflow tract of the left ventricle).

The endothelial prominences of the cardiac conus and the arterial trunk originate from neural crest cells migrating from the edges of the neural folds in the rhombencephalon region. Abnormalities in the migration, proliferation, or differentiation of these cells can lead to congenital malformations affecting this region, including Tetralogy of Fallot, pulmonary stenosis, common arterial trunk, and transposition of the great vessels. Cases often show simultaneous cardiac and facial malformations in affected individuals, as neural crest cells also contribute to craniofacial development.

The interventricular septum comprises a thick muscular portion and a thin membranous portion formed by the lower atrioventricular endocardial cushion, the right endocardial prominence (ridge) of the cardiac conus, and the left endocardial prominence (ridge) of the cardiac conus. When these three components fail to fuse, the persistence of a common ventricular septal defect occurs, often accompanied by other compensatory defects.

The volume of the primitive ventricles begins to increase at the end of the fourth week through the continuous growth of the myocardium on the exterior and the formation of diverticula and trabeculae on the interior.

The muscular interventricular septum results from the approximation and fusion of the medial walls of the ventricles. However, sometimes the fusion is incomplete, leaving a more or less profound gap in the apical region. The space between the free edge of the muscular ventricular septum and the fused endocardial cushions allows communication between the two ventricles.

The interventricular opening, situated above the muscular portion of the interventricular septum, diminishes with the formation of the cardiac conus septum. Along the upper part of the muscular interventricular septum, the tissue corresponding to the lower endocardial cushion undergoes growth, leading to the complete closure of the interventricular opening. This tissue fuses with the adjacent regions of the cardiac conus septum, resulting in the full closure of the interventricular opening and forming the membranous component of the interventricular septum.

The primordia of the semilunar valves become visible as small tubercles when the septation of the arterial trunk is nearly complete, occurring at the level of the main endocardial prominences of the trunk. There are two pairs of such prominences—one for the aortic canal and another for the pulmonary canal. On both canals, a third tubercle emerges on the opposite side of the endocardial prominences of the trunk. The gradual resorption of tissue from the surface of these tubercles leads to the formation of the semilunar valves, with contributions from cells of the neural crest.

Formation of the heart's conduction system begins with the pacemaker function initially provided by the tissue located in the caudal portion of the left half of the cardiac tube. This role is later assumed by the sinus venosus. As the sinus is integrated into the right atrium, the pacemaker tissue relocates near the opening of the superior vena cava, giving rise to the sinoatrial node.

The atrioventricular node and the His bundle have dual origins: cells from the left wall of the sinus venosus and cells from the atrioventricular canal. Following the incorporation of the sinus venosus into the right atrium, these cells find their final position at the base of the interatrial septum.

Anomalies in heart development can manifest in various ways. In twins, one might encounter acardia, where one twin lacks a heart.

Positional anomalies can lead to dextrocardia, characterized by the bulboventricular loop forming to the left, causing the heart apex to be on the right. This anomaly often accompanies partial or total inversion of thoracic and abdominal viscera, known as situs inversus. Cardiac ectopia may occur due to incomplete or exaggerated descent or a defect in the sternum or pericardium resulting from the non-fusion of lateral folds in the thoracic region during the fourth week. This condition may make the heart partially or completely visible on the surface of the chest.

Internal anomalies arise from septation defects or variations in the number of cavities. Examples include malformations of the endocardial cushions at the atrioventricular orifice, the septum primum failing to fuse with the intermediate septum, a common atrium due to the absence of the interatrial septum, absence of the interventricular septum with a biatrial trilocular heart, and complete transposition of the great vessels associated with septal defects allowing exchanges between systemic and pulmonary circulation.

Multiple anomalies can coexist in the same heart, with Tetralogy of Fallot being a common combination. This condition often involves pulmonary artery stenosis, persistent interventricular opening, right ventricular hypertrophy, and infundibular stenosis (obstruction of blood flow from the right ventricle) with a dextroposed aorta.

References

1. Anatomia Omului, Volumul I: Embriologie; Semestrul I; Prof. univ. dr. med. Andrei Motoc; Editura „Victor Babeș”, Timișoara, 2018

2. Embriologie - Sinteze didactice; Romeo Chiriac, Anca Indrei ;Editura Fundatiei Chemarea, Iasi, 1997

3. Embriologie Umană; Lidia Chircor, Loredana Surdu;Editura Ex Ponto, Constanța, 2014

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