11. Formation and derivatives of the heart tube. Partitioning of the cardiac chambers. Malformations

Fun fact: this topic took 211 minutes to write.

Learning objectives

  • Describe the structure of the heart tube, and what arises from its different parts
  • What is the primary heart field?
  • What is the secondary heart field?
  • What is the origin of endocardium, myocardium, and epicardium?
  • What is the role of lateral folding in the development of the heart?
  • What is cardiac looping?
  • Describe the origin of the different parts of the atria
  • Describe the formation of the interatrial septum
  • Describe the formation of the pulmonary veins
  • Describe the formation of the atrioventricular valves
  • Describe the formation of the ascending aorta and pulmonary trunk
  • Describe the formation of the outflow tracts of the ventricles
  • Describe the formation of the interventricular septum
  • Name some teratogens known to cause heart defects
  • What is patent foramen ovale?
  • What is dextrocardia, and why does it occur?
  • What is total anomalous pulmonary venous return?
  • What is an atrial septal defect?
  • What is a ventricular septal defect?
  • What is tetralogy of Fallot, and why does it occur?

Formation of the heart tube

The structure and derivatives of the heart tube

From cranial to caudal, the heart tube consists of five parts:

  • Truncus arteriosus
  • Bulbus cordis
  • Primitive ventricle
  • Primitive atrium
  • Sinus venosus

The truncus arteriosus is continuous with the aortic sac cranially, from which the aortic arches develop. It gives rise to the ascending aorta and the pulmonary trunk.

The bulbus cordis connects the primitive ventricle to the truncus arteriosus. It gives rise to the outflow tracts of the left and right ventricles.

The primitive ventricle gives rise to the trabeculated part of the ventricles, while the primitive atrium gives rise to the trabeculated part of the atria.

The sinus venosus has a right and a left horn, from which the heart tube receives venous blood. Each horn receives blood from three veins: the vitelline, umbilical, and common cardinal veins. The right horn gives rise to the smooth part of the right atrium while the left horn gives rise to the coronary sinus.

The primary heart field

Around day 16 a type of stem cell called heart progenitor cells migrate through the primitive streak and settle in the splanchnic mesoderm cranially to the neural folds. Here, they form a horseshoe-shaped region called the primary heart field.

The primary heart field gives rise to part of the atria and the left ventricle.

The secondary heart field

A secondary heart field is also formed by heart progenitor cells, but it lies more caudally, closer to the floor of the pharynx.

The secondary heart field gives rise to the rest of the atria, the right ventricle, and the truncus arteriosus.

Formation of the tube itself

Some of the heart progenitor cells in the primary heart field differentiate into blood islands, while some differentiate into cardiac myoblasts. The blood islands give rise to blood cells and vessels, which will fuse to form a horseshoe-shaped tube, which the myoblasts surround. At this point this region is know as the cardiogenic region.

After the lateral folding at around day 22, the two sides of the horse-shoe fuse and form a single heart tube. The heart tube consists of an inner endothelial lining and an outer myocardial layer. Venous blood enters at the caudal end, and the heart pumps blood out of the cranial end. The heart begins to beat at approximately day 21.

Formation of the epicardium

Mesenchymal cells located in the dorsal mesocardium, the mesoderm which attaches the heart tube to the dorsal side of the pericardial cavity, form the proepicardial organ. This organ proliferates and migrates over the surface of the myocardium, where it will form the epicardium. At this point the heart tube has three layers.

Cardiac looping

The straight heart tube undergoes cardiac looping during week 4, due to the continuous elongation of the heart tube. During this process, the heart tube folds onto itself, forming the cardiac loop. This establishes the normal left-right axis of the heart, causing the heart to assume its position in the left part of the thorax, with the atria lying more posteriorly and the ventricles lying more anteriorly. The heart now has its characteristic shape when viewed from the outside, but on the inside it’s still a linear tube, with one atrium and one ventricle.

Molecular regulation of heart development

Endoderm lying anteriorly to the heart progenitor cells induce the development of the heart. The endoderm secretes a signalling molecule called BMP. This molecule induces NKX2.5, the master gene for heart development.

Formation of the atria

The right horn of the sinus venosus forms the smooth-walled part of the right atrium, while the smooth-walled part of the left atrium arises from the pulmonary vein. The smooth-walled part is separated from the trabeculated part of the atria by the crista terminalis. The trabeculated parts of the atria, the atrial appendages, arise from the primitive atrium.

Septum primum

The septum primum grows from the roof of the common atrium towards the floor and divides the atrium in two. However, it leaves a small lumen between the atria called the ostium primum. Blood can still travel between the ventricles through this opening.

Another lumen opens in the septum primum as some of its cells die by programmed cell death. This lumen is the ostium secundum. The ostium primum then closes as the septum primum fuses completely with endocardial cushions.

Septum secundum and foramen ovale

A second interatrial septum forms next to the first one. This is the septum secundum. This septum doesn’t fuse completely, allowing an opening to remain. This opening is called the foramen ovale. Blood will flow from the right atrium through the foramen ovale and the ostium secundum into the left atrium.

At birth the pressure inside the left ventricle increases, causing the septum primum and septum secundum to press against each other. This closes the ostium secundum and foramen ovale, leaving only the fossa ovalis where the foramen ovale was. The two atria are now completely separated with no communication between them.

Pulmonary veins

The pulmonary veins arise from the dorsal mesocardium. Mesenchymal cells in the dorsal mesocardium form a dorsal mesenchymal protrusion, in which a pulmonary vein develops. The dorsal mesenchymal protrusion protrudes into the left atrium while the septum primum grows, “depositing” the pulmonary vein in the left atrium. The pulmonary vein then branches, forming four veins.

Formation of the atrioventricular valves

The atrioventricular valves form as four so-called endocardial cushions grow from the walls of the atrioventricular canal and fuse with each other. Fusion of the superior and inferior endocardial cushions divides the common atrioventricular canal into two separate canals, one right and one left.

Endocardial cushions in the left atrioventricular canal fuse and form the mitral valve, while cushions in the right canal fuse and form the tricuspid valve. The valves become fibrous an remain attached to the papillary muscles of the ventricular wall by the chordae tendinae.

Formation of the ascending aorta and the pulmonary trunk

During week 5 pairs of opposing ridges called the truncus swellings appear in the truncus arteriosus. These swellings grow spirally toward the aortic sac, twisting around each other, before they fuse and form the aorticopulmonary septum. This septum divides the truncus arteriosus into the ascending aorta and the pulmonary trunk.

Formation of the ventricles

The trabeculated part of the ventricles arise from the primitive ventricle, while the outflow tracts arise from the conus cordis, the cranial end of the bulbus cordis.

Outflow tracts

The conus cordis is divided into the outflow tracts of the two ventricles by the conus swellings. These swellings develop along the walls of the conus cordis. After fusing together, these swellings separate the conus cordis into the outflow tract of the right ventricle and the outflow tract of the left ventricle.

Interventricular septum

The interventricular septum consists of a thick muscular part and a thin membranous part. The muscular part forms when the medial walls of the expanding ventricles merge, but it leaves an interventricular foramen superiorly.

After formation of the aorticopulmonary septum the septum will grow inferiorly and eventually fuse with the muscular part of the interventricular septum. This closes the interventricular foramen and gives rise to the membranous part of the interventricular septum.

Semilunar valves

The semilunar valves form from tubercles found on the truncus swellings.

Malformations

Causes of cardiac malformations

Cardiac malformations, commonly known as heart defects, are the most common type of birth defects. They can occur in infants with other malformations as well, but often occur alone.

Multiple teratogens are known to cause heart defects, including the rubella virus, thalidomide, retinoic acid (RA), alcohol, and maternal diabetes.

Patent foramen ovale

Patent foramen ovale (PFO) refers to a foramen ovale which doesn’t close at or soon after birth and instead remains open. This is very common, occurring in 20 – 30% of the population. This is usually asymptomatic, but this opening from the right heart to the left allows for blood clots from the venous system to enter the arterial system, a phenomenon called paradoxical embolism.

Dextrocardia

Dextrocardia refers to the presence of the heart of the right side of the thorax instead of the left. This occurs due to the heart tube looping incorrectly during cardiac looping. Dextrocardia may occur alone or with situs inversus, where all organs are mirrored.

Total anomalous pulmonary venous return

Total anomalous pulmonary return (TAPVR) is a heart defect where the pulmonary veins drain to the systemic venous circulation (e.g. the vena cava) instead of the left atrium. This defect is only compatible with life if the infants also has an atrial or ventricular septal defect, which is necessary for blood to enter the left heart.

Atrial septal defect

An atrial septal defect (ASD) is a heart defect where there is an opening in the interatrial septum. This occurs most commonly due to the ostium secundum not closing.

Ventricular septal defect

A ventricular septal defect (VSD) is a heart defect where there is an opening in the interventricular septum. It’s the most common congenital cardiac malformation. Most defects close spontaneously as the child grows.

Tetralogy of Fallot

Tetralogy of Fallot (ToF) is a heart defect caused by anterior displacement of the aorticopulmonary septum, causing unequal division of the truncus arteriosus. This causes four separate malformations, hence the name “tetralogy”:

  • Pulmonary infundibular stenosis (narrow right ventricular outflow tract)
  • Ventricular septal defect
  • An overriding aorta
  • Right ventricular hypertrophy

Persistent truncus arteriosus

Persistent truncus arteriosus is a heart defect caused by failure of the truncus swellings to form. As such, the truncus arteriosus is never divided into pulmonary trunk and aorta.

Summary

  • Describe the structure of the heart tube, and what arises from its different parts
    • From cranial to caudal:
    • Truncus arteriosus
      • -> ascending aorta and pulmonary trunk
    • Bulbus cordis
      • -> outflow tracts of the ventricles
    • Primitive ventricle
      • -> trabeculated parts of ventricles
    • Primitive atrium
      • -> trabeculated parts of atria
    • Sinus venosus
      • Left horn -> coronary sinus
      • Right horn -> smooth part of atrium
  • What is the primary heart field?
    • A horseshoe-shaped region of heart progenitor cells inside splanchnic mesoderm
  • What is the secondary heart field?
    • A region of heart progenitor cells which lie more caudally than the primary field
  • What is the origin of endocardium, myocardium, and epicardium?
    • Heart progenitor cells -> blood islands -> endocardium
    • Heart progenitor cells -> myoblasts -> myocardium
    • Mesenchymal cells of dorsal mesocardium -> proepicardial organ -> epicardium
  • What is the role of lateral folding in the development of the heart?
    • During lateral folding the two sides of the horseshoe-shaped heart tube will fuse into a single heart tube
  • What is cardiac looping?
    • A process where the heart loops onto itself during week 4, causing it to assume its normal position in the thorax and the normal organization of the heart chambers
  • Describe the origin of the different parts of the atria
    • Right horn of sinus venosus -> smooth part of right atrium
    • Pulmonary vein -> smooth part of left atrium
    • Primitive atrium -> trabeculated part of both atria
  • Describe the formation of the interatrial septum
    • First the septum primum forms, leaving the ostium primum
    • Then the ostium secundum forms in the septum primum
    • Then the ostium primum closes
    • Then the septum secundum forms, leaving the foramen ovale
    • At birth the foramen ovale closes as the septum primum and secundum press against each other
  • Describe the formation of the pulmonary veins
    • Pulmonary vein originates in the dorsal mesenchymal protrusion of the dorsal mesocardium, which protrudes into the left atrium
    • The pulmonary vein then branches into four
  • Describe the formation of the atrioventricular valves
    • AV valves form as endocardial cushions grow and fuse together
  • Describe the formation of the ascending aorta and pulmonary trunk
    • Truncus swellings in the truncus arteriosus grow spirally toward the aortic sac, eventually fusing and forming the aorticopulmonary septum
    • This divides the truncus arteriosus into the ascending aorta and the pulmonary trunk
  • Describe the formation of the outflow tracts of the ventricles
    • These tracts are formed as conus swellings develop along the walls of the conus cordis and fuse together
  • Describe the formation of the interventricular septum
    • The muscular part of the septum forms when the medial walls of the expanding ventricles merge
    • The membranous part forms when the aorticopulmonary septum grows inferiorly and fuses with the muscular part
  • Name some teratogens known to cause heart defects
    • Rubella virus, thalidomide, retinoic acid (RA), alcohol, and maternal diabetes
  • What is patent foramen ovale?
    • A foramen ovale which doesn’t close at or soon after birth
    • It’s present in 20 – 30% of the population
  • What is dextrocardia, and why does it occur?
    • It’s a condition where the heart lies on the right side of the thorax
    • It occurs due to incorrect cardiac looping
  • What is total anomalous pulmonary venous return?
    • A condition where the pulmonary veins don’t drain into the left atrium
  • What is an atrial septal defect?
    • A condition where there is a defect in the interatrial septum
  • What is a ventricular septal defect?
    • A condition where there is a defect in the interventricular septum
  • What is tetralogy of Fallot, and why does it occur?
    • A condition caused by anterior displacement of the aorticopulmonary septum, causing four malformations:
    • Pulmonary infundibular stenosis (narrow right ventricular outflow tract)
    • Ventricular septal defect
    • An overriding aorta
    • Right ventricular hypertrophy

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