Lecture 3 2020 Cardiology 1

What happens after formation of the trilaminar germ layers?

Embryo growth and differentiation proceed rapidly.

What happens to the lateral mesoderm?

The lateral mesoderm begins to split into parietal and visceral mesoderm.

How does the embryo begin to fold?

The embryo begins to fold in both the cranial-caudal and in the lateral directions, forming the primitive body cavities.

What does lateral folding result in?

Neural tube closure.

Where does the primitive gut tube form?

In the endoderm.

Where do progenitor heart cells come from?

Progenitor heart cells come from the original epiblast, then migrate into the newly formed lateral plate mesoderm cranial to the neural folds.

Note: They form the primary hearth field (PHF)

When does the primary heart field (PHF) form?

They form the primary heart field (PHF) at about days 16-18.

How are the cells of the primary heart field patterned?

These cells are patterned by the laterality forming genes so that even at the stage of the PHF they are already destined for right and left atrial, and right and left ventricular formation.

What shape do these cells form?

These cells form a horseshoe shaped area. It includes the nearby endoderm to form the progenitors of cardiac muscle cells (myoblasts), blood cells and blood vessels.

What does lateral folding do to the two horns of the cardiogenic region?

Lateral folding brings the two horns of the cardiogenic region together, forming the primordial heart tube from progenitor heart cells, in the splanchnic (visceral) layer of the mesoderm of the lateral plate.

Where do these tubes merge together?

These tubes merge together at all but the most caudal end.

What happens to the cranial “bend of the horseshoe”?

The cranial, “bend of the horseshoe” expands to become part of the ventricles and outflow tract.

What does fusion produce?

Fusion produces a single tube with aortic and venous poles.

What type of folding also occurs during formation of the heart? and what does continued bending by the growing neural structures do?

• Cranio-caudal folding also occurs

• Moves the Primary Heart Field from its anterior position to a position within the developing thorax, by about day 21.

What will the SHF contribute to?

This SHF will contribute to formation of the ventricular outflow tracts.

Where do the cells of the secondary heart field arise from?

Neural crest cells.

Where do Neural Crest cells migrate?

Neural Crest cells migrate from the rapidly folding neural tube to the splanchnic mesoderm in front of the pharynx to form the secondary heart field.

What is taking place elsewhere even as the heart and outflow tract are forming?

Vasculogenesis and angiogenesis are taking place elsewhere, paralleling the midline structures of the heart and other developing systems, and forming the primitive dorsal aortae and venous system.

What is vasculogenesis?

Formation of blood vessels de-novo from blood islands.

What is angiogenesis?

New vessels sprout from existing ones.

How does the pericardium begin to form?

The pericardium begins to form from mesothelial cells that overlie the myocardium, and from other cells that originate near the outflow tract structures.

What does angiogenesis result in?

Angiogenesis results in connections of the heart tube to the developing arterial and venous systems at the outflow and atrial ends, respectively.

What is happening to the newly formed cardiac tube at day 21-22?

The newly formed cardiac tube, at this point (day 21-22) is already beating.

Note: Specialized cells already exist that spontaneously depolarize in a rhythmic pattern. The different parts of the heart tube are beginning to differentiate into specialized structures.

What is the next step in the heart’s development?

To loop into the typical heart shape and position.

Where do the atrial (inflow) portions of the heart move?

Cranially and to the (embryo’s) left.

Where does the ventricular region move?

Caudally and to the (embryo’s) right.

When is the basic cardiac morphology shown?

About 28 days, after folding of the cardiac tube is completed.

How are the venous and arterial structures initially arranged? and where do the right and left sinus horns empty?

• Initially, venous and arterial structures are paired.

• Both the right and left sinus horns empty into the common atrium.

What happens to venous flow with further development?

Venous flow shifts completely to the right.

What happens to the left vitelline and umbilical veins and the left sinus horn?

They degenerate.

What does the left sinus horn ultimately become?

The coronary sinus and oblique vein of the left atrium.

What happens to the right sinus horn and veins?

The right sinus horn and veins enlarge secondary to increased blood flow, and form the venae cavae.

What happens once looping of the cardiac tube is complete?

The basic form of the heart is established.

Why is septation necessary?

Septation is necessary to create the left and right atria, ventricles, and the outflow tract

What do endocardial cushions form from? What eventually happens to these endocardial cushions?

• Endothelial-lined endocardial matrix tissue that eventually is filled with both endocardial and neural crest cells.

• These endocardial cushions eventually grow together to create septae and separate the different cardiac chambers.

What does the final atrial septum derive from and what does it create?

Formation of two overlapping septae. Creates a valved opening between the right and left atrial chambers.

What happens first during formation of the atrial Septa?

The septum primum grows downward from the roof of the atrium toward the (fusing) anterior and posterior endocardial cushions.

Because the septum primum is sickle shaped, what remains open?

The ostium primum remains open, and is the last part of the septum to fuse.

Note:

What does apoptosis in the upper portion of the septum result in?When does the ostium secundum form? and What does this maintain?

• Another opening, the ostium secundum.

• Just before the ostium primum closes.

• The open connection between the right and left atria.

Where does the septum secundum start growing?

From the atrial roof toward the endocardial cushions, to the right of the septum primum.

Note: It covers the ostium secundum, but never completely closes it.

What is the net result of atrial septation?

A valve-closed foramen ovale.

What does the foramen ovale allow during fetal circulation? and What happens to the foramen ovale after birth?

• Free passage of blood from right to left during fetal circulation.

• Closes shut with increased left sided pressures after birth, preventing left to right shunting after the fetal period.

How does the ventricular septum form?

• The muscular portion (inferiorly) forms as the ventricular walls grow together and fuse.

• There is a crescentic interventricular foramen present until about week 7.

What closes the interventricular foramen?

Formation the membranous portion of the interventricular septum closes the interventricular foramen.

What structures are involved in this complex process?

A portion from the endocardial cushion, and portions from the right and left bulbar ridges as they form to partition the outflow tract.

How are the AV valves, papillary muscles, and chordae tendineae formed, and what do the chordae tendineae attach?

• Endocardial cushion tissue, under the influence of specific growth factors, transforms into mesenchymal fibrous tissue contributing to the formation of the AV valves.

• The myocardial tissue of the ventricular walls cavitates and breaks down to form the papillary muscles and chordae tendineae.

• The chordae tendineae attach the papillary muscles to the AV valves.

Where do cells from the neural crest migrate, what do they contribute to, and what does this explain?

Cells from the neural crest migrate to the cono-truncal area and contribute to the formation of the outflow tract and the face and skull. This explains the coexistence of some congenital cardiac conditions and cranio-facial abnormalities.

How is the outflow tract formed?

• Ridges form in the bulbus cordis and the truncus arteriosus. These ridges begin to grow together, and downward (caudally). They fuse with the anterior endocardial cushion to form the outflow tract and complete the partitioning of the ventricles.

• These ridges grow from cells in the secondary heart field, which derive from neural crest cells.

What happens as the outflow tract ridges grow?

As they grow, they spiral 180 degrees, bringing the pulmonary outflow tract anteriorly to exit from the right ventricle, and the aorta rotates posteriorly to exit the left ventricle.

How are the pulmonary and aortic valves formed?

The semilunar valves form as the outflow tract partitioning is nearing completion. These valves form from valve swellings in the walls of the outflow tract that then remodel and hollow out to form the thin walled valves.

How can atrial septal defects (ASDs) occur?

ASDs can occur due to failure of either the septum primum or septum secundum to form properly, including absence of septum secundum or excessive resorption of septum primum.

How can ventricular septal defects (VSDs) occur, and which type is more clinically significant?

VSDs can occur due to defects in either the muscular or membranous portions of the interventricular septum. Membranous defects are less common (20% vs 80%) but are usually more significant clinically.

What defects can occur from abnormal conotruncal septation?

Transposition of the great vessels occurs when the outflow tract fails to spiral properly. Tetralogy of Fallot—VSD, overriding aorta, pulmonary stenosis, and right ventricular hypertrophy—is a result of anterior displacement of the conotruncal septum.