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Embryology of the heart

Contents

Introduction

For thousands of years, the heart has been considered one of the most important organs in the body. Aristotle even believed that other organs existed just to cool it, including the brain and lungs (which we now know perform their own vital functions). Although it may not be exactly as Aristotle once thought, the heart does perform a role that is absolutely necessary for survival. Every part of the body depends on the heart’s ability to pump, every second of every minute of every day, starting before we are even born. In fact cardiovascular system is the first major system to function in the embryo.

Heart (Anterior vein of right ventricle in green) - ventral view

The heart tube and embryonic vessels

Development of the heart begins in the third week with the formation of two endothelial strands called the angioblastic cords. These cords canalize forming two heart tubes, which fuse into single heart tube by the end of the third week due to lateral embryonic folding. By the fourth week, the developing heart receives blood from three pairs of veins: the vitelline veins, umbilical veins, and common cardinal veins. The vitelline veins carry poorly oxygenated blood from the yolk sac, and enter the sinus venosus; the umbilical veins carry oxygenated blood from the chorion, the primordial placenta; and the common cardinal veins carry poorly oxygenated blood from the rest of the embryo.

As the primordial liver develops in close association with the septum transversum, the hepatic cords join and surround epithelial-lined spaces, forming the primordial hepatic sinusoids. These primordial sinusoids become connected to the vitelline veins. Vitelline veins pass through the septum transversum and enter sinus venosus, also called as venous end of the heart. Left vitelline veins regress while right vitelline veins form the hepatic veins, and a network of vitelline veins around the duodenum form the portal vein.

As the development of liver progresses, umbilical veins lose connection with heart and empty into liver. The right umbilical vein and cranial part of the left umbilical vein degenerate during seventh week of gestation, leaving only the caudal part of the left umbilical vein. The caudal part of the left umbilical vein carries oxygenated blood to the embryo from the placenta. The umbilical vein is connected to the inferior vena cava (IVC) via the ductus venosus, a venous shunt that develops in the liver. This bypass directs most of the blood directly to the heart from placenta without passing through liver.

Umbilical vein - ventral view

The embryo is drained primarily by the cardinal veins, with the anterior cardinal vein draining the cranial part of the embryo and the posterior cardinal vein draining the caudal part. These two join to form the common cardinal vein, which enters the sinus venosus.

By the eighth week, the anterior cardinal veins are connected by a vessel running obliquely between them. This oblique vessel allows for the shunting blood from the left anterior cardinal vein to the right. Once the caudal part of the left anterior cardinal vein degenerates, this oblique anastomotic vessel becomes the left brachiocephalic vein. The right anterior cardinal vein and right common cardinal vein eventually become the superior vena cava (SVC), and the posterior cardinal veins contribute to the common iliac veins and the azygos vein.

As the subcardinal and supracardinal veins form, they first supplement but soon replace the posterior cardinal veins. The subcardinal veins appear first, and eventually form parts of the left renal vein, suprarenal vein, gonadal vein, and inferior vena cava (IVC). Above the kidneys, anastomoses join the supracardinal veins, forming the azygos and hemiazygos veins. Below the kidneys, the right supracardinal vein contributes to IVC, while the left supracardinal vein degenerates.

In the fourth and fifth weeks of development, the pharyngeal arches form. These are supplied by the pharyngeal arch arteries, which connect the aortic sac to the two dorsal aortae. The dorsal aortae extend the length of the embryo, eventually fusing in the caudal part of the embryo to form the lower thoracic/abdominal aorta. The rest of the right dorsal aorta degenerates, while the remainder of the left dorsal aorta becomes the primordial aorta.

The dorsal aortae give off the intersegmental arteries, which supply the  somites and their derivatives. These intersegmental arteries become the vertebral arteries in the neck region, the intercostal arteries in the thorax, the lumbar arteries and common iliac arteries in the abdomen, and the lateral sacral arteries in the sacral region. The very caudal end of the dorsal aorta gives rise to the median sacral artery, and any other intersegmental arteries regress.

The umbilical vesicle (i.e. yolk sac), allantois, and chorion are supplied by unpaired branches of the dorsal aorta. The umbilical vesicle is supplied by the vitelline arteries, and once part of the umbilical vesicle forms the primordial gut, this region is supplied by the vitelline arteries as well. The vitelline arteries give rise to the celiac artery, which supplies the foregut; the superior mesenteric artery, which supplies the midgut; and the inferior mesenteric artery, which supplies the hindgut.

The two umbilical arteries, contained within the umbilical cord, carry poorly oxygenated blood from the embryo to the placenta. The proximal part of these arteries become the internal iliac and superior vesical arteries, while the distal parts regress and become the medial umbilical ligaments.

Development of the layers of the heart

As the heart tubes fuse, the primordial myocardium begins to form from the splanchnic mesoderm around the pericardial cavity. This primordial myocardium becomes the middle, muscular layer of the heart. Separated from the primordial myocardium by gelatinous tissue called cardiac jelly, the heart begins to develop as a thin tube. This endothelial tube becomes the endocardium, the innermost layer of the heart. Epicardium, the outermost layer, originates from mesothelial cells from the outer surface of the sinus venosus.

Heart - histological slide

Growth and folding of the heart tube

As the cranial part of the embryo folds, the heart tube elongates. As it elongates, the heart tube develops alternating constrictions and expansions, forming the bulbus cordis, ventricle, atrium, and sinus venosus. The bulbus cordis has multiple components, including the truncus arteriosus, conus arteriosus, and conus cordis. The truncus arteriosus is cranial to the aortic sac, to which it is connected, and gives off the pharyngeal arch arteries. Blood leaves the heart via the pharyngeal arch arteries, and returns to the sinus venosus of the heart via the umbilical, vitelline, and common cardinal veins. The bulbus cordis and ventricles grow at a faster rate than other parts of the developing heart, and because of this the heart bends and folds in on itself, forming the bulbo-ventricular loop. As this bending occurs, the atrium and sinus venosus move so that they are dorsal to the truncus arteriosus, bulbus cordis, and ventricle. During this time, the sinus venosus also develops lateral extensions, the left and right horns.

The heart is initially attached to the dorsal wall of the pericardial cavity by a mesentery called the dorsal mesocardium, but as the heart grows it begins to fill the pericardial cavity and the central part of the dorsal mesocardium degenerates. The loss of part of this mesentery allows a communication to form between the left and right sides of the pericardial cavity, the transverse pericardial sinus.

Circulation of blood through the primitive heart

The sinus venosus receives blood from the common cardinal veins, umbilical veins and vitelline veins. The common cardinal veins carry blood from the embryo; the umbilical veins carry blood from the placenta; and the vitelline veins carry blood from the umbilical vesicle.

After entering the sinus venosus, blood flows through the sinuatrial valves into the primordial atrium. It then flows from the primordial atrium into the primordial ventricle via the atrioventricular (AV) canal. When the primordial ventricle contracts, it pumps blood into the bulbus cordis and through the truncus arteriosus, into the aortic sac. From there, blood enters the pharyngeal arch arteries, and then the dorsal aortae, which allows it to travel back to the embryo, placenta, and umbilical vesicle.

Partitioning of the developing heart

In the middle of the fourth week, the atrioventricular canal, primordial atrium and ventricle start to partition, and this process is completed by the end of week eight. It begins with the formation of the endocardial cushions, specialized extracellular matrix tissue related to myocardial tissue. At the end of the fourth week, these cushions appear on the ventral and dorsal walls of the AV canal and start to grow toward each other. They eventually fuse, separating the AV canal into left and right components, partially separating the atrium and ventricle and acting as AV valves.

The primordial atrium becomes separated into the right and left atria by two septa, the septum primum and septum secundum. The septum primum appears first in the form of a thin membrane, growing out of the roof of the primordial atrium toward the endocardial cushions, leaving an opening between its edge and endocardial cushion. This opening is called the foramen primum, and it allows blood to continue to be shunted from the right atrium to the left. It progressively shrinks and eventually closes as the septum primum elongates and fuses with the endocardial cushions, forming the primordial AV septum. Before the foramen primum closes completely, however, apoptosis of cells in the middle of the septum primum forms perforations in the septum. These perforations form a new second opening, the foramen secundum, which allows oxygenated blood to continue to flow from the right atrium to the left even after the foramen primum has closed.

The muscular septum, the septum secundum, grows immediately adjacent to the septum primum, just to its right. It grows downward from the ventro-cranial wall of the atrium during the fifth and sixth weeks of development, gradually overlapping the foramen secundum in the septum primum. By overlapping the foramen secundum without fusing to the septum primum, an incomplete barrier between the atria is formed. At this point in development, the opening between the atria is called the foramen ovale, and it allows oxygenated blood to continue to flow from the right atrium, under the flap of the septum secundum, through the foramen secundum, and into the left atrium. This arrangement also prevents blood from flowing in the opposite direction, from the left atrium to the right atrium: the thin septum primum gets pressed up against the more firm and inflexible septum secundum, blocking blood from flowing through the foramen ovale. Although the cranial part of the septum primum slowly regresses, some parts of the septum primum remain attached to the endocardial cushions. These residual parts of the septum primum form the valve of the foramen ovale.

Valve of foramen ovale - lateral-left view

After a baby is born, the pressure in the left atrium increases significantly, becoming much higher than the pressure in the right atrium. This causes the septum primum to be pushed against the septum secundum and the valves of the foramen primum to fuse with the septum secundum, functionally closing the foramen ovale. When this occurs, the foramen ovale becomes the fossa ovalis and the two septae form a complete barrier between the atria.

Fossa ovalis of the heart - lateral-right view

The sinus venosus, its derivatives, and development of the right atrium

The sinoatrial orifice, the opening of the sinus venosus into the single primordial atrium, is initially located in the posterior wall of the primordial atrium. This changes, however, at the end of the fourth week, when the right sinual horn grows larger than the left. This unequal growth moves the sinuatrial orifice to the right, shifting it into what will become the adult right atrium. As the right sinual horn continues to grow, blood from the head and neck region of the embryo flows into it via the SVC, and blood from the placenta and the rest of the body of the embryo flows into it via the IVC. As the heart continues to develop, the sinus venosus gets integrated into the wall of the right atrium as the smooth part of the internal surface of the right atrium, the sinus venarum. The rest of the internal surface of the right atrium and auricle has a thicker, trabeculated appearance; these parts of the adult atrium originate from the primordial atrium. The transition from the smooth to the rough internal surface of the right atrium is demarcated on the inside of the atrium by a ridge called the crista terminalis, which originates from the cranial part of the right sinoatrial valve, and on the outside by a groove called the sulcus terminalis. The caudal part of the right sinoatrial valve forms the valves of the IVC and coronary sinus.

The left sinual horn develops into the coronary sinus; and the left sinuatrial valve eventually fuses with the septum secundum, becoming part of the interatrial septum.

Interatrial septum - lateral-right view

The primary pulmonary vein, its derivatives, and development of the left atrium

The majority of the inner wall of the left atrium is smooth and is derived from the primordial pulmonary vein, which develops from the dorsal atrial wall just left of the septum primum. As the left atrium grows, the primordial pulmonary vein, as well as its main branches, become integrated into the atrial wall. This results in four pulmonary veins entering into the left atrium. The left auricle has the same origin as the right auricle: the primordial atrium. As such, its internal surface is trabeculated.

Development of the ventricles

The primordial ventricle begins its division into two ventricles with the growth of the median ridge, a muscular interventricular (IV) septum with a superior free edge that arises from the floor of the primordial ventricle, close to the apex of the heart. Dilation of the developing ventricles on either side of this septum is responsible for the initial increase in the septal height, with additional growth occurring due to the contribution of ventricular myocytes from both sides of the heart.

Between the upper free edge of this septum and the endocardial cushions, there remains an opening called the IV foramen. This foramen allows blood to continue to flow between the right and left ventricles until its closure at the end of the seventh week, when the left and right bulbar ridges fuse with the endocardial cushion, forming the membranous part of the IV septum. The bulbar ridges form in the fifth week as proliferations of mesenchymal neural crest cells in the walls of the bulbus cordis. The membranous part of the IV septum results when tissue from the right side of the endocardial cushion extends to the muscular part of the IV septum, ultimately merging with the aorticopulmonary septum and muscular IV septum. Once the IV foramen closes and the membranous part of the IV septum forms, the aorta becomes the sole outflow tract of the left ventricle, and the pulmonary trunk becomes the sole outflow tract of the right ventricle. As the ventricles continue to develop, cavitation results in the formation of muscular bundles. While some of these persist as trabeculae carneae (irregular columns of muscle on the inner surface of the ventricles), others form the papillary muscles and chordae tendinae (heart strings), which connect the papillary muscles to the AV valves.

Posterior papillary muscle - lateral-left view

The bulbus cordis and truncus arteriosus

In the truncus arteriosus, ridges similar to, and continuous with, the bulbar ridges form from mesenchymal neural crest cells. The migration of these cells is induced by bone morphogenic protein (BMP) and other signaling pathways. These bulbar and truncal ridges spiral 180-degrees. Fusion of these ridges forms a spiral aorticopulmonary septum that divides the bulbus cordis and truncus arteriosus into the aorta and pulmonary trunk.

As the heart continues to develop, the bulbus cordis becomes integrated into the ventricular walls as the smooth parts of the ventricles. In the right ventricle, the bulbus cordis becomes the conus arteriosus, which contributes to the pulmonary trunk; and in the left ventricle, the bulbus cordis becomes the aortic vestibule, the region of the left ventricle just inferior to the aortic valve.

Formation of the cardiac valves

The aortic and pulmonic semilunar valves each develop from three swellings of subendocardial tissue present around the opening of aorta and pulmonary trunk. They evolve into three thin cusps.

Anterior cusp of mitral valve - cranial view

The tricuspid and mitral AV valves form from proliferations of tissue surrounding the AV canals. The tricuspid valve develops three cusps, whereas the mitral (i.e. bicuspid) valve develops two.

Development of the conducting system

Initially, the primordial atrium functions as the developing heart’s pacemaker; but the sinus venosus soon takes over this role. In the fifth week, the sinoatrial (SA) node develops in the right atrium near the opening of the SVC. After the sinus venosus is integrated into the heart, cells from its left wall can be found near the opening of the coronary sinus, at the base of the interatrial septum. With the addition of some cells from the AV region, the AV node and bundle are formed just above the endocardial cushions. Fibes originating from the AV bundle project from the atrium into the ventricle and divide into left and right bundle branches, which can be found throughout the ventricular myocardium. Although the SA node, AV node, and AV bundle eventually receive nervous innervation from outside the heart, the primordial conducting system develops before this occurs.

Heart conductive system - histological slide

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Show references

References:

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Article, Review and Layout:

  • Nadia Solomon
  • Uruj Zehra
  • Adrian Rad

Illustrators:

  • Heart (Anterior vein of right ventricle in green) - ventral view - Yousun Koh
  • Umbilical vein - ventral view - Irina Münstermann
  • Heart - histological slide - Smart In Media
  • Valve of foramen ovale - lateral-left view - Yousun Koh
  • Fossa ovalis of the heart - lateral-right view - Yousun Koh
  • Interatrial septum - lateral-right view - Yousun Koh
  • Posterior papillary muscle - lateral-left view - Yousun Koh
  • Anterior cusp of mitral valve - cranial view - Yousun Koh
  • Heart conductive system - histological slide - Smart In Media
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