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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

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

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

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

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

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

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

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

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

Heart conductive system - histological slide

Clinical Notes

Sudden infant death syndrome

Sudden infant death syndrome (SIDS) or “crib death” describe the unexpected death of a seemingly healthy infant, typically within the first year of life. It is a diagnosis of exclusion: the cause of an unexpected infant death may be identified as SIDS only after all other explanations have been effectively ruled out. SIDS can be associated with a number of factors, with some suggested causes including abnormalities in brainstem development, abnormalities in neuroregulation of cardio-respiratory control, and abnormalities of the heart’s electrical conducting system.

Dextrocardia

When the heart develops normally, it lies more on the left side with the apex pointing left. In dextrocardia, this positioning is reversed: the heart is located more to the right with the apex pointing right and all the vessels reversed, as if the heart and its vessels developed as a mirror image of a normal heart.

This is the most common positional abnormality of the heart, and occurs when the heart tube bends to the left instead of to the right, displacing the heart to the right. This may occur with or without situs inversus, in which the positions of the major abdominal organs are reversed or mirrored as well (i.e. the liver develops on the left side instead of the right, the stomach develops on the right side instead of the left, etc.). In either case, this condition is not typically associated with other cardiac defects.

Ectopia cordis

Ectopia cordis is a very rare congenital condition in which the heart ends up outside of the thoracic cavity. This occurs when lateral folds fail to fuse to form the thoracic wall during the fourth week, resulting in abnormal development of the sternum and pericardium. Most affected infants die shortly after birth due to cardiac failure, hypoxemia, or infection, but surgery can be attempted as long as there are no severe cardiac defects. This intervention involves covering the heart with skin.

Atrial septal defects

An atrial septal defect (ASD) allows for left to right shunting of blood: oxygenated blood from the left atrium is able to flow into the right atrium, where it mixes with poorly oxygenated blood on the right side before being pumped into the right ventricle and subsequently the pulmonary circulation.

The most common type of ASD is a patent foramen ovale, with a probe patent foramen ovale being present in approximately 25% of the population. When a foramen ovale is probe patent, a probe can be passed from one atrium to the other through the fossa ovalis. A patent foramen ovale results from failure of the flap of the valve of the foramen ovale to fuse with the septum secundum after birth, leaving a communication between the atria. If this opening between the atria is small, the defect is not clinically significant.

There are four types of ASDs that are clinically significant: ostium secundum defect, ostium primum defect (i.e. endocardial cushion defect with a foramen primum defect), sinus venosus defect, and common atrium. Ostium secundum defects are the most common, followed by ostium primum defects.

Ostium secundum ASDs, although common, are one of the least severe forms of congenital heart diseases (CHDs). These occur in the region of the fossa ovalis, and involve defects in the septum primum and septum secundum. Abnormal resorption of the septum primum during the development of the foramen secundum leads to a patent foramen ovale. If the location of resorption is aberrant, the septum primum adopts a fenestrated appearance. If resorption of the septum primum is excessive, the septum primum will be too short to effectively close the foramen ovale. If the septum secundum fails to develop normally and results in the formation of an atypically large foramen ovale, it may be too large to be closed by a normal-sized septum primum. Very large ostium secundum ASDs may result from a combination of these developmental defects.

Ostium primum ASDs occur when the septum primum fails to fuse with the endocardial cushions, leaving a patent foramen primum. A cleft in the anterior cusp of the mitral valve tends to co-occur.

Sinus venosus ASDs form in the interatrial septum near the entry of the SVC. These can be due to incomplete resorption of the sinus venosus within the right atrium, or they can result from maldevelopment of the septum secundum.

A common atrium occurs when there is complete absence of interatrial septum, it might be due to combination of ostium secundum, ostium primum, and sinus venosus defects.

ASDs vary in severity from clinically insignificant and asymptomatic until late in adult life to potentially life-threatening. Different signs and symptoms include:

  • shortness of breath on exertion
  • easy fatigability
  • edema of the lower limb or abdomen
  • frequent respiratory infections
  • palpitations

ASDs are also associated with a murmur which is widely split and a fixed second heart sound (S2). The left to right shunt moves blood from the left atrium to the right atrium, increasing atrial and ventricular volumes on the right side. This increases the amount of blood flowing through the pulmonic valve and into the pulmonary circulation, which results in a delay in the closure of the pulmonic valve. Unlike in normal physiological splitting, with an ASD closure of the pulmonic valve is significantly delayed regardless of breath (the delay is the same during inhalation and exhalation).

ASDs tend to occur more frequently in females. Down syndrome (trisomy 21) is also associated with ASDs, particularly ostium primum defects.

Ventricular septal defects

A ventricular septal defect (VSD) is the most common type of CHD accounting for approximately 25% of cases. Most VSDs occur in the membranous part of the IV septum. They can also occur in the muscular part of the IV septum, but this is less common. Small VSDs often close on their own during the first year of life, while larger VSDs can remain and allow shunting of oxygenated blood from the left ventricle to the right ventricle, with more shunting in larger VSDs. Infants with severe VSDs often have other cardiac anomalies as well, including transposition of the great arteries or an underdeveloped outlet chamber; and, like ASDs, VSDs are associated with Down syndrome. On cardiac auscultation, VSD presents with a harsh holosystolic murmur that is loudest at the tricuspid area, the fourth intercostal space at the left sternal border.

Patent ductus arteriosus

A patent ductus arteriosus (PDA) occurs when the ductus arteriosus, which usually closes shortly after birth and forms the ligamentum arteriosum, fails to do so and instead remains open. This creates a left to right shunt, allowing oxygenated blood from the high-pressure aorta to flow into the low-pressure pulmonary artery and mix with poorly oxygenated blood heading to the lungs. This defect tends to occur more frequently in females than males, and is associated with a continuous machine-like murmur that is best heard in the infraclavicular region. PDA can be seen in infants with congenital rubella infection, infants born prematurely or at high altitudes, and infants with particular chromosomal anomalies.

Eisenmenger syndrome

When a left to right shunt (ASD, VSD, PDA) is left uncorrected, Eisenmenger syndrome can eventually result. The increased pulmonary blood flow that results from a left to right shunt leads to remodeling of the right ventricle and pulmonary vasculature, which leads to pulmonary artery hypertension. The subsequently increased pressure in the right ventricle results in right ventricular hypertrophy. Eventually, the increased strength of the hypertrophied right ventricle reverses the shunt so that poorly oxygenated blood from the right heart now moves into the left heart and mixes with oxygenated blood. The increased distribution of poorly oxygenated blood to the body via the systemic circulation leads to late cyanosis.

Persistent truncus arteriosus

A persistent truncus arteriosus occurs when the truncal ridges and aorticopulmonary septum fail to separate the truncus arteriosus into the aorta and pulmonary trunk, creating a right to left shunt. The most common type of persistent truncus arteriosus is a single arterial trunk that gives off the ascending aorta and pulmonary trunk, supplying the systemic, pulmonary, and coronary circulations. This defect always occurs with a VSD, and is one of the main cardiac defects associated with diGeorge (22q11) syndrome.

Transposition of the great arteries

In a normal heart, the aorta arises from the left ventricle and the pulmonary trunk arises from the right ventricle. With transposition of the great arteries, this relationship is reversed: the aorta arises from the right ventricle, and the pulmonary trunk arises from the left ventricle, with the aorta typically lying anterior and to the right of the pulmonary trunk. Because the AV connections tend to be normal--with the right atrium joined to the right ventricle, and the left atrium joined to the left ventricle--the result is a complete separation between the systemic and pulmonary circulations. As such, this condition is incompatible with life unless an ASD (typically a patent foramen ovale), VSD, or PDA is also present, creating a right to left shunt that allows for blood to mix and oxygenated blood to be delivered to the aorta. This results in right ventricular hypertrophy, since the right ventricle in these patients is now part of the high-resistance systemic circuit delivering blood to the body; and left ventricular atrophy, since the left ventricle functions as part of the low-resistance pulmonary circulation.

In affected infants in which the only shunt present is a PDA, surgical intervention will be necessary within days of birth. This is due to the tendency of the ductus arteriosus to close after birth, obliterating the shunt and forming the ligamentum arteriosum.

Transposition of the great vessels is believed to be associated with defective neural crest cell migration, and/or abnormal development of the conus arteriosus during the time that the bulbus cordis is being incorporated into the ventricles. Regardless of the exact cause, the ultimate result is the aorticopulmonary septum failing to spiral.

This is the most common cause of cyanotic heart disease in neonates. It is also frequently seen in infants of mothers who have diabetes.

Unequal division of the truncus arteriosus

Unequal division of the truncus arteriosus results when division of the truncus arteriosus above the level of the valves creates one large artery and one small artery. This leads to misalignment of the aorticopulmonary septum with the IV septum and produces a VSD, which is typically straddled by the larger vessel.

This anomaly is associated with two types of pulmonary stenosis: pulmonary valve stenosis, and infundibular stenosis; both of which may be present in a single patient. In pulmonary valve stenosis, the cusps of the pulmonary valve are fused together. This forms a dome, narrowing the valvular opening. Infundibular stenosis occurs when the conus arteriosus of the right ventricle is unable to fully develop. If the outflow of blood is severely obstructed, hypertrophy of the right ventricle will be observed as well.

Tricuspid atresia

Tricuspid atresia occurs when there is fusion of the tricuspid valve leaflets or absence of the tricuspid valve altogether, such that the AV canal is blocked and blood cannot flow from the right atrium to the right ventricle and into the pulmonary circulation. This typically results in a hypoplastic right ventricle and a hypertrophic left ventricle, and is not compatible with life without the co-occurrence of septal defects, such as an ASD (typically a patent foramen ovale) or VSD, allowing for shunting of blood from the right heart to the left heart. The mixing of poorly oxygenated blood from the right heart with oxygenated blood in the left heart means the body receives blood with a lower oxygen content than normal, which results in cyanosis.

Tetralogy of Fallot

The most common cause of cyanosis in early childhood, Tetralogy of Fallot is a classic constellation of four cardiac anomalies:

  • pulmonary infundibular stenosis
  • an overriding aorta
  • VSD
  • right ventricular hypertrophy – caused by anterior and superior displacement of the infundibular septum

Pulmonary stenosis blocks the right ventricular outflow tract, and the extent of the obstruction is the most important prognostic factor in this condition. The pulmonary trunk also tends to be small, and there may be stenosis of the pulmonary artery as well. The presence of pulmonary stenosis means the right ventricle has to work harder to try to move blood into the pulmonary artery; this results in right ventricular hypertrophy and the shunting of blood through the VSD into the left ventricle. A “tet spell” occurs when right ventricular outflow tract obstruction is aggravated, such as from crying, exercise, or fever. This increases the shunting of blood from the right to the left ventricle, worsening the cyanosis. In response, a child will squat: this increases systemic vascular resistance, which increases left ventricular pressure and decreases the right to left shunt, effectively reducing the cyanosis.

Cyanosis is an important sign of this condition and babies who have tetralogy of Fallot may tire easily while feeding. They are not able to gain weight or grow as quickly as children who have healthy hearts. Diagnosis is usually done in the first week of infancy due to prominent signs and symptoms, and physical examination and certain diagnostic tests confirm the diagnosis. Diagnostic tests include chest X-ray, echocardiography, electrocardiogram, and pulse oximetry. Tetralogy of Fallot is repaired with open heart surgery either soon or later in the infancy.  

Along with persistent truncus arteriosus, Tetralogy of Fallot is associated with diGeorge syndrome (in which case one will also see characteristic facial features, such as wide set eyes).

Total anomalous pulmonary venous return

In total anomalous pulmonary venous return, the pulmonary veins–containing blood recently oxygenated by the lungs–drain into into the right atrium instead of the left. This occurs with either an ASD or PDA, which is necessary to allow blood from the right heart to be shunted to the left in order to maintain cardiac output. Symptoms may appear soon after birth, or they may be delayed depending in part on the blockage of the veins draining towards heart. The defect is typically repaired by open heart surgery in early infancy.

Aortic stenosis and atresia

Aortic stenosis occurs when the edges of the aortic valve leaflets fuse. This forms a dome and reduces the opening through which blood can flow from the left ventricle into the aorta. As a result, the left ventricle must work harder to force blood into the aorta through the narrowed valve, which leads to left ventricular hypertrophy. Aortic stenosis can be congenital, or acquired through damage to the valve and dystrophic calcification (normal calcification of tissues that occurs with aging). The congenital form of aortic stenosis occurs in 3-6% of congenital heart diseases and is more common in males compared to females.

In subaortic stenosis, a ring of fibrous tissue narrows the aorta just below the valve. This tissue is formed during embryonic development, but usually degenerates after the valve forms. Subaortic stenosis occurs when this tissue fails to degenerate.

Aortic atresia occurs when the aortic valve or part of the aorta itself is completely obstructed.

In aortic stenosis, cardiac auscultation reveals a systolic crescendo-decrescendo heart murmur that is loudest at the right sternal border in the second intercostal space.

Coarctation of the aorta

Coarctation of the aorta is a constriction of the aorta seen in 10% of patients with CHDs. There are two main classifications of coarctations: infantile, or preductal; and adult, or postductal.

In infantile coarctations, the aortic arch proximal to the ductus arteriosus is hypoplastic. This results in narrowing of the aorta between the left subclavian artery and the ductus arteriosus, which is often patent. Because the aorta is narrowed proximal to the PDA, pressures in the aorta after the coarctation are reduced; this allows the PDA to deliver poorly oxygenated blood from the right heart and pulmonary artery into the aorta and subsequently the systemic circulation. In response to the increased blood flow, the pulmonary trunk dilates and the right heart becomes hypertrophied.

In adult coarctations, a ridge of tissue forms and constricts the aorta adjacent to the ligamentum arteriosum. This tissue is made up of smooth muscle and elastic fibers that are continuous with the aortic media. This constriction increases the pressure in the vessels proximal to the coarctation, which results in dilation of the aorta and its branches (the brachiocephalic, left common carotid, and left subclavian arteries) and hypertrophy of the left ventricle.

Recent understandings of aortic coarctation suggest that it typically occurs in the form of a discrete narrowing of the proximal thoracic aorta just opposite to the insertion of ductus arteriosus (juxtaductal).

In some cases coarctation of the aorta may be the only CHD, but in most cases it is accompanied by a bicuspid aortic valve. Additionally, co-occurrence with a septal defect, aortic valve stenosis, or mitral valve stenosis is not uncommon, and these cases are referred to as complex coarctations. If a coarctation is severe, infants are more likely to present with tachypnea and physical examination may reveal systolic murmurs and palpable thrills. Because narrowing of the aorta occurs after branching of the brachiocephalic, left common carotid, and left subclavian arteries supplying blood to the head and upper extremities, there is a discrepancy in the blood flow (and therefore blood pressure) between the upper and lower extremities: as a result, pulses below the coarctation are diminished and delayed. Surgical repair is usually performed by 3-5 years of age.

Coarctation of the aorta occurs twice as often in males as females; although the infantile form is also frequently observed in females with Turner syndrome (45 XO), along with a bicuspid aortic valve.

Congenital long QT syndrome

Congenital long QT syndrome is an inherited disorder named for its characteristic electrocardiogram (ECG or EKG) finding of a prolonged QT-interval. This reflects an increase in the amount of time that it takes for cardiac muscle to repolarize between heartbeats, and is due to defects in various ion channels on the cardiac myocytes. This disorder increases the risk of a patient developing a polymorphic ventricular tachycardia (ventricles pumping too quickly) called Torsades de pointes. This condition is very dangerous, as it can potentially lead to ventricular fibrillation, in which electrical signaling occurs at such a rapid rate that the ventricles quiver rather than pump, severely compromising cardiac output. As such, this can lead to sudden cardiac death.

Almost 75% of cases of long QT syndrome are associated with gene mutations. One type of congenital long QT syndrome is Jervell and Lange-Nielsen syndrome, an autosomal recessive condition in which patients experience conduction abnormalities of the heart as well as sensorineural deafness. Another more common type of congenital long QT syndrome is Romano-Ward syndrome, which is inherited in an autosomal dominant manner but is not associated with deafness. Treatment for inherited long QT syndrome can involve medications, medical devices, surgery, or lifestyle changes.

Brugada syndrome

In Brugada syndrome, the heart’s normal rhythm is disrupted. This results in irregular heartbeats and a subsequently heightened risk of developing ventricular tachyarrhythmias, which can lead to syncope (fainting), seizures, and potentially even sudden cardiac death. Patients with this syndrome usually remain asymptomatic; however, arrhythmic complications are observed in 17-42% of the individuals. This is an autosomal dominant condition that tends to be more commonly observed among Asian males. Classic ECG pattern reflects a pseudo-right bundle branch block, with elevations of the ST segment in leads V1-V3 (reflecting abnormalities in the septal and anterior regions of the heart).

Ebstein’s anomaly

Ebstein’s anomaly refers a specific abnormality of the right heart, and represents 0.5% of patients with congenital heart diseases. The main pathology lies in the tricuspid valve, which is displaced downward towards right ventricle. The anterior leaflet also tends to be enlarged. These anomalies typically lead to tricuspid regurgitation, which results in a dilated right atrium and atrialized right ventricle, which is thin and dilated in a manner similar to the atrium. Valvular dysfunction can eventually lead to right heart failure.

The most common clinical presentation of patients with Ebstein’s anomaly is exertional dyspnea, palpitations, and cyanosis. Older children may develop a murmur and arrhythmias. Echocardiography is the primary modality to diagnose the condition. Other heart conditions such as ASD, arrhythmias, and Wolff-Parkinson-White (WPW) syndrome (the presence of an accessory pathway that allows electrical signals to travel directly from the atria to the ventricles, bypassing the AV node) can also be associated.

Genetics and environmental factors are both linked with this syndrome. In some cases, fetal exposure to lithium during pregnancy due to treatment of the mother (for bipolar disorder, for example) can result in Ebstein’s anomaly in the infant.

Clinical case

An infant is born to a young woman who recently immigrated to the United States. She notes no complications during her pregnancy, except for a brief period early on when she experienced a fever and some joint pain for a few days. Examination of the infant reveals cataracts and a rash of bluish spots. The doctor also notices that the infant does not respond strongly to sound, and cardiac auscultation reveals a continuous machine-like murmur.

This infant presents with the classical features of a congenital rubella infection. Rubella, otherwise known as German measles, is a togavirus--an enveloped, single-stranded, positive-sense RNA virus--that typically presents with a fever, pink maculopapular rash, joint pain, and post-auricular lymphadenopathy (swollen lymph nodes behind the ears). Although the rash is strongly associated with rubella, it is not present in all cases, and patients who do not experience it may assume they have contracted a different virus like influenza, and not connect their symptoms with rubella. In the United States, rubella is one of the viruses covered by the MMR (measles, mumps, rubella) vaccine, one of a series of vaccinations provided in infancy; but this regimen is not utilized worldwide. When contracted by an unvaccinated mother during pregnancy, rubella can severely affect fetal development. Infants with congenital rubella infection may present with any number of cardiac abnormalities, including septal defects, pulmonary artery stenosis, and PDA, although PDA is the most common anomaly associated with maternally-acquired rubella infection in early pregnancy. Other classic features associated with congenital rubella are cataracts, sensorineural deafness, and a “blueberry muffin rash” due to dermal extramedullary hematopoiesis.

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Show references

References:

  • Kumar, V., Abbas, A. K., & Aster, J. C: Robbins Basic Pathology, Ninth Ed., Elsevier Saunders (2013), p. 370-4.
  • Le, T., Bhushan, V., Sochat, M., et al: First Aid for the USMLE Step 1 2017, McGraw-Hill Education (2017), p. 165, 178, 277, 288-90.
  • Moore, K. L., Persaud, T. V. N., & Torchia, M. G: Before we are Born: Essentials of Embryology and Birth Defects, 8th ed., Saunders (2013), p. 189-211
  • Sadler, T. W: Langman’s Medical Embryology, Thirteenth Ed., Wolters Kluwer Health (2015), p. 194.
  • Brugada syndrome. NIH US National Library of Medicine: Genetics Home Reference, (accessed 25 of April 2017).
  • Findlen, P. & Bence, R.: A History of the Heart: Early Scinece Lab, Stanford University, (accessed 27 of Aril 2017).
  • Jervell and Lange-Nielsen syndrome. NIH US National Library of Medicine: Genetics Home Reference, (accessed 25 of April 2017).
  • Romano-Ward syndrome. NIH US National Library of Medicine: Genetics Home Reference, (accessed 25 of April 2017).

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
© Unless stated otherwise, all content, including illustrations are exclusive property of Kenhub GmbH, and are protected by German and international copyright laws. All rights reserved.

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