Embryology of the heart

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.