Learning objectives
Key terminology

The early development of the cardiovascular system is essential, to provide the growing embryo with oxygen and nutrients. Therefore, it is the first main organ system that is functional. In time, the land marks in the development of the heart are:

Stages in heart
development

In the third week of embryonic development, a longitudinal string of cells, called an angioblastic cord, arises from the mesoderm on both the left and right side of the embryo. The cords develop into hollow tubes, known as the endocardial heart tubes. At the same time, the lateral sides of the embryo fold inwards. As a result, the two tubes come together in the midline of the embryo. By the end of week 3, the tubes fuse to form the primitive tubular heart.

Heart tube formation

The primitive heart now consists of three layers:

• a thin endothelial inner layer, which later becomes the endocardium
• a layer of cardiac jelly 
• a thick muscular outer layer, which later becomes the myocardium

As the heart tube grows, certain parts widen and others narrow. The superior and inferior ends of the tube are fixed, so the tube is forced to fold and turn as it grows. During this process, the four future chambers of the heart become located in the correct location in relation to the body and each other.

The result is an S-shaped heart with five distinct parts:

• sinus venosus
• primordial atrium
• primordial ventricle
• bulbus cordis
• truncus arteriosus

Heart looping

The heart starts beating just after the endocardial tubes fuse into one primitive heart tube. Initially, blood flow is uncoordinated and in two directions, from superior to inferior and vice versa. By the end of week 4, the heart contraction becomes coordinated and blood flows in one direction, from the inferior to the superior end of the heart. The sinoatrial valves, which are located between the sinus venosus and the primordial atrium, prevent backflow of blood from the heart into the venous system.

After looping of the heart, septation and remodeling takes place, to divide the heart in two atria and two ventricles. Upon completion of development, the heart has only one inflow tract and one outflow tract, and has a unidirectional blood flow.

By the end of week 4, two structures start to develop that divide the primordial atrium into the left and right atrium: the endocardial cushions and the septum primum.

Endocardial cushions:

• are fused thickenings of the atrioventricular (AV) canal
• grow from the dorsal and ventral wall
  • dividing the canal into a right and a left AV canal
  • partially dividing the atria and ventricles
• function as AV valves

Septum primum:

• is a thin, crescent-shaped membrane 
• grows from the roof of the atrium towards the endocardial cushions
  • partially dividing the atrium into the right and left atrium
• leaves an opening, the foramen primum, between the septum and the endocardial cushions

Endocardial cushions
and septum primum

While the endocardial cushions grow, the AV canal moves from the right side of the heart towards the center. As a consequence, the right and left AV canals that result from fusion of the cushions, connect the two atria to their corresponding ventricles.

The septum primum continues to grow, and eventually fuses with the endocardial cushions. As a consequence, the foramen primum decreases in size and ultimately disappears. Simultaneously, a new opening arises from perforations in the central part of the septum primum. Through this so-called foramen secundum, the right-to-left blood flow in the atria is sustained.

Atrial and ventricular
septation

During weeks 5 and 6, a second dividing membrane develops between the atria, the septum secundum.

Septum secundum:

• is a crescent-shaped, thick, muscular membrane
• grows from the roof of the right atrium, on the right of the septum primum
  • overlapping the foramen secundum
  • incompletely dividing the atrium into the right and left atrium
• leaves an opening between the septum and the endocardial cushions, which together with the forum secundum forms the foramen ovale

As the septum secundum grows, the cranial part of the septum primum regresses. The remaining part of the septum primum, which is attached to the endocardial cushions, forms a flap that functions as a valve for the foramen ovale. It allows right-to-left blood flow through the atria, but prevents flow the other way around.

Septum secundum
and foramen ovale

During the same period, the pulmonary vein develops as a sprout from the left arterial wall. As the atrium grows, the pulmonary vein is gradually incorporated into the wall up to the level of its main branches. As a result, four pulmonary veins drain into the left atrium.

After incorporation of the sinus venosus and the pulmonary vein into the right and left atrial walls respectively, the remnants of the primitive atrium become ventral flaps, known as the auricles.

The truncus arteriosus and bulbus cordis form the outflow tract of the primordial heart that is connected to the primordial ventricle. The outflow tract gets divided at the same time as ventricle septation takes place, starting in week 6.

Septation starts when bulbar and truncal ridges arise in the wall of the bulbus cordis and the truncus arteriosus respectively. The ridges twist into a 180-degree spiral and fuse into the spiral aorticopulmonary septum.

The outflow tract is now divided into two arterial vessels, which spiral around one another and are continuous with the left and right ventricle respectively:

• aorta
• pulmonary trunk

Outflow tract
septation

In the primitive heart, the sinus venosus forms the inflow tract of the heart. It is located in the center of the primordial atrium, and consists of a right and a left horn. Between week 4 and week 8, the inflow tract remodels extensively.

Right horn of the sinus venosus:

• enlarges
• moves towards the right, opening into the future right atrium
• gets incorporated into the atrium wall

Left horn of sinus venosus:

• decreases in size
• develops into the coronary sinus

Sinoatrial valves:

• right sinoatrial valve - develops into the valve of the IVC, the valve of the coronary sinus, and the crista terminalis
• left sinoatrial valve - gets incorporated into the interatrial septum

By the end of week 8, there is a single inflow tract that drains blood from the superior and inferior vena cava, and the coronary sinus, into the right atrium.

During weeks 5 and 6, a partitioning wall, the interventricular septum, develops to divide the primordial ventricle into the left and right ventricle.

Interventricular septum:

• is a thick, muscular membrane
• grows from the ventricle floor, close to the apex
• grows due to ventricle enlargement and cell division
  • incompletely dividing the ventricle into the right and left ventricle
• leaves an opening, the interventricular foramen, between the septum and the endocardial cushions

The interventricular foramen allows blood flow between the left and right ventricle. By the end of week 7, the foramen is closed by a thinner membrane. This forms the membranous part of the interventricular septum, and completes the separation of the ventricles.

During heart development, several valves arise that prevent backflow and ensure unilateral blood flow through the heart.

Sinus venosus valves:

• are present at two locations
  • valve of the inferior vena cava
  • valve of the coronary sinus
• form from the right sinoatrial valves of the primitive heart
• valve of the inferior vena cava - directs blood flow through the foramen ovale, from the right atrium to the left atrium
• valve of the coronary sinus - prevents backflow of blood from the right atrium to the coronary sinus

Atrioventricular valves:

• are present at two locations
  • tricuspid valves - three cusps between the right atrium and the right ventricle
  • mitral valves - two cusps between the left atrium and the left ventricle
• are thin-walled, fibrous membranes
• form from bulging of tissue around the AV canal
• are initially thick and muscular, but become thin after hollowing out and remodeling
• connect to the ventral wall by connective tissue cords (chordae tendineae), to prevent inversion of the valves
• prevent backflow of blood from the ventricle into the atrium

Semilunar valves:

• present at two locations
  • three cusps between the aorta and the left ventricle
  • three cusps between the pulmonary trunk and the right ventricle
• are thin-walled, fibrous membranes
• form from bulging of tissue around the opening of the aorta and the pulmonary trunk
• are initially thick and muscular, but become thin after hollowing out and remodeling
• prevent backflow of blood from the arterial system into the heart

There are no valves between the superior vena cava and the right atrium, or between the left atrium and the pulmonary veins.

While the heart remodels, the heart wall develops as well, resulting in three final layers.
Endocardium:

• is the thin, inner lining of the heart
• is continuous with the vascular system
• provides signals that influence, the development of the myocardium, conduction system and endocardial cushions, and the septation of the outflow tract

Myocardium:

• is the thickest, middle tissue layer of the heart
• forms the muscular walls of the heart and muscular part of the interventricular septum
• contains specialized muscle cells that allow coordinated muscle contraction
• develops and remodels under the influence of signals from, among other structures, the endocardium and epicardium

Epicardium:

• is the thin, protective outer lining of the heart
• fuses with the pericardium, which forms a sac around the heart
• develops relatively late, after the primitive heart tube has formed
• plays an important role in the development of the coronary vascular system, the myocardium, atrioventricular valves, and conduction system
• may play a role in repair of heart tissue after damage, eg, damage caused by infarction.

Proper development of the three layers, and their interaction during this process, is essential for the development and growth of the heart, and as a consequence, its contractile performance and rhythmicity. In addition, the combined influence of the three layers is essential for the development of the coronary vasculature and the conduction system.

The start of the heartbeat at day 22 or 23 is not initiated and directed by nerve cells, but originates from the cardiac cells themselves. Initially, the heartbeat is uncoordinated, and various regions beat with different beating patterns. The atria beat with a higher frequency than the ventricles, and function as an interim pacemaker. Starting in week 5, three structures form, which develop into the conduction system.

Sinoatrial (SA) node:

• originates from the right wall of sinus venosus that incorporates into the right atrium 
• is located at the junction of right common cardinal vein and wall of right atrium
• is the dominant pacemaker with fastest intrinsic rhythm
• directly stimulates simultaneous left and right atrial contraction

Atrioventricular (AV) node:

• originates from both the AV region, and the left wall of sinus venosus that incorporates into the interatrial septum
• is located at the base of interatrial septum, just superior to the endocardial cushions
• delays impulse passage from the atria to ventricles

Atrioventricular (AV) bundle:

• originates from both the AV region, and the left wall of sinus venosus that incorporates into the interatrial septum
• runs from the AV node through the interventricular septum to the deepest parts of the ventricles
• branches into multiple bundles
  • bundle of His 
  • right bundle branch 
  • left bundle branch
  • Purkinje fibers 
• propagates fast passage of impulses from the AV node towards all parts of the ventricles

The SA node, AV node, and AV bundle become connected to numerous nerves, which innervate them and thereby influence the heart rate. However, the conduction system is already complete before the nerves that innervate it have developed.

Cardiac conduction
system

Before blood circulation starts, the embryo and mother exchange nutrients, oxygen, and waste materials by diffusion. As the embryo grows, diffusion is no longer sufficient to supply the whole body, and a circulation system is needed.

The primitive circulation system develops concurrently with heart development. By the end of week 4, three components can be distinguished:

• yolk sac circulation
• chorion circulation
• embryonic body circulation

Primitive embryonic
circulation

Circulation to the yolk sac is essential in the second and third embryonic week, when there is no circulation through the placenta yet. At that stage, the yolk sac provides the embryo with nutrients. Furthermore, the wall of the yolk sac is the place of first blood and blood vessel development.

The chorion forms the embryonic part of the placenta. This part-embryonic, part-maternal organ contains a fine network of closely associated embryonic and maternal blood vessels. In this network, nutrients and oxygen get transported from the mother to the embryo, and waste materials get transported in the other direction.

When the heart begins to beat, three pairs of veins from the three circulations empty via the sinus venosus into the embryonic heart:

• vitelline veins 
• umbilical veins 
• anterior and posterior cardinal veins, which join close to the heart to form the common cardinal veins

Blood flows into the primordial atrium from the sinus venosus. The sinoatrial valves between the two spaces prevent reflux of the blood. Next, the blood flows into the primitive ventricle via the atrioventricular canal. As the ventricle contracts, blood is pumped out of the heart via the bulbus cordis and truncus arteriosus.

Blood flow through
primitive heart

The heart pumps the blood into the arterial system. By the end of week 4, the main components of the arterial system are:

• the aortic sac 
• a pair of dorsal aortas 
• the vitelline arteries 
• the umbilical arteries 

The primitive vascular system of the embryo enables transport of nutrients, oxygen, and waste to and from all body parts.

Fetal oxygen, nutrient and waste flows

Because the fetal lungs are not functional, only a very small fraction of blood from the heart flows into the fetal pulmonary circulation. In contrast to the adult lungs, the fetal lungs do not provide gas exchange. Instead, the fetus obtains oxygen-rich blood from the mother via the umbilical vein and sinus venosus.

This results in differences when the fetal circulation is compared to the adult circulation, because in the fetus, oxygen-rich blood:

• enters the heart into the right atrium instead of the left atrium
• cannot get into the systemic circulation via the right ventricle

To allow the distribution of oxygen-rich blood from the heart throughout the whole body, two shunts exist in the fetal circulation: the foramen ovale and ductus arteriosus.

The foramen ovale allows blood flow from the right atrium to the left atrium. As a result:

• blood flow continues to the left ventricle via the atrioventricular canal.
• blood is pumped into the aorta towards the body from the left ventricle

The ductus arteriosus allows blood flow from the pulmonary trunk to the aorta. As a result:

• blood from the right atrium flows to the right ventricle
• blood is pumped into the pulmonary trunk towards the lungs by the right ventricle
• blood flows into the aorta via the ductus arteriosus, instead of flowing into the lungs

However, before the oxygen-rich blood from the umbilical vein arrives in the heart for further distribution, the oxygen-content decreases at several locations.

• The liver: oxygen is extracted from the blood by the liver.
• The inferior vena cava: oxygen-rich blood mixes with oxygen-poor blood from the inferior part of the body.
• The right atrium: oxygen-rich blood mixes further with oxygen-poor blood from the superior vena cava.
• The left atrium: the oxygen-rich blood mixes further with a small amount of oxygen-poor blood from the lungs.

To minimize the decrease in oxygen content, several fetal structures exist.

The ductus venosus allows approximately half of the blood from the umbilical vein to bypass the liver. As a result:

• blood from the ductus venosus flows directly into the inferior vena cava
• blood flow continues to the right atrium

The valve of the inferior vena cava directs blood flow in the right atrium towards the foramen ovale. As a result:

• most of the blood flows from the right atrium to the left atrium
• blood flow continues via the left ventricle towards the body

Fetal circulation

The foramen ovale, ductus venosus, and valve of the inferior vena cava together enable blood with the highest possible oxygen-content to flow out of the left ventricle. This first supplies the heart, head, neck, and upper limbs. The liver also receives oxygen-rich blood, because approximately half of the blood in the umbilical vein flows via the liver and hepatic vein to the inferior vena cava.

The ductus arteriosus allows blood flow from the right ventricle into the dorsal aorta. This blood has medium oxygen content, due to mixture of blood in the heart. In the dorsal aorta, it mixes further with the oxygen-rich blood from the left ventricle. The resulting medium-oxygen-content blood supplies the posterior part of the embryo.

Prenatal oxygen
saturation

While the blood flows throughout the body, it delivers oxygen and nutrients to tissues and organs, and the oxygen content drops. Most of the blood (65%) flowing through the descending aorta returns directly to the placenta, to take up more oxygen and nutrients. The remaining 35% of the descending blood flow continues more distally and provides oxygen to the lower half of the body.

Remodeling of the primitive vascular system, in parallel with heart remodeling, ensures an efficient circulatory system throughout fetal life. Moreover, the system allows quick adaptation to the change in oxygen and nutrient supply at birth, ensuring continued efficient circulation directly after birth.

Between weeks 4 and 8, the most important changes that take place in the vascular system include:

• Venous vessels
  • The cranial parts of the left common cardinal, umbilical, and vitelline veins (connecting to the sinus venosus) regress.
  • The remaining parts of the cardinal veins are replaced by the subcardinal and supracardinal veins, and give rise to several vessels, including:
    • superior vena cava
    • inferior vena cava
    • venous vasculature of the kidneys, adrenal glands, and reproductive system
  • The remaining parts of the vitelline veins give rise to the hepatic vein and the portal vein.
  • The right umbilical vein regresses completely.
  • The remaining part of the left umbilical vein develops into a single umbilical vein running via the liver.
• Arterial vessels
  • The paired dorsal aortas fuse to form a single dorsal aorta.
  • Six pairs of aortic arches arise between the aortic sac and the dorsal aorta, and develop into the:
    • vasculature of the upper thorax, head, and face
    • aortic arch, with contribution from the aortic sac and dorsal aorta
    • pulmonary arteries
    • ductus arteriosus
  • The vitelline arteries give rise to the celiac artery and mesenteric arteries.
  • The umbilical arteries remain connected to the placenta and give rise to several vessels, including the internal iliac artery and superior vesical artery.

At birth, the following events affect the circulatory system:

• The circulation via the umbilical vessels to and from the placenta stops.
• The lungs expand and become functional.

The neonate no longer retrieves oxygen from the mother's blood, but from the lungs. Air fills and stretches the lungs, which results in a drop of vascular resistance, an increase in blood flow, and a thinning of its artery walls. Cutting off the umbilical vessels causes a drop in blood pressure in the inferior vena cava. As a result of the pressure changes in the systemic and pulmonary circulation, pressure in the right atrium decreases and pressure in the left atrium increases. This leads to anatomical changes, and subsequently, circulatory changes.

The following events cause, and result from, closure of the foramen ovale:

• The left atrial pressure becomes higher than the right atrial pressure.
• The flap of the foramen ovale gets pressed onto the septum secundum, and thereby closes the foramen ovale.
• The complete right ventricle output flows into the pulmonary circulation.
• A temporary reversal of blood flow from the aorta to the pulmonary trunk takes place through the ductus arteriosus, due to low pulmonary vascular resistance.

The following events cause, and result from, ductus arteriosus constriction:

• The inflation of the lungs releases substances that stimulate smooth muscle contraction upon high oxygen levels.
• The ductus arteriosus muscles contract, thereby constricting the vessel.
• A small blood shunt from the aorta to the pulmonary artery often sustains for a few days after birth.

After these changes, the cardiovascular system consists of two parallel circulatory systems: the systemic circulation and the pulmonary circulation.

In the systemic circulation:

• oxygen-rich blood is pumped from the left ventricle to the body
• oxygen-poor blood returns from the body to the right atrium

In the pulmonary circulation:

• oxygen-poor blood is pumped from the right ventricle to the lungs
• oxygen-rich blood returns from the lungs to the left atrium

Neonatal circulation

The cutting of the umbilical cord makes the umbilical vessel non-functional. The umbilical arteries actively constrict to prevent blood loss, while blood flow in the umbilical vein continues momentarily until the umbilical cord is tied. A sphincter in the ductus venosus constricts and thereby closes the bypass around the liver. Furthermore, the valve of the inferior vena cava regresses.

Some changes occur directly after the first breath, while most take several hours or even days to complete. Often, temporary blood flow through the foramen ovale, the ductus arteriosus, and the ductus venosus is sustained.

Complete anatomical closure of the structures occurs over the first months after birth. The remnants of the umbilical vessels, ductus arteriosus, and ductus venosus form the following non-functional ligaments, respectively:

• medial umbilical ligament and ligamentum teres
• ligamentum arteriosum
• ligamentum venosum

The valve of the foramen ovale adheres to the septum secundum. It leaves an impression on the left side of the interatrial septum, and the edge of the septum secundum remains as a round fold. In the adult heart, this is still visible, and is known as the fossa ovalis.

Postnatal pressure and
oxygen saturation

Congenital heart diseases (CHDs) are structural or functional defects of the heart, or large vessels associated with the heart, that are present at birth. They are caused by incomplete or faulty heart development, which can occur at any stage of heart development. Often, the cause is not known, but genetic factors, teratogens, or a combination of both, play a role. The majority of CHDs do not cause problems during fetal life. However, after birth, they affect normal circulation and can cause symptoms. Some defects are minor and may only be detected later in life, while others are fatal at birth. CHDs are relatively common, with an incidence of approximately 8 in 1000 (see reference) neonates.

Congenital heart defects can be subdivided into three types:

• anomalies without a shunt
• anomalies with a left-to-right shunt
• anomalies with a right-to-left shunt

Anomalies with a right-to-left shunt, and sometimes with a left-to-right shunt, result in a mix of oxygen-poor and oxygen-rich blood in the left atrium. This causes a reduction in oxygen saturation, leading to cyanosis.

Anomalies without a shunt, and most with a left-to-right shunt, result in an overloaded left ventricle. These disorders are considered acyanotic.

The most common congenital heart diseases, and their proportion of all CHDs, are: (see reference)

• ventricular septal defects (14-16%, not taking into account defects that close spontaneously)
• coarctation of the aorta (8-11%)
• atrial septal defects (6-10%) (see reference)
• atrioventricular septal defects (endocardial cushion defects) (4-10%)
• tetralogy of Fallot (9-14%)
• transposition of the great arteries (10-11%)

  Note:

  When examining for congenital heart diseases in infants and children, their size and age should be taken into account. Always obtain the weight, height, and age of the patient and calculate the body surface area (BSA).

An atrial septal defect (ASD) refers to the presence of an abnormal opening in the interatrial septum. Before birth, a shunt between the atria (through the foramen ovale) is functional, and an ASD is thus not significant at that stage. However, after birth, the interatrial septum should be completely closed, to separate the atria. In case of an ASD, a left-right shunt occurs due to the higher pressure in the left atrium. As a result, oxygen-rich blood mixes with oxygen-poor blood in the right atrium.

Atrial septal defect

Atrial septal defects are subdivided according to the location of the defect:

• ostium secundum defect (70-75% of all ASDs) (see reference)
• ostium primum defect (15-20% of all ASDs) (see reference)
• sinus venosus defect (5-10% of all ASDs) (see reference)

ASDs are common and occur approximately twice as often in females than in males (see reference). The majority of small (< 8 mm) ostium secundum defects close spontaneously within 1.5 years after birth (see reference). Closure of ostium secundum defects during adulthood, and spontaneous closure of ostium primum and sinus venosus defects, is unlikely.

Symptoms usually do not arise during childhood, but become evident with increasing age or physiological changes (ie pregnancy). Most defects are detected during adulthood and the majority is diagnosed when the patient reaches the age of 50. Mild symptoms may be controlled with medication, but more severe symptoms require surgical closure of the defect.

Pathogenesis Congenital: caused by developmental malformation of the interatrial septum.

• Usually occurs isolated and sporadic, but occasionally as part of a genetic syndrome.

Clinical signs and symptoms
Symptoms vary and depend on the size of the defect and the shunt.

• frequently asymptomatic during infancy, childhood, and young adulthood
• dyspnea 
• fatigue
• reduced exercise tolerance
• peripheral edema
• atrial arrhythmias
• palpitations
• syncope

Cardiac auscultation

• ejection-type murmur
• holosystolic murmur
• S2 fixed split murmur
• high pitched diastolic murmur due to pulmonary regurgitation (Graham Steell murmur)
• widely split, fixed S2 at upper left sternal border in children
• no murmur at site of shunt

Ultrasound findings
Assessment relies on more than one criterion.

• 2D
  The following anomalies may be noted by the sonographer:
  • a defect in the interatrial septum; best visualized in the subcostal four-chamber view as the ultrasound beam is perpendicular to the septum
  • right ventricular dilation with paradoxical septal wall motion
  • interventricular septum flattening
  • right atrial dilation
  • usually a small left atrium
  • main pulmonary artery and pulmonary branch dilation
  • T-shaped artifact of the cardiac crux in the apical four-chamber view; increased echogenicity at the edge of the interatrial septum
  • "clapping of hands" defect; indicates a cleft mitral valve, in case of an ostium primum defect
  • mitral valve prolapse; in case of an ostium secundum defect

  
  2D image of an
  atrial septal defect

• Doppler
  The following anomalies may be noted by the sonographer:
  • left-to-right flow across the defect, with color Doppler 
  • left-to-right flow across the defect, with pulsed wave Doppler 
  • turbulent flow in the pulmonary artery
  • tricuspid regurgitation 
  • pulmonary regurgitation
  • possibly, pulmonary stenosis
  • mitral regurgitation, if a cleft mitral valve is present

  
  Doppler image of an
  atrial septal defect

• Saline contrast technique
  When using the saline contrast technique the sonographer may demonstrate and assess:
  • the presence, location and size of an atrial septal defect
  • the presence of a persistent left superior vena cava
  • the presence of a pulmonary arteriovenous fistula

  
  Saline contrast image
  of an atrial septal defect

Assessment of the ASD and associated anomalies

The sonographer performs the following assessments to determine the location and type of defect and the size of the shunt (insignificant, small, or large): 

• location and type of defect
• direction of shunt
• measurement of the size of the defect
• measurement of the entire length of the interatrial septum
• measurement of the right ventricular outflow tract (RVOT) and left ventricular outflow tract (LVOT) diameter; a RVOT diameter increase and LVOT diameter decrease indicates a large atrial septal defect
• RVOT velocity time integral (VTI) and LVOT VTI; a RVOT VTI increase and LVOT VTI decrease indicates a large atrial septal defect
• calculation of the Qp/Qs shunt ratio, with the RVOT VTI and LVOT VTI

• measurement of the tricuspid valve and mitral valve annulus diameters; increased in case of an ASD
• assessment of the presence and severity of tricuspid regurgitation, pulmonary regurgitation, pulmonary stenosis, mitral regurgitation
• assessment of the presence of a persistent left superior vena cava or a pulmonary arteriovenous fistula

Additional imaging/tests

• Physical examination may demonstrate skeletal malformation.
• Electrocardiography (ECG) 
• Chest x-ray may demonstrate cardiomegaly, with prominence of the pulmonary vasculature.
• Transesophageal echocardiogram (TEE) may provide clearer images of an ASD, depending on the location of the defect.

Treatment

• Observation 
  • to asses for spontaneous closure
  • in case of small defects and shunts, pulmonary arterial hypertension, pregnancy, severe left or right ventricular dysfunction
• Medication
  • to treat heart failure symptoms 
  • to control arrhythmias
• Surgical
  • septum repair
  • mitral valve repair, when a mitral valve cleft is presen
  • mitral valve replacement, rarely, when a mitral valve cleft is present

Prognosis

• Small defects (Qp/Qs =< 0.7:1) are of no clinical importance. (see reference)
• Survival without intervention is 50% after the age of 40 to 50. (see reference)
• Low risk surgery shows good results; surgical mortality rates and complications increase with increasing age at time of septum repair. 

Complications 

• heart failure
• pulmonary hypertension
• cyanosis
• Eisenmenger's syndrome
• arrhythmias
• paradoxical emboli
• stroke
• transcatheter device complications

A ventricular septal defect (VSD) refers to the presence of an abnormal opening in the interventricular septum. The defect is caused by incomplete growth or fusion of the septum.

As a result, blood shunts from the left to the right ventricle, due to the pressure difference between them. Oxygen-rich blood from the left ventricle mixes with oxygen-poor blood from the right ventricle, and recycles through the pulmonary circulation. This can lead to an overload of the left ventricle and pulmonary circulation, and circulation of blood with a lower oxygen content through the body.

Ventricular
septal defect

Ventricular septal defects are subdivided according to the location of the defect:

• perimembranous defects (70-80% of all VSDs) (see reference)
• trabecular muscular defects (5-20% of all VSDs) (see reference)
• outlet defects (5-7% of all VSDs) (see reference)
• inlet defects (5-10% of all VSDs) (see reference)

The magnitude of a shunt, its impact on the circulation, and the resulting symptoms depend on the size of the defect and the resistance of the pulmonary vasculature. Small defects only cause minor left-to-right shunts (Qp/Qs < 1.75:1) (see reference) and do not affect pulmonary circulation. Larger defects, and the resulting larger shunts (Qp/Qs > 2:1) (see reference), cause an overload pattern in the left ventricle and hypertrophy of the right ventricle. Furthermore, they cause hypertension and elevated resistance of the pulmonary artery. Over time, the increased vascular resistance in the lungs causes a reversal of shunt direction (becoming a right-to-left shunt), leading to Eisenmenger's syndrome and possibly heart failure and death.

VSDs are common and are often diagnosed in infants, and when the defect is large, within the first few weeks of life. Maternal drug and alcohol abuse increase the fetal risk of a VSD. The defect may occur isolated or in conjunction with other cardiac anomalies. Small defects do not cause symptoms and often close spontaneously in the first few years after birth. Persistent small defects usually do not require medical or surgical intervention. Larger defects do not close spontaneously and, even when asymptomatic, require surgical closure.

Pathogenesis

• Congenital: caused by developmental malformation of the interventricular septum.
• May occur isolated and sporadic, or in combination with other cardiac anomalies (eg tetralogy of Fallot, transposition of the great arteries).

Clinical signs and symptoms

Symptoms vary and depend on the size of the defect and the shunt.

• asymptomatic, in case of a small VSD
• chest pain
• syncope
• yanosis
• clubbing
• tachypnea or some respiratory difficulty
• symptoms of heart failure
• symptoms of Eisenmenger's syndrome

Cardiac auscultation

• holosystolic murmur, heard best along the left sternal border; often associated with a systolic thrill
• in large shunts, a S3 is heard
• holodiastolic murmur of aortic regurgitation
• holosystolic murmur of mitral regurgitation
• holodiastolic regurgitation or pulmonary regurgitation (Graham Steell murmur)

Ultrasound findings

Assessment relies on more than one criterion.

• 2D
• The following anomalies may be noted by the sonographer:
  • a defect in the interventricular septum; all sonographic windows (parasternal long and short axis, apical, and subcostal) are required to localize the defect 
  • left atrial dilation, in case of a large shunt
  • left ventricular dilation, in case of a large shunt
  • main pulmonary and pulmonary branch dilation, in case of a large shunt
  • right ventricular hypertrophy, in case of a large shunt
  • aortic valve prolapse
  • left ventricular systolic dysfunction
  • T-shaped artifact of the cardiac crux in the apical four-chamber view

  
  2D image of a
  ventricular septal defect

• Doppler
  • The following anomalies may be noted by the sonographer:
  • high, turbulent blood flow across the defect, with color Doppler
  • aortic regurgitation
  • mitral regurgitation
  • tricuspid regurgitation

  
  Doppler image
  of a ventricular
  septal defect

• Saline contrast technique
• When using the saline contrast technique, the sonographer may demonstrate and assess:
  • the presence, location, and size of the ventricular septal defect

  
  Saline contrast
  image of a
  ventricular
  septal defect

Assessment of the VSD and associated anomalies

The sonographer performs the following assessments to determine the location and type of defect and the severity of the shunt (small, moderate, large): 

• location and type of defect
• direction of shunt
• measurement of the size of the defect
• measurement of the entire length of the interventricular septum 
• systolic pressure difference
• pulmonary pressure (right ventricular systolic pressure); an increase confirms a VSD
• RVOT velocity time integral (VTI) and LVOT VTI
• calculation of the Qp/Qs shunt ratios, with the RVOT VTI and LVOT VTI

• assessment of the presence and severity of tricuspid regurgitation, aortic regurgitation, and mitral regurgitation

Additional imaging/tests

• Physical examination may demonstrate signs and symptoms of aortic or mitral regurgitation, or Eisenmenger's syndrome
• Electrocardiography (ECG) may demonstrate ventricular and atrial enlargement.
• Chest x-ray may demonstrate cardiomegaly.
• Transesophageal echocardiogram (TEE) may provide clearer images of VSD, depending on the location of the defect.
• Cardiac catheterization for determination of artery pressures, pulmonary resistance, and oxygen rise in right ventricle.

Treatment

• Observation
  • to assess for spontaneous closure
  • in case of small defects and shunts
• Medical
  • to reduce afterload
  • to treat heart failure symptoms 
• Surgical
  • septum repair; surgical patch when Qp/Qs >= 1.5/1, presence of aortic regurgitation, left heart dilation, and/or infective endocarditis (see reference)

Prognosis

• Approximately 80% of all VSDs detected in the first month close spontaneously (see reference).
• Small defects are associated with a good prognosis, but involve a higher risk of endocarditis.
• Untreated (large) VSDs can lead to heart failure and early death; mortality rates are 27% by the age of 20, 53% by the age of 40, and 69% by the age of 60 (see reference).
• Medical treatment improves moderate or large defects and shunts in 6 to 24 month old infants (see reference).
• Surgery involves a low risk and excellent results and long-term prognosis; surgical 
• mortality rate is < 2% (see reference).
• Survival rate after medical or surgical intervention over a 25-year period is 87% (see reference).

Complications heart failure

• growth failure
• pulmonary hypertension
• cyanosis
• Eisenmenger's syndrome
• arrhythmias
• paradoxical emboli
• stroke
• post-operative complications

A patent foramen ovale (PFO) is a variant of an atrial septal defect that occurs due to incomplete closure of the atrial septum. Normally, the septum primum and septum secundum fuse after birth, and get completely sealed within one year. If this does not happen, a patent opening between the left and right atrium persists. This has the potential for blood shunting from right to left, especially in combination with conditions that increase right atrial pressure.

Patent foramen ovale

The PFO size will increase with age as the heart grows, and the atrial septum may become abnormally mobile or form an aneurysm. Here, hemostasis and clot formation may take place, which can result in an embolic event like a stroke, when blood shunting is induced. PFO is very common and post-mortem examinations have shown that it occurs in 25 to 30% of the adult population. However, it is clinically detected in only 10 to 15% of the population (see reference).

Pathogenesis

• Congenital: caused by defective fusion of the septum primum and the septum secundum, and thus failure of the interatrial septum to close after birth.

Clinical signs and symptoms

• usually asymptomatic
• migraine
• transient ischemic attack (TIA) or stroke, due to paradoxical emboli across the shunt
• sleep apnea
• cyanosis, upon breath holding or crying
• neurologic decompression sickness, in scuba divers

Cardiac auscultation

• no specific findings

Ultrasound findings
Assessment relies on more than one criterion.

• 2D
  The following anomalies may be noted by the sonographer:
  • possibly an interatrial flap; may be visualized from the subcostal view, using the Valsalva and Mueller techniques
  • no other atrial septal defect
  • possibly aneurysmal dilation of the interatrial septum

  
  2D image of a patent
  foramen ovale

• Doppler
  The following anomalies may be noted by the sonographer:
  • no valvular abnormalities
  • "flame of color" in the middle of the interatrial septum, with color Doppler
  • right-to-left shunt; visualized with Valsalva or Mueller techniques 
  • no flow across the shunt may be visible with color Doppler, if pulmonary pressure is not adequate enough to force the flap open

  
  Color Doppler of a
  patent foramen ovale

  Note:

  Color Doppler only detects approximately 30% of all PFOs. Transesophageal echocardiography (TEE) provides clearer visualization of the interatrial septum and may be required to visualize the right-to-left shunt.

• Saline contrast technique with Valsalva and Mueller maneuvers
  When using the saline contrast technique with the Valsalva or Mueller maneuver, the sonographer may demonstrate:
  • the presence of an interatrial shunt

  
  Saline contrast image of
  a patent foramen ovale

Assessment of the PFO
The sonographer performs the following assessments to determine the presence of a PFO:

• assessment of the present of a shunt across the atrial septum
• onfirmation of the type of atrial septal defect

Additional imaging/tests

• Transesophageal echocardiogram (TEE) with Valvalva and Mueller maneuvers, for clearer visualization of the interatrial septum and detection of a possible right-to-left shunt. 
• TEE with the saline bubble contrast technique and Valsalva and Mueller maneuvers.
• Transcranial Doppler (TCD) with saline bubble injection and Valsalva and Mueller maneuvers. The PFO is graded by the number of bubbles detected in the middle cerebral artery with Doppler within three cardiac cycles.

Transcranial Doppler
image of a patent
foramen ovale

Treatment

• Usually no treatment
• Medical 
  • to treat hemostasis and blood clotting
• Surgical
  • surgical patent foramen closure, when PFO > 25 mm (see reference)
  • catheter patent foramen closure, in case of recurrent cryptogenic stroke

Prognosis

• Asymptomatic PFOs are not clinically significant, do not require treatment, and patients have an excellent prognosis.
• Patients with a PFO have a higher incidence of migraine headaches.
• Patients who had a cryptogenic stroke or ischemic attack, suspected to be caused by paradoxic emboli, may have a higher risk of a subsequent recurrent stroke or ischemic attack.
• Scuba divers with a PFO have a risk of nitrogen gas embolism.

Complications

• emboli
• cyanosis
• post-surgery complications

In the fetus, the ductus arteriosus is essential for efficient circulation of oxygen-rich blood and protection of the lungs. However, after birth, the ductus arteriosus needs to close, to completely separate the pulmonary and systemic circulation. The muscles in the vessel wall contract within 10 to 15 hours after birth, due to a rise in the blood oxygen level and a decline in prostaglandin levels. This results in closure of the vessel, which is usually complete within 2 to 3 weeks. If the vessel does not completely close, a patent ductus arteriosus (PDA) remains and allows shunting between the aorta and pulmonary artery.

Patent ductus
arteriosus

Due to pressure differences, blood generally flows from the aorta to the pulmonary artery via the PDA. However, blood flow can be bidirectional or, depending on underlying pathologies, from the pulmonary artery to the aorta. The high volume and pressure of this blood flow can cause damage of a variable degree, depending on gestational age at delivery, the size of the PDA, and pulmonary vascular resistance. A small shunt may not cause symptoms until later in life, while a larger shunt can lead to pulmonary artery hypertension, increased pulmonary vascular resistance, heart failure, and eventually Eisenmenger's syndrome.

A patent ductus arteriosus is very common in premature infants, and occurs two to three times as often in females than in males. Furthermore, a maternal rubella infection during the first trimester, and giving birth at a high altitude, are associated with a higher risk of fetal PDA. The patent ductus arteriosus may be closed by medication in preterm neonates, or otherwise surgically.

Pathogenesis

• Congenital: caused by a failure to close the ductus arteriosus after birth.
• Premature birth involves a higher risk of PDA.
• Maternal rubella and birth at high altitude are associated with a higher risk of PDA.

Clinical signs and symptoms
Symptoms vary and depend on the gestational age at delivery, size of the shunt, and pulmonary resistance.

• In infants:
  • asymptomatic, if the shunt is small
  • cyanosis
  • repeated respiratory infections
  • symptoms of heart failure
  • bounding peripheral pulses
• In older patients:
  • asymptomatic, if the shunt is small
  • cyanosis of the lower extremities
  • atrial arrhythmia
  • heart failure
  • chest pain
  • infective endocarditis
  • pulmonary hypertension
  • Eisenmenger's syndrome

Cardiac auscultation

• continuous "machinery" murmur heard throughout systole and diastole
• absence of a murmur may indicate pulmonary hypertension
• laterally displaced apical impulse
• S1 typically normal, S2 often obscured by murmur

Ultrasound findings
Assessment relies on more than one criterion.

• 2D
  The following anomalies may be noted by the sonographer:
  • shunt between the aorta and at the pulmonary artery base; may be directly visualized in the parasternal short-axis and suprasternal views 
  • left atrial dilation
  • left ventricular dilation
  • main pulmonary artery dilation

  
  2D image of a patent
  ductus arteriosus

• M-Mode
  The following anomalies may be noted by the sonographer:
  • left ventricular dilation with hyperkinetic wall motion
  • left atrial dilation
• Doppler
  The following anomalies may be noted by the sonographer:
  • left-to-right shunt with blood flow towards the transducer (red); visualized with color Doppler in the parasternal short axis view
  • left-to-right shunt with blood flow away from the transducer (blue); visualized with color Doppler in the suprasternal notch views 
  • turbulent color flow with aliasing at the bifurcation of the pulmonary artery; visualized with color Doppler
  • turbulent blood flow, possibly left-to-right, bidirectional or right-to-left; visualized with color Doppler and pulsed/continuous wave Doppler
  • reversed blood flow in the descending thoracic or abdominal aorta

  
  Color Doppler image
  of a patent
  ductus arteriosus

Assessment of the PDA

• The sonographer performs the following assessments of the shunt: 
• measurement of the length and diameter of the shunt; this is important for possible surgical closure
• measurement of the diameter of the left atrium (LA) and the aortic root (Ao)
• calculation of the LA/Ao ratio in M-mode; a LA/Ao ratio > 1.4:1 indicates a PDA (see reference)

  
  M-mode - LA/Ao
  ratio in patent
  ductus arteriosus

• mitral valve velocity; may be increased
• tricuspid valve velocity; may be decreased 
• LVOT velocity and VTI and RVOT velocity and VTI; a LVOT velocity and VTI increase and RVOT velocity and VTI decrease indicates a PDA

Additional imaging/tests

• Physical examination may demonstrate:
  • widened pulse pressure
  • cyanosis, possibly in lower extremities
• Electrocardiography (ECG) possibly demonstrates left atrial and ventricular enlargement.
• Chest x-ray may demonstrate normal features or pulmonary congestion.
• Transesophageal echocardiogram (TEE) may be used for visualization of the ductus arteriosus.

Treatment

• Medical
  • to decrease prostaglandins and stimulate ductus arteriosus closure, in preterm neonates
• Surgical
  • surgical closure

Prognosis

• Spontaneous closure of the PDA is common (72%) in premature neonates (< 30 weeks) (see reference).
• Neonates with a low birth weight and a PDA have a higher risk of developing chronic lung disease.
• The mortality rate per year in untreated patients is approximately 0.4% until the age of 20, 1 to 1.5% between 20 and 30, 2 to 2.5% between 30 and 40, and 4% over the age of 40 (see reference).
• Medical closure is often effective when treated within 2 weeks after birth.
• Surgical closure has a high success rate and low morbidity rate.

Complications

• endocarditis
• heart failure
• pulmonary vascular obstructive disease
• aortic rupture
• post-surgery complications (incomplete closure)

Transposition of the great arteries (TGA) is a common developmental disorder in which the aorta and the pulmonary artery are connected to the wrong ventricle. This means that the aorta arises from the morphological right ventricle, and the pulmonary artery arises from the morphological left artery. Although the cause is unclear, it is suggested to result from defective development of the outflow tract, when the bulbus cordis becomes incorporated into the ventricles.

Due to the wrong connection of the outflow tracts, the pulmonary and systemic circulations run completely separately and parallel. As a result, oxygen-rich blood from the lungs returns into the left atrium and flows, via the left ventricle, back into the lungs. On the other hand, oxygen-poor blood from the body returns into the right atrium and flows, via the right ventricle, back into the body. This condition is incompatible with life, as the oxygen-rich blood cannot be distributed throughout the body.

Transposition of
the great arteries

Transposition of the great arteries can be subdivided, according to the associated heart anatomy:

• D-transposition, which is the typical form of TGA
• L-transposition

TGA is an isolated occurrence in most cases (50-75%) (see reference), but may be associated with other cardiac defects. Some associated anomalies are unfavorable (ventricular outflow tract stenosis or obstruction, coarctation of the aorta, valve anomalies, coronary artery anomalies), while others allow shunting of blood, which results in a mixing of oxygen-rich and oxygen-poor blood. This enables transport of oxygen-rich blood through the body and thus survival.

The most common cardiac anomalies that allow shunting in TGA are:

• atrial septal defect or patent foramen ovale
• ventricular septal defect
• patent ductus arteriosus

TGA is the most common cause of cyanosis in neonates, and occurs more frequent in males than in females. Cyanosis is prominent within a day, but in the presence of a shunt, TGA may not be diagnosed until after the first few weeks of life. Without intervention, patients usually die within a few months, but the outcome and survival rate after surgery are good.

Pathogenesis

• Congenital: caused by developmental malformation of aorticopulmonary septum.
• Maternal diabetes, exposure to teratogens, and the use of antiepileptic drugs are associated with a higher risk of fetal TGA.
• Mutations in multiple genes may contribute to the development of TGA.

Clinical signs and symptoms

• neonatal cyanosis, of variable degree depending on associated cardiac defects
• heart failure

Cardiac auscultation

• systolic ejection murmur
• diastolic flow murmur
• single and loud S2
• holosystolic murmur, mid-diastolic rumble in case of large ventricular defect

Ultrasound findings
Assessment relies on more than one criterion.

• 2D
• The following anomalies may be noted by the sonographer:
  • valve leaflet thickening
  • valve leaflet defects
  • commonly, ventricular septal defects
  • pulmonary artery arising from the left ventricle; parasternal long-axis view visualizes bifurcation of the pulmonary artery posteriorly from left ventricle
  • a vessel that gives rise to coronary, head, and neck arteries connected to the right ventricle; visualized in the parasternal long-axis view
  • the two great arteries run parallel; visualized in the parasternal long-axis and subcostal view
  • usually, the aorta appears anterior and right of the pulmonary artery; visualized in the parasternal short-axis view
  • reduced systolic function

  
  2D image of transposition
  of the great arteries

• Doppler
• The following anomalies may be noted by the sonographer:
  • left sided tricuspid (systemic) regurgitation
  • ventricular septal defect
  • LVOT stenosis, usually subvalvular
  • RVOT stenosis, usually subaortic

  
  Doppler image of
  transposition of the
  great arteries

Assessment of the TGA and associated anomalies

The sonographer performs the following assessments to determine the exact anatomy of the heart and great vessel,s and the presence and severity of associated anomalies: 

• locations and relations of the atria and ventricles; visualized in the four-chamber view
• locations of the great vessels, and their relation to each other and to the atria; visualized in the parasternal long-axis view, parasternal short-axis view, and subcostal view
• assessment of the presence and severity of a shunt across a ventricular septal defect, if present
• assessment of the presence and severity of tricuspid regurgation, LVOT stenosis, and RVOT stenosis, if any present
• assessment of valve anomalies
• assessment of systolic function
• assessment of the presence of associated anomalies, eg, patent ductus arteriosus, atrial septal defect and patent foramen ovale.

Additional imaging/tests

• Physical examination
• Hyperoxia test to demonstrate cyanosis.
• Electrocardiography (ECG) may demonstrate ventricular hypertrophy.
• Chest x-ray may demonstrate dextrocardia in half the cases, and cardiomegaly.
• Transesophageal echocardiogram (TEE) may be used for improved imaging of associated lesions.
• Cardiac catheterization (coronary arteriography) use is limited, but may clarify coronary artery anomalies.

Treatment

• Medical 
  • prostaglandin E1 infusion to open and maintain a patent ductus arteriosus
  • correct for metabolic acidosis
  • treat hypoxemia
• Surgical
  • surgical repair
• Sometimes, balloon atrial septostomy to create an opening in the atrial septum
• pacemaker implantation, in case of associated AV conduction anomalies
• repair of associated lesions (VSD, pulmonary stenosis, tricuspid valve anomaly)

Prognosis

• Prognosis depends on the specific anatomy of the TGA, the associated anomalies, and the type of intervention. 
• Mortality rates in untreated infants are 30% within 1 week, 50% within 1 month, and 90% within 1 year (see reference).
• Long-term survival rate after surgical intervention is approximately 80 to 90% (see reference).

Complications

• heart failure
• arrhythmia
• Eisenmenger's syndrome
• post-surgery complications, in case of Mustard or Senning repair

Marfan's syndrome is caused by a mutation in the fibrillin-1 gene, which results in defective connective tissue production and maintenance. The disorder affects several organs and tissues, including the aorta, ocular lens, and bones. Defective connective tissue around the aorta leads to thinning and stiffening of its walls, which results in dilation of the aorta. The destruction of the connective tissue is continuous, so dilation of the aorta progresses as a result. Ultimately, this can lead to an aortic aneurysm and aortic dissection, which are life-threatening conditions.

Marfan's syndrome

Marfan's syndrome often also affects the atrioventricular valves. They are commonly thickened, and either the mitral or tricuspid valves, or both, prolapse in 50 to 80% of cases (see reference). In addition, regurgitation of the valves may be present at variable degrees.

Marfan's syndrome is one of the more common life-threatening disorders caused by mutation of a single gene. Due to the different structures that are affected and the progressive nature of the disorder, patients display a variety of symptoms, depending on their age. The severity of the disorder depends on aorta size and its growth rate. Exercise, and forceful static exercise in particular, increases aortic stress and puts patients at a higher risk. Pregnancy can also cause complications in women with Marfan's syndrome, especially during the third trimester and shortly after delivery.

Pathogenesis

• Congenital: caused by defective connective tissue formation due to abnormal fibrillin proteins.
• Results from an inherited or new (25%-30% of the cases) mutation of the fibrillin-1 gene on chromosome 15 (see reference).
• Causes thinning of aortic wall, dilation of aortic segments, and increased stiffness, ultimately leading to aortic dissection and rupture.

Clinical signs and symptoms
Symptoms vary and depend on the age of the patient and the stage of aortic dilation.

• thin, elongated limbs
• symptoms of mitral valve disease, in > 50% of the cases (see reference)
• visual problems, due to dislocation of ocular lens
• severe chest pain, in case of acute aortic dissection
• family history of Marfan's syndrome symptoms
• low back pain, and numbness or weakness in legs
• dyspnea
• palpitations

Cardiac auscultation

• decrescendo diastolic murmur from aortic regurgitation
• ejection click at apex, followed by holosystolic murmur from mitral regurgitation

Ultrasound findings
Assessment relies on more than one criterion.

• 2D
  The following anomalies may be noted by the sonographer:
  • aortic root dilation
  • aortic aneurysm
  • aortic dissection; most common cause of death
  • proximal main pulmonary artery dilation
  • mitral valve thickening and prolapse
  • tricuspid valve thickening and prolapsed
  • bicuspid aortic valve
  • mitral annular calcification
  • left ventricular dilation

  
  2D image of an
  enlargedaortic root in
  Marfan's syndrome

• Doppler
  The following anomalies may be noted by the sonographer:
  • aortic regurgitation
  • mitral regurgitation
  • dilated cardiomyopathy (rare)

  
  Color Doppler of an
  enlarged aortic root in
  Marfan's syndrome

Assessment of the Marfan's syndrome anomalies
The sonographer performs the following assessments to determine the presence of the involved anomalies and the severity of the aortic dilation:

• measurement of aorta diameter; an abnormally large aorta size (aortic root size > 1.9 cm/m²) (see reference) compared to gender and body surface area (BSA) indicates aortic dilation

• serial measurement of the largest diameter of the aortic root, sinotubular junction and ascending aorta; assessment of aortic dilation over time is important to determine the severity
• proximal main pulmonary artery dilation
• measurement of mitral valve and tricuspid valve thickness; increased in case of Marfan's syndrome
• assessment of mitral annular calcification
• assessment of systolic function; decreased in Marfan's syndrome
• measurement of left atrial size; increased in Marfan's syndrome
• assessment of the presence and severity of aortic regurgitation, mitral regurgitation, and dilated cardiomyopathy

Additional imaging/tests

• Physical examination may demonstrate
  • positive wrist and thumb signs (Walker sign and Steinberg sign) 
  • reduced upper-to-lower body segment ratio (0.85 vs 0.93), or arm span-to-height ratio > 1.05 (see reference)
  • scoliosis > 20^o (see reference)
  • reduced elbow extension (< 170^o) (see reference)
  • malformed hip joint (protrusio acetabuli) at any degree
• Ophthalmology examination may demonstrate lens dislocation. 
• Genetic testing demonstrates a mutation in the fibrillin 1 gene in 95% of the patients with classic Marfan's syndrome (see reference).
• Electrocardiography (ECG) may demonstrate arrhythmias.
• Chest x-ray may demonstrate enlargement of aorta and cardiac outline.
• Cardiac MR or CT can be used if ultrasound is inadequate, and may demonstrate an aortic aneurysm with an intimal flap and false lumen.
• Transesophageal echocardiogram (TEE) may be used to visualize the distal ascending and descending aorta and improvement of prosthetic valve assessment.

Treatment

• Observation
  • growth of the aorta needs to be routinely monitored in patients
  • moderate restriction of excercise
• Medical 
  • reduce aortic pressure and hence reduce progression of the aortic dilation
• Surgical
  • surgical replacement of aorta
  • surgical repair of valves, in case of valve prolapse

Prognosis

• Without intervention, life expectancy is reduced by approximately one third. 
• Contact sports, competitive athletics, and isometric exercise involve a high risk of acute aortic dissection (see reference).
• An aortic ratio increase of > 5% per year indicates a poor outcome (see reference).
• Higher mortality and event rates are involved when aortic root dimension > 5 cm, aortic ratio > 3, or aortic size index >= 4.25 cm/m² (see reference).
• Medical therapy delays aortic dilation and improves life expectancy.
• Elective surgical replacement of the aortic root and proximal aorta involves a very low mortality rate and improves life expectancy to nearly normal.
• Urgent and emergency surgical replacement of the aortic root and proximal aorta involve a higher mortality rate.

Complications

• mitral valve prolapse in 50 to 80% of the cases (see reference)
• arrhythmia
• post-surgery complications

Coarctation of the aorta (CoA) is a congenital, localized narrowing of the aortic lumen, distal of the left subclavian artery and usually around the ductus arteriosus. Rarely, aortic coarctation takes place in the abdominal aorta. It is unclear what causes the constriction, but hemodynamic factors and abnormal extension of ductus arteriosus tissue may play a role.

After closure of the ductus arteriosus at birth, the narrowing results in less arterial blood flow to the lower part of the body and more pressure on the upper part of the body. This causes hypertension in the upper extremities, left ventricular overload, and bad perfusion of abdominal organs and lower extremities.

Coarctation of
the aorta

The narrowing is usually discrete, but a longer segment of constriction may occur. CoA can be subdivided according to the location of the constriction in relation to the ductus arteriosus:

• preductal
• juxtaductal (90% of all cases) (see reference)
• postductal

CoA may occur alone, but is often associated with the following cardiovascular disorders:

• bicuspid aortic valve (50-80% of all cases) (see reference)
• patent ductus arteriosus (50% of all cases) (see reference)
• ventricular septal defect (35-40% of all cases) (see reference)
• aortic stenosis (15% of all cases) (see reference)
• Turner syndrome

Coarctation of the aorta occurs twice as often in males as in females. Symptoms depend on the severity of the constriction, the presence of associated disorders, and the level of pulmonary resistance. Severe CoA is usually detected in neonates presenting with symptoms of heart failure. Less severe cases may be detected in children, due to signs of hypertension, or CoA may be asymptomatic. Asymptomatic patients often developed collateral vessels that bypass the coarctation, preventing the development of heart failure.

In neonates, prostaglandin E2 infusion may be used to reopen the ductus arteriosus and thereby increase blood flow to the lower part of the body. When untreated, aortic coarctation can lead to left ventricular failure, rupture of the aorta, brain disease, and hypertensive cardiovascular disease in adults.

Pathogenesis

• Congenital, the cause is unknown.
• Genetic and environmental factors may play a role.

Clinical signs and symptoms
Symptoms vary and depend on the location, size, and severity of the constriction, associated anomalies, and the pulmonary resistance.

• asymptomatic
• systemic hypertension, in the upper-body in particular
• possibly leg claudication
• symptoms of heart failure
• cold extremities
• headache
• fatigue
• chest pain

Cardiac auscultation

• systolic murmur
• apical aortic ejection click, in the cases of bicuspid aortic valve
• S4
• systolic ejection murmur in a bicuspid aortic valve
• aortic regurgitation murmur in a bicuspid aortic valve

Ultrasound findings
Assessment relies on more than one criterion.

• 2D
  The following anomalies may be noted by the sonographer:
  • aortic narrowing or pinching; may be visualized at the suprasternal notch
  • possibly, pulsation increase proximal to the lesion at the aortic arch
  • left subclavian artery dilation, due to a pressure increase
  • post-stenotic thoracic aorta dilation; may be visualized in a high left parasternal imaging window
  • left ventricular hypertrophy
  • left atrial dilation
  • bicuspid aortic valve
  • systolic dysfunction

  
  2D image of coarctation
  of the aorta

• M-mode
  • left ventricular hypertrophy
  • left atrial enlargement
  • bicuspid aortic valve
• Doppler
  • color aliasing at the site of the narrowing
  • narrowed turbulent flow on spectral Doppler
  • tardus parvus pulse changes in the spectral Doppler of the abdominal aorta

  
  Doppler image -
  coarctation of the aorta

Assessment of the coarctation of the aorta

The sonographer performs the following assessments to determine the presence and severity of a coarctation: 

• location of coarctation (preductal, juxtaductal, postductal)
• measurement of velocity across the site of narrowing
• measure the peak pressure gradient across aortic narrowing; increase > 25 mm Hg
• assessment of the presence and severity of bicuspid aortic valve, patent ductus arteriosus, ventricular septal defect, aortic stenosis
• assessment of the presence of collateral vessels that bypass the coarctation; 
• indirect compensatory arterial flow through collateral vessels may be indicated by a reduction of the amplitude of the abdominal aortic spectral trace

Additional imaging/tests

• Physical examination may demonstrate:
  • elevated systolic blood pressure in upper extremities, > 20mm Hg compared to the legs (see reference)
  • normal or decreased systolic blood pressure in lower extremities
  • impalpable femoral pulses
  • cyanosis with exercise, in case of preductal coarctation
  • prominent suprasternal notch pulsation
• Electrocardiography (ECG) may demonstrate hypertrophy of the left ventricle and left atrial enlargement.
• Chest x-ray may demonstrate cardiomegaly.
• Transesophageal echocardiogram (TEE) may be used to:
  • asses diameter and cross-section area of coarctation in the descending thoracic aorta 
  • assist during balloon angioplasty dilation

Treatment

• Observation
  • lifelong follow-up of patients should take place to monitor potential recoarctation and development of long-term complications
• Medical
  • reopen the ductus arteriosus and allow blood flow to lower part of the body, in neonates
  • treat hypertension
  • treat heart failure
• Surgical
  • surgical correction
  • balloon angioplasty, with or without stent

Prognosis

• Without intervention, the mortality rate is 90% by the age of 50 (see reference).
• Surgical repair has a good outcome and low mortality rates of < 5% for infants and < 1% for older children (see reference).
• Balloon angioplasty has a high success rate (80-90%) and a good long-term outcome, with better event-free rates in children than in infants and neonates (see reference).
• Residual coarctation is common after both surgical intervention and balloon angioplasty (6-33%), occurring more frequently in younger patients, and requiring repeated intervention (see reference).

Complications

• renal failure
• hypertension
• post-surgery complications

Tetralogy of Fallot is a congenital disorder that involves a combination of four defects:

• overriding aorta
• ventricular septal defect (perimembranous)
• pulmonary stenosis
• right ventricular hypertrophy

Each of these aspects can vary in severity, affecting the onset and severity of symptoms and the required intervention. The ventricular septal defect is usually large, and allows bidirectional shunting. The concurrent obstruction of the pulmonary artery due to stenosis results in a blood shunt from the right to the left ventricle. From both ventricles, a large proportion of blood flows into the overriding aorta. This causes low oxygen saturation of the body, and subsequent symptoms of cyanosis.

The severity of the disorder largely depends on the severity of the right ventricular outflow obstruction. Mild pulmonary stenosis causes a left-to-right shunt in the heart, while severe stenosis results in the right-to-left shunt that causes the cyanotic symptoms. Physical activities, especially in children up to 2 years, can cause a sudden increase in right ventricular outflow obstruction. The subsequent increase in right-to-left shunt and sudden decrease in systemic oxygen saturation results in tet spells.

Tetralogy of Fallot is often associated with other cardiovascular anomalies, including a right aortic arch (25% of all cases), abnormal coronary artery anatomy, and atrial septal defects. Typically, tetralogy of Fallot becomes apparent in infants, but it may be detected during prenatal ultrasound examination.

Pathogenesis

• Congenital: caused by defective development of the right ventricular outflow tract. 
• Maternal diabetes, phenylketonuria (PKU), retinoic acid intake, and several chromosomal anomalies may be associated with the development of tetralogy of Fallot.

Clinical signs and symptoms
Symptoms vary and depend on the severity of the different aspects of the disorder and the presence of associated anomalies.

• progressive cyanosis
• tet spells
• exercise intolerance
• dyspnea with feeding
• poor growth
• symptoms of heart failure

Cardiac auscultation

• harsh, systolic ejection murmur
• single S2
• pulmonary regurgitation
• aortic regurgitation murmur

Ultrasound findings
Assessment relies on more than one criterion.

• 2D
  The following anomalies may be noted by the sonographer:
  • overriding aorta, which is displaced to the right; visualized in the parasternal long-axis, the apical five-chamber, and the subcostal views
  • ventricular septal defect (usually perimembranous); visualized in the parasternal long-axis, the apical five-chamber, and the subcostal
  • right ventricular hypertrophy; visualized in the parasternal long-axis, the apical five-chamber and the subcostal views
  • pulmonary stenosis; best visualized from the parasternal short-axis view
  • right ventricle hypertrophy and dilation
  • left ventricle is smaller than the right ventricle
  • systolic dysfunction

  
  2D image of tetralogy
  of Fallot

• M-mode may provide a limited assessment of the overriding aorta17
• Doppler
  The following anomalies may be noted by the sonographer:
  • narrowing in the right ventricular outflow tract (RVOT)
  • ventricular septal defect

  
  Doppler image of
  tetralogy of Fallot

Assessment of the tetralogy of Fallot anomalies
The sonographer performs the following assessments to determine the presence and severity of the involved anomalies:

• location and severity of RVOT stenosis (subvalvular or valvular); best visualized in the parasternal short-axis and subcostal views
• assessment of the severity of the ventricular septal defect
• assessment of the presence and severity of associated anomalies, eg, atrial septal defect
• assessment of right ventricular hypertrophy

Additional imaging/tests

• Physical examination may demonstrate:
  • cyanosis
  • clubbing
• Electrocardiography (ECG) may demonstrate:
  • right ventricular hypertrophy
  • right axis deviation
• Chest x-ray/cardiac MRI/CT may demonstrate cardiomegaly with a boot-shaped heart.
• Cardiac catheterization is rarely performed, but may be used to obtain a pressure gradient between the right ventricular infundibulum and the main pulmonary artery.

Treatment

• Observation
  • lifelong follow-up of patients should take place to monitor the development of long-term complications
• Medical 
  • open the ductus arteriosus to allow shunting of oxygen-rich blood to the aorta, in neonates
  • prevent and treat tet spells
  • treat anemia or polycythemia
• Surgical
  • complete surgery
  • palliative surgery
  • repair of associated anomalies
  • balloon angioplasty to stretch the pulmonary outflow tract

Prognosis

• Without intervention, the mortality rate is 25% by the age of 12 months, 45% by the age of 5 years, 70% by the age of 10 years, and 95% by the age of 40 years (see reference).
• Surgical repair involves a mortality rate of < 5%, good long-term outcomes, and a long-term survival rate of approximately 85% (see reference).

Complications

• progressive infundibular stenosis
• hypoxic spells
• coagulopathies
• cerebral vascular accident
• infective endocarditis
• acquired aortic valve disease
• arrhythmias
• post-surgery complications

Ebstein anomaly is a rare congenital malformation of the leaflets of the tricuspid valve and the right ventricle. The normal tricuspid valve is located between the right atrium and right ventricle, and has three leaflets: an anterior, a posterior, and a septal leaflet.

Ebstein anomaly involves the following abnormal features:

• The septal and posterior leaflets are adhered to the underlying myocardium.
• The functional annulus of the valve is displaced downwards. 
• The part of the right ventricle above the annulus ("atrialized" part) is dilated.
• The anterior leaflet is tethered, fenestrated, and generally redundant.
• The right atrioventricular junction is dilated.

The malformation and dilation of the right ventricle and regurgitation of the tricuspid valve impair forward blood flow through the right side of the heart and ejection into the pulmonary circulation. This causes cyanosis, right-sided heart failure, arrhythmias, and possibly sudden cardiac death.

Ebstein anomaly

The severity of the anomaly can be classified, based on the degree of leaflet displacement and dilation of the right ventricle, as assessed by echocardiography. Another method to assess the severity is based on the exact anatomy that is present, as observed during surgery. Ebstein anomaly is often associated with many other cardiovascular anomalies, including atrial septal defects (in 80-94% of the cases, usually with a right-to-left shunt) (see reference), ventricular septal defects, pulmonary stenosis, and aortic and mitral valve anomalies.

The anatomical severity, the patient's age, hemodynamics, the degree of right-to-left shunting, and the associated anomalies determine the onset and the variety of symptoms. Commonly, Ebstein anomaly is detected prenatally, or shortly after birth. Children may suffer progressive right-sided heart failure, but most reach adulthood. Asymptomatic patients may do well for several years, while severe cases need early surgical intervention.

Pathogenesis

• Congenital: caused by developmental malformation of the tricuspid valve leaflets. 
• Genetic, reproductive, and environmental factors may play a role. 
• Associated with maternal use of lithium during pregnancy. 

Clinical signs and symptoms
Symptoms vary and depend on the specific tricuspid valve anatomy and the presence of associated anomalies.

• Neonates
  • cyanosis
  • heart failure
  • cardiomegaly
• Older children and adults
  • dyspnea
  • fatigue
  • progressive cyanosis
  • palpitations
  • symptoms of right-sided heart failure
  • arrhythmias

Cardiac auscultation

• widely split S1
• "sail" sound
• widely and persistently split S2
• systolic murmur of tricuspid regurgitation
• diastolic rumble, caused by increased flow across tricuspid valve

Ultrasound findings

Assessment relies on more than one criterion.

• 2D
  The following anomalies may be noted by the sonographer:
  • right ventricular enlargement with paradoxical septal motion
  • tricuspid septal and posterior leaflet displacement; visualized in the apical four-chamber view
  • tethering of the tricuspid valve
  • restricted movement of the tricuspid valve leaflets
  • tricuspid valve annulus dilation
  • right atrium dilation
  • atrialized right ventricle; best visualized in the apical four-chamber view at end diastole phase

  
  2D image of
  Ebstein anomaly

• Doppler
  The following anomalies may be noted by the sonographer:
  • tricuspid regurgitation
  • tricuspid stenosis 
  • patent foramen ovale 
  • atrial septal defect (predominantly right-to-left shunt) 
  • valvular pulmonic stenosis/atresia

  
  Doppler image of
  Ebstein anomaly

Assessment of the anomalies present in Ebstein anomaly

The sonographer performs the following assessments to determine the presence and severity of the involved anomalies:

• measurement of the tricuspid septal and posterior leaflet displacement; measured from the level of the mitral valve annulus in the apical four-chamber view, displacement >= 8 mm/m2 body surface area is considered Ebstein anomaly (see reference)

  
  Measurement of
  leaflet displacement

• assessment of the severity and location of tricuspid regurgitation, tricuspid stenosis, and tricuspid valve annulus dilation
• assessment of the presence and severity of associated anomalies, including atrial septal defects, ventricular septal defects, patent foramen ovale, pulmonary stenosis, aortic and mitral valve anomalies
• assessment of right atrium dilation

Additional imaging/tests

• Electrocardiography (ECG) may demonstrate right ventricular enlargement.
• Chest x-ray may demonstrate cardiomegaly.
• CT may demonstrate reduced vascularity without pulmonary enlargement.
• Cardiac MRI may provide additional information on valvular regurgitation, and volume and function of the right ventricle.
• Transesophageal echocardiography (TEE) may provide clearer images of the cardiac defects.

Treatment

• Medical 
  • treat heart failure
  • treat arrhythmias, in combination with surgical intervention40
  • prophylaxis for endocarditis
• Surgical
  • tricuspid valve replacement
  • plication with closure of atrial septal defect
  • annuloplasty for tricuspid regurgitation
  • catheter ablation for supraventricular arrhythmias
  • Fontan procedure
  • heart transplantation

Prognosis

• Symptomatic neonates have a poor prognosis, 20 to 40% die within 1 month, and > 50% die within 5 years (see reference).
• Without intervention, mortality is approximately 12% in children and adolescents (see reference).
• Early mortality after surgery is approximately 5 to 9%, mortality within 20 to 25 year after surgery is approximately 8 to 20% (see reference).

Complications

• heart failure
• paradoxical embolization
• brain abscess
• sudden death
• bacterial endocarditis
• transient ischemic attacks
• stroke
• post-surgery complications

Pulmonary stenosis is a congenital narrowing of the pulmonary outflow tract, commonly due to fusion of the valve cusps. This results in restricted blood flow through the pulmonary valve, or right ventricular outflow tract, towards the pulmonary artery. As a result, there is volume and pressure overload of the right ventricle, and therefore, right ventricular dilation.

Pulmonary stenosis can be classified according to the location of the constriction:

• valvular (80% of the cases) (see reference)
• subvalvular, when below the valve
• supravalvular, when above the valve

Pulmonary stenosis

Pulmonary stenosis mainly affects children, but often does not cause symptoms until adulthood. Pulmonary stenosis is associated with exposure to rubella during pregnancy, and in particular in the first trimester.

Pathogenesis

• Congenital: most often caused by malformation of pulmonary valve tissue and of the bulbus cordis.
• Usually occurs sporadic, but may occur as part of tetralogy of Fallot or another syndrome.

Clinical presentation

• asymptomatic
• dyspnea
• fatigue
• reduced exercise tolerance
• cyanosis
• peripheral edema
• sudden death

Cardiac auscultation

• harsh systolic ejection murmur
• widely split S2

Ultrasound findings

• 2D
  The following anomalies may be noted by the sonographer:
  • thickened pulmonary valve leaflets with restricted opening
  • right ventricle dilation
  • right ventricular hypertrophy
  • post-stenotic dilation of the main pulmonary artery
  • "D-shaped" flattening interventricular septal motion due to right ventricular pressure overload 
  • possibly, enlargement of the right atrium
  • possibly, dilated inferior vena cava (IVC)

  
  Post-stenotic dilated
  pulmonary artery

• M-mode
  The following anomalies may be noted by the sonographer:
  • increased RVIDd
  • normal LVIDd and LVIDs
  • normal  fractional shortening (FS)

  
  M-mode image of
  normal ventricles

• Doppler
  The following anomalies may be noted by the sonographer:
  • a turbulent jet leading into the pulmonary artery; visualized with color Doppler
  • a dense turbulent jet; visualized with spectral Doppler
  • a subvalvular or supravalvular stenotic lesion; visualized with pulsed-wave Doppler
  • tricuspid regurgitation with elevated peak flow, consistent with elevated right ventricular pressures

  
  Color Doppler of a
  dense turbulent jet

Assessment of the pulmonary stenosis severity

The sonographer performs the following assessments to determine the degree (mild, moderate, or severe) of pulmonary stenosis:

• assessment of the location and severity of the stenosis
• measurement of mean and peak pressure gradients
• measurement of LVOT VTI
• measurement of the pulmonary valve area by the continuity equation

Additional imaging/tests

• Physical examination
• Pulmonary angiography may demonstrate domed leaflets.
• Electrocardiography (ECG) is usually normal in mild pulmonary stenosis but right ventricle hypertrophy may be noted as severity increases.
• Chest x-ray may demonstrate a normal-sized heart but a possible prominent pulmonary artery.
• Cardiac catheterization is indicated only if pulmonary stenosis is severe.

Treatment 

• Medicine
  • to treat underlying condition
  • to treat heart failure symptoms
• Surgical
  • balloon valvuloplasty to stretch and open the valve
  • valvotomy
  • balloon angioplasty, with or without stent

Prognosis

• The prognosis is dependent on severity and prognosis of underlying disorder.
• Generally good; mild pulmonary stenosis does not require treatment.
• Treatment of severe pulmonary stenosis has an excellent long-term outcome.

Complications

• right heart failure
• endocarditis

References

Textbooks

Feigenbaum H, Armstrong F, Ryan T. Feigenbaum's Echocardiography 6th ed. Lippincott Williams & Wilkins: Philadelphia, 1994.

Moore KL, Persaud TVN. Before we are born: essentials of embryology and birth defects 5th ed. W.B. Saunders company: Philadelphia, 1998.

Reynolds T. The Echocardiographer's Pocket Reference. 3rd ed. Phoenix, Arizona: Arizona Heart Institute, 2007.

Web articles

Attenhofer Jost CH, Connolly HM, Dearani JA, Edwards WD, Danielson GK. Ebstein's anomaly. Circulation. 2007 Jan 16;115(2):277-285.
PMID: 17228014

Bailliard F, Anderson RH. Tetralogy of Fallot. Orphanet J Rare Dis. 2009 Jan 13;4:2.
PMID: 19144126

Charpie JR, Maher KO. Transposition of the Great Arteries. eMedicine.
Available at:
http://emedicine.medscape.com/article/900574-overview.
Accessed May 20, 2010.

Chen H. Marfan Syndrome. eMedicine.
Available at:
http://emedicine.medscape.com/article/946315-overview.
Accessed May 25, 2010.

Greenberg SB. Tetralogy of Fallot. eMedicine.
Available at:
http://emedicine.medscape.com/article/350898-overview.
Accessed May 26, 2010.

Ha HI, Seo JB, Lee SH, Kang JW, Goo HW, Lim TH, Shin MJ. Imaging of Marfan syndrome: multisystemic manifestations. Radiographics. 2007 Jul-Aug;27(4):989-1004.
PMID: 17620463

Hoffman JI, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol. 2002 Jun 19;39(12):1890-900.
PMID: 12084585

Jude DP, Dietz HC. Marfan's syndrome. Lancet. 2005 Dec 3;366(9501):1965-76.
PMID: 16325700

Kean MG, Pyeritz RE. Medical management of Marfan syndrome. Circulation. 2008 May 27;117(21):2802-13.
PMID: 18506019

Love BA, Mehta D, Fuster VF. Evaluation and management of the adult patient with transposition of the great arteries following atrial-level (Senning or Mustard) repair. Nat Clin Pract Cardiovasc Med. 2008 Aug;5(8):454-467.
PMID:18594551

Love BA, Portman MA. Atrial septal defect, patent foramen ovale. eMedicine.
Available at:
http://emedicine.medscape.com/article/894483-overview.
Accessed May 27, 2010.

Markham LW, Cribbs MG. Atrial Septal Defect. eMedicine.
Available at:
http://emedicine.medscape.com/article/162914-overview.
Accessed May 14, 2010.

Martins P, Castela E. Transposition of the great arteries. Orphanet J Rare Dis. 2008 Oct 13;3:27.
PMID: 18851735

The Merck manual for healthcare professionals. Atrial Septal Defect (ASD) (Ostium Secundum Defect).
Available at:
http://www.merck.com/mmpe/sec19/ch287/ch287b.html?qt=atrial septal defect&alt=sh#sec19-ch287-ch287b-2073.
Accessed May 17, 2010.

The Merck manual for healthcare professionals. Coarctation of the aorta.
Available at:
http://www.merck.com/mmpe/sec19/ch287/ch287f.html.
Accessed May 25, 2010.

The Merck manual for healthcare professionals. Tetralogy of Fallot.
Available at:
http://www.merck.com/mmpe/sec19/ch287/ch287g.html.
Accessed May 26, 2010.

The Merck manual for healthcare professionals. Transposition of the Great Arteries.
Available at:
http://www.merck.com/mmpe/sec19/ch287/ch287h.html.
Accessed May 20, 2010.

The Merck manual for healthcare professionals. Ventricular Septal Defect (VSD).
Available at:
http://www.merck.com/mmpe/sec19/ch287/ch287c.html.
Accessed May 20, 2010.

Milliken JC, Galovich J. Patent Ductus Arteriosus. eMedicine.
Available at:
http://emedicine.medscape.com/article/162796-overview.
Accessed March 15, 2010.

Milliken JC, Galovich J. Ventricular Septal Defect. eMedicine.
Available at:
http://emedicine.medscape.com/article/162692-overview.
Accessed March 15, 2010.

Neish SR. Patent Ductus Arteriosus. eMedicine.
Available at:
http://emedicine.medscape.com/article/891096-overview.
Accessed March 15, 2010.

Ramaswamy P, Anbumani P, Srinivasan K. Ventricular Septal Defect, General Concepts. eMedicine.
Available at:
http://emedicine.medscape.com/article/892980-overview.
Accessed May 20, 2010.

Rao P, Seib PM. Coarctation of the Aorta. eMedicine.
Available at:
http://emedicine.medscape.com/article/895502-overview.
Accessed May 25, 2010.

Sadowski SL. Congenital cardiac disease in the newborn infant: past, present, and future.
Crit Care Nurs Clin North Am. 2009 Mar;21(1):37-48, vi.
PMID: 19237042

Shah SN, Calderon DM. Patent Foramen Ovale. eMedicine.
Available at:
http://emedicine.medscape.com/article/156863-overview.
Accessed March 16, 2010.

Singh VN, Sharma RK, Reddy HK, Nanda NC. Ventricular Septal Defect. eMedicine.
Available at:
http://emedicine.medscape.com/article/351705-overview.
Accessed May 19, 2010.

Wallace DJ, Erogul M, Pflieger K. Pulmonic Valvular Stenosis. eMedicine.
Available at:
http://emedicine.medscape.com/article/759890-overview.
Accessed March 15, 2010.

Writing group members, Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, et al. Heart disease and stroke statistics 2010 update: a report from the American Heart Association. Circulation. 2010 Feb 23;121(7):e46-e215.
PMID: 20019324

Websites

Echocardiology.org: Echocardiography tutorials. Congenital Disease.
Available at:
www.echocardiology.org/.
Accessed May 14, 2010.

U.S. Department of Health & Human Services. Health Information Privacy. The Health Insurance Portability Act of 1996 (HIPAA) Privacy Rule.
Available at:
http://www.hhs.gov/ocr/privacy/index.html.
Accessed June 10, 2010.

Bibliography

Textbooks

Feigenbaum H, Armstrong F, Ryan T. Feigenbaum's Echocardiography 6th ed. Lippincott
Williams & Wilkins: Philadelphia, 1994.

Larsen WJ. Human Embryology 3rd ed. Churchill Livingstone: Philadeplhia, 2001. Online book preview.
Available at:
http://books.google.co.nz/books?id=H5qw-jiMc44C&pg=PA159&lpg=PA159&dq=fusion+paired+dorsal+aortas+human&source=bl&ots=08Ic8JaJD9&sig=s1x9pVt5bx-2EqWN6Ek6H-tZgAg&hl=en&ei=H3LnS4RRiPyyA96q9JoJ&sa=X&oi=book_result&ct=result&resnum=9&ved=0CDgQ6AEwCA#v=onepage&q&f=false.
Accessed May 17, 2010.

Moore KL, Persaud TVN. Before we are born: essentials of embryology and birth defects 5th ed. W.B. Saunders company: Philadelphia, 1998.

Rana MW. Human embryology made easy. Harwood Academic Publishers: Amsterdam, 1998. Online book preview.
Available at: http://books.google.co.nz/books?id=JIFV2L3tjKEC&pg=PA127&lpg=PA127&dq=fusion+paired+dorsal+aortas+human&source=bl&ots=uFe1Z12gHl&sig=I5cTkhloxwqBF3pggEFZWASX27M&hl=en&ei=H3LnS4RRiPyyA96q9JoJ&sa=X&oi=book_result&ct=result&resnum=7&ved=0CDAQ6AEwBg#v=onepage&q&f=false
Accessed May 17, 2010.

Reynolds T. The Echocardiographer's Pocket Reference. 3rd ed. Phoenix, Arizona: Arizona Heart Institute, 2007.

Zwiebel W, Pellerito J. Introduction to vascular ultrasonography. 5th ed. Saunders: Philadelphia, 2004.

Web articles

Attenhofer Jost CH, Connolly HM, Dearani JA, Edwards WD, Danielson GK. Ebstein's anomaly. Circulation. 2007 Jan 16;115(2):277-285.
PMID: 17228014

Bailliard F, Anderson RH. Tetralogy of Fallot. Orphanet J Rare Dis. 2009 Jan 13;4:2.
PMID: 19144126

Bashore TM. Adult congenital heart disease: right ventricular outflow tract lesions. Circulation. 2007 Apr 10;115(14):1933-47.
PMID: 17420363

Bochmann L, Sarathchandra P, Mori F, Lara-Pezzi E, Lazzaro D, Rosenthal N. Revealing new mouse epicardial cell markers through transcriptomics. PLoS One. 2010 Jun 28;5(6):e11429.
PMID: 20596535

Boullin J, Morgan JM. The development of cardiac rhythm. Heart 2005 Jul;91(7):874-5.
PMID: 15958352

Charpie JR, Maher KO. Transposition of the Great Arteries. eMedicine.
Available at:
http://emedicine.medscape.com/article/900574-overview.
Accessed May 20, 2010.

Chen H. Marfan Syndrome. eMedicine.
Available at:
http://emedicine.medscape.com/article/946315-overview.
Accessed May 25, 2010.

Di Meglio F, Castaldo C, Nurzynska D, et al. Epithelial-mesenchymal transition of epicardial mesothelium is a source of cardiac CD117-positive stem cells in adult human heart. J Mol Cell Cardiol. 2010 Jun 4.
PMID: 20566360

Greenberg SB. Tetralogy of Fallot. eMedicine.
Available at:
http://emedicine.medscape.com/article/350898-overview.
Accessed May 26, 2010.

Ha HI, Seo JB, Lee SH, Kang JW, Goo HW, Lim TH, Shin MJ. Imaging of Marfan syndrome: multisystemic manifestations. Radiographics. 2007 Jul-Aug;27(4):989-1004.
PMID: 17620463

Hoffman JI, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol. 2002 Jun 19;39(12):1890-900.
PMID: 12084585

Jude DP, Dietz HC. Marfan's syndrome. Lancet. 2005 Dec 3;366(9501):1965-76.
PMID: 16325700

Kean MG, Pyeritz RE. Medical management of Marfan syndrome. Circulation. 2008 May 27;117(21):2802-13.
PMID: 18506019

Lie-Venema H, van den Akker NM, Bax NA, et al. Origin, fate, and function of epicardium-derived cells (EPDCs) in normal and abnormal cardiac development. ScientificWorldJournal. 2007 Nov 12;7:1777-98.
PMID:18040540

Love BA, Mehta D, Fuster VF. Evaluation and management of the adult patient with transposition of the great arteries following atrial-level (Senning or Mustard) repair. Nat Clin Pract Cardiovasc Med. 2008 Aug;5(8):454-467.
PMID:18594551

Love BA, Portman MA. Atrial septal defect, patent foramen ovale. eMedicine.
Available at:
http://emedicine.medscape.com/article/894483-overview.
Accessed May 27, 2010.

Markham LW, Cribbs MG. Atrial Septal Defect. eMedicine.
Available at:
http://emedicine.medscape.com/article/162914-overview.
Accessed May 14, 2010.

Martins P, Castela E. Transposition of the great arteries. Orphanet J Rare Dis. 2008 Oct 13;3:27.
PMID: 18851735

The Merck manual for healthcare professionals. Atrial Septal Defect (ASD) (Ostium Secundum Defect).
Available at:
http://www.merck.com/mmpe/sec19/ch287/ch287b.html?qt=atrial septal defect&alt=sh#sec19-ch287-ch287b-2073.
Accessed May 17, 2010.

The Merck manual for healthcare professionals. Coarctation of the aorta.
Available at:
http://www.merck.com/mmpe/sec19/ch287/ch287f.html.
Accessed May 25, 2010.

The Merck manual for healthcare professionals. Other less common congenital cardiac anomalies.
Available at:
http://www.merck.com/mmpe/sec19/ch287/ch287n.html#sec19-ch287-ch287l-2252i.
Accessed May 26, 2010.

The Merck Manual for Healthcare Professionals. Patent Ductus Arteriosus (PDA).
Available at:
http://www.merck.com/mmpe/sec19/ch287/ch287e.html.
Accessed May 21, 2010.

The Merck manual for healthcare professionals. Pulmonic stenosis.
Available at:
http://www.merck.com/mmpe/sec07/ch076/ch076h.html?qt=pulmonary%20stenosis&alt=sh.
Accessed May 28, 2010.

The Merck manual for healthcare professionals. Tetralogy of Fallot.
Available at:
http://www.merck.com/mmpe/sec19/ch287/ch287g.html.
Accessed May 26, 2010.

The Merck manual for healthcare professionals. Transposition of the Great Arteries.
Available at:
http://www.merck.com/mmpe/sec19/ch287/ch287h.html.
Accessed May 20, 2010.

The Merck manual for healthcare professionals. Ventricular Septal Defect (VSD).
Available at:
http://www.merck.com/mmpe/sec19/ch287/ch287c.html.
Accessed May 20, 2010.

Milliken JC, Galovich J. Patent Ductus Arteriosus. eMedicine.
Available at:
http://emedicine.medscape.com/article/162796-overview.
Accessed March 15, 2010.

Milliken JC, Galovich J. Ventricular Septal Defect. eMedicine.
Available at:
http://emedicine.medscape.com/article/162692-overview.
Accessed March 15, 2010.

Muñoz-Chápuli R, Macías D, González-Iriarte M, Carmona R, Atencia G, Pérez-Pomares JM. The epicardium and epicardial-derived cells: multiple functions in cardiac development. Rev Esp Cardiol. 2002 Oct;55(10):1070-82.
PMID: 12383393

Neish SR. Patent Ductus Arteriosus. eMedicine.
Available at:
http://emedicine.medscape.com/article/891096-overview.
Accessed March 15, 2010.

Olivey HE, Svensson EC. Epicardial-myocardial signaling directing coronary vasculogenesis. Circ Res. 2010 Mar 19;106(5):818-32
PMID: 20299672

Ramaswamy P, Anbumani P, Srinivasan K. Ventricular Septal Defect, General Concepts. eMedicine.
Available at:
http://emedicine.medscape.com/article/892980-overview.
Accessed May 20, 2010.

Rao P, Seib PM. Coarctation of the Aorta. eMedicine.
Available at:
http://emedicine.medscape.com/article/895502-overview.
Accessed May 25, 2010.

Riaz K. Ebstein anomaly. eMedicine.
Available at:
http://emedicine.medscape.com/article/154447-overview.
Accessed May 27, 2010.

Sadowski SL. Congenital cardiac disease in the newborn infant: past, present, and future.
Crit Care Nurs Clin North Am. 2009 Mar;21(1):37-48, vi.
PMID: 19237042

Shah SN, Calderon DM. Patent Foramen Ovale. eMedicine.
Available at:
http://emedicine.medscape.com/article/156863-overview.
Accessed March 16, 2010.

Singh VN, Sharma RK, Reddy HK, Nanda NC. Ventricular Septal Defect. eMedicine.
Available at:
http://emedicine.medscape.com/article/351705-overview.
Accessed May 19, 2010.

Swan L, Wilson N, Houston AB, Doig W, Pollock JCS, Stewart Hillis W. The long-term management of the patient with an aortic coarctation repair. Eur Heart J. 1998 Mar;19(3):382-6.
PMID: 9568441

Wallace DJ, Erogul M, Pflieger K. Pulmonic Valvular Stenosis. eMedicine.
Available at:
http://emedicine.medscape.com/article/759890-overview.
Accessed March 15, 2010.

Writing group members, Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, et al. Heart disease and stroke statistics 2010 update: a report from the American Heart Association. Circulation. 2010 Feb 23;121(7):e46-e215.
PMID: 20019324

Websites

Echocardiology.org: Echocardiography tutorials. Congenital Disease.
Available at:
www.echocardiology.org/.
Accessed May 14, 2010.

The Free Dictionary by Farlex. Medical dictionary.
Available at:
http://medical-dictionary.thefreedictionary.com.
Accessed June 10, 2010.

Gaffer RF. Atlas of human embryos. The endowment for human development.
Available at:
http://www.ehd.org/classics/gasser_ch5.php#VI.
Accessed May 17, 2010.

LeVert E, Goodgame R. Shortness of breath in a patient with cirrhosis: diagnostic questions. Medscape General Medicine 3(2), 2001.
Available at:
http://www.medscape.com/viewarticle/405520_2.
Accessed May 19, 2010.

Sulik KK, Bream Jr PR, Poe T, Bindra K. Embryo Images Normal and Abnormal Mammalian Development tutorial - Cardiovascular system.
Available at:
http://www.med.unc.edu/embryo_images/unit-cardev/cardev_htms/cardevtoc.htm.
Accessed May 17, 2010.

Swiss virtual campus. Human embryology - online course in embryology for medicine students. Organogenesis - module 16: cardiovascular system.
Available at:
http://www.embryology.ch/anglais/pcardio/planmodcardio.html.
Accessed May 17, 2010.

U.S. Department of Health & Human Services. Health Information Privacy. The Health Insurance Portability Act of 1996 (HIPPA) Privacy Rule.
Available at:
http://www.hhs.gov/ocr/privacy/index.html.
Accessed March 4, 2010.