Tetralogy of Fallot

OVERVIEW: What every practitioner needs to know

Are you sure your patient has tetralogy of Fallot? What are the typical findings for this disease?

The most common signs and symptoms seen for a newborn with tetralogy of Fallot include: 1) a loud heart murmur (systolic ejection murmur at the left upper sternal border due to pulmonic stenosis and/or holosystolic murmur at the left mid sternal border due to a ventricular septal defect); and 2) cyanosis.

The next most common sign is tachypnea, especially in patients with tetralogy of Fallot where there is only mild right ventricular outflow tract obstruction. These are the so-called “pink Tets.” The tachypnea is due to pulmonary overcirculation, resulting from left to right flow across the ventricular septal defect.

The child or adolescent with repaired tetralogy of Fallot

The most common physical finding for a child or adolescent with repaired tetralogy of Fallot (TOF) is a residual heart murmur. This is often a combination of a systolic ejection murmur due to residual right ventricular outflow tract obstruction (i.e., subpulmonary or pulmonary valve stenosis) and a diastolic murmur due to pulmonary regurgitation. Sometimes a holosystolic murmur may be heard if there is a residual ventricular septal defect. The diastolic murmur is best heard using the stethoscope’s bell, as it is a low pitched sound.

A child/adolescent with repaired TOF will have a thoracic surgical scar. This will be a midline sternotomy scar after full repair; a lateral thoracotomy scar is often seen if the patient previously received palliation with a Blalock-Taussig shunt.

Children and adolescents with repaired tetralogy of Fallot are often asymptomatic and often have good exercise tolerance on treadmill testing with VO₂ max similar to age matched peers. Such patients, though, are at risk for ventricular dysrhythmias, particularly as their QRS duration on EKG exceeds 180 ms. They may experience these rhythm abnormalities as palpitations, chest pain, dizziness, lightheadedness, or syncope. Primary multivariate analysis has shown that a QRS duration of 180 ms or more is predictive of ventricular tachycardia and sudden death, while age at repair is predictive of sudden death and atrial flutter/fibrillation. Other complications include progressive pulmonary insufficiency or stenosis, tricuspid regurgitation, aortic insufficiency, branch pulmonary stenosis, and heart failure. Signs of heart failure include jugular venous distention, peripheral edema, and hepatosplenomegaly.

What are the anatomic defects present in patients with tetralogyof Fallot?

Tetralogy of Fallot was first recognized in 1673. It bears the name of Étienne-Louis Fallot, who coined the term “tetralogy.” His description of “L’anatomie pathologique de la maladie bleu” first appeared in 1888.

The constellation of cardiac findings is thought to be due to anterior deviation of the conal septum, which results in 4 anatomic findings seen in the accompanying image (See Figure 1):

Figure 1.

1) Large ventricular septal defect

2) Overriding aorta

3) Subpulmonary (or infundibular) stenosis

4) Right ventricular hypertrophy

What other disease/condition shares some of these symptoms?

Cyanotic congenital heart diseases classically include the “5 T’s”:

1. Tetralogy of Fallot

2. Truncus arteriosus

3. Transposition of the great arteries (TGA)

4. Tricuspid atresia

5. Total anomalous pulmonary venous return

Tetralogy of Fallot, however, falls on a wide spectrum and can mirror cardiac lesions ranging from isolated pulmonary valve stenosis to degrees of Double Outlet Right Ventricle.

What caused this disease to develop at this time?

The etiology of congenital heart disease is an area of active research. It is currently still believed to be a combination of genes and environment. While no single isolated factor has been identified, some associations have been made.

DiGeorge syndrome (22q11.2 deletion syndrome) is the most common underlying genetic association for tetralogy of Fallot (TOF), seen in 10%-16% per literature review. This syndrome may also be associated with other conotruncal defects, such as truncus arteriosus and double outlet right ventricle.

Trisomy 21 (Down syndrome) is the next most common genetic abnormality associated with TOF.

More rare, mutations in NKX2.5, JAG1 (found in Allagile’s syndrome), FOG27, trisomy 13, and CHARGE syndrome can be seen in association with TOF.

Because DiGeorge Syndrome is common, screening with fluorescent in situ hybridization study (FISH) should be routine, and recognition of key features is important, so that appropriate interventions can be undertaken when needed. These features include: phenotypic facies , developmental delay/ learning disabilities/ speech delay, hypocalcemia (due to parathyroid under-development), and immune deficiency (related to thymic hypoplasia).

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Critically ill patients will require immediate cardiopulmonary support to maintain organ perfusion and oxygenation. In a stable patient, first confirm the presence of central cyanosis, defined by a reduced arterial O2 saturation. An ABG would be helpful to help differentiate cardiac versus respiratory disease asthe most likely etiology for cyanosis. The differential for cyanosis includes cyanotic heart disease, but could also be caused by hypoventilation, ventilation/perfusion mismatch, aveloar diffusion impairment, and hematologic disorders.

Pre- and post-ductal saturations are also helpful in determining the presence of right to left shunt across the ductus, and can be used as a secondary measure for the degree of pulmonary stenosis or lung disease.

Would imaging studies be helpful? If so, which ones?

• EKG (See Figure 2)

• CXR (See Figure 3)

• Echocardiogram

Figure 2.

Figure 3.

EKG and CXR can be readily obtained. The EKG will often show right ventricular hypertrophy and often times combined ventricular hypertrophy. The CXR can reveal the heart size and shape. TOF carries the classic “boot-shaped” heart shadow. It can also reveal other possible pulmonary pathologies or suggestion of increased pulmonary vascularity related to the cardiac condition.

Bedside echocardiography can easily be performed in the Newborn Nursery or Neonatal Intensive Care Unit (NICU), and allows complete definition of the cardiac anatomy. Echocardiography uses ultrasound and requires specialized skills for image acquisition and interpretation, but can be performed for a newborn without sedation. There is no radiation. The complete echocardiogram for TOF requires that parasternal long axis, parasternal short axis, apical 4 chamber, subcostal sagittal, subcostal coronal, and suprasternal notch imaging be performed. The reader is referred to texts in echocardiography for detailed discussion of image acquisition.

While in past decades cardiac catheterization (See Figure 4) may have been performed, today rarely are ancillary imaging studies required to define the anatomy of tetralogy of Fallot for the newborn or infant. Even the presence of additional ventricular septal defects, the anomalous coronary crossing the RVOT, or branch pulmonary stenoses, which might complicate TOF repair for the infant, can usually be defined by echocardiography.

Figure 4.

Imaging studies for evaluation of the child/ adolescent/ young adult with repaired tetralogy of Fallot

Follow-up for a patient with repaired tetralogy of Fallot (TOF) requires periodic echocardiograms with ancillary testing including EKG, exercise stress testing, and cardiac magnetic resonance (CMR) imaging (See Figure 5). Holter monitoring or cardiac catheterization may be indicated based on symptoms or echo findings. In the long-term, patients with repaired TOF often have residual pulmonary regurgitation, which results in right ventricular (RV) dilation and possibly RV dysfunction. The amount of pulmonary regurgitation and RV dilation can best be quantified by CMR (See Figure 7).

Figure 5.

Figure 6.

Figure 7.

Retrospective studies have shown that once the end-diastolic volume (indexed to body surface area) is larger than 170 ml/m² and end-systolic volume index > 85 ml/m², remodeling of the RV is less likely to occur after pulmonary valve replacement.

Confirming the diagnosis

The diagnosis of Tetralogy of Fallot is confirmed by echocardiogram. Timing for repeat surgery for pulmonary valve replacement is multifactorial. Currently, the most accepted guidelines are by Dr. Tal Geva which include MRI criteria for patients with repaired tetralogy of Fallot and moderate or severe pulmonary regurgitation.

If you are able to confirm that the patient has tetralogy of Fallot, what treatment should be initiated?

For the profoundly cyanotic neonate with tetralogy of Fallot, initiation of intravenous prostaglandin (PGE) therapy may be helpful. In this case of tetralogy of Fallot with severe right ventricular outflow tract obstruction (i.e., hypoplastic pulmonary valve, main and branch pulmonary arteries), this therapy can provide a reliable source of pulmonary blood flow by maintaining the patency of the ductus ateriosus.

Operative management will necessarily follow, as such patients cannot be discharged to home on PGE.

In some centers, such patients may receive palliation with an aortopulmonary shunt – usually via a Blalock-Taussig shunt (See Figure 8). In past eras, alternative central shunts were more commonly used (e.g., Waterston shunt being between the ascending aorta and right pulmonary artery or the Potts shunt being between the descending aorta and left pulmonary artery). Other centers may choose primary repair of the newborn, although optimal timing of TOF repair is thought to be between 3 and 6 months of age.

Figure 8.

Complete operative repair involves patch closure of the ventricular septal defect (VSD), appropriately direct the oxygenated blood in left ventricle to the aorta and relief of right ventricular outflow tract obstruction. This may include: 1) subpulmonary muscle resection, 2) right ventricular outflow tract patch placement to increase the diameter of this area, either via a non-transannular patch or a transannular patch or 3) placement of a right ventricular to pulmonary arterial conduit (used for the atretic pulmonary valve and main pulmonary artery or when a coronary artery crosses the RV outflow tract).

In the long term, patients with repaired tetralogy of Fallot require lifelong follow-up by congenital cardiologists, due to failing pulmonary valves and associated regurgitation, risk of arrhythmias, and guidance regarding lifelong considerations such as activity restrictions, pregnancy, etc.

Patients with TOF will require repeat surgeries over their lifetime. This is because repair of the right ventricular outflow tract often, unfortunately, often involves disruption of the pulmonary valve integrity. Pulmonary regurgitation may become progressively more severe as patients age and may lead to increasing right ventricular dilation. This valve will have to be replaced to preserve right ventricular function. Any valve replacement is only estimated to last 10-15 years.

What are the adverse effects associated with each treatment option?

Adverse effects are possible with each operation.

For patients who receive initial palliation with an aortopulmonary shunt, the following may be seen:

1) Tachypnea – This may occur if a shunt is too large, leading to pulmonary overcirculation; it requires medical therapy (e.g., diuretic and/or afterload reduction).

2) Hypoxia – This may occur if a shunt is too small, or may be progressive as the patient outgrows the shunt. Sudden hypoxia (especially in the perioperative period) should suggest shunt thrombosis.

3) Distortion of the pulmonary arteries (See Figure 9) – This may occur long-term after any shunt into a branch pulmonary artery; it may or may not lead to clinical symptoms.

Figure 9.

For patients who receive a transannular RVOT patch as part of the TOF repair, the following may be seen:

1) Pulmonary regurgitation may be seen due to disruption of the integrity of the pulmonary valve.

2) Increased end-diastolic right ventricular volume (See Figure 10) may be seen due to increased pulmonary regurgitation.

Figure 10.

3) Aneurysm of the right ventricular outflow tract may be seen; this area is often dyskinetic or even akinetic.

4) As a consequence of progressive RV dilation, risk for ventricular ectopy increases.

For patients who receive a right ventricular to pulmonary arterial conduit , the following may be seen:

1) Conduit stenosis (See Figure 11) can occur, due to the relatively small size of the conduit as the patient ages. This is especially a problem in adolescence and young adulthood if the conduit was placed when the patient was an infant, small toddler, or child. Furthermore, depending on the conduit type, stenosis may occur due to progressive calcification. Such a conduit will result in a louder systolic murmur, increased right ventricular hypertrophy, and increased right ventricular pressure. The patient typically tolerates this, but may experience shortness of breath with exertion or may develop arrhythmias.

Figure 11.

2) Conduit regurgitation may be seen even if the originally placed conduit contained a valve, as progressive deterioration of conduit valves has been described.

Repair of the ventricular septal defect may lead to interventricular conduction delay or right bundle branch block (as was seen in Figure 6).

Tricuspid regurgitation can result immediately after TOF repair if the VSD is repaired by the surgeon approaching it through the tricuspid valve; care must be taken to protect the tricuspid valve chordal apparatus and septal leaflet integrity. Late after TOF repair, tricuspid valve regurgitation can also be seen and is thought to be related to progressive RV dilation, which leads to stretch of the tricuspid annulus.

While rare, injury to a coronary artery during repair of tetralogy of Fallot has been described and can result in regional wall motion abnormalities on echocardiogram and as delayed enhancement (myocardial scar) on CMR imaging (See Figure 12).

Figure 12.

In the past decade, transcatheter pulmonary valve replacement (e.g., Melody ^® Transcatheter Pulmonary Valve, first implanted by Prof. Philipp Bonhoeffer in 2000, Figure13), has become increasingly available for use in select patients who require pulmonary valve replacement after their initial repairs. This technique was limited to redo of TOF patients who have already had an operative pulmonary valve replacement with a conduit. With the most recent FDA approval of the Edwards Sapien^®valve, novel approaches have allowed transcather pulmonary valve replacement in “native” pulmonary valves (those without a valved conduit).

Figure 13.

Figure 14.

What are the possible outcomes of tetralogy of Fallot?

Selected newborns with tetralogy of Fallot may require initial palliation with an aortopulmonary shunt (traditionally a Blalock-Taussig shunt) due to concerns regarding the adequacy of pulmonary blood flow. This operation is usually done without bypass and has a post-operative hospital course of about 1 week to 10 days, depending on the institution, with hospitalization prolonged by efforts to assure adequacy of oral feeding to assure patient growth prior to discharge.

In the current era, patients born with tetralogy of Fallot (TOF) can expect to undergo operative repair of this heart disease within the first year of life. In fact, most centers prefer to complete TOF repair between 3 and 6 months of age. Advantages to waiting include size at the time of operation in addition to allowing the RV to hypertrophy in response to pulmonary stenosis with the theory that the RV will be able to better sustain the pulmonary regurgitation that will inevitably occur, therefore minimizing RV dysfunction.

Operative mortality for TOF repair varies based on a center’s experience with congenital heart surgery. According to the 2011 Society for Thoracic Surgery (STS) Report, on average, mortality following TOF repair with ventriculotomy and transannular patch repair is about 1.5%, while that following right ventricular to pulmonary artery conduit placement is 3.9%.

Postoperative inpatient hospitalization is about 1 to 2 weeks, but varies by institution and with type of operation. The 2011 STS Report gives a mean length of stay for TOF repair with ventriculotomy and transannular patch of 11.7 days with median of 7.0 days; for TOF repair with conduit, the mean length of stay is 12.7 days with median of 7.0 days.

Finally, while the prognosis is good for survival, most patients with repaired TOF will require re-operation later in life (most often in the 2nd decade or beyond), particularly as pulmonary regurgitation becomes significant and leads to right ventricular dilation and dysfunction. One might expect 3-4 pulmonary valve replacements within a lifetime. While the exact timing of pulmonary valve replacement is controversial particularly in children and teenagers,there are accepted guidelines in adults. Other long-term risks include arrhythmias, RV failure, increased operative risks with subsequent surgeries, pregnancy-related complications, and sudden death.

The frequency of arrhythmias increases after the age of 45, typically consistent of atrial tachycardias (20%) and ventricular arrhythmias (15%). Inducible ventricular tachycardia (VT) is a predictor for clinical VT related sudden death. This may be part of the evaluation prior to PVR or if there are significant symptoms such as syncome, documented VT, or wide QRS complex.

What will you tell the family about risks/benefits of the available treatment options?

The estimated surgical mortality for TOF is <2% in the current era. Increased operative risks coincide with the health of the patient and additional morbid conditions that may be present. Risks of operation include: cardiac arrest, rhythm disturbances, bleeding, pneumothorax, pleural effusions, chylothorax, infection, stroke, renal failure, and presence of residual defects (including residual right ventricular outflow tract obstruction, residual VSD, pulmonary regurgitation, and tricuspid regurgitation).

Furthermore, long-term follow up is required to monitor for worsening valve dysfunction, outflow tract obstruction, ventricular dilation and dysfunction, and arrhythmias; patients may manifest symptoms at long-term follow-up, including exercise intolerance, rhythm disturbances, and heart failure.

However, young patients with repaired TOF have reported quality of life similar to healthy peers.

Untreated TOF will ultimately lead to a reduced lifespan if not fatal in the initial period. The patient would be at risk for cyanosis-related conditions, particularly polycythemia and associated risks of stroke. Poor growth and nutrition are likely. Symptoms such as syncope and dyspnea would be expected. Interestingly, TOF is the most common form of cyanotic heart disease to reach adulthood untreated, although it is a rare occurrence.

What causes tetralogy of Fallot and how frequent is it?

Tetralogy of Fallot (TOF) is the most common cyanotic heart disease. It occurs in about 3.5% of all infants born with congenital heart disease. As with most congenital heart disease, its precise cause is unknown, although it has been postulated that the 4 features of TOF result from the anterior deviation of the conal septum. Most cases seem sporadic, although the recurrence risk in siblings is about 3% if there are no other affected first-degree relatives. Thus, genetic counseling should be offered to the family, and fetal echocardiography should be provided to the mother for all subsequent pregnancies.

Gene mutations associated with tetralogy of Fallot (TOF) include: 1) 22q11.2; 2) 10p13-14; 3) TBX1 genetic variants; and 4) trisomy 21, among others.

Environmental toxins have been studied in association with congenital heart disease, with a recent study showing an association between maternal carbon monoxide exposure at 3 to 8 weeks’ gestation and presence of tetralogy of Fallot in the offspring (odds ratio = 2.04, 95% confidence interval: 1.26, 3.29) when individuals from the highest quartile of exposure were compared with those from the lowest exposure quartile. Further study of the effects of environmental toxins on gene mutation and phenotypic expression is suggested by the authors.

Furthermore, while low socioeconomic status has been associated with many acquired diseases, the link with congenital heart disease is still under investigation and has yielded varying results. In one study , slightly increased odds ratios for socioeconomic factors (such as low level of maternal and paternal education, blue-collar occupation, and low household income) were associated with occurrence of TOF in offspring; yet, confidence intervals included 1 (no increased risk).

How do these pathogens/genes/exposures cause the disease?

Although congenital heart defects (CHDs) are a common (7/1000 live births) and serious group of birth defects, relatively little is known about the causes.

There are no established prevention strategies; screening of subsequent pregnancies is recommended due to the increased risk of congenital heart disease (4%-6%) in subsequent fetuses. This allows for better planning and for counseling. It is presumed that some factor or combination of factors (genetic/ environmental) contributes to the anterior deviation of the conal septum that leads to the 4 features of tetralogy of Fallot: 1) conoventricular septal defect, 2) overriding aorta, 3) subpulmonary stenosis, and 4) right ventricular hypertrophy.

Other clinical manifestations that might help with diagnosis and management

Although less common in this era, when early repair of tetralogy of Fallot occurs, hypercynaotic “tet” spells can still occur and should be recognized by the care providers so that prompt therapy can be given. These spells occur due to increased right ventricular outflow tract (RVOT) obstruction and can be precipitated when a patient is intravascularly volume depleted (such as when the patient is taking nothing by mouth in preparation for a sedated echocardiogram). Thus, in this setting, “tet” spells can be prevented by providing intravenous hydration if a prolonged period without fluids/food is anticipated.

The hypercyanotic “tet” spell is recognized by noting profound cyanosis and a disappearance of the typical ejection systolic murmur, indicating that RVOT obstruction has become so severe that there is little to no forward blood flow into the branch pulmonary arteries and significant right to left shunting across the ventricular septal defect. The infant may be hyperpneic, irritable, and becoming progressively more cyanotic.

First-line therapy is to calm the infant and provide supplemental oxygen. Placing the infant or child in the knee-to-chest position can increase systemic venous return to the heart and augment blood flow across the RVOT; it also increases systemic vascular resistance (SVR).

If the patient does not have an intravenous line (IV), intramuscular morphine sulfate can be given (0.1 to 0.2 mg/kg) to abort the spell. If an IV is present, an IV fluid bolus of saline (10 to 20 cc/kg) can be given with good result. However, placing an IV in an already profoundly cyanotic patient can exacerbate the spell. Oxygen and IM morphine should be attempted first in this case.

Additional medications that have been useful in the treatment of hypercyanotic “tet” spells include:

1) IV ketamine (1 to 3 mg/kg IV ) to increase systemic vascular resistance (SVR) and also to provide sedation.

2) IV phenyleprine (a selective alpha adrenergic agent) may be used to increase SVR.

3) β blocker therapy (oral propranolol) to decrease heart rate, provide for more diastolic filling time, and possibly relax infundibular spasm.

A hypercyanotic “tet” spell should prompt hospitalization with close observation until operative intervention can be scheduled.

What complications might you expect from the disease or treatment of the disease?

N/A

Are additional laboratory studies available; even some that are not widely available?

N/A

How can tetralogy of Fallot be prevented?

Tetralogy of Fallot can be associated with DiGeorge syndrome (22q11.2 deletion being most common). As such, genetic counseling of patients with conotruncal cardiac defects, like tetralogy of Fallot, should be routine practice. DiGeorge syndrome is thought to exist in about 15% of such patients. If a parent is found to have the same genetic mutation for DiGeorge syndrome as the child, then the recurrence risk for future children is 50%. Most (90%) affected individuals with 22q11.2 deletion have had a spontaneous mutation. If initial FISH testing is negative for 22q11.2 mutation, more specialized testing for other mutations (such as 10p13-14) should be undertaken.

The genetics of congenital heart disease is an area of active research. For instance, a recent study demonstrates that rare TBX1 genetic variants are present in a small proportion of patients with non-syndromic TOF.

While the general risk for congenital heart disease is just less than 1%, this risk increases to ~ 4%-6% for a patient with congenital heart disease and no evidence of DiGeorge syndrome. As such, appropriate counseling should be given to the patient. The female adult patient with repaired tetralogy of Fallot may have residual disease that makes her at slightly higher risk for obstetric complications.

In a recent study by Mayo Clinic and the Boston Adult Congenital heart Disease Program, pregnancy outcomes for patients with repaired tetralogy of Fallot were found to be generally favorable. All patients undergoing a trial of labor or cesarean delivery had neuraxial analgesia or anesthesia. Recognition and management of congestive heart failure was necessary in 19% of deliveries.

In a recent retrospective review of 157 pregnancies in 74 female patients with repaired TOF, cardiovascular events occurred during 8.1% of the pregnancies, and were mainly supraventricular arrhythmias. Obstetric and offspring events occurred in approximately 59% and 34% pregnancies, respectively, including offspring mortality in 6.4%. The most important predictor was use of cardiac medication before pregnancy (odds ratio for cardiac events 11.7, 95% CI 2.2-62.7; odds ratio for offspring events 8.4, 95% CI 1.4-48.6). In pregnancies with cardiovascular events, significantly more small-for-gestational-age children were born (P value < 0.01).

In a Danish retrospective study, there were 54 pregnancies in 25 women with repaired TOF. The recorded rate of spontaneous abortion was 15%, and the infertility rate was 3.4%. There were 41 live births, with a median weight at birth of 3.2 kg. Only 1 newborn was small for gestational age, and no infant was born before the 36th week. The recurrence rate of congenital heart disease was high, at 9.8%. Cardiac complications during or after pregnancy were not observed, and only one woman had pre-eclampsia.

Hence, for certain individuals with repaired TOF effective means of birth control may be advised. For those who do become pregnant, follow up in high risk obstretrics is advised and fetal echocardiography should be undertaken at ~16 – 20 weeks’ gestation.

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