Pathophysiology, clinical features, and diagnosis of tetralogy of Fallot

Contributor disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jul 2016. | This topic last updated: May 06, 2015.

INTRODUCTION — In 1888, Etienne-Louis Arthur Fallot described three cyanotic patients with four similar anatomic features (figure 1) [1]:

●Stenosis of the pulmonary artery

●Intraventricular communication

●Deviation of the origin of the aorta to the right

●Concentric right ventricular hypertrophy

 

This constellation of findings has since become known as tetralogy of Fallot (TOF).

The pathophysiology, clinical features, and diagnosis of TOF will be reviewed here. The management and outcome of this disorder are discussed separately. (See "Management and outcome of tetralogy of Fallot".)

EPIDEMIOLOGY — The prevalence of TOF in the United States is approximately 4 to 5 per 10,000 live births [2,3]. This defect accounts for about 7 to 10 percent of cases of congenital heart disease and is one of the most common congenital heart lesions requiring intervention in the first year of life [4]. TOF occurs equally in males and females [5].

ANATOMY — The exact embryologic abnormality that accounts for TOF is unknown. What is recognized is that during development, there is anterior and cephalad deviation of the infundibular septum. This results in a malaligned ventricular septal defect (VSD), with the aortic root overriding the defect and leading to subsequent right ventricular outflow obstruction (figure 1). The ensuing right ventricular hypertrophy is thought to be a response to the large VSD and right ventricular outflow obstruction with resultant systemic right ventricular systolic pressure.

Ventricular septal defect — The VSD in TOF is most commonly a single large malaligned subaortic defect located in the perimembranous region of the septum (image 1). The VSD can extend into the muscular septum. There are rarely other muscular ventricular septal defects. (See "Pathophysiology and clinical features of isolated ventricular septal defects in infants and children".)

Right ventricular outflow obstruction — The right ventricular outflow obstruction is often at multiple levels (image 2):

●The anterior and cephalad deviation of the infundibular septum results in subvalvar obstruction

●Hypertrophy of muscular bands in this region can further accentuate subvalvar obstruction

●The pulmonary valve annulus is usually hypoplastic, although in some instances it is of normal size

●The pulmonary valve itself is frequently bicuspid and stenotic

 

In addition, it is not uncommon to identify an area of supravalvar narrowing in the main pulmonary artery at the sinotubular ridge. There may also be further obstruction at the branch pulmonary arteries. These may be diffusely hypoplastic or have focal areas of stenosis, most commonly at the proximal branch pulmonary arteries. The proximal left pulmonary artery near the site of ductal insertion is a frequent location for stenosis (image 3A-B).

Overriding aorta — Overriding aorta is a congenital anomaly, in which the aorta is displaced to the right over the VSD rather than the left ventricle. This results in blood flow from both ventricles into the aorta.

The degree of aortic override of the VSD can vary widely and is one of the major factors used by some groups to differentiate between TOF and double outlet right ventricle. If one defines double outlet right ventricle as the absence of aortic/mitral valve fibrous continuity, then the degree of override is not relevant to diagnosis. If, however, one defines double outlet right ventricle as a condition with greater than 50 percent aortic override, then, by definition, the degree of aortic override in TOF is limited.

Associated cardiac features — There are a number of frequently associated anatomic features that are important to look for when evaluating a patient with TOF, since they affect therapy. Associated cardiac anomalies occur in about 40 percent of patients with TOF.

●Approximately 25 percent of patients have a right aortic arch. This is particularly important to identify if one is contemplating a palliative shunt.

 

●Abnormalities of the coronary arteries, such as the left anterior descending arising from the right coronary artery, are seen in about 9 percent of patients [6]. These are important to identify prior to complete repair, since the course of the artery may run directly across the right ventricular outflow tract; inadvertent transection could have catastrophic consequences.

 

●Occasionally, patients have significant aorticopulmonary collateral vessels that may require attention prior to or at the time of surgery.

 

●A patent ductus arteriosus, multiple ventricular defects, and complete atrioventricular septal defects may be present.

 

●Infrequently, aortic valve regurgitation is present due to aortic cusp prolapse.

 

GENETIC FACTORS — Although TOF may present as part of a known syndrome, this lesion typically occurs sporadically without other anomalies.

Surveys of patients with nonsyndromic TOF have reported the following genetic abnormalities:

●In one study of 114 patients with nonsyndromic TOF, 4 percent of patients had mutations in transcription factor NKX2.5., which appears to have a role in cardiac development [7].

 

●In genome-wide surveys of patients with nonsyndromic TOF and their parents, de novo copy number variants were estimated to be present in about 10 percent of sporadic cases of TOF compared to less than 0.1 percent in controls at several chromosomal locations [8].Several reports have associated TOF with mutations in TBX1 and ZFPM2 [9-11].

 

●MTHFR polymorphism has also been associated with an increased risk of development of TOF [12].

 

Further investigation is required to determine the role of these mutations and polymorphisms in the evolution of TOF.

Approximately 15 percent of patients with TOF present with associated syndromes [9,13-19]:

●Down syndrome (trisomy 21).

 

●Alagille syndrome (mutations in JAG1). TOF as the sole manifestation of JAG1 mutations without other evidence of Alagille syndrome has also been reported [20]. (See "Inherited disorders associated with conjugated hyperbilirubinemia", section on 'Alagille syndrome'.)

 

●DiGeorge and velocardiofacial syndromes (deletion on chromosome 22q11). There may be susceptibility genes for TOF within the latter region of chromosome 22q11 in children without extracardiac anomalies [18,21,22], and 22q11.2 deletion syndrome is unrecognized in many adult patients with TOF [23]. (See "DiGeorge (22q11.2 deletion) syndrome: Epidemiology and pathogenesis".)

 

PATHOPHYSIOLOGY — The physiologic consequences of TOF are largely dependent upon the degree of right ventricular outflow obstruction. Since the VSD is typically large and unrestrictive, the pressure in the right ventricle reflects that of the left ventricle. As a result, the direction of blood flow across the VSD will be determined by the path of least resistance for blood flow, not by the size of the VSD. If the resistance to blood flow across the obstructed right ventricular outflow tract is less than the resistance to flow out of the aorta into the systemic circulation, blood will naturally shunt from the left ventricle to the right ventricle and into the pulmonary bed. In this situation, there is predominately a left-to-right shunt and the patient will be acyanotic.

As the degree of right ventricular outflow obstruction increases, the resistance to blood flow into the pulmonary bed also increases. If the right ventricular obstruction is significant enough to increase resistance, it will be easier for blood to cross the VSD from the right ventricle into the left ventricle and go out the aorta, which now becomes the path of least resistance. This right-to-left shunt across the VSD will result in a large volume of desaturated blood entering the systemic circulation and cyanosis and polycythemia will ensue (figure 1).

One of the physiologic characteristics of TOF is that the right ventricular outflow obstruction can fluctuate. An individual with minimal cyanosis can develop a dynamic increase in right ventricular outflow tract obstruction with a subsequent increase in right-to-left shunt and the development of cyanosis. In the most dramatic situation, there can be near occlusion of the right ventricular outflow tract with profound cyanosis. These episodes are often referred to as "tet spells" or "hypercyanotic spells". The exact etiology of these episodes is unclear, although there have been a number of proposed mechanisms, including increased infundibular contractility, peripheral vasodilatation, hyperventilation, and stimulation of right ventricular mechanoreceptors [24].

CLINICAL PRESENTATION — The clinical presentation of the patient with TOF is dependent upon the degree of right ventricular outflow obstruction:

●Children with severe obstruction and inadequate pulmonary flow typically present in the immediate newborn period with profound cyanosis.

 

●Children with moderate obstruction and balanced pulmonary and systemic flow may be noticed during elective evaluation for a murmur. These children may also present with hypercyanotic (“tet”) spells when RVOT is obstructed during periods of agitation. In addition, some affected newborns will be detected by an evaluation prompted by a failed oximetry screening test.

 

●Children with minimal obstruction may present with pulmonary overcirculation and heart failure.

 

Most children with this lesion are symptomatic and cyanotic; there is a subgroup, however, with typical morphology and hemodynamics that remains clinically asymptomatic for a period of time (pink variant). In general, the earlier the onset of systemic hypoxemia, the more likely it is that severe pulmonary outflow tract stenosis or atresia is present.

Physical examination — On inspection, individuals with TOF are usually comfortable and in no distress. However, during hypercyanotic (tet) spells, they will become hyperpneic, and infants will often become agitated. If cyanosis is present, it is most easily seen in the nail beds and lips.

On palpation, one may appreciate a prominent right ventricular impulse and occasionally a systolic thrill. Hepatomegaly is uncommon. Peripheral pulses are usually normal, although the presence of prominent pulses may suggest the existence of a significant patent ductus arteriosus or aorticopulmonary collaterals.

Cardiac auscultation — On auscultation, the first heart sound is normal, and the second heart sound is most commonly single because the pulmonic component is rarely audible. Third and fourth heart sounds are uncommon. An early systolic click along the left sternal border may be heard, which is thought to be due to flow into the dilated ascending aorta. (See "Auscultation of heart sounds".)

Murmur — The murmur in TOF is due primarily to the right ventricular outflow obstruction, not the VSD. The murmur is typically crescendo-decrescendo with a harsh systolic ejection quality; it is appreciated best along the left mid to upper sternal border with radiation posteriorly. It can, however, have a more regurgitant quality that can be easily mistaken for a VSD. (See "Auscultation of cardiac murmurs in adults".)

The murmur is due both to the degree of obstruction and to the amount of flow across the obstruction. In TOF, unlike isolated valvar pulmonary stenosis, the amount of flow across the right ventricular outflow tract will decrease as the obstruction increases, due to the shunting of blood right-to-left across the VSD. Thus, as the obstruction increases, the murmur will become softer. During severe hypercyanotic (tet) spells, the murmur may actually disappear due to the markedly diminished flow across the obstruction.

DIAGNOSIS — The diagnosis of TOF is generally made by echocardiography. Other tests that are often performed during the evaluation of TOF include electrocardiogram and chest radiography. Findings from these studies are often suggestive but not conclusive for the diagnosis of TOF. Cardiac catheterization is sometimes needed to further delineate anatomy and hemodynamic changes.

Echocardiography — Two-dimensional echocardiography and Doppler examination allow assessment of all essential features of TOF and have a crucial role in diagnosis and preoperative evaluation. Complete echocardiographic evaluation may obviate the need for other imaging or diagnostic studies before surgical repair. Most of the information can be achieved with transthoracic echocardiography, but occasionally transesophageal echocardiography may be helpful for specific questions raised with transthoracic echocardiography. A complete study must address:

●The location and number of VSDs

●The anatomy and severity of right ventricular outflow tract obstruction

●The coronary artery and aortic arch anatomy

●The presence of any associated anomalies

 

Ventricular septal defect — The characteristic large malaligned VSD must be evaluated in multiple views. The degree of aortic override can be best assessed in parasternal long axis and apical views (movie 1 and movie 2). The extension of the defect from the membranous septum, beneath the tricuspid valve, and into the infracristal outlet septum is well seen in the parasternal short axis view; extension into the supracristal region, if present, can be seen in this view as well (movie 3). Potential extension of the defect posteriorly toward the inlet septum, or apically into the trabecular septum, can be examined in apical views; the transducer is swept through serial imaging planes from the more caudal views of the inlet septum to the anteriorly angulated views, showing the overriding aorta in continuity with both the mitral and tricuspid valves.

The subcostal views are also helpful to delineate the bounds of the VSD, allowing particularly good representation of the relationship between the defect and the tricuspid and aortic valves. The subcostal right oblique view, obtained by rotating the transducer counterclockwise from the coronal views, is also helpful in identifying any potential extension of the defect into the supracristal region. In the rare cases of restrictive VSD in this lesion, this view also defines abnormal tricuspid valve attachments [25,26].

Right ventricular outflow obstruction — The multiple levels and severity of obstruction in the right ventricular outflow tract can also be evaluated by echocardiography (image 4 and movie 4). Parasternal short axis and subcostal coronal and sagittal views allow the best examination of the infundibulum and pulmonary valve. These views demonstrate the anterior deviation of the conal septum and the infundibular muscle bundles that contribute to infundibular obstruction. The size of the usually hypoplastic pulmonary annulus can be assessed and compared to normal values for patient size and body surface area. This is important to establish the potential need for a transannular patch. The pulmonary valve may appear thickened and may dome in these views.

Pulmonary arteries — The size and anatomy of the main pulmonary artery, the pulmonary arterial confluence, and the proximal branch pulmonary arteries can also be assessed in parasternal short axis views. The proximal branch pulmonary arteries should be assessed as far distally as possible in high parasternal views and in suprasternal notch long and short axis views, directing the transducer into the left and right chest (movie 5 and movie 6).

Coronary arteries — The proximal coronary anatomy should be defined echocardiographically in patients with TOF. In addition to examining the coronary anatomy in the traditional short axis view, the examination should include sweeping the transducer anterior to the pulmonary outflow tract in parasternal long and short axis views (movie 7) [27-29]. This permits the identification of variations in coronary anatomy, including the origin of the left anterior descending from the right coronary artery or dual vessel supply to the anterior descending distribution; in these situations, coronary branches crossing anteriorly complicate the surgical approach to relief of right ventricular outflow tract obstruction.

Aortic arch — Aortic arch situs and the branching patterns of the brachiocephalic arteries are defined in the suprasternal notch long and short axis views. Complete evaluation of the arch in these views is also important in delineating the presence of additional potential sources of pulmonary blood flow, including aorticopulmonary collaterals and a patent ductus arteriosus. (See "Clinical manifestations and diagnosis of patent ductus arteriosus in term infants, children, and adults".)

Atrial and ventricular septa — The echocardiographic evaluation of patients with TOF is completed by using both two dimensional imaging and color flow mapping of the atrial septum and ventricular septum in multiple imaging planes. This assessment defines additional atrial and ventricular septal defects and evaluates potential abnormalities of pulmonary and systemic venous return and the rare associated occurrence of left sided obstructive lesions.

Hemodynamic echocardiographic assessment — As noted above, the large and generally unrestrictive defect in this lesion permits equalization of right and left ventricular pressures. The direction and degree of shunting is determined by the balance of resistance to flow into the systemic and pulmonary circulations and, to a large degree, by the severity of right ventricular outflow tract obstruction. The modified Bernoulli equation, applied to the peak flow velocity in the right ventricular outflow tract, can be used to calculate the outflow tract gradient:

   ΔP  =  4V2

Where ΔP = peak pressure gradient between the right ventricle and the pulmonary artery (mmHg), V = velocity obtained by continuous wave Doppler interrogation of the right ventricular outflow tract. The pulmonary artery pressure can be estimated by subtracting this pressure gradient from the systemic blood pressure.

While the modified Bernoulli equation is not valid in the setting of tunnel-like and/or multiple levels of obstruction, values obtained with this method correlate with those obtained in the cardiac catheterization laboratory [30]. In practice, the contributions of the infundibulum value and branch pulmonary arteries cannot be separated by Doppler interrogation.

In patients with minimal right ventricular outflow tract obstruction, the gradient across the right ventricular outflow tract will be low; the estimated pulmonary arterial pressure will be elevated; and shunting through the VSD, as assessed by pulsed Doppler and color flow mapping, will be predominantly left-to-right through much of the cardiac cycle. (See "Pathophysiology and clinical features of isolated ventricular septal defects in infants and children".)

In patients with a large left-to-right shunt, left atrial and left ventricular dilation may be apparent by two dimensional imaging. In patients with more severe right ventricular outflow tract obstruction, the estimated pulmonary artery pressure is normal, and pulsed Doppler and color flow mapping demonstrate increasing right-to-left shunting at the ventricular septal defect during the cardiac cycle.

Electrocardiogram — The ECG in TOF typically shows right atrial enlargement and right ventricular hypertrophy. Right axis deviation, prominent R waves anteriorly and S waves posteriorly, an upright (waveform 1) T wave in V1 (after two days of life), and a qR pattern in the right sided chest leads may also be seen (waveform 1). (See "ECG tutorial: Chamber enlargement and hypertrophy".)

Chest x-ray — The classic chest x-ray of a patient with TOF demonstrates a "boot shaped" heart with an upturned apex and a concave main pulmonary artery segment (image 5). The heart size is often normal, and pulmonary flow will appear normal or decreased. A right aortic arch can be seen in 25 percent of patients.

Cardiac catheterization — Although echocardiography can reveal the anatomy in many patients with TOF, cardiac catheterization may still be necessary to further delineate the structure. It is particularly helpful for assessing levels of right ventricular outflow obstruction, branch pulmonary artery stenosis or hypoplasia, coronary artery anatomy, presence of aorticopulmonary collaterals, and presence of accessory ventricular septal defects.

The hemodynamic findings at catheterization typically reveal normal or only mildly elevated filling pressures. The left and right ventricular systolic pressures are equal and systemic due to the presence of the large VSD. Pulmonary artery pressures are normal or low. Saturations will indicate the degree of right-to-left shunting.

Angiographic assessment should be geared toward the information that is needed; biplane angiography is ideal. A right ventricular injection will often adequately demonstrate the multiple levels of right ventricular obstruction as well as the anatomy of the branch pulmonary arteries (image 2). This is typically done with the AP camera angled in a cranial and left anterior oblique projection, which allows better delineation of the branch pulmonary arteries. The lateral camera is kept in straight lateral projection, which provides excellent visualization of the infundibular and pulmonary valve anatomy (image 6).

An aortic root injection will usually provide adequate identification of the coronary arteries, although selective injections may occasionally be needed. The coronary arteries usually are seen well with the AP camera in a right anterior oblique (RAO) projection and the lateral camera in a long axial oblique projection. The arch and descending aorta may also be seen in this view and provide evidence of the presence of a patent ductus arteriosus or collateral vessels. If collateral vessels are identified, selective injections are helpful to assess the areas of the pulmonary bed that they supply and whether they are the sole supply to these areas.

The ventricular septal defect is best seen from a left ventricular injection in a long axial oblique projection (image 1). With the AP camera in an RAO projection, one will often also see the infundibular obstruction from left to right flow across the VSD (image 7).

Cardiac catheterization can also play a therapeutic role in some patients with TOF. Balloon valvuloplasty of the pulmonary valve can improve pulmonary flow in many children; there may also be an increase in pulmonary valve annulus size that may decrease the need for transannular patch repair [31,32]. (See "Natural history and treatment of pulmonic stenosis in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Basics topic (see "Patient information: Tetralogy of Fallot (The Basics)")

 

SUMMARY AND RECOMMENDATIONS — Tetralogy of Fallot (TOF) is a cyanotic congenital heart disorder that encompasses four anatomic features: right ventricular hypertrophy, ventricular septal defect (VSD), overriding aorta, and right ventricular (RV) outflow obstruction. (See 'Anatomy' above.)

●In the United States, the prevalence of TOF is about 3.9 per 10,000 live births. TOF accounts for 7 to 10 percent of congenital heart disease. (See 'Epidemiology' above.)

 

●Although TOF typically occurs sporadically without other anomalies, it can be present as part of a known syndrome or genetic disorder, such as Down syndrome. In addition, other associated cardiac anomalies occur in about 40 percent of patients with TOF. (See 'Genetic factors' above and 'Associated cardiac features' above.)

 

●The pathophysiologic effects of TOF are largely dependent upon the degree of RV outflow obstruction. The direction of blood flow across the VSD is determined by the path of least resistance for blood flow and not by the size of the VSD. If the resistance to the RV outflow is lower than systemic resistance, then there is a predominant left-to-right flow, and the patient is not cyanotic. However, with significant RV obstruction, there will be a right-to-left shunt across the VSD, resulting in cyanosis (figure 1). (See 'Pathophysiology'above.)

 

●The clinical presentation is dependent on the degree of RV outflow obstruction and determines whether there is a left-to-right (acyanotic) or right-to-left shunt. In general, the earlier the onset of systemic hypoxemia, the more likely it is that severe pulmonary outflow tract stenosis or atresia is present. In addition to persistent cyanosis in severely affected patients, other findings include intermittent hypercyanotic (tet) spells, crescendo-decrescendo harsh systolic ejection murmur, and a single second heart sound. (See 'Clinical presentation' above.)

 

●The diagnosis of TOF is typically made by echocardiography, which can usually delineate the location and number of VSDs, the anatomy and severity of RV outflow tract obstruction, the coronary artery and aortic arch anatomy, the presence of any associated anomalies, and the hemodynamic abnormalities associated with the anatomical defects. (See 'Echocardiography' above.)

 

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Thomas Graham Jr, MD, who contributed to an earlier version of this topic review.

Use of UpToDate is subject to the Subscription and License Agreement.