Tetralogy of Fallot

La Maladie Bleue, as described by Louis Arthur Etienne Fallot in 1888 [1], is the clinical description of the physiology created by a combination of anatomic malformations now referred to as tetralogy of Fallot. The cardinal features (Figure 1) consist of an interventricular communication, or ventricular septal defect, biventricular connection of the aortic root, which overrides the muscular ventricular septum, obstruction of the right ventricular outflow tract, and right ventricular hypertrophy [2]. Each component can vary in its severity, with the variation directly affecting the manifestation and management of the disease.

Tetralogy of Fallot occurs in 3 of every 10,000 live births. It is the commonest cause of cyanotic cardiac disease in patients beyond the neonatal age, and accounts for up to one-tenth of all congenital cardiac lesions [3].

The embryological basis of the combination of lesions is antero-cephalad deviation of the developing outlet ventricular septum, or its fibrous remnant should this septum fail to muscularise. Such deviation, however, can be found in the absence of subpulmonary obstruction, as in the so-called Eisenmenger ventricular septal defect [4]. So as to produce the features of tetralogy of Fallot, therefore, it is also necessary to have abnormal morphology of the septoparietal trabeculations that encircle the subpulmonary outflow tract [5]. The combination of the deviated outlet septum and the hypertrophied septoparietal trabeculations produce the characteristic right ventricular outflow tract obstruction of tetralogy of Fallot (Figure 1). The deviation of the muscular outlet septum is also responsible for creating the malalignment type ventricular septal defect, and results in the aortic override. The associated hypertrophy of the right ventricular myocardium is the haemodynamic consequence of the anatomical lesions created by the deviated outlet septum.

The initial presentation of tetralogy of Fallot varies depending on the severity of the obstruction of blood flow to the lungs. Most patients will present in the neonatal period with mild-to-moderate cyanosis, but typically without respiratory distress. More uncommonly, patients with very mild right ventricular outflow tract obstruction at birth may be diagnosed at a couple months of age as the obstruction worsens resulting in newly noticed cyanosis and a louder murmur. Because patients with tetralogy of Fallot have obstruction to pulmonary blood flow, they will not present with signs of heart failure such as failure to thrive. Irritability and lethargy are rarely seen in patients with tetralogy of Fallot except in the setting of a hypercyanotic spell. Clubbing is also highly unusual in the modern era since newly diagnosed patients undergo surgical repair before clubbing has time to develop.

The second heart sound in patients with tetralogy of Fallot may be single and loud, and a harsh systolic ejection murmur will be present, emanating from the obstructed subpulmonary outflow tract. Flow across the interventricular communication in tetralogy of Fallot is usually not turbulent, and therefore not audible. Patients with severe obstruction, and very little antegrade flow across the subpulmonary outflow tract, will be more significantly cyanotic and have a less prominent murmur.

Once the lesion is suspected, an electrocardiogram and chest radiograph should be performed. The electrocardiogram will demonstrate right axis deviation and prominent right ventricular forces, with large R waves in the anterior precordial leads and large S waves in the lateral precordial leads [19]. Although the electrocardiogram is similar to that of a normal newborn, the right ventricular hypertrophy and right axis deviation will not normalize in a patient with tetralogy of Fallot. The classical chest radiograph will demonstrate a boot-shaped cardiac silhouette. This is due to upward displacement of the right ventricular apex as a consequence of the right ventricular hypertrophy, and a narrowing of the mediastinal shadow due to the hypoplastic pulmonary outflow tract.

Diagnosis is confirmed with echocardiography. The severity of the subpulmonary obstruction, its dynamic component, the size of the right and left pulmonary arteries, and any additional sources of flow of blood to the lungs will all be delineated (Figures 6, 7a, 7b). The degree of aortic override, the size of the interventricular communication, as well as the presence of other associated lesions, will be identified (Figure 8). Cardiac catheterisation is now rarely needed due to the high sensitivity and specificity of echocardiographic images.

The aetiology is multifactorial. Associated chromosomal anomalies can include trisomies 21, 18, and 13, but recent experience points to the much more frequent association of microdeletions of chromosome 22. As many as one-eighth of patients will have chromosomal abnormalities, such as trisomy 21, 18, or 13 [3]. Up to one-fifth of patients with tetralogy and pulmonary stenosis, and two-fifths of those with tetralogy and pulmonary atresia, will have microdeletions of chromosome 22q11.2 [12, 20, 21]. The deletion, manifested by varying degrees of palatal abnormalities, dysmorphic facies, learning disabilities, immune deficiencies, and hypocalcaemia, is frequently referred to as the DiGeorge Syndrome.

The risk of recurrence in a family is approximately 3%.

Associations with maternal intake of retinoic acid during the first trimester, poorly controlled diabetes, and untreated phenylketonuria have also been described [11].

Tetralogy of Fallot can be diagnosed antenatally as early as 12 weeks of gestation [22]. In a population-based study, however, only half of the cases were detected during routine obstetric ultrasonic screening [23]. In general, patients who are referred for foetal echocardiography with a suspicion of tetralogy of Fallot have the most severe phenotypes [23]. Other reasons for referral for foetal echocardiography include discovery of extra-cardiac malformations, or known chromosomal abnormalities. As a result, patients referred for foetal echocardiography tend to have worse outcomes when compared to patients who are diagnosed postnatally [23]. The foetus with tetralogy can be delivered vaginally, but efforts should be made for delivery to occur in a centre where paediatric cardiologists are available to aid in the postnatal care.

The differential diagnosis of any cyanotic patient with a murmur will include persistent pulmonary hypertension of the newborn, as well as other cyanotic lesions such as critical pulmonary stenosis, Ebstein's malformation, transposed arterial trunks, common arterial trunk, totally anomalous pulmonary venous connection, and tricuspid atresia.

Clinical management is determined by the degree and type of subpulmonary obstruction, in combination with the preference of the centre for the timing of surgical intervention. Depending on the severity of obstruction within the subpulmonary outflow tract, an infusion of prostaglandin may be initiated to preserve ductal patency, and provide a stable source of flow of blood to the lungs. Patients who require such an infusion will most likely require surgical intervention prior to discharge from the hospital. For those patients who have adequate forward flow through the subpulmonary outflow tract after ductal closure, management consists of close follow-up until a complete repair is performed.

Some centres will perform complete repairs in all neonates. Others will palliate symptomatic neonates, and perform a complete repair in all patients at the age of 4 to 6 months.

Palliation, which frequently does not require cardiopulmonary bypass, establishes a secure source of flow of blood to the lungs by placing a prosthetic tube between a systemic and a pulmonary artery. The most common type of aorto-pulmonary shunt is known as the modified Blalock-Taussig shunt. This consists of a communication between a subclavian and pulmonary artery on the same side. A complete repair, always performed under cardiopulmonary bypass, consists of closing the interventricular communication with a patch channeling the left ventricle to the aortic root, relief of the subpulmonary obstruction, and reconstruction, if necessary, of the pulmonary arteries.

Complete neonatal repair provides prompt relief of the volume and pressure overload on the right ventricle, minimises cyanosis, decreases parental anxiety, and eliminates the theoretical risk of stenosis occurring in a pulmonary artery due to a palliative procedure. Patients who undergo a successful complete repair during the neonatal period will be unlikely to require more than one intervention in the first year of life, but are not free from reintervention. Concerns regarding such neonatal complete repairs include exposure of the neonatal brain to cardiopulmonary bypass, and the increased need to place a patch across the ventriculo-pulmonary junction when compared to older age at repair [24, 25]. Patches placed across the ventriculo-pulmonary junction, so-called transannular patches, create a state of chronic pulmonary regurgitation, which increases morbidity in young adults, producing exercise intolerance and ventricular arrhythmias. If left untreated, this increases the risk of sudden death [26‐28]. The effect of cardiopulmonary bypass on the neonatal brain, and the associated risk of longer stay in hospital and the intensive care unit, is not trivial. Studies of neurodevelopmental outcomes of neonates undergoing cardiopulmonary bypass compared to older children have shown lower intelligence quotients in patients exposed to bypass as neonates [29]. Longer periods of bypass, and longer stays in the intensive care unit, have been associated with an increased risk for neurological events and abnormal neurological findings on follow-up [30, 31]. While some studies have not found cyanosis itself to be responsible for cognitive problems in children with congenitally malformed hearts [32], others have implicated chronic cyanosis as a factor contributing to impaired motor skills, decreased academic achievement, and worsened behavioural outcomes [33, 34]. In the absence of randomised control trials, assessing the risk and benefits of the two surgical strategies has been notoriously difficult.

In summary, patients with cyanotic tetralogy of Fallot will either undergo neonatal complete repair or neonatal palliation with an aortopulmonary shunt followed by a complete repair at four to six months of age. Peri-operative mortality rates for either surgical approach is less than 3% [24, 25] and since neither strategy has shown superior results, surgical management remains dependent on the protocols preferred by the individual centres.

Studies of immediate and long-term follow-up in tetralogy of Fallot reveal excellent outcomes. Patients born 30 years ago with tetralogy of Fallot have an 85% long-term rate of survival, and in the absence of serious residuae are able to lead normal lives as evidenced by the ability to carry successful pregnancies for example [35‐40]. Chronic issues that face the current population of adults subsequent to their surgical repair include the haemodynamic manifestations of chronic pulmonary regurgitation, recurrent or residual pulmonary stenosis, and ventricular arrhythmias. The prognosis of patients born in the current era is expected to be substantially improved due to advances in surgical and medical management that have occurred over the past couple of decades. As for all patients with congenitally malformed hearts, the management of the patient with tetralogy of Fallot does not end at the time of complete repair. Follow-up by cardiologists trained in congenital cardiac disease will remain a life-long experience.

Questions that remain regarding the management of tetralogy of Fallot pertain to the preference of surgical timing, as discussed above, and to the residual lesions of the disease. The management of young adults with pulmonary regurgitation or residual pulmonary stenosis is complex. A balance must be achieved between limiting the haemodynamic burden on the right ventricle, and minimizing the life-time number of surgical interventions required for a given patient. Cardiac magnetic resonance imaging has progressed significantly in the past ten years (Figures 9a and 9b). This provides reliable objective data, in addition to echocardiography and exercise testing, that physicians can use to determine the optimal timing of reintervention [41‐43]. Recent advances in interventional cardiac catheterisation now provide safe options for treatment other than cardiac surgery. Devices such as the percutaneously placed pulmonary valve have shown promising results in the management of selected patients with pulmonary regurgitation and stenosis [44, 45]. Ongoing advances in diagnostics and minimally invasive procedures will continue to help improve the care of these adult patients with tetralogy of Fallot.