Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease (CHD). In neglected untreated cases, the mortality rate is about 33% in the first year of life and about 50% in the first 3 years of life [1]. However, advances in diagnosis, surgical techniques, and postoperative treatment have led to increasing number of patients reaching adulthood with a dramatic increase in survival rate to almost 90% at 30 years. TOF was originally named after the French scientist “Arthur Louis Etienne Fallot” who published a paper in 1988 entitled “Contribution a ‘l’anatomie pathologique de la maladie bleue” [2]. He described four anatomical features that were almost always present in all post-mortem specimens of the blue patients “la maladie bleue” in his own words. These anatomical features consist of a tetrad of (1) ventricular septal defect (VSD), (2) aortic overriding, (3) right ventricular outflow tract (RVOT) obstruction, and (4) right ventricular (RV) hypertrophy [3].
Pathophysiology
The main pathophysiological features of TOF are the antero-cephalic deviation of the cono-ventricular septum and hypertrophy of the septoparietal trabeculations of the RVOT [3]. The antero-cephalic deviation of the cono-ventricular septum results in a mal-aligned VSD in continuity of the aortic valve [4]. Thus, the aortic valve has a biventricular connection with variable degrees of overriding the RV. In addition, the mal-alignment between the cono-ventricular septum and the septoparietal trabeculations of the RVOT results in hypertrophy of the RVOT and subsequent pulmonary valvular or infundibular stenosis [5,6,7,8]. The hemodynamic effect of RVOT obstruction is right ventricular hypertrophy which is the fourth pathological feature of TOF [3].
Clinical presentation and diagnosis
Although TOF is the most common cyanotic congenital heart disease, only a small percentage of cases are deeply cyanotic since birth after closure of the ductus arteriosus. This group of cyanotic patients is referred to as “blue TETs” while the acyanotic group is referred to as “pink TETs”. Blue TETs typically have severe pulmonary stenosis or atresia. Sometimes, these patients may remain undiagnosed in the first days or weeks of life due to the presence of moderate to large patent ductus arteriosus (PDA) which maintains adequate blood flow to lungs and present with profound cyanosis after duct closure necessitating emergency surgery to maintain adequate pulmonary blood flow.
Pink TETs may have mild desaturation with arterial oxygen saturation in the range of 80–90% or even normal oxygen saturation depending on the degree of pulmonary stenosis and the presence of PDA or major aorto-pulmonary collateral arteries (MAPCAs). Usually, the baseline oxygen saturation gradually decreases as the right ventricular hypertrophy (RVH) progress and subsequently the degree of RVOTO. These patients should be closely followed up to determine the appropriate time of surgical intervention before cyanosis worsens. Pink TETs can develop episodic profound hyper-cyanosis “cyanotic spells” with arterial oxygen saturation drop to below 50% and manifest by sudden marked increase in cyanosis, shortness of breath, agitation, and loss of consciousness. These cyanotic spells result from dynamic changes in the pulmonary and systemic resistance which is thought to be due to infundibular muscle spasms with large dynamic increase in RVOT obstruction resulting in severe right to left shunting of blood through the VSD [9].
Clinical examination of TOF patients can reveal variable degrees of cyanosis, ranging from mild to severe generalized cyanosis. Clubbing may be seen in neglected cases. On auscultation, an ejection systolic murmur can be heard due to RVOT obstruction which usually soften or disappear during cyanotic spells as a result of marked decrease of blood flow across RVOT. The VSD typically has no appreciable murmur because of its large size and systemic level pressure in the RV. Usually, there is no splitting of second heart sound because of small pulmonary valve and low post-stenotic pulmonary artery pressure [9]. Electrocardiogram shows right ventricular hypertrophy and right axis deviation.
Classical finding in chest radiography is the “boot-shaped” heart resulting from RVH and small pulmonary knob and the lung is usually oligemic due to decreased pulmonary blood flow.
Echocardiography is the diagnostic modality of choice. It provides complete evaluation of the anatomy, estimation of pressure gradient across the RVOT, identification of the level of RVOT obstruction, and delineation of coronary artery anatomy [10]. Prenatal echocardiography is highly accurate in the in utero diagnosis of TOF, although the degree of pulmonary stenosis is usually difficult to be determined. More data are needed to identify the effect of prenatal diagnosis on long-term survival [11]. Three-dimensional echocardiography is not yet superior to two-dimensional echocardiography in diagnosis and preoperative assessment of TOF, though it may be of great value in long-term follow-up of functional and morphological changes to the RV in repaired TOF patients [12].
Before the advanced techniques in echocardiography, cardiac catheterization was used to be the gold standard for the diagnosis of TOF. However, in the current days, the use of cardiac catheterization is limited and preserved only for cases with unclear anatomy of branch pulmonary arteries and to confirm the presence of anomalous coronary artery. As a good alternative to invasive cardiac catheterization, three-dimensional computed tomography and magnetic resonance imaging play an important role in the evaluation of TOF anatomy. These modalities can accurately reveal branch pulmonary arteries, aortic arch anatomy, and also delineate coronary anomalies.
Cardiac magnetic resonance (CMR) is currently considered as one of the most used modalities for long-term evaluation of repaired TOF patient. CMR measurements of RV volumes and function and accurate quantification of pulmonary valve regurgitation volume and fraction, in addition to monitoring the progress of pulmonary regurgitation and RV dilatation, are superior to those obtained by two-dimensional and three-dimensional echocardiography [13, 14]. These CMR measurements are becoming very dependable indications for timing of re-interventions and most importantly the timing of pulmonary valve replacement [15].
In addition to standard CMR protocols, time-resolved 3D phase contrast MRI (also called 4D flow MRI) improves the visualization and quantification of blood flow in the cardiovascular system that helps in obtaining more detailed information about vascular hemodynamics. Thus, this technique may be a promising method to accurately evaluate altered blood flow in patients with CHD with complex anatomy and hemodynamics.
Medical management
There is no definitive medical management of TOF patients, and the only definitive management is surgical repair. However, there are few significant medical adjuncts, the most important of which is the Prostaglandin E1 (PGE1) which is used in profoundly cyanosed neonates to maintain the patency of ductus arteriosus [16]. PGE1 is given as a continuous intravenous infusion at a dose of 0.01–0.1 μg/kg/min, to maintain ductal patency, thus providing maintained pulmonary blood flow until definitive surgical correction or palliative surgery by establishment of systemic to pulmonary shunt. Administration of PGE1 is mainly limited to the first week of life, after which PGE1 rarely results in duct opening. The most important and significant side effect of PGE1 is apnea which may require endotracheal intubation and mechanical ventilation.
Other medical adjuncts are mainly aiming to prevention or treatment of cyanotic spells. Beta-blockers may be used in prevention of these spells by reducing the muscular spasm in the RVOT infundibulum [17, 18]. However, it has been shown that TOF patients receiving beta-blockers are at increased risk of inotropes dependence and temporary pacing following surgical repair [19]. Thus, earlier surgical management is recommended in patients with paroxysmal spells requiring beta-blockers.
Acute management of cyanotic spells includes placing the patient in knee head position, proper oxygenation, sedation, volume resuscitation, and alpha-receptor antagonists like phenylephrine which cause systemic vasoconstriction, increase systemic vascular resistance, decrease right to left shunting of the blood across the VSD, and thus increase the pulmonary blood flow [20]. However, any TOF patient requiring such therapy should be referred for urgent surgical management.
Surgical options
Before the introduction of surgical interventions for TOF, the mortality was about 35% of patients at the first year of life, 50% at the age of 3 years and the survival after the age of 30 years was rare [21]. Nowadays, almost all patients that undergo surgical correction are expected to reach adult life.
The best timing for elective surgical repair is now considered to be within the first year of life [22, 23]. Early surgical repair before the age of 3 months has been reported to be associated with extended intensive care stay and hospitalization [22], So such an early repair should be reserved only for patients with severe cyanosis or cyanotic spells. Late surgical correction after the age of 1 year may be associated with complications of long-lasting right ventricle pressure overload and cardiomyopathy due to long-term hypoxemia, which has been related to ventricular dysfunction and arrhythmias [22].
Complete surgical repair
The aim of the corrective surgery is to completely close the VSD and relieve the RVOT obstruction, with preservation of the right ventricular and pulmonary valve functions. Surgical approach during the early years of corrective surgery was through right ventriculotomy. However, from the mid-sixties, transatrial-transpulmonary approaches with or without patch repair of the outflow tract improved early to middle-term outcome [24]. Currently, surgical correction of TOF may consist of complete relief of RVOT obstruction with extensive resection of infundibular muscles, but often at the expense of pulmonary valve regurgitation, or sometimes accepting residual obstruction in order to preserve pulmonary valve function, aiming to minimizing late surgical sequalae [23].
Palliative procedures
Palliative procedures are usually performed in patients who are unfit or have contraindications to corrective surgery including aberrant coronary arteries, hypoplastic or small caliber pulmonary arteries, and associated cardiac malformations. The aim of palliative surgery is to increase the pulmonary blood flow so as to promote the growth of pulmonary arteries in preparation for corrective surgery at second stage. Various types of palliative procedures have been developed over time. The current palliative surgery procedure of choice is the modified Blalock-Taussig (MBT) shunt, where a Gore-Tex graft is placed between one of the arch vessels and the pulmonary artery. Typically, the shunt is placed on the opposite side of the aortic arch; thus, a patient with a left sided aortic arch receives a right sided MBT shunt. This shunt increases pulmonary blood flow and helps the pulmonary arteries to grow [25].
