Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease (CHD). The anatomical essence of TOF is the anterocephalad deviation of the infundibular septum, which causes various degree of right ventricular outflow tract (RVOT) obstruction and subsequent right ventricular (RV) hypertrophy.^1–3 The malalignment of the infundibular septum results in a biventricular connection of the aortic valve, i.e., aortic override, and a subaortic ventricular septal defect (VSD) (Fig. 68-1). Although the characteristics of the intracardiac anomalies are predominantly determined by the anterocephalad deviation of the infundibular septum,³ the subsequent degree of RVOT obstruction (RVOTO) varies significantly, yielding a wide spectrum of anatomy and physiology within the entity. The reported natural history of untreated tetralogy discloses survival rates of approximately 75 percent and 30 percent at 1 and 10 years of age, respectively.⁴ The major causes of death in patients with unrepaired TOF include severe hypoxia (62 percent) and cerebrovascular events (30 percent).⁵ Surgical strategies for management have evolved from staged repair with an initial systemic-to-pulmonary shunt and subsequent late repair to primary intracardiac repair in early infancy. Clinical outcomes have dramatically improved along with the evolution of surgical strategy.⁶ In this chapter, clinical presentation, diagnosis, and current therapeutic strategies for TOF with pulmonary stenosis are discussed. TOF with pulmonary atresia is discussed in Chapter 69. Two important subgroups, namely TOF with absent pulmonary valve (PV) and TOF with atrioventricular septal defect (AVSD) are discussed in the latter part of this chapter.

The prevalence of TOF is 0.21 to 0.36 per 1000 live births as reported in the Baltimore-Washington Infant Study and other large cohort studies,^7,8 accounting for approximately 7 to 10 percent of all forms of CHD. The exact etiology is largely unknown. Most cases are sporadic, although rare familial cases with a missense mutation in JAG1 (jagged 1 gene) have been reported.⁹ The risk of recurrence in siblings is approximately 1 to 3 percent.^10,11 Microdeletion of chromosome 22q11 is strongly related to some forms of CHD including TOF. 22q11 deletion is seen in 12 to 20 percent of the patients with TOF.¹²

The unifying anatomic feature for TOF is the anterocephalad deviation of the muscular outlet septum relative to the limbs of the septomarginal trabeculation. The subpulmonary stenosis is caused by the deviated outlet septum combined by the hypertrophied septoparietal trabeculations and results in a “squeeze” effect. Anterocephalad deviation of the outlet septum can also be seen in the absence of significant subpulmonary stenosis. This clinical condition is also known as “pink” tetralogy and the septal defect as an “Eisenmenger VSD.”¹³ The infundibulum is generally longer than that of normal hearts,¹⁴ although there is a significant variability in infundibular length. The infundibulum can also be completely absent.² Additional subpulmonary stenosis can be caused by a hypertrophied moderator band or infundibular trabeculations. RV hypertrophy is generally mild at birth, and becomes prominent over time.

As a result of the deviated infundibular septum, the aorta is shifted anteriorly toward the RV, thus overriding the interventricular septum. The degree of aortic override varies from 15 to 95 percent.² If there is more than 50 percent override of the aorta, the lesion is referred to as tetralogy-type double outlet RV (Chapter 71).¹⁵ The anatomical features of those hearts are essentially the same as those observed in typical tetralogy.

The VSD in tetralogy is located just beneath the overriding aorta and is usually large and unrestrictive. It can rarely be restricted by tricuspid valve tissue or septal hypertrophy.¹⁶ The majority of VSDs are perimembranous (80 percent), but they can occasionally be subarterial or doubly committed.² In a typical TOF VSD, the defect is cradled by the anterior–superior rim (that inserts to the deviated outlet septum) and the posterior–inferior rim of the septomarginal trabeculation. The anterior–superior margin of the defect is the muscular outlet septum and the ventriculo-infundibular fold (the roof of the outlet septum). The inferior–posterior margin of the defect is muscular. Separating these two limbs is an area of fibrous continuity between aortic and tricuspid valve leaflets, which incorporates the remnant of perimembranous septum (membranous flap). The VSD can also be called a conal septal malalignment defect, and differs from the typical perimembranous defect in that it is rare for chords of tricuspid valve to attach to the margins. The atrioventricular (AV) conduction axis is located around the apex of the triangle of Koch and penetrates the central fibrous body in the area of the remnant of the perimembranous septum. Approximately one-fifth of tetralogy patients have a muscular margin along the entire perimeter of the VSD, a feature most frequently seen in the Asian population.¹⁷ In this defect, the posterior–inferior rim of the septomarginal trabeculation inserts on the outlet septum and the perimembranous region is entirely intact. The rarest type of VSD is the doubly committed juxta-arterial defect, which is more common among patients from the Far East, South America, and Mexico. Unlike the vast majority of the VSDs in tetralogy, this form of tetralogy is characterized by the fact that the anterior–superior rim of the defect is a fibrous raphe between the leaflets of the aortic and PVs. The muscular outlet septum is deficient.

The PV in patients with TOF is most commonly bicuspid and characterized by a small annulus and thickened, dysplastic leaflets. There can occasionally be a tricuspid arrangement of the leaflets but they are usually small and dysplastic as well. PV leaflets are sometimes absent, and this is frequently associated with markedly dilated main pulmonary artery (PA) and its branches, resulting in a completely different physiology (absent PV syndrome).¹⁸ Stenosis is also common in the left PA, main PA, and the branch PA bifurcation.¹⁹ The left PA often originates more distally from the main PA and takes off with an abnormal acute angle, which may result in left PA stenosis. The left PA can be isolated and supplied by an arterial duct (discontinuous branch pulmonary arteries). Major aortopulmonary collateral arteries (MAPCAs) can coexist but are more common in the setting of TOF and pulmonary atresia (see Chapter 69).

A patent oval foramen or atrial septal defect is the most commonly associated lesion seen in patients with tetralogy (also known as pentalogy of Fallot). Other associated lesions include additional muscular VSDs, straddling of the tricuspid valve, common AV valve (TOF with AVSD), and right aortic arch. It is not uncommon to have coronary artery anomalies, including anomalous origin of the anterior descending coronary artery from the right coronary artery (2–3 percent), the presence of an accessory left anterior descending artery from the right coronary artery (5–6 percent), and a single coronary artery.²⁰ These coronary artery abnormalities may have surgical implications in terms of RVOT reconstruction.

The pathophysiology of TOF largely depends on the particular anatomical features and, most importantly, on the degree of RVOTO. Neonates or infants with TOF who do not have established RVOTO may have a moderate to large left-to-right shunt through the large VSD. The physiology in this situation is similar to that of an isolated VSD with pulmonary overcirculation. As RVOT muscle obstruction develops over time, the direction of the shunt at the VSD level may become bidirectional. In neonates with severe RVOTO, the direction of the shunt across the VSD can be exclusively or predominantly from right to left. For severe forms of TOF, pulmonary blood flow can be entirely duct-dependent.

The direction of the shunt at the atrial level is typically from left to right or bidirectional. The shunt can be bidirectional or predominantly from right to left if pulmonary vascular resistance is still high in the neonatal period, or if the RV has reduced compliance due to progressive RV hypertrophy.

Clinical Presentation

Neonates with severe RVOTO may present with significant persistent cyanosis at birth. Profound cyanosis may result in metabolic acidosis, compensatory tachypnea, and respiratory alkalosis. Pulmonary perfusion is, in this context, often duct-dependent. If the arterial duct is widely open, patients may not disclose intense cyanosis in spite of the presence of RVOTO. Infants with moderate RVOTO may present with cyanosis in the first few weeks of life with a systolic murmur. Development of cyanosis is usually correlated with the development of infundibular stenosis and RV hypertrophy. Infants with mild or minimal RVOTO may present with nonspecific symptoms of congestive heart failure because of a large left-to-right shunt. Possible symptoms include feeding, poor weight gain and tachypnea. There is generally no cyanosis but may become prominent as RVOTO develops. Older patients may have clubbing of fingers, although it is rarely observed in developed countries in the current era.

Patients with significant RVOTO may experience cyanotic spells, which are common among unrepaired patients who are older than 6 months. Many physiologic changes, such as dehydration, fever with resultant tachycardia and decrease in systemic vascular resistance may decrease relative pulmonary blood flow and trigger a cyanotic spell. Although infundibular spasm has been thought to cause cyanotic spells, this hypothesis is currently not supported. A cyanotic spell typically lasts 15 to 60 min. A long-lasting spell may result in brain damage or even death. Administration of vasoconstrictors, β-blockers, volume and sedation may be critical for stabilization. Older patients with severe cyanosis may assume a typical “squatting” position. The physiologic consequence of this posture is the increase in systemic vascular resistance with subsequent improvement in pulmonary perfusion and with left-to-right shunting across the VSD.

The presence of cyanosis and a systolic ejection murmur along the left upper sterna border is the common characteristics of moderate-to-severe form of TOF in neonates and infants. A shorter ejection murmur may indicate severe RVOTO, which may correlate with the severity of cyanosis. The second heart sound is typically single and of normal intensity. A continuous murmur may be audible when the arterial duct is patent. The parasternal RV impulse may be increased and a thrill may be palpable. Patients will usually have a normal growth pattern, although growth may be delayed if patients with associated syndromes such as DiGeorge syndrome, 22q11 deletion and trisomy 21. In such circumstances, various degrees of facial dysmorphism are also common. Infants with TOF who have minimal or mild RVOTO may have clinical features of congestive heart failure, such as tachypnea, hepatomegaly, and poor weight gain. The parasternal impulse may be increased.

Radiographic findings in patients with moderate-to-severe forms of TOF include decreased pulmonary vascular markings, upturned apex of the heart and pulmonary concavity of the upper-left cardiac border. The latter two features form a “boot-shaped heart” on a chest radiograph (Fig. 68-2). A right aortic arch can be found in up to 15 percent of the patients with TOF. In acyanotic infants with TOF CXR may be normal or may have signs of increase in pulmonary blood flow, such as cardiomegalyand increase in pulmonary vascular markings. The electrocardiogram usually shows normal sinus rhythm, rightward QRS axis, and various degrees of RV hypertrophy.

Echocardiography is by far the most important and effective diagnostic modality for detailing anatomic features of TOF. Nature and degree of RVOTO and deviated infundibular septum can be well documented by the subcostal right anterior oblique view (Fig. 68-3). The degree of aortic override and presence or absence of straddling of the mitral or tricuspid valve apparatus can be assessed in the parasternal long-axis view (Fig. 68-4A). Type of the VSD and presence or absence of additional muscular VSDs should be screened by multiple views (Fig. 68-4B). Other important structures to be assessed include size and morphology of the PV, size of main and branch PAs, and the presence or absence of an arterial duct. Detection of an anomalous coronary artery (anomalous origin of the left anterior descending artery or a large coronal branch of the right coronary artery crossing the RVOT) is of great importance for surgical decision-making and can be usually achieved by echocardiography. Aortopulmonary collateral arteries may be visualized if they are present and relatively large in size, but require delineation by angiography or computerized tomography if suspected.

Since echocardiography can provide detailed anatomic and physiologic information, the role of cardiac catheterization in the diagnosis TOF is currently somewhat limited. Cardiac catheterization may be useful when the presence of large aortopulmonary collateral arteries is suspected or to delineate the PA size if they appear small on echocardiography. Cardiac catheterization has, however, an important role if percutaneous intervention is contemplated or if the branch PAs cannot be completely assessed echocardiographically or if other imaging modalities are unsuccessful or unavailable.

The major role of medical management is to stabilize or optimize the patient’s condition until palliation or definitive surgical treatment is undertaken. Severely cyanotic neonates with TOF require administration of PGE₁ and/or intubation with mechanical ventilation. Prostaglandin may or may not be helpful in increasing pulmonary blood flow, depending on the presence or absence of a patent arterial duct. Prompt surgical or catheter-based management is required in this situation. Infants with TOF who have progressive cyanosis with or without cyanotic spells require β-blocker administration, which is usually effective to prevent recurrence. Early elective surgery is indicated if a patient requires therapy with β-blockers for progressive cyanosis or experiences a persistent fall in arterial saturation below 80 percent. Spelling patients may require intensive treatment with sedation, systemic vasoconstriction, volume repletion and β-blockade followed by urgent surgery. Acyanotic patients with TOF may not require any medical management until surgery. Patients with TOF who have minimal RVOTO and have pulmonary overcirculation may require diuretic therapy.

The diagnosis of the lesion is per se indication for surgery. There have been significant paradigm shifts in the surgical strategy for this entity over time. In the current era, there are still, however, considerable differences in surgical management among different institutions. We highlight to follow the evolution of the surgical approach to this malformation, and describe our current management strategy.

The presence of TOF had been uniformly lethal until the introduction of the systemic-to-pulmonary shunt by Alfred Blalock in 1944 (see Chapter 58).²¹ This, other forms of shunts, and closed valvotomy procedures represented the only form of therapy until C. Walton Lillehei performed the first intracardiac repair under direct vision.²² The repair was achieved then with a large vertical right ventriculotomy (Fig. 68-5). The VSD was closed with direct suture closure technique and RVOT muscle bundle resection was performed with a specifically designed infundibulectomy scissor. Remarkably, six of ten patients undergoing repair of TOF with parental cross-circulation survived. The role of cross-circulation was soon replaced by the heart–lung machine²³ but the fundamental concept of TOF repair through a right ventriculotomy remained. Given the early excellent results with this approach, many believed that intracardiac repair of TOF with a transannular patch and a transventricular VSD repair was a definitive repair. Over time, these patients went, however, on to develop RV dilatation, tricuspid insufficiency, atrial and ventricular arrhythmias, dysfunction and sudden death.^24,25

A transatrial approach for repairing TOF was first reported by Hudspeth in 1963.²⁶ This approach was later popularized by Edmunds²⁷ and Kawashima,²⁸ who reported successful early survival, superior pulmonary competence and RV performance in a substantial number of patients. These excellent results were reproduced in high-volume centers and extended to include patients with additional anatomical abnormalities such as abnormal coronary arteries.²⁹

The transatrial approach to VSD closure may better preserve RV geometry by avoiding a large right-ventriculotomy even if the pulmonary annulus is crossed. Residual mild-to-moderate RVOT stenosis with a preserved PV annulus and PV competency may be better at preserving long-term RV performance in those patients with favorable anatomic substrate. RV hypertrophy in the setting of residual stenosis may play a protective role against the dilatation associated with significant pulmonary insufficiency, thereby preserving long-term RV geometry and function.

Our current management algorithm is shown in Figure 68-6. Asymptomatic patients with TOF are electively operated at 5 to 6 months of age. Earlier repair is indicated when arterial saturation (SaO₂) falls below 80 percent, or if the patient experiences one or more cyanotic spells. The strategy for critically cyanotic neonates is based on body weight and on the presence or absence of risk factors that may preclude neonatal repair. Neonates whose body weight is greater than 2.3 kg undergo primary repair unless a contraindication is present. The contraindications for primary neonatal repair include body weight less than 2.3 kg, prematurity below 36 weeks, pathologic biventricular hypertrophy, intracranial hemorrhage, sepsis/infection, and significant end-organ dysfunction. The neonates who are not suitable for primary repair are assessed for possible catheter-based intervention. Balloon dilatation and/or placement of RVOT stent are performed in these cases if feasible. Patients who are palliated by RVOT dilation or stent placement undergo elective repair at 3 to 6 months of age, or earlier if SaO₂ decreases below 80 percent. The patients who are not suitable for surgery or catheter-based intervention are kept on PGE₁ until the patients’ growth approaches 2.5 kg or the factor(s) precluding surgery are no longer present. Our policy is to avoid the placement of a Blalock-Taussig shunt in the neonatal period or in early infancy because of the known incidence of significant pulmonary overcirculation, PA distortion, shunt thrombosis, and seromas.³⁰ In our experience and with this approach, primary repair has resulted in less than 1 percent morality over the past 15 years.