A 29-year-old man born with tetralogy of Fallot (TOF) underwent repair when he was 9 months of age. Repair consisted of creation of a right ventriculotomy, just inferior to the pulmonary valve. Through the ventriculotomy, the surgeon closed a large ventricular septal defect (VSD) and resected muscle in the subpulmonary area of the right ventricular outflow tract (RVOT). Upon completion, the surgeon placed a large transannular patch to repair the ventriculotomy.

Approximately 14 years later, he was found to have severe pulmonary valve regurgitation complicated by severe right ventricle (RV) dilation and dysfunction and subsequently underwent pulmonary valve (PV) replacement. At the age of 29, a cardiac magnetic resonance imaging (MRI) demonstrated severe RV dilation with an RV end-diastolic volume index (RVEDVI) of 200 mL/m², mildly decreased RV function, and severe pulmonary regurgitation (PR). His pulmonary arteries were confluent without stenosis, but he had mild tricuspid regurgitation and a dilated right atrium (RA). The left ventricle (LV) ejection fraction (EF) was low-normal (50%-55%) and his aorta was mildly dilated with mild aortic valve regurgitation. From an extracardiac standpoint, he was noted to have a left superior vena cava (SVC) draining to a dilated coronary sinus and had a right aortic arch.

Shortly after his MRI, he underwent a third surgical procedure consisting of PV replacement. Following surgery, his RV did positively remodel, but unfortunately the RV size and function did not completely normalize. One month following surgery, he developed atrial flutter. He underwent electrical cardioversion and was started on anticoagulation and antiarrhythmic therapy. Unfortunately 6 months after his last surgery, while running, he suddenly collapsed and died.

CASE EXPLANATION

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  TOF is one of the most common cyanotic congenital heart lesions for which infants undergo palliative repair. There is excellent long-term survival but young adults can often suffer from multiple complications.

  
  
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  This case demonstrates several long-term complications that are known to occur after TOF repair including severe pulmonary regurgitation, severe RV enlargement, and the occurrence of arrhythmias that can lead to sudden cardiac death.

EPIDEMIOLOGY

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  TOF is the most common form of cyanotic congenital heart disease.

  
  
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  About 3.5% of all infants born with congenital heart disease have TOF which corresponds to 0.28 out of every 1000 live births.¹

  
  
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  It affects males and females approximately equally.¹

  
  
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  Most cases are sporadic, however, the risk of recurrence in siblings is approximately 2% to 3%, and the risk of the offspring of a patient having TOF (in the absence of 22q.11.2 deletion) is 3% to 4%.^{2, 3}

  
  
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  It has been suggested that for many countries there are now more adults living with TOF than children.⁴

ETIOLOGY

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  Although the majority of TOF appears to occur sporadically, its increased recurrence in some pedigrees and in consanguineous populations implies a central role for genetics.⁵

  
  
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  22q11.2 deletion has been found to be present in up to 25% of patients with TOF,⁶ and single gene mutations have been found in other patients. In up to 50% to 60% of TOF patients the casual mutation remains unknown.⁴

  
  
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  TOF patients may be syndromic or nonsyndromic. Most common identified cause of syndromic TOF is the 22q11.2 microdeletion which has a prevalence of approximately 1 per 6 to 10,000 live births.⁷ The 22q11.2 microdeletion is found in patients with DiGeorge syndrome or velocardiofacial syndrome.

  
  
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  DiGeorge syndrome is characterized by conotruncal defects (TOF, pulmonary atresia with ventricular septal defect, persistent arterial trunk, interrupted aortic arch, isolated arch anomalies, and ventricular septal defect), immunodeficiency, neonatal hypocalcemia, developmental or psychiatric abnormalities, facial dysmorphisms, and palatal defects.

  
  
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  In those TOF patients without an overt syndrome, the prevalence of 22q11.2 deletions has been estimated at 6%.⁸ Major chromosomal abnormalities are responsible for the second most common cause of syndromic TOF. These include Down syndrome (trisomy 21), Edward syndrome (trisomy 18), and Patau syndrome (trisomy 13).⁹

  
  
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  Smaller deletions, duplications, and single gene mutations have also been described in syndromic patients with TOF. These include mutations in the TBX5 gene which causes Holt-Oram syndrome, and mutations in the JAG1 and NOTCH2 genes that cause Alagille syndrome.^{10, 11, 12}

  
  
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  There are 12 single genes that have been associated with nonsyndromic TOF patients.⁴ Some studies have shown that these mutations can be inherited from a phenotypically normal parent suggesting either varying penetrance of the gene, or the possibility of a “multiple hit” model. However, evidence to support a multiple hit model is sparse.^{4, 13, 14}

  
  
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  Some environmental maternal exposures have been associated with an increased risk of TOF or other conotruncal defects; these include maternal pregestational diabetes, vitamin, febrile, or viral illnesses, and exposure to organic solvents.

ANATOMY

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  TOF is the result of the 4 anatomic features: a ventricular septal defect, an overriding (rightward deviating) aorta, right ventricular outflow tract obstruction, and right ventricular hypertrophy (Figure 4-1).

  
  
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  Many believe the anterocephald deviation of the outlet septum (the muscular structure that separates the subaortic from the subpulmonary outlets) is the primary pathologic event with the other features of TOF being sequelae^{15, 16, 17} (Figure 4-2).

  
  
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  The VSD is almost always large and unrestrictive, except rarely when its right ventricular margin is shielded by accessory tricuspid valve tissue or if septal hypertrophy narrows the defect. It is usually perimembranous in 80% of cases with most of the remainder having a posteroinferior rim.¹⁵

  
  
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  Rarely there may be an absence, or near absence, of the infundibular septum. In this circumstance, the cusps of the aortic and pulmonic valves are in fibrous continuity forming the superior border of the VSD. This type of VSD is called doubly committed. There is debate regarding whether this should truly be called TOF because the outlet septum is absent or only present as a fibrous remnant or raphe. Postnatally, however, the anatomy does exhibit all 4 components of TOF as the free wall of the subpulmonary infundibulum can possess hypertrophied trabeculations and may be obstructive after the closure of the defect. Therefore, having a doubly committed VSD is commonly thought of as a variant of TOF.^{15, 18, 19}

  
  
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  The aorta will always be rightward malpositioned and clockwise rotated. The aorta may override the VSD by 15% to 95% which has led to some debate on whether hearts with an aorta overriding the VSD by greater than 50% should be considered double-outlet right ventricles. Those patients with a significant aortic override may require larger patches during repair to connect the left ventricle to the aorta.^{1, 15, 20}

  
  
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  Multilevel obstruction to pulmonary blood flow is almost universally seen in TOF patients, but with variability in the severity from patient to patient. Infundibular stenosis is present in almost all TOF patients which is likely due to the narrowed diameter of the infundibular region.^{15, 21} The anterocephalad deviation and hypertrophy of the septoparietal trabeculations likely play a role in this narrowing, as well as trabeculations of the anterior limb of the septomarginal band. Other levels of right ventricular outflow tract obstruction may include hypertrophy of the moderator band and apical trabeculations which may give an appearance of a double-chambered right ventricle (DCRV).¹⁵

  
  
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  The pulmonary valve is usually thickened, bicuspid, and may cause valvular stenosis.¹ The main pulmonary artery and its branches are highly variable in their anatomy, but hypoplasia of the pulmonary arteries has been reported to be as frequent as 50%. Stenosis usually occurs at branch points from the bifurcation onward^{15, 22} (Figures 4-3A and 4-3B).

  
  
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  TOF with pulmonary atresia is often considered an extreme variant of TOF with significant variability in pulmonary blood supply (some coming from aortopulmonary collaterals) and clinical presentation.¹ The absence of pulmonary valve leaflets occurs in approximately 3% to 6% of patients with TOF.^{23, 24} Despite the absence of leaflets there is still usually RVOT obstruction. This is often not caused by infundibular stenosis, but primarily by a ring of tissue at the level where the pulmonary valve leaflets would be expected. There is an association with an aneurysmal main and branch pulmonary arteries that may compromise airways and respiratory function.^{25, 26} In 50% of patients with this variant there is a right-sided aortic arch, and there is an association of an absent or aortic origin of a branch PA.¹

  
  
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  TOF with an atrioventricular septal defect (AVSD) should be excluded in patients with Down syndrome with an apparent isolated TOF. A primum component atrial septal defect may not be present, and the only manifestation of an AVSD may be a “cleft” left atrioventricular valve. The RVOT obstruction protects the pulmonary vasculature from overcirculation, and the patient from heart failure. Therefore, repair of an AVSD in this setting can usually be done later than those with an isolated AVSD and at the time of repair for the TOF.¹

  
  
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  Coronary artery abnormalities occur in approximately 5% to 7% of patients.²⁷ The most common being the left anterior descending artery coming from the right coronary artery which occurs in approximately 3% of patients (Figure 4-4). This becomes significant from a surgical standpoint if the anomalous artery crosses the RVOT as it may require the use of a change in surgical technique during repair to avoid transecting the anomalous artery.¹⁵ A single coronary artery (usually from the left sinus) is the second most common coronary anomaly. This single artery usually divides early into a left and right branch, one of which may cross the RVOT²⁷ (Figure 4-5).

  
  
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  In 20% to 25% of TOF patients there is right-sided aortic arch with mirror image branching^{24, 28} (Figure 4-6). In isolation this causes no additional morbidity, however, if there is a persistent left ligamentum arteriosum a complete vascular ring is formed. A patent foramen ovale, atrial septal defect, or a second muscular inlet VSD may also be seen in patients with TOF.¹⁵

PATHOPHYSIOLOGY

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  The hemodynamics of tetralogy of Fallot depend on the degree of right ventricular (RV) outflow tract obstruction (RVOTO).

  
  
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  The VSD is usually nonrestrictive, and the RV and LV pressures are often equalized. If the obstruction is severe, the intracardiac shunt is from right to left, and pulmonary blood flow may be markedly diminished. In this instance, blood flow may depend on the patent ductus arteriosus (PDA) or bronchial collaterals.

  
  
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  The wide range of clinical presentations of TOF is the result of a morphologic spectrum relating to the degree of right ventricular outflow tract obstruction. Although there is variability in the degree of RVOT obstruction, there seems to always be sufficient obstruction to protect the pulmonary vasculature from developing pulmonary vascular disease.

  
  
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  Children that have severe obstruction have a large right-to-left shunt with little pulmonary blood flow, and severe cyanosis. These children usually require immediate intervention at the time of birth.

  
  
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  Those children with little obstruction and adequate pulmonary blood flow may have minimal cyanosis at birth (“pink tets”), but can develop heart failure during the first few weeks or months of life as the pulmonary vascular resistance falls and they shunt more left to right.

  
  
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  In addition, infundibular stenosis and RV hypertrophy typically worsen during the first 6 months of life resulting in increasing right-to-left shunting and the development of cyanosis at rest.¹

DIAGNOSIS

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  The majority of TOF patients present in infancy, but some patients can rarely present in adulthood if the RVOT obstruction is mild. In the current era, many patients with TOF are diagnosed during fetal life with a fetal echocardiogram.²

Physical Examination in the Unrepaired Infant With TOF

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  If not found prenatally, many clinicians will suspect TOF based on the presence of cyanosis and the rest of the cardiac examination.

  
  
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  The auscultatory findings in a newborn with TOF include a normal first heart sound, a single second heart sound, a loud systolic ejection murmur at the left lower sternal border that radiates to the back (due to flow across the narrowed RVOT not the nonrestrictive VSD).¹

Electrocardiogram

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  The electrocardiogram (ECG) findings in TOF patients typically show sinus rhythm with a normal or rightward axis and right ventricular hypertrophy. If an AVSD is present, there may be left-axis deviation. Because of disruption of the electrical conduction pathways during surgical repair, more than 90% of patients will have a right bundle branch block after surgical repair.²⁹

  
  
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  Over time, the QRS duration may increase if there are significant residual right-sided lesions leading to progressive RV dilation and associated RV dysfunction^{1, 30, 31} (Figure 4-7).

Chest Radiography

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  On chest radiograph, the typical normal cardiac size with an upturned apex (boot-shaped heart) may be seen. This is related to the RV hypertrophy, deficiency of the main PA segment, and reduced pulmonary vascularity.

  
  
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  Currently, because many patients are repaired early, prior to acquiring significant RV hypertrophy, the typical “boot-shaped heart” is not seen as often. A right-sided aortic arch may be seen on the chest radiograph as a bulge to right of the upper mediastinum, and an impression to the right of the trachea, in addition to the absence of the usual left-sided aortic knuckle^{1, 32} (Figure 4-8).

Echocardiography

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  Echocardiography is an important tool in diagnosing TOF. It is the best modality to assess for the anterior and cephalad deviation of the outlet septum, the position of the VSD, and the degree of RVOT obstruction.

  
  
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  It is also a key instrument in looking for associated anomalies such as atrial septal defects, additional VSDs, a right-sided aortic arch, and coronary artery anomalies. It is of great use intraoperatively during primary repair to check the VSD closure and relief of RVOT obstruction.

  
  
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  Echocardiography is routinely used in follow-up to assess ventricular size and function, atrioventricular valve competence, and to assess for long-term complications such as pulmonary regurgitation.

Cardiac MRI

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  In the preoperative period, MRI is usually used for assessment of patients with vascular abnormalities such as major aortopulmonary collaterals.

  
  
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  Postoperatively, it is useful in adults after repair to assess ventricular volumes and function (especially right ventricular sizes and function in the setting of pulmonary regurgitation), severity of pulmonary regurgitation, and pulmonary artery anatomy.

  
  
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  The use of MRI is limited in patients with pacemakers or defibrillators and also in patients with arrhythmias or claustrophobia.¹

Cardiac CT Angiogram/Cardiac Catheterization

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  Invasive angiography has largely been replaced by other imaging techniques as a diagnostic tool for TOF. At times, however, it can be used to obtain hemodynamic data, such as shunt fractions and the degree of right ventricular outflow tract obstruction. Angiography may also be used to evaluate abnormal coronary arteries or peripheral pulmonary artery anatomy.

  
  
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  High-resolution CT scans are a common noninvasive alternative to assess cardiovascular anatomy in patients with TOF.