Developmental and Anatomic Aspects

Tetralogy of Fallot affects approximately 7.5 % of all children born with a congenital heart defect. It is characterized by subpulmonary stenosis, a subaortic ventricular septal defect, dextroposition of the aortic orifice, and right ventricular hypertrophy, the latter being a secondary feature to the volume and pressure overload of the ventricular septal defect and subpulmonary stenosis, respectively.

During normal development, the outlet portion of the heart needs to evolve from a single myocardial tube to a situation where the separated aorta and pulmonary trunk achieve their definitive positional relationship. This process requires proper septation of the outlet portion of the heart. Formation of the aortopulmonary septum (future outlet septum), orchestrated by neural crest cells, will result in separation of the common trunk into an aorta and pulmonary trunk. Asymmetrical, mainly subpulmonary myocardial contributions from the so-called second heart field will result in marked lengthening of the subpulmonary myocardium and will “push” the pulmonary trunk to its definitive position left anterior to the aorta.⁸ After proper development, the right ventricular outflow tract (RVOT) is characterized by the presence of a muscular subpulmonary infundibulum forming a circular muscular tube below the pulmonary valve. The posterior wall of the infundibulum, also known as the crista supraventricularis, is situated between the tricuspid valve and the pulmonary valve. The crista supraventricularis forms the summit of the ventriculo-infundibular fold (VIF), a fold of myocardium at the posterolateral wall of the RVOT, and extends toward the ventricular septum into the trabecula septomarginalis (Figure 102-1). The latter continues over the interventricular septum and contains the right bundle branch. The crista supraventricularis also encompasses the outlet septum (the muscular septum separating the aortic en pulmonary outlets), situated in between the ventriculo-infundibular fold and trabecula septomarginalis, which is small and not recognizable as a separate structure in the normal heart. In TOF, however, there is an anterior deviation of the outlet septum that, in contrast to normal, can be recognized as a separate structure, which is regarded as a pathognomonic feature of TOF (see Figure 102-1). The deviation of the outlet septum causes malalignment with the remainder of the ventricular septum, resulting in a subaortic, and in most cases perimembranous, ventricular septal defect. The deviation of the outlet septum also contributes to the subpulmonary stenosis. The amount of displacement and hypertrophy of the outlet septum determines the severity of the stenosis. The morphology of TOF encompasses a broad spectrum, with on the one end very slight malformations and cyanosis and on the other end severe forms of the disease with pulmonary atresia.

Type and Timing of Surgical Repair and Its Potential Relation to Risk Factors for Ventricular Arrhythmias

After the first intracardiac repair of TOF in 1954 by Lillehei in a 10 month-old boy, subsequent series of early surgical interventions reported a high perioperative mortality leading to a “two-stage repair” with a palliative shunt to augment pulmonary blood flow, followed by total repair later in childhood.

Total repair included (patch) closure of the perimembranous or muscular VSD and relief of the infundibular or valvular RVOT obstruction. This repair was initially performed through a vertical or transverse right ventriculotomy often combined with the use of an RVOT or a transannular patch to augment the restrictive RVOT or to relieve the stenosis of the pulmonary orifice. The malformation and type of repair are important determinants of potential reentrant tachycardia circuits, which is a common underlying mechanism of VT in repaired TOF.⁸ Areas of dense fibrosis owing to surgical incisions, but also patch material and the valve annuli, can form regions of conduction block that define reentry circuit borders and create intervening isthmuses of myocardial bundles that might contain the critical reentry circuit isthmus of a macroreentrant VT. Four anatomic isthmuses related to VT in repaired TOF have been identified⁹: isthmus 1 bordered by the tricuspid annulus and the scar or patch in the anterior RVOT, isthmus 2 between the pulmonary annulus and the RV free wall incision or RVOT patch sparing the pulmonary valve annulus, isthmus 3 between the pulmonary annulus and the VSD patch or septal scar, and isthmus 4 between the VSD patch or septal scar and the tricuspid annulus in patients with muscular VSDs (see Figure 102-1).

The right ventriculotomy and the frequent use of a transannular patch with consecutive pulmonary regurgitation and chronic volume overload often resulted in RV dilatation and dysfunction, which is associated with VT and SCD in the long term (Table 102-1). Consequently, a combined transatrial-transpulmonary approach has been introduced. Currently, patch augmentation is avoided or usually limited to the pulmonary annulus whenever possible. This approach does not only positively affect RV function but can also prevent the anatomic isthmuses 1 and 2.

Reentrant tachycardias are promoted by slow conduction. Interstitial fibrosis owing to longstanding cyanosis and pressure overload, functionally prolongs the pathway for impulse propagation and can provide the substrate for slow conduction. In addition, cell-to-cell coupling can be diminished because of decreased gap junction density and altered connexin expression and distribution, as observed in clinical and experimental cardiomyopathies also contributing to slow conduction.

Myocardial histopathologic changes, in particular interstitial fibrosis of the muscular tissue of the crista supraventricularis, are more pronounced in patients who were operated at older age, specifically beyond the age of 4 years, and are thus subjected to long standing cyanosis (SaO₂ < 80%) and higher end-diastolic RV pressure (>12 mm Hg).¹⁰ The clinical gold standard to detect ventricular fibrosis is late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR). Myocardial LGE was present in both the RV and LV of adults after repair of TOF and was related to increased age, and adverse clinical effects such as ventricular dysfunction and specifically RV LGE were associated with atrial and ventricular arrhythmias.¹¹

Histopathologic changes can also contribute to the occurrence of complex ventricular ectopy, which has been considered a risk factor for fatal ventricular arrhythmias (VA). In particular, older age at repair has been associated with a higher grade of ventricular ectopy. Only 11% of patients in whom repair was performed between the ages of 4 and 15 years showed complex ectopy on Holter monitoring 6 to 12 months after operation, compared with 39.4% of patients who underwent surgery beyond the age of 15 years.¹⁰ The age dependency of the occurrence of complex ventricular ectopy could also be demonstrated in uncorrected patients. No significant ventricular ectopy (defined as Lown ≥ 2, <30 uniform PVCs/h) was observed in patients 0 to 7 years old. In contrast, 58% of patients 16 years or older had complex ectopy, with 21% having runs of nonsustained VT. Of interest in corrected patients, the relation of complex ventricular ectopy and time of repair persisted and was independent of the duration of follow-up or of the postoperative hemodynamic status.¹² Although a higher grade of ectopy and nonsustained VT have been associated with VT inducibility, inconsistent data exist regarding their association with SCD. Accordingly, treatment of asymptomatic complex ventricular ectopy is not recommended.¹³ Primary repair in infancy before the age of 18 months is common practice since the early 90s and can be performed with low perioperative mortality. Avoiding long-standing prolonged hypoxemia and pressure overload can reduce the histopathologic changes and the substrate for slow conduction, complex ventricular ectopy, and fatal VA.

Despite early operation, progressive pulmonary regurgitation occurs in almost all patients after transannular patch repair and is an important reason for reintervention. Although often tolerated, pulmonary regurgitation ultimately leads to RV dilatation and dysfunction, which can be further aggravated by residual RVOT obstruction. Moderate to severe PR and abnormal RV hemodynamics in particular, and increased RV end-systolic pressure have been associated with VT and SCD. In addition, a wide QRS (>180 ms) and an increase in QRS duration have consistently been reported as risk factor for SMVT and SCD.⁵ In particular, RV dilatation but not restrictive RV physiology has been associated with QRS prolongation, referred to as mechanoelectrical interaction.¹⁴

Impairment of RV function and LV hemodynamics have important roles. A moderate to severe left ventricular systolic dysfunction—defined as ejection fraction (EF) of less than 39% and 20%, respectively—was also more common in patients with TOF and (aborted) SCD.¹⁵ In addition, an left ventricular end diastolic pressure (LVEDP) ≥ 12 mm Hg was a strong and independent predictor of appropriate ICD shocks in patients with TOF who received an ICD for primary prevention.¹⁶

Effect of Pulmonary Valve Replacement and Intraoperative Cryoablation on Ventricular Arrhythmias

In selected patients, a reduction in QRS duration after pulmonary valve replacement (PVR) was related to a reduction in RV EDV assessed by CMR, which further supports the occurrence of mechanoelectrical interaction.¹⁷ A QRS duration greater than 180 ms 6 months after PVR, or no reduction of the QRS duration postoperatively, were strong predictors of adverse events defined as all-cause mortality, reoperation for pulmonary regurgitation, heart failure or VT.¹⁸