Challenges in Managing Arrhythmias in Adult Tetralogy of Fallot

Though contemporary advances in surgical techniques lead to significant improvement in the long-term survival of patients with tetralogy of Fallot (TOF)^{1, 2}, cardiac arrhythmias have emerged as the principal cause of mortality and morbidity in patients who have survived after surgical repair.^1,2 Approximately half of the adult patients of repaired TOF (rTOF) suffer from either sustained arrhythmia, or requirement of an active arrhythmia intervention in their lifetime.³ Arrhythmias in adult rTOF patients may contribute to sudden cardiac death as well as increase the incidence of heart failure and stroke.⁴ Structural remodeling of atrium and ventricle from hemodynamic stress along with fibrosis from surgical scar contribute to the milieu for arrhythmia substrate and reentry is the commonest mechanism for tachyarrhythmias in this population.⁴ Both atrial and ventricular arrhythmias demonstrate a positive correlation with the age of presentation, age of first surgery, previous shunt surgery, and the number of surgical repairs.^3,4

Sustained atrial arrhythmia is documented in up to 20% of adult patients with rTOF.³ Intra atrial reentrant tachycardia (IART) due to micro reentry around atriotomy scar and Cavotricuspid isthmus (CTI) dependent atrial flutter are common in this population.^3,4 Although the overall prevalence of AF in the rTof population is low, AF is the commonest atrial arrhythmia after the age of 45 years.³ IART in rTOF is usually of right atrial origin, and right atrial dilatation and atriotomy scar are common determinants of IART.⁴ In contrast, AF is commonly associated with left-sided heart disease including left ventricular dysfunction and left atrial dilatation.³ Irrespective of mechanisms and site of origin, sustained atrial arrhythmia is associated with progression to heart failure, need for reoperation, ventricular arrhythmia, increased hospitalization, and death.^5,6

Although pharmacotherapy is recommended as first-line therapy for atrial arrhythmia, the acute success rate of radiofrequency catheter ablation (RFCA) is high for right atrial tachycardia (IART and CTI dependent flutter) and RFCA may be considered as an initial strategy in selected patients.⁷ Considering progressive structural remodeling and the extensive nature of arrhythmia substrate, long-term maintenance of sinus rhythm might be difficult despite the high acute success, and repeat procedures may be necessary.⁸ Compared to right atrial tachycardia, AF ablation in rTOF patients carries low acute success and a high recurrence rate.⁸ Class IC antiarrhythmic agents are commonly used for rhythm control for AF in the general population. However, severe structural remodeling in the operated congenital heart disease population may increase the proarrhythmic risk of this group of pharmacological agents. ⁹ AV nodal blocking agent should be considered to control ventricular rate in patients with unsuccessful rhythm control. ⁷

Systemic embolism is another dreaded complication of atrial arrhythmias and the CHA2DS2-VASc score underestimates the thromboembolic risk in patients with complex congenital heart disease.¹⁰ Considering the complexity of congenital heart disease as the strongest risk factor for thromboembolism, all patients with atrial arrhythmia and rTOF should be considered for long-term oral anticoagulation therapy irrespective of CHA2DS2-VASc score.^7,10 An individualized approach may be considered in patients with high HAS-Bleed score.⁴

Adult TOF patients are also predisposed to bradyarrhythmia due to atrial scarring and postoperative damage of atrioventricular conduction.³ Pacemaker implantation for bradyarrhythmia in these patients is recommended by the guidelines proposed by the American College of Cardiology/American Heart Association and the PACES/HRS Expert Consensus Statement on the Recognition and Management of Arrhythmias in Adult Congenital Heart Disease.¹¹ However, increased risk of systemic embolization should be taken into account in patients with the residual shunt. Anti-tachycardia pacing may be useful in reducing arrhythmia recurrence in selected patients with pacing indications and recurrent IART requiring long-term antiarrhythmic drugs and or radiofrequency ablation. ¹²

Unlike patients without congenital heart disease, heart failure in rTOF patients is commonly contributed by progressive right ventricular dilatation and dysfunction.^13,14 However, LV dysfunction is reported in 20-25% of patients.¹³ RV cardiac resynchronization therapy (RV-CRT), consisting of resynchronization of septal and RV-free walls, is found to improve electromechanical and clinical outcomes in rTOF patients with RV dysfunction, and RBBB.^15,16 Considering the universal occurrence of RBBB following surgical correction of TOF and the suboptimal response of biventricular CRT in patients with RBBB, there were concerns about the response of biventricular CRT in patients with TOF and systemic LV dysfunction. However, LV electrical desynchrony is demonstrated after total correction despite the presence of RBBB and biventricular CRT is reported to improve outcomes in rTOF and at least moderate LV systolic dysfunction. ¹⁷ Biventricular CRT is recommended in presence of concomitant LV systolic dysfunction. ¹¹

Sudden cardiac death due to malignant ventricular arrhythmias is a leading cause of death in patients with TOF.^1,2 Approximately 15% of patients with rTOF are reported to develop sustained ventricular arrhythmia, monomorphic ventricular arrhythmia being the most common.^3,4 Older age at the time of repair, previous palliative shunt, high BMI, left ventricular diastolic dysfunction, QRS prolongation (≥180 ms), QRS fragmentation (fQRS), high ventricular arrhythmia burden on ambulatory monitoring, right ventricular hypertrophy, atrial arrhythmias, and abnormal left ventricular longitudinal function are reported to predict a high risk of ventricular tachycardia.^18-20 Pregnancy-induced acceleration of RV remodeling may be responsible for an increase in the short term as well as the long-term increase in ventricular arrhythmias following pregnancy.²¹ Approximately, two-thirds of rTOF patients with monomorphic VT have preserved left ventricular function and LV systolic dysfunction is more common in patients with VF.^3,18 Monomorphic VT in operated TOF patients is usually of left bundle branch block morphology suggesting an origin from right ventricular pathology. The monomorphic VTs are maintained by macro reentry, and slow and heterogenous conduction around structural barriers like the surgical patch and/or scar creates the substrate for reentry. ^22-24 An autopsy study on post-mortem TOF specimens demonstrated four types of anatomically defined isthmus (AI) around the right ventricular outflow tract (RVOT). The isthmuses between tricuspid annulus and RV incision/RVOT patch (AI 1) and between PV and VSD patch (AI 3) are more common than those between RV incision/RVOT patch and pulmonary valve (AI 2) and between VSD patch and tricuspid annulus (AI 4).²² Electrophysiological studies demonstrated that presence of AI with slow conduction (CV<0.05 m/s) creates the substrate for spontaneous and induced monomorphic VT.²⁴ Routine use of transatrial-transpulmonary technique and early age of repair surgery are associated with reduced presence of AI 1 and 2.²² AI 3 is narrowest and most arrhythmogenic due to highest degree of fibrosis.²⁴

AICD implantation is indicated in patients with a history of events (resuscitated SCD or hemodynamically non-tolerated VT) or those with high risk of future events.²⁵ Khairy et al suggested a point-based risk stratification score based on the presence of Prior palliative shunt, QRS duration of ≥ 180 ms, non-sustained VT, Ventriculostomy incision, LVEDP ≥ 12 mm of Hg, and Inducible sustained ventricular tachycardia.¹⁸ A score of ≥ 6 is considered high risk and a score ≤ 2 as low risk for future malignant ventricular arrhythmia. Patients with six risk factors carry significantly higher annual SCD risk compared to those with four risk factors (14% vs 3%). Electrophysiological study and VT induction by programmed ventricular stimulation (PVS) may be used for further risk stratification in rTOF patients with non-invasive risk factors including LV systolic or diastolic dysfunction, NSVT, QRS duration ≥ 180 ms or extensive RV fibrosis on cMRI.²⁵ A positive EPS with inducible sustained monomorphic or polymorphic VT is associated with a relative risk of 4.⁷ for VT or SCD in the future.²⁶ Considering the potential complication of hemodynamic instability by inducible fast VT, substrate mapping to identify the slowly conducting AI may be used for invasive risk stratification.²⁴ The presence of slowly conducting AI correlates with VT inducibility whereas the absence of slowly conducting AI is associated with non-inducibility for VT during electrophysiologic provocation as well as the absence of clinical VT in mid-term follow-up. Around 10% of adult rTOF TOF patients have AICD implantation and approximately one in three patients are found to receive appropriate ICD therapies during a median follow-up of 3.7 years. ^3,18

Unfortunately, AICD-related complications are higher in this population and up to 40% of patients are found to experience ICD-related complications, the most common being inappropriate ICD shock affecting 25% of patients followed by lead-related complications. ²⁰ Atrial arrhythmias are the most common cause of inappropriate shock and other causes include lead dysfunction and sinus tachycardia. Other complications include pocket infections, pocket hematomas, and lead endocarditis. Subcutaneous ICD may reduce long-term complications of indwelling transvenous lead. However, the requirement of pacing for bradyarrhythmia, absence of anti-tachycardia pacing, and screening failure may limit the use of SICD in the relatively young population. ²⁷

Long-term therapy is indicated in patients with recurrent ICD therapy. β-blockers, amiodarone, and sotalol are commonly used to suppress ventricular arrhythmia.¹⁸ Considering the high success rate, RFCA is indicated as the first line of therapy in recurrent macro-reentrant monomorphic VT.²³ Although RV volume overload from pulmonary regurgitation provides a significant contribution to proarrhythmic remodeling, pulmonary valve replacement does not reduce the risk of VT despite hemodynamic improvement.²⁸ A strategy of empiric surgical ablation of AI during PVR may be considered as an alternative to reduce VT recurrence. A retrospective study by our group demonstrated that substrate ablation of AI before AICD implantation may reduce the appropriate ICD shock by 85% in patients who received AICD for secondary prevention. ²⁹

In conclusion, both tachy and brady arrhythmias are prevalent in adult patients with rTOF and provide a significant contribution to long-term mortality and morbidity. Despite significant progress in understanding the mechanisms and management, treatment of arrhythmias might be difficult in this patient population. Prevention of sudden cardiac death is particularly challenging. Identification of appropriate risk factors and prospective validation of those factors may improve risk stratification. Large-scale prospective evaluation of modification of reentrant VT circuits by RFCA and or surgical ablation will be helpful to identify effective modalities of suppressing ventricular arrhythmia recurrence.