Sudden cardiac death in adults with congenital heart disease

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1 For reprint orders, please contact Sudden cardiac death in adults with congenital heart disease Expert Rev. Cardiovasc. Ther. 7(12), (2009) Sing-Chien Yap and Louise Harris Author for correspondence Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, Toronto, ON, Canada Tel.: Fax: Sudden cardiac death is one of the leading causes of death in patients with congenital heart disease, especially in patients with repaired cyanotic and left heart obstructive lesions. While the overall annual incidence of sudden cardiac death is relatively low, estimated at 0.09% per year, this nonetheless represents a many-fold increase over that of comparable age-matched control populations. The most frequent cause of sudden cardiac death is believed to be arrhythmic, usually ventricular arrhythmia. Most studies investigating risk factors for ventricular arrhythmia and/or sudden cardiac death have focused on patients with repaired tetralogy of Fallot and patients with Mustard/Senning repair for complete transposition of the great arteries. Despite a multitude of risk factors, their predictive value for the occurrence of sudden cardiac death is relatively low. Current experience with implantable cardioverter defibrillators in this patient population is limited to observational studies and the selection of patients for prophylactic implantable cardioverter defibrillator implantation is impeded both by the absence of randomized trials and weak predictors. Catheter ablation of ventricular tachycardia has emerged as a promising therapy for abolishing or reducing the burden of arrhythmia but experience is still limited and the impact on long-term outcome uncertain. Future studies will have to focus on improving risk stratification of patients with congenital heart disease. Keywords: ablation arrhythmia congenital heart disease implantable cardioverter defibrillator sudden cardiac death tetralogy of Fallot transposition of great arteries Patients with congenital heart disease (CHD) represent a unique patient population as their life expectancy has changed dramatically in the last 50 years owing to advances in cardiac surgery and perioperative care. Currently, the vast majority of infants born with CHD will survive into adulthood, leading to an increase in the prevalence of adults with CHD in the general population and a change in age distribution [1]. The estimated population of adults with CHD in the USA and Canada is approximately 850,000 and 100,000, respectively [1,2]. Despite these advances, surgical repair of the underlying defect usually does not mean that these patients are cured [3]. Adolescents with CHD are confronted with alternate sources of morbidity and mortality, central among which are cardiac rhythm disorders [4 8]. Ventricular arrhythmias usually arise as the unintended consequence of prior reparative surgery and may tragically lead to sudden cardiac death (SCD) of a young individual. Despite the improved hemodynamic outcome, SCD is still one of the leading causes of death (15 26%) in patients with CHD [9 11]. SCD is defined as the unexpected death from a cardiac cause occurring within a short time, generally within 1 h of onset of symptoms, or unwitnessed death during sleep, in people without prior conditions that would appear fatal [12]. The relative risk of late SCD in patients who have previously undergone surgery for CHD is substantial compared with the general population. The identification of patients with CHD who are at high risk of SCD poses a challenge but is essential to evaluate potential treatment modalities. Catheter ablation, arrhythmia surgery and implantable cardioverter defibrillators (ICDs) are promising treatment modalities. This article aims to review the magnitude of SCD in patients with CHD, mechanisms of SCD, identification and treatment of high-risk patients. Magnitude of the problem Despite numerous reports on SCD, there is a paucity of demographic data on SCD in patients with CHD. Characteristics of three studies that focus on the mode of death in patients with CHD are summarized in Table 1, including 180 cases of SCD in 12,117 patients /ERC Expert Reviews Ltd ISSN

2 Yap & Harris Table 1. Mode of death in patients with CHD. Study (year) Location Subjects (n) Oechslin et al. ( ) Silka et al. ( ) Nieminen et al. ( ) Total deaths (n [%]) Sudden cardiac death (%) Nonsudden cardiac death (%) CHF Perioperative Other CV Noncardiac death (%) ON, Canada 2609 * 197 (7.6) [10] OR, USA (4.9) [11] Finland (9.8) [9] * Only adult patients. More than 30 days after first operation. CHF: Congestive heart failure; CV: Cardiovascular. Ref. [9 11]. The mode of death was classified as sudden in 15 26% of all deaths. Although SCD is one of the most important modes of death, fortunately the annual incidence of SCD in the total CHD population is relatively low (0.09% per year) [11]. When applied to the entire adult CHD population in the USA and Canada, that accounts for approximately 765 and 90 events per year, respectively. The risk of late SCD varies with the specific lesion and with the age of the patient. Although SCD can occur in nearly any CHD lesion, Silka et al. found, in an unselected CHD population, the highest annual incidence of SCD in patients with repaired aortic stenosis (0.54% per year), complete transposition of the great arteries (TGA; 0.49% per year), tetralogy of Fallot (TOF; 0.15% per year), and aortic coarctation (0.13% per year) [11]. Approximately 73% of SCD were estimated to be arrhythmic. Survival curves for SCD suggest a threshold occurring years postoperatively when the PDA ASD UVH VSD Misc. TOF COA TGA AII Deaths (%) SCD CHF Perioperative Other Noncardiac Figure 1. Mode of death in different congenital heart disease groups. ASD: Atrial septal defect; CHF: Congestive heart failure; COA: Aortic coarctation; Misc.: Miscellaneous; PDA: Patent ductus arteriosus; Perioperative: Death within 30 days of second, third or fourth operation; SCD: Sudden cardiac death; TGA: Transposition of great arteries; TOF: Tetralogy of Fallot; UVH: Univentricular heart; VSD: Ventricular septal defect. Redrawn with permission from [9]. risk of SCD begins to increase, thus occurring predominantly in adulthood [11]. In a recent large population-based study in Finland (n = 5919), SCD occurred in 88 patients during the 45-year follow-up period at a mean age of 19.3 years. Figure 1 shows the mode of death stratified per congenital heart defect. In patients with complete TGA, aortic coarctation and TOF, SCD accounted for 28, 26 and 24% of all deaths, respectively. Interestingly, there also appeared to be a gender difference: male patients with TOF and complete TGA died suddenly more often than female patients (relative risk: 3.9) [9]. Tetralogy of Fallot Tetralogy of Fallot is the most common form of cyanotic congenital heart defect, accounting for 10% of all congenital heart malformations. Early repair of TOF is now advocated, with a 30-year survival rate of almost 90% [13,14]. Despite the improved survival rate, SCD has been recognized as a devastating late complication of surgical correction of TOF. The prevalence of SCD in large follow-up studies has varied from 2.0 to 8.3% [9,11,13 15]. In the largest cohort study of 793 patients with repaired TOF, 10.4% developed atrial flutter/fibrillation, 11.9% experienced sustained ventricular tachycardia (VT) and 8.3% died suddenly at 35 years from repair [15]. Complete transposition of the great arteries Between the 1970s and the 1990s, patients with complete TGA generally underwent complex intra-atrial baffling procedures of the Mustard/Senning repair, switching the atrial inflow and resulting in a subaortic right ventricle (RV). These procedures have provided excellent short-term clinical results and improved long-term survival [16]. The reported prevalence of SCD is % [17 21] and the estimated incidence at 19 years of follow-up is 8.0% [20]. Lange et al. demonstrated that survival 25 years after the Mustard or Senning procedure was 86.0% for hospital survivors [22]. Independent risk factors for late mortality in the multivariate analysis were ventricular septal defect closure at the time of the atrial switch operation and the Mustard operation. Interestingly, relatively more Mustard patients died of SCD compared with the Senning patients, who died preferentially of progressive congestive heart failure. This difference in mode of death has been 1606 Expert Rev. Cardiovasc. Ther. 7(12), (2009)

3 Sudden cardiac death in adults with congenital heart disease Review Table 2. Relative risk for specific arrhythmias in common congenital heart defects. Arrhythmia VT/SCD IART AF WPW SA node dysfunction Spontaneous AV block Traumatic AV block VSD ASD + + TOF AS TGA (M/S) AVSD Fontan CC-TGA Ebstein s anomaly : Slight risk; ++: Moderate risk; +++: High risk. AF: Atrial fibrillation; AS: Aortic stenosis; ASD: Atrial septal defect; AV: Atrioventricular; AVSD: Atrioventricular septal defect; CC-TGA: Congenital corrected transposition of the great arteries; IART: Intra-atrial re-entrant tachycardia; M/S: Mustard or Senning operation; SA: Sinoatrial; SCD: Sudden cardiac death; TGA: Complete transposition of great arteries; TOF: Tetralogy of Fallot; VSD: Ventricular septal defect; VT: Vetricular tachycardia; WPW: Wolff-Parkinson-White syndrome. Reproduced with permission from [30]. described previously by the Toronto Mustard group and Zurich Senning group [16]. The use of autologous atrial tissue may reduce the incidence of arrhythmias compared with the Mustard procedure. Furthermore, a meta-analysis has shown that sinus node dysfunction was more common after the Mustard procedure [23]. These findings can contribute to the increased incidence of SCD in Mustard patients. Over the last decade, the atrial baffle procedure has been replaced with the arterial switch procedure. This new approach not only offers hemodynamic advantages by retaining the left ventricle (LV) in the systemic circulation but has also moderated the late complications of intra-atrial re-entrant tachycardia (IART) and sinus node dysfunction in this condition [24]. This change from atrial to arterial switch has led to improved longterm survival after hospital discharge. A recent single-center study from Munich, Germany, showed the highest survival at 20 years after arterial switch (96.6%), followed by Senning (92.6%) and Mustard (82.4%) [25]. Fontan patients Patients who have undergone the Fontan repair comprise a large spectrum of CHD with a single-ventricle physiology. The classic Fontan operation (valved conduit between the right atrium and pulmonary artery) has been replaced largely by modifications of the procedure using a staged approach, ultimately leading to direct caval pulmonary artery connections with a lateral tunnel or extracardiac conduit repair. SCD is responsible for 9 16% of deaths in Fontan patients [9,26]. Khairy et al. recently reported the long-term outcome of 261 Fontan patients demonstrating a freedom from death or transplantation of 83% at 20 years of follow-up [26]. The most common causes of death were perioperative mortality (68%), SCD (9.2%), thromboembolism (7.9%) and heart failure (6.6%). The annual event rate for SCD was 0.15% per year. Despite the occurrence of SCD, no risk factors for SCD could be identified [26]. Eisenmenger syndrome Pulmonary arterial hypertension develops in approximately 5 10% of adults with CHD. Eisenmenger syndrome represents an extreme form of pulmonary arterial hypertension and usually occurs in the setting of uncorrected or delayed correction of CHD associated with large left-to-right shunt flows. The current prevalence of Eisenmenger syndrome patients at tertiary centers has been estimated at 4% [10]. Sudden death (19 63%) and progressive heart failure are the most important modes of death [10,27 29]. One of the largest cohort studies (n = 171) of adults with Eisenmenger syndrome demonstrated a SCD rate of 6.2% (total mortality: 11.3%) during a median follow-up of 5.6 years [27]. Predictors of mortality were a history of clinical arrhythmia, QRS duration and QTc interval, signs and symptoms of heart failure, impaired liver function (low serum albumin), and low potassium levels [27]. Mechanism of sudden cardiac death The cause of SCD is believed to be most frequently arrhythmic in nature including VT, ventricular fibrillation and complete heart block [11], although other circulatory and hemodynamic mechanisms have also been identified (e.g., aneurysm rupture, stroke and acute ventricular failure). Although many individuals with CHD have stable anatomic and functional substrates that could potentially lead to developing life-threatening VT, only a relatively small number of patients actually experience SCD. It is likely that a transient trigger, such as ischemia or hypoxia during exercise or 1:1 atrioventricular (AV) conduction in IART, modulates the underlying substrate and provokes ventricular arrhythmias [12]. The identified risk factors (see later) have a high sensitivity for the occurrence of VT or SCD, probably defining the essential substrate for SCD; however, they often lack specificity and, thus, predictive power. The necessary complex interplay between anatomic/functional substrates and triggers, could explain the relatively poor predictive value of many risk factors

4 Yap & Harris Table 3. Proposed risk factors for vetricular tachycardia or sudden cardiac death in patients with tetralogy of Fallot and transposition of the great arteries with Mustard or Senning repair. Variable Tetralogy of Fallot TGA (M/S repair) Clinical Older age at repair [13,15,53,106,139,140] Smaller size at operation [17] Use of right ventriculotomy [141] Associated anatomic lesions [51] Symptoms of (pre)syncope [139] Presence of symptoms [142] Transannular patch [15] NYHA III [51] Prior palliation [55] Hemodynamic Post-operative RVSP >60 mmhg [53,139,140,143] Moderate/severe TR [21,51] LV dysfunction [49,144] Subaortic RV dysfunction [21,51] Moderate/ severe PR [15,49,54] Post-operative RVOTO >40 mmhg [145] RV dilatation [146] RVOT aneurysm [54] History of sustained VT [49] Electrocardiographic QRS 180 ms [15,48 50] QRS 140 ms [51] High-grade ventricular ectopy [53 55,58] Documented atrial flutter or AF during follow up [19,21,142,147] QRS prolongation during follow-up [15] Complete heart block [17] Complete heart block [140,148] Increased QT, ORS and JT dispersions [48,146,149,150] Late potentials on SAECG [61] Reduction in heart rate variability [76] Pathologic heart rate turbulence [79] CMR RV LGE [87,91] RV LGE [90] Electrophysiology Inducibility of VT at EP study [55,151] AF: Atrial fibrillation; CMR: Cardiovascular magnetic resonance; EP: Electrophysiology; LGE: Late gadolinium enhancement; M/S: Mustard or Senning; NYHA: New York Heart Association; PR: Pulmonary regurgitation; RV: Right ventricle; RVOTO: Right ventricular outflow tract obstruction; RVSP: Right ventricular systolic pressure; SAECG: Signal-averaged ECG; TGA: Complete transposition of great arteries; TR: Tricuspid regurgitation; VT: Ventricular tachycardia. The potential electrophysiologic mechanisms of SCD vary according to the underlying anatomic defect and method of surgical repair. Table 2 presents the principal forms of CHD along with an estimate of the relative risk for specific arrhythmias in each condition [30]. Rapidly conducted IART or brady cardia may be responsible for some cases of SCD; however, most events appear to involve VT. Patients at highest risk for VT are those who have undergone a ventriculotomy or patching of a ventricular septal defect (e.g., TOF). The macroreentry circuit involves the narrow conduction corridors, which are defined by regions of surgical scar/patch in conjunction with natural conduction barriers, such as the tricuspid or pulmonary valve annulus [31]. Alternatively, VT can develop in the setting of a more generalized myopathic process (ventricular hypertrophy or subaortic ventricular dysfunction) without discrete ventricular scars (e.g., aortic stenosis or atrial switch procedure for complete TGA). The Fontan operation and atrial switch operations for complete TGA (Mustard/Senning repair) result in extensive suture lines and abnormal hemodynamics, predisposing patients to sinus node dysfunction and IART [19,32]. In patients with Mustard/Senning repair for complete TGA the actuarial rate of loss of sinus rhythm and occurrence of IART 20 years after repair is 60 and 24%, respectively [17]. Intra-atrial re-entrant tachycardia is the most commonly found tachyarrhythmia in patients with CHD, and is a macroreentrant rhythm with a circuit around patches, atriotomy incisions and other atypical conduction obstacles [33]. Generally, IART tends to be slower than typical flutter, with atrial rates in the range of bpm. Such slowed rates increase the possibility of 1:1 AV conduction with the potential for hypotension, ischemia, VT or cardiac arrest [34 36]. Furthermore, the requirement of anti-arrhythmic agents to treat IART or other atrial tachy arrhythmias exposes these patients to the potential proarrhythmic consequences of these medications, especially in patients with depressed ventricular function, and represents another potential mechanism for SCD. Other potential electrophysiologic mechanisms for SCD are the existence of accessory pathways and AV block. Wolff Parkinson White syndrome is especially prevalent in patients with Ebstein s 1608 Expert Rev. Cardiovasc. Ther. 7(12), (2009)

5 Sudden cardiac death in adults with congenital heart disease Review anomaly and patients with congenitally corrected TGA owing to the coexistence of an Ebstein s-like malformation of the systemic AV valve. Accessory AV and atriofascicular pathways are found in 25% of patients with Ebstein s anomaly, and are more often right-sided and multiple compared to patients with structurally normal hearts [37,38]. SCD may occur in the setting of atrial flutter or atrial fibrillation with rapid anterograde conduction over accessory pathways. There is a high incidence of disorders of AV conduction in CHD patients, which is the result of either developmental abnormalities or direct trauma during surgical correction. Congenitally corrected TGA and atrioventricular septal defects are notorious for AV block owing to the anatomic displacement of the AV node outside the normal triangle of Koch, rendering it susceptible to injury during catheter and surgical procedures [39,40]. Approximately 20% of patients with congenitally corrected TGA will develop spontaneous complete AV block by adulthood [41,42]. Furthermore, closure of VSD, surgery for left-heart outflow obstruction and replacement of an AV valve may be complicated by transient or permanent AV block [43]. Coronary artery abnormalities are commonly associated with CHD [44]. Anomalous origin of a coronary artery from the opposite sinus has been most frequently associated with myocardial ischemia, ventricular arrhythmias and SCD, particularly when the anomalous coronary courses between the great arteries [45,46]. Potential mechanisms leading to myocardial ischemia include slit-like ostium of the anomalously arising coronary artery compromising flow reserve, acute angle from the aorta altering flow patterns, and deformation of the anomalous coronary within the aortic wall during exercise [46]. Finally, the potential role of ion channelopathies in the occurrence of SCD in patients with CHD is unclear. A recent prospective study of patients with apparently unexplained cardiac arrest and no evidence of cardiac disease demonstrated that the cause of cardiac arrest could be identified in half of all patients using a systematic approach directing genetic testing [47]. Two-thirds of diagnosed cases were based on primary electrical disease (i.e., long- QT syndrome, catecholamine-induced polymorphic VT, Brugada syndrome or early repolarization), and the remaining third had a structural basis (i.e., coronary spasm and arrhythmogenic RV cardiomyopathy). The prevalence of ion channelopathies in CHD patients is currently unknown. Identification of high-risk patients The clinical profile of patients at high risk for SCD is influenced by the underlying CHD. However, most studies seeking risk factors for VT or SCD have involved patients with TOF and complete TGA (Mustard/Senning repair) (Table 3). Knowledge of the contribution of individual risk factors to the risk of SCD facilitates determination of which patients may benefit from cardiac surgery or interventional electrophysiologic therapies, such as ICD/CRT devices or radiofrequency ablation. Standard 12-lead ECG, ambulatory Holter monitoring & exercise testing The ECG features that help to identify patients at an increased risk for SCD include the presence of pre-excitation, heart block, intraventricular conduction defects and increased QT dispersion. A QRS duration of 180 ms or higher is predictive of VT/SCD in TOF [15,48 50], while a QRS duration of over 140 ms is associated with the highest risk of VT/SCD in patients with Mustard repair [51]. Progressive prolongation of the QRS duration during follow-up has also been identified as a marker for VT/SCD in TOF [15]. The largest cohort study in patients with TOF (n = 793) demonstrated that QRS of 180 ms or longer, high rate of QRS prolongation, older age at repair and transannular patch repair were independent predictors of clinical VT or SCD [15]. The hypothesis is that early lengthening of the QRS duration after TOF repair results from surgical injury to the right bundle branch and myocardium, whereas later widening may reflect RV volume or pressure overload [48]. In patients with Ebstein s anomaly, an accessory pathway may not always be present as pre-excitation on the 12-lead ECG, and it is recommended that all patients undergoing surgery have preoperative electrophysiologic evaluation [52]. Ambulatory Holter monitoring and exercise testing are considered appropriate initial screening tools in patients with symptoms of syncope, near syncope or palpitations. Holter monitoring can provide insight into the relationship between symptoms and the occurrence of arrhythmias. Although the presence of frequent or complex ventricular ectopy (modified Lown grade 2) is an independent predictor of sustained VT in patients with CHD [53 55], its predictive value for SCD is poor [15,56]. Older reports suggest an advantage of exercise testing over resting ECG to assess clinical risk of VT [57,58]. Signal-averaged ECG Demonstration of late potentials using signal-averaged ECG (SAECG) is a sensitive noninvasive method to detect the presence of delayed activation in ventricular myocardium, indicative of slow conduction and the substrate for reentrant monomorphic VT [59]. Measurements are usually expressed as total filtered QRS duration, low-amplitude (<40 µv) signal duration of the terminal filtered QRS, and root-mean-square voltage of the terminal 40 ms of the QRS. Interestingly, a previously positive SAECG can be rendered negative by radiofrequency ablation of an inducible slow conduction pathway [60]. While a positive test has been identified as a risk factor for VT in patients with surgically repaired CHD [60 64], the SAECG has had limited application in the risk assessment of patients with CHD. Microvolt T-wave alternans Microvolt T-wave alternans (MTWA) testing is a promising noninvasive clinical technique for risk stratification of adults with ischemic and nonischemic cardiomyopathy who are at high risk of future ventricular arrhythmic events [65 67]. However, recent prospective randomized trials (e.g., MASTER, ABCD and Sudden Cardiac Death in Heart Failure Trial [SCD-HeFT] substudy) have shown conflicting results regarding the predictive power of MTWA for ventricular tachyarrhythmic events in ischemic cardiomyopathy patients with prophylactic ICD implantation [68 70]. Currently, only two small studies have focused on MTWA in patients with CHD [71,72]. Alexander et al. demonstrated that sustained MTWA was associated with a higher risk of cardiac

6 Yap & Harris Table 4. Outcome of implantable cardioverter defibrillator therapy in patients with congenital heart disease. Parameter Alexander et al. [102] Berul et al. [115] Yap et al. [104] Khairy et al. [83] Type of study Single-center Multicenter Multicenter Multicenter Number of CHD patients Mean age at implant (years) * Median duration of follow-up (years) 1.4 * 7.5 * Type of CHD (n [%]) TOF 19 (59.4) 84 (41.2) 40 (62.5) 121 (100) TGA 5 (15.6) 35 (17.2) 7 (10.9) AS/CoA 4 (12.5) 29 (14.2) 2 (3.1) Other 4 (12.5) 56 (27.5) 15 (23.4) Secondary prevention(%) * Primary prevention(%) * Patients with appropriate shock(%) * Patients with inappropriate shocks(%) * Periprocedural complications(%) 14 * 12 * 13 5 Late complications(%) 38 * 26 * Mortality (%) * Only studies with > 25 patients were included. * Data for the total ICD population, including primary electrical disease and cardiomyopathy. AS: Aortic stenosis; CHD: Congenital heart disease; CoA: Aortic coarctation; TGA: Complete transposition of great arteries; TOF: Tetralogy of Fallot. arrest, ventricular arrhythmias and a clinical classification of high risk (odds ratio: 10.8; 95% CI: ) [71]. Current limitations are the high rate of indeterminate studies (~25%) due to excessive noise levels. Large prospective studies in high-risk patients with CHD are required to determine the role of MTWA testing as a potential risk stratifier for VT or SCD. Cardiac autonomic nervous system Cardiac autonomic nervous dysfunction is associated with an increased risk of death in ischemic and nonischemic cardiomyopathy patients [73]. Markers of reduced vagal activity include decreased heart rate variability (HRV) and decreased baroreflex sensitivity. Impaired cardiac autonomic nervous activity is common in patients with CHD [74 76]. It is important to note that noninvasive parameters of cardiac autonomic nervous activity reflect autonomic modulation at the sinus node, which is taken as a surrogate for autonomic actions at the ventricular level. HRV (a measure of tonic vagal activity) measures beat-to-beat variations of sinus-initiated RR intervals, with its Fourier-derived parameters. A novel parameter is heart rate turbulence (HRT), reflecting the physiologic biphasic response of the sinus node to premature ventricular contractions, most likely due to an autonomous baro reflex (a measure of reflex vagal activity) [77,78]. A recent prospective study in 43 patients with CHD showed that a pathologic HRT (turbulence onset 0% and a turbulence slope < 2.5 ms) was the strongest independent risk factor for (aborted) SCD (hazard ratio: 59.3; 95% CI: ), even after adjustment for HRV, functional status, history of arrhythmia and neurohormonal activity [79]. Subaortic ventricular function Left ventricular dysfunction is the most important predictor of total and sudden cardiac death in patients with ischemic and nonischemic cardiomyopathy. The SCD-HeFT and Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) have demonstrated that patient selection for prophylactic ICD implantation based on impaired LV function (ejection fraction < 30 35%) is effective in reducing SCD [80,81]. Limited data exist on the use of subaortic ventricular dysfunction as a predictor of SCD in CHD, as much of the literature has focused on the assessment of subpulmonary ventricular function. LV dysfunction has gained increasing attention as a potential predictor of SCD in patients with TOF [49,82]. One hypothesis is that while abnormal RV hemodynamics with the associated RV stretch and scarring provide the substrate for VT, impaired LV function may contribute to the clinical outcome of such arrhythmias. This was demonstrated by a cardiac MRI study in 88 patients with repaired TOF, which showed that RV dilatation and LV dysfunction (ejection fraction < 45%) were independent predictors of poor outcome (i.e., death, sustained VT, or increase in NYHA class to grade III or IV) [82]. Furthermore, in a recent study of patients with TOF who received a prophylactic ICD, a LV end-diastolic pressure of 12 mmhg or higher was the strongest predictor of the occurrence of appropriate ICD discharges [83]. Late reduction in subaortic ventricular function (anatomic RV) is a well-recognized outcome after the Mustard/Senning procedure [16,17,84]. It has been suggested that deterioration of subaortic ventricular function is inevitable in patients with Mustard/Senning 1610 Expert Rev. Cardiovasc. Ther. 7(12), (2009)

7 Sudden cardiac death in adults with congenital heart disease Review procedures, as the anatomic RV is not capable of supporting the systemic circulation. Impaired myocardial perfusion and impaired coronary flow reserve have been suggested as potential mechanisms for ventricular dysfunction [85]. Schwerzmann et al. showed that, in an adult Mustard population (n = 149), the incidence of sustained VT and/or SCD was 9% during a follow-up of 9 ± 6 years after first presentation to an adult congenital cardiac clinic [51]. Univariate risk factors for sustained VT and/or SCD included subaortic RV dysfunction (ejection fraction < 39%), congestive heart failure (NYHA class III), QRS duration of 140 ms or longer, severe tricuspid regurgitation and associated cardiac lesions. Assessment of ventricular function may be challenging in patients with CHD owing to abnormal ventricular geometry, use of conduits or the presence of a functionally single ventricle physiology. MRI, cardiac computed tomography or radionuclide angiography can be useful when echocardiography does not provide accurate assessment of ventricular function. Late gadolinium enhancement cardiovascular magnetic resonance Autopsy specimens have suggested a causative role of myocardial fibrosis in the occurrence of late SCD in patients with TOF [86]. Cardiovascular magnetic resonance with late gadolinium enhancement (LGE) can detect myocardial fibrosis. Studies in patients with TOF have shown that LGE was commonly seen in locations reflecting surgical resection, incision, patching, suturing or vent insertion [87]. However, in patients with Mustard/Senning repair (no ventricular surgical scars) LGE has also been found extensively in the subaortic RV. The presence of scarring in this situation could be explained by pressure overload of the subaortic RV, preoperative hypoxemia, inadequate coronary artery supply of the increased RV mass [88] or reduction of myocardial flow reserve [89]. There is an association between LGE in the RV, and global and regional systolic dysfunction in patients with TOF and complete TGA (Mustard/Senning repair) [87,90 92]. Cross-sectional studies have shown that the extent of RV LGE was also associated with clinical arrhythmias [87,90]. Interestingly, Wald et al. demonstrated that in patients with TOF, regional dysfunction and extent of LGE are greatest in the RV outflow tract [91]. A lower RV outflow tract ejection fraction was associated with sustained VT. These findings mandate larger prospective follow-up studies to validate the prognostic role of LGE for VT/SCD. Electrophysiologic testing Electrophysiologic testing is usually reserved for patients with symptoms or suspected VT. It is considered a promising tool for identifying patients at higher risk of VT [55,93]. Khairy et al. conducted a large multicenter study of 252 patients with TOF who underwent programmed ventricular stimulation [55]. In a Table 5. Risk score for appropriate implantable cardioverter defibrillator shocks in primary prevention of tetralogy of Fallot patients. Variable Exp(b) Points attributed Prior palliative shunt Inducible sustained ventricular tachycardia QRS duration 180 ms Ventriculotomy incision Nonsustained ventricular tachycardia Left ventricular end diastolic pressure 12 mmhg Total points 0 12 Adapted from [117]. multivariate analysis controlling for known noninvasive risk factors, inducible sustained monomorphic or polymorphic VT was an independent risk factor for subsequent events (relative risk: 4.7; 95% CI: ) during the follow-up period of 6.5 ± 4.5 years. However, confounding-by-indication may play an important role as many patients who were scheduled for programmed ventricular stimulation also received an ICD. ICD implantation may result in a detection bias that overestimates the predictive ability of programmed ventricular stimulation because patients with inducible VT are more likely to receive these devices that detect and record VT. Interestingly, analyses performed in patients with and without ICD yielded similar results (relative risk: 4.7 vs 4.9). Although the generalizability of the data has to be confirmed by other prospective studies, the data are promising. Furthermore, diagnostic electrophysiologic testing is also valuable for evaluation of sinus and AV node function, evaluating reentry circuits in IART using electro-anatomical mapping and determining the conduction properties of accessory pathways [30]. Treatment Surgical repair of residual lesions Successful relief of RV outflow obstruction during repair of TOF often requires sacrifice of pulmonary valve competence. The resultant regurgitation can be tolerated hemodynamically but, eventually, the volume load can cause RV dysfunction. It has been postulated that abnormalities in RV and pulmonary valve function may directly modulate the arrhythmic risk through mechanoelectrical interaction [48]. In particular, patients with severe pulmonary regurgitation secondary to RV outflow patching appear to be at high risk. This modulation of arrhythmic potential by the hemodynamic effect of pulmonary regurgitation and/or RVOT obstruction is of special interest, since this may be amenable to surgical correction. Pulmonary valve replacement (PVR) has been shown to dramatically reduce the amount of pulmonary and tricuspid regurgitation and to lead to a reduced size of the RV cavity [94 96]. Furthermore, application of intraoperative electrophysiological mapping and cryoablation reduce the incidence of preexisting atrial and ventricular arrhythmias [97]. However, reports have demonstrated either lack of improvement

8 Yap & Harris Table 6. Catheter ablation of ventricular tachycardia in patients with congenital heart disease. Study (year) CHD type (n) Patients (n) Gonska et al. (1996) Morwood et al. (2004) Furushima et al. (2005) TOF (9), VSD (4), PS (2), TGA/VSD with arterial switch (1) TOF (8), VSD (3), Ebstein (1), UVH (1), AS (1) Induced VT (n) Acute success * Duration of FU (months) Recurrence rate Ref /16 (88%) 16 ± 9 1/14 (7%) [130] /12 (83%) 46 ± 24 4/10 (40%) [132] TOF (4), DORV (3) /7 (57%) 61 ± 29 0/4 (0%) [131] Kriebel et al. (2007) TOF (10) /8 (100%) 35 (3 52) 2/8 (25%) [129] Zeppenfeld et al. (2007) TOF (9), AVSD (1), TGA/VSD with arterial switch (1) /11 (100%) 30 ± 29 1/11 (9%) [31] Total TOF (40), VSD (7), other (11) /54 (87%) 8/47 (17%) Only studies with more than five patients were included. * Acute success of attempted ablation of VT when mapping was possible. Recurrence rate in successfully ablated patients. AS: Aortic stenosis; AVSD: Atrioventricular septal defect; FU: Follow-up; PS: Pulmonary stenosis; TGA: Complete transposition of great arteries; TOF: Tetralogy of Fallot; UVH: Univentricular heart; VSD: Ventricular septal defect; VT: Ventricular tachycardia. or even a decline in RV function after PVR, as well as variable effects on QRS duration [98 100]. Some authors have suggested that the association between RVOT dyskinesis/fibrosis and global RV dysfunction may play a role and that extensive remodeling of the RV (i.e., exclusion of fibrotic/dyskinetic segments in the RV free wall) might be necessary during PVR [91]. Currently, there are no prospective studies evaluating the impact of PVR on the subsequent risk of SCD. Two recent retrospective matched cohort studies failed to identify a beneficial effect of PVR on the incidence of subsequent VT or death [99,101]. Harrild et al. performed a cohort study of 98 patients with TOF who had undergone PVR for RV dilatation [101]. Compared with a group of age- and QRS duration-matched controls, PVR did not result in improved survival or decreased incidence of VT. Study limitations are the use of a nonrandomized study design and small sample size. Implantable cardioverter defibrillators In the current era, the ICD is the mainstay therapy for primary and secondary prevention of SCD, and ICDs are being used with increasing frequency in the CHD population. Although it is tempting to extrapolate the use of ICDs from trials of acquired heart disease to patients with CHD, convincing data that they increase survival do not exist. Information on the outcome of ICD in patients with CHD is limited [83, ]. The most common CHD diagnosis among ICD recipients is TOF, followed by complete TGA and left heart obstructive lesions (Table 4) [ ]. Approximately 23.4% of adult CHD patients will receive an appropriate shock during a mean follow-up of 3.7 years; by contrast, 40.6% will receive an inappropriate shock during the same time period [104]. This high risk of inappropriate shocks reflects the active lifestyle of this young patient population, the propensity for coexisting atrial tachy arrhythmias [106,107] and the higher susceptibility for lead failure, which has been related to growth in the pediatric population [102]. Antiarrhythmic drugs (e.g., b-blockers or amiodarone) can reduce the burden of inappropriate shocks due to supraventricular or sinus tachycardia. Other strategies are the use of two VT detection zones with activation of antitachycardia pacing, and the use of tailored SVT discrimination algorithms [104,108]. Even without the evidence of randomized, controlled trials, there is consensus that SCD survivors with CHD are suitable candidates for ICD implantation [109]. No consensus exists for primary prevention patients with CHD. Khairy et al. performed a multicenter cohort study of 121 patients with TOF and ICDs, with an observed 7.7% annual shock rate of appropriate discharges in primary prevention patients [83]. This shock rate exceeds reported rates in primary prevention studies of hyper trophic cardio myopathy (5%) and ischemic or nonischemic cardio myopathy with a left ventricular ejection fraction less than 35% (5.1%) [80,110]. In TOF, patients who received an ICD as primary prevention, an elevated LV end-diastolic pressure ( 12 mmhg) and non sustained VT independently predicted appropriate ICD discharges [83]. Khairy et al. devised a risk score defining low-risk (0 2 points), intermediate-risk (3 5 points) and high-risk patients (6 12 points) (Table 5). Although annualized rates of appropriate ICD shocks were 0, 3.8 and 17.5%, respectively, suggesting proper identification of TOF patients at risk for appropriate shocks, the risk score was applied to patients who were already carefully selected based on their clinical symptoms (i.e., syncope, presyncope or palpitations). This approach to patient selection for prophylactic ICD implantation in TOF stands in contrast to that in patients with complete TGA (Mustard/Senning repair). A recent multicenter study demonstrated that the annual rate of appropriate shocks was only 0.5% per year in patients who received an ICD as primary prevention [35]. Primary reasons for implantation were: (pre)syncope, nonsustained VT, subaortic RV dysfunction, inducible sustained VT and QRS duration of 180 ms or longer. There are a number of technical challenges regarding the use of ICDs in patients with CHD that mandate careful planning prior to device implant, including the complexity of the cardiac 1612 Expert Rev. Cardiovasc. Ther. 7(12), (2009)

9 Sudden cardiac death in adults with congenital heart disease Review TA 1 RVOT patch (transannular) TA 1 2 [4/11] Pulmonary valve TA 3 [10/11] [11/11] [11/11] RV incision 4 [3/11] VSD patch Figure 2. Localization of anatomic boundaries (blue dashed lines) for ventricular tachycardia after repair of congenital heart disease and the resulting anatomic isthmuses (red circles). RVOT: Right ventricular outflow tract; VSD: Ventricular septal defect. Reproduced with permission from [31]. anatomy, associated extracardiac abnormalities, and underdeveloped or obstructed venous access. Various transvenous, epicardial, intrathoracic and subcutaneous lead implant techniques have been introduced to address these problems [111,112]. Intracardiac shunting is a risk for paradoxic emboli and precludes the insertion of transvenous leads. Furthermore, the risk of late complications (mostly lead failure) in the pediatric population seems higher when compared with the adult population (Table 4), which is probably related to growth-related distortion [102]. Studies including pediatric and young adult ICD patients indicate a lead failure incidence of 15 20%, with lead fractures and insulation breech being the most common events [102, ]. Finally, special attention has to focus on the psychological burden of ICD therapy in the patient with CHD. DeMaso et al. conducted the largest study investigating the effect of an ICD on quality of life in children and adolescents [116]. They determined in 20 patients with ICD (mean age: 14.8 years; CHD incidence: 45%) whether anxiety, depression, family functioning and quality of life were related to cardiac illness severity. ICD patients appear to experience lower physical functioning in their quality of life than healthy controls. However, most do not appear to experience clinical levels of depression or anxiety. Psychosocial functioning was more strongly correlated with their feelings of anxiety and depression, as well as their family functioning, and not severity of their cardiac illness. Children with an ICD reported no significant differences when compared with their healthy peers, suggesting a quite optimistic appraisal of functioning. The available studies suggest that ICDs provide mortality benefit, but children may experience a disproportionate number of shocks, lead failures and inappropriate shocks. Proactive management of psychosocial concerns in ICD patients is indicated and professional psychological counseling of patients and their families should be made available. Risk stratification for prophylactic ICD The goal of risk stratification is to identify the subset of patients who will benefit from the use of prophylactic ICD therapy (i.e., absence of prior clinical sustained ventricular arrhythmias or aborted SCD). Unfortunately, no randomized ICD trials exist for patients with CHD. Despite this drawback, the overall survival of CHD patients has only improved during the last few decades. Meticulous interpretation of available data is mandatory for the correct use of ICDs in this patient population, balancing the potential risk-benefit ratio of these devices. An interesting probabilistic approach to risk stratification in TOF patients was provided by Khairy et al., and can be used as guidance [117]. Considering the established association between the benefit of ICDs and the incidence of SCD in a control population in large randomized trials with ischemic and nonischemic cardiomyopathy, the authors used an annual incidence of SCD of 3.5% as a threshold to consider ICD therapy. Given these assumptions, a risk factor should have a positive likelihood ratio of at least 24.1 to prompt ICD consideration (in a population with a baseline annual SCD risk of 0.15%) [117]. No known risk factor has this kind of discriminative power. Khairy et al. suggest that risk stratification should begin by considering a combination of independent noninvasive risk factors (Table 5) [117]. On the basis of these risk factors, patients can

10 Yap & Harris be classified into low- (<1% per year), intermediate- (1 11.5% per year) or high-risk groups (>11.5% per year). Considering the Bayesian inference, only patients with an intermediate risk may benefit from the diagnostic discrimination of an electro physiologic study (positive likelihood ratio: 3.77; negative likelihood ratio: 0.28). Low-risk patients should be treated conservatively and high-risk patients should receive an ICD. The limitation with the aforementioned model is that we do not know whether the currently known risk factors are independent and what their exact likelihood ratio is. Furthermore, the use of appropriate ICD shocks as a surrogate marker for SCD may overestimate the risk of SCD [118], leading to an overestimation of the discriminative power of the electrophysiologic study. Despite these limitations, it is currently the best approach for risk stratification of patients with TOF, as large randomized trials will not be feasible in the near future. An interesting debate is whether patients with CHD and a subaortic ventricular ejection fraction below 30% should undergo prophylactic ICD implantation [119,120]. A reduced LV ejection fraction is established as one of the strongest risk factors for SCD and total cardiac mortality in adults with ischemic and nonischemic heart disease [121,122]. The current ACC/AHA/HRS guidelines on device-based therapy recommend ICD therapy in patients with ischemic or nonischemic cardiomyopathy with a LV ejection fraction lower than 30 35% [109]. We previously described that subaortic ventricular dysfunction could be an important risk factor for SCD. The argument in favor of prophylactic implantation of an ICD in CHD patients with severe subaortic ventricular dysfunction is the projected high risk of SCD. However, the heterogeneity of CHD with limited numbers of patients in different subgroups precludes the demonstration of a clear association between severely depressed subaortic ventricular function and SCD. Furthermore, competing nonarrhythmic causes of mortality in CHD patients with severely depressed ventricular function may potentially reduce the benefit of an ICD. Khairy et al. demonstrated recently that prophylactic ICD implantation in patients with Mustard or Senning repair was associated with a very low annual appropriate shock rate (0.5% per year) [47]. Of this group 70% had at least moderate dysfunction of the subaortic RV and 35% had a subaortic RV ejection fraction of 35% or lower. At present, we believe it is too premature to extrapolate the policy of prophylactic ICD implantation based on subaortic ventricular function alone to the CHD population. Cardiac resynchronization therapy The CARE-HF trial has clearly shown that cardiac resynchronization therapy (CRT) reduces the incidence of SCD in adult patients (normal cardiac anatomy) with systolic heart failure (NYHA III IV; LV ejection fraction < 35%) and dyssynchrony [123,124]. The experience with CRT in patients with CHD is very limited [ ]. Recently, Cecchin et al. identified all patients who underwent CRT implantation between 2002 and 2007 in the Children s Hospital Boston [126]. Overall, 46 patients had CHD (77%) and 14 had dilated cardiomyopathy (23%). The largest CHD group was single ventricle (28%) followed by congenitally corrected TGA (24%). The implantation approach for CRT system implantation was epicardial in 63%, transvenous in 28% and hybrid in 8%. Median ejection fraction increased from 34 to 44% early post-crt (p < 0.001). After a median follow-up time of 0.7 years, an improvement in functional status (improvement in NYHA classification or 10% improvement in EF) was observed in 87% of patients with sufficient follow-up data. The subaortic LV and single-ventricle group had the best response to CRT. Conversely, patients with a subaortic RV had an overall poor response to CRT, which may be explained partly by the older age at CRT implantation (median: 27 years). These results are encouraging, but the effect of CRT on SCD in CHD is unknown. Furthermore, the technical challenges are greater than in adults with normal cardiac anatomy. Studies focusing on the long-term benefit of CRT are mandated. Catheter ablation of arrhythmias Electroanatomic mapping (e.g., Biosense CARTO, EnSite NavX, noncontact mapping) has substantially improved our understanding of arrhythmia mechanisms and substrates in patients with VT and CHD [31,129]. Recent studies have addressed the role of catheter ablation in the treatment of VT in patients with CHD [31, ]. Currently, only five case series with a total of 58 patients have been published addressing the effect of ablation of VT in patients with CHD. Acute ablation success was achieved during 47 of the 54 procedures (87%) where an ablation was attempted (Table 6). The recurrence of VT during long-term follow-up was documented in eight of 47 cases (17%). This is not surprising considering the difficulty of radiofrequency lesion creation in the often thick-walled chamber like the right ventricle of TOF. Most published experience with ablation of VT in patients with CHD involves patients with TOF. Zeppenfeld et al. performed 3D substrate mapping of the RV in patients with CHD (mainly TOF patients) and identified four anatomically defined isthmuses that were responsible for reentrant tachycardias (Figure 2). These isthmuses were located between: the superior aspect of the tricuspid valve annulus and scar/patch in the anterior RV outflow tract (most common isthmus: 73%); the pulmonary valve annulus and scar in the anterior RV outflow tract; the septal patch and pulmonary valve annulus; and the septal patch and tricuspid valve annulus through the region of the ventriculoinfundibular fold. Currently, ablation of VT is used predominantly as a means to reduce the shock burden in patients with an ICD. Catheter ablation of IART is now used at many centers as an early intervention in preference to long-term drug therapy and, in particular, for those patients who have demonstrated the propensity for 1:1 conduction [ ]. The technique has evolved rapidly since the introduction of electroanatomic mapping for improved circuit localization and irrigated-tip or largetip ablation for more effective lesion creation [136]. The critical isthmus in patients with four-chamber hearts (e.g., Mustard/ Senning patients or TOF patients) is commonly located at the 1614 Expert Rev. Cardiovasc. Ther. 7(12), (2009)